US20050159790A1 - Stimulation for treating and diagnosing conditions - Google Patents

Abstract

A method is provided for facilitating a diagnosis of a condition of a subject, including applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG, and configuring the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject. The method also includes sensing a quantity of the molecules from a site outside of the brain of the subject, following initiation of application of the current.

Description

CROSS-REFERENCES TO RELATED AND APPLICATIONS
• The present application:
• • (a) is a continuation-in-part of (i) International Patent Application PCT/IL03/00338, filed Apr. 25, 2003, (ii) International Patent Application PCT/IL03/00508, filed Jun. 13, 2003, and (iii) U.S. patent application Ser. No. 10/783,113, filed Feb. 20, 2004, and
  • (b) claims priority from U.S.Provisional Patent Application 60/506,165 to Shalev, filed Sep. 26, 2003.
• The '338 application claims priority from (a) U.S.Provisional Patent Application 60/376,048 to Shalev, filed Apr. 25, 2002, and (b) U.S.Provisional Patent Application 60/461,232 to Gross et al., filed Apr. 8, 2003.
• The '508 application claims priority from (a) U.S.Provisional Patent Application 60/388,931, filed Jun. 14, 2002, and (b) U.S. patent application Ser. No. 10/294,310 to Gross et al., filed Nov. 14, 2002, which claims priority from: (i) U.S.Provisional Patent Application 60/400,167, filed Jul. 31, 2002, and (ii) U.S.Provisional Patent Application 60/364,451, filed Mar. 15, 2002.
• The '113 application (a) claims priority from U.S.Provisional Patent Application 60/506,165, filed Sep. 26, 2003, and (b) is a continuation-in-part of U.S. patent application Ser. No. 10/258,714, filed Jan. 22, 2003, which is a US national phase application of International Patent Application PCT/IL01/00402, filed May 7, 2001, which claims priority from U.S.Provisional Patent Application 60/203,172, filed May 8, 2000.
• All of the above-mentioned applications are assigned to the assignee of the present application and are incorporated herein by reference.
FIELD OF THE INVENTION
• The present invention relates generally to medical procedures and electronic devices. More specifically, the invention relates to the use of electrical devices for implantation in the head, for example, in the nasal cavity. The invention also relates to methods for using odorants to induce or to inhibit neural activity for the treatment and/or diagnosis of a clinical condition. The invention also relates to apparatus and methods for administering drugs, for treating stroke and headaches such as migraine and cluster headaches, and for improving cerebral blood flow.
BACKGROUND OF THE INVENTION
• The blood-brain barrier (BBB) is a unique feature of the central nervous system (CNS) which isolates the brain from the systemic blood circulation. To maintain the homeostasis of the CNS, the BBB prevents access to the brain of many substances circulating in the blood.
• The BBB is formed by a complex cellular system of endothelial cells, astroglia, pericytes, perivascular macrophages, and a basal lamina. Compared to other tissues, brain endothelia have the most intimate cell-to-cell connections: endothelial cells adhere strongly to each other, forming structures specific to the CNS called “tight junctions” or zonula occludens. They involve two opposing plasma membranes which form a membrane fusion with cytoplasmic densities on either side. These tight junctions prevent cell migration or cell movement between endothelial cells. A continuous uniform basement membrane surrounds the brain capillaries. This basal lamina encloses contractile cells called pericytes, which form an intermittent layer and probably play some role in phagocytosis activity and defense if the BBB is breached. Astrocytic end feet, which cover the brain capillaries, build a continuous sleeve and maintain the integrity of the BBB by the synthesis and secretion of soluble growth factors (e.g., gamma-glutamyl transpeptidase) essential for the endothelial cells to develop their BBB characteristics.
• Because of the BBB, certain non-surgical treatments of the brain based upon systemic introduction of compounds through the bloodstream have been ineffective or less effective. For example, chemotherapy has been relatively ineffective in the treatment of CNS metastases of systemic cancers (e.g., breast cancer, small cell lung cancer, lymphoma, and germ cell tumors), despite clinical regression and even complete remission of these tumors in non-CNS systemic locations. The most important factors determining drug delivery from blood into the CNS are lipid solubility, molecular mass, and electrical charge. A good correlation exists between the lipid solubility of a drug, expressed as the octanol/water partition coefficient, and the drug's ability to penetrate or diffuse across the BBB. This is particularly relevant for drugs with molecular weights smaller than 600 dalton (Da). The normal BBB prevents the passage of ionized water soluble drugs with a molecular weight greater than 180 Da. Most currently-available effective chemotherapeutic agents, however, have a molecular weight between 200 and 1200 Da. Therefore, based both on their lipid solubilities and molecular masses, the passage of many agents is impeded by the BBB.
• In addition to transcellular diffusion of lipophilic agents, there are several specific transport mechanisms to carry certain molecules across the brain's endothelial cells. Specific transport proteins exist for required molecules, such as glucose and amino acids. Additionally, absorptive endocytosis and transcytosis occur for cationized plasma proteins. Specific receptors for certain proteins, such as transferrin and insulin, mediate endocytosis and transport across the cell.
• Non-surgical treatment of neurological disorders is generally limited to systemic introduction of compounds such as neuropharmaceuticals and other neurologically-active agents that might remedy or modify neurologically-related activities and disorders. Such treatment is limited, however, by the relatively small number of known compounds that pass through the BBB. Even those that do cross the BBB often produce adverse reactions in other parts of the body or in non-targeted regions of the brain.
• There have been a number of different studies regarding efforts to cross the BBB—specifically, with regard to overcoming the limited access of drugs to the brain. Such efforts have included, for example, chemical modification, development of more hydrophobic analogs, or linking an active compound to a specific carrier. Transient opening of the BBB in humans has been achieved by intracarotid infusion of hypertonic mannitol solutions or bradykinin analogs. Also, modulation of the P-glycoprotein, whose substrates are actively pumped out of brain cells into capillary lumens, has been found to facilitate the delivery of drugs to the brain. However, due to the inherent limitations of each of the aforementioned procedures, there is still a need for more generic, effective, and predictable ways to cross the BBB.
• It would also be desirable to develop controllable means for modulating cerebral blood flow. Many pathological conditions, such as stroke, migraine, and Alzheimer's disease, are significantly affected or exacerbated by abnormal cerebral blood flow.
• Alzheimer's disease (AD) is the most common form of both senile and presenile dementia in the world and is recognized clinically as relentlessly progressive loss of memory and intellectual function and disturbances in speech (Merritt, 1979, A Textbook of Neurology,6th edition, pp. 484-489, Lea & Febiger, Philadelphia, which is incorporated herein by reference). Alzheimer's disease begins with mildly inappropriate behavior, uncritical statements, irritability, a tendency towards grandiosity, euphoria, and deteriorating performance at work; it progresses through deterioration in operational judgment, loss of insight, depression, and loss of recent memory; and it ends in severe disorientation and confusion, apraxia of gait, generalized rigidity, and incontinence (Gilroy & Meyer, 1979, Medical Neurology, pp. 175-179, MacMillan Publishing Co., which is incorporated herein by reference,). Alzheimer's disease is found in about 10% of the population over the age of 65 and 47% of the population over the age of 85 (Evans et al., 1989, JAMA, 262: 2551-2556, which is incorporated herein by reference).
• Alzheimer's Disease is characterized by the accumulation of insoluble, 10 nm filaments containing β-amyloid (Aβ) peptides, localized in the extracellular space of the cerebral cortex and vascular walls. These 40 or 42 amino acid long Aβ peptides are derived from the larger β-amyloid precursor protein (βAPP) through the endopeptidase action of β and γ secretases. In addition, the post-translational action of putative aminopeptidases results in a heterogeneous shortening of the 40 or 42 amino acid long Aβ peptides that either terminate atresidue 40 or 42 and, therefore, are designated as ApN-40 and AβN-42. In familial forms of AD, the pathological appearance of the Aβ peptides in the brain is driven by the presence of mutations in the βAPP gene or in the genes coding for theproteins presenilin 1 and 2.
• Sporadic AD accounts for more than 95% of the known AD cases. Its etiology, however, remains obscure. An accepted view is that sporadic AD results from the interplay between an individual's genetic factors and the environment, leading to the deposition of Aβ, neurodegeneration, and dementia. Despite this emerging perspective, insufficient effort has been made in identifying factors responsible for Aβ accumulation in the brain.
• The etiology of Alzheimer's disease is unknown. Evidence for a genetic contribution comes from several important observations such as the familial incidence, pedigree analysis, monozygotic and dizygotic twin studies, and the association of the disease with Down's syndrome (for review see Baraitser, 1990, The Genetics of Neurological Disorders,2nd edition, pp. 85-88, which is incorporated herein by reference). Nevertheless, this evidence is far from definitive, and it is clear that other factors are involved.
• Alzheimer's Disease is a neurodegenerative disease characterized by a progressive decline of cognitive functions, including loss of declarative and procedural memory, decreased learning ability, reduced attention span, and severe impairment in thinking ability, judgment, and decision making. Mood disorders and depression are also often observed in AD patients. It is estimated that AD affects about 4 million people in the USA and 20 million people worldwide. Because AD is an age-related disorder (with an average onset at 65 years), the incidence of the disease in industrialized countries is expected to rise dramatically as the population of these countries ages.
• AD is characterized by the following neuropathological features:
• • massive loss of neurons and synapses in the brain regions involved in higher cognitive functions (association cortex, hippocampus, amygdala). Cholinergic neurons are particularly affected.
  • neuritic (senile) plaques that are composed of a core of amyloid material surrounded by a halo of dystrophic neurites, reactive type I astrocytes, and numerous microglial cells (Selkoe, D. J., Annu Rev Neurosci 17: 489-517, 1994; Selkoe, D. J., J Neuropathol Exp Neurol 53: 438-447, 1994; Dickson, D. W., J Neuropathol Exp Neurol 56: 321-339, 1997; Hardy, J. et al., Science 282: 1075-1079, 1998; Selkoe, D. J., Cold Spring Harb Symp Quant Biol 61: 587-596, 1996, all of which are incorporated herein by reference. The major component of the core is a peptide of 39 to 42 amino acids called the amyloid P protein, or Aβ. Although the Aβ protein is produced by the intracellular processing of its precursor, APP, the amyloid deposits forming the core of the plaques are extracellular. Studies have shown that the longer form of Aβ (Aβ42) is much more amyloidogenic than the shorter forms (Aβ40 or Aβ39).
  • neurofibrillary tangles that are composed of paired-helical filaments (PHF) (Ray et al., Mol Med Today 4: 151-157, 1998; Brion, Acta Neurol Belg 98: 165-174, 1998, both of which are incorporated herein by reference). Biochemical analyses revealed that the main component of PHF is a hyper-phosphorylated form of the microtubule-associated protein τ. These tangles are intracellular structures, found in the cell body of dying neurons, as well as some dystrophic neurites in the halo surrounding neuritic plaques. Both plaques and tangles are found in the same brain regions affected by neuronal and synaptic loss.
• Although the neuronal and synaptic loss is universally recognized as the primary cause of the decline of cognitive functions, the cellular, biochemical, and molecular events responsible for this neuronal and synaptic loss are subject to fierce controversy. The number of tangles shows a better correlation than the amyloid load with the cognitive decline (Albert, Proc Natl Acad Sci USA 93: 13547-13551, 1996, which is incorporated herein by reference). On the other hand, a number of studies showed that amyloid can be directly toxic to neurons, resulting in behavioral impairment (Ma et al., Neurobiol Aging 17: 773-780, 1996, which is incorporated herein by reference). It has also been shown that the toxicity of some compounds (amyloid or tangles) could be aggravated by activation of the complement cascade, suggesting the possible involvement of inflammatory process in the neuronal death.
• Genetic and molecular studies of some familial forms of AD (FAD) have recently provided evidence that boosted the amyloid hypothesis (Ii, Drugs Aging 7: 97-109, 1995; Price et al., Curr Opin Neurol 8: 268-274, 1995; Hardy, Trends Neurosci 20: 154-159, 1997; Selkoe, J Biol Chem 271: 18295-18298, 1996, all of which are incorporated herein by reference). The assumption is that since the deposition of Aβ in the core of senile plaques is observed in all Alzheimer cases, if Aβ is the primary cause of AD, then mutations that are linked to FAD should induce changes that, in one way or another, foster Aβ deposition. There are 3 FAD genes known so far (Hardy et al., Science 282: 1075-1079, 1998; Ray et al., Mol Med Today 4: 151-157, 1998, both of which are incorporated herein by reference), and the activity of all of them results in increased Aβ deposition, a very compelling argument in favor of the amyloid hypothesis.
• The first of the 3 FAD genes codes for the Aβ precursor, APP (Selkoe, J Biol Chem 271: 18295-18298, 1996, which is incorporated herein by reference). Mutations in the APP gene are very rare, but all of them cause AD with 100% penetrance and result in elevated production of either total Aβ or Aβ42, both in vitro (transfected cells) and in vivo (transgenic animals). The other two FAD genes code forpresenilin 1 and 2 (PS1, PS2) (Hardy, Trends Neurosci 20: 154-159, 1997, which is incorporated herein by reference). The presenilins contain 8 transmembrane domains and several lines of evidence suggest that they are involved in intracellular protein trafficking, although their exact function is still unknown. Mutations in the presenilin genes are more common than in the APP genes, and all of them also cause FAD with 100% penetrance. In addition, in vitro and in vivo studies have demonstrated that PS1 and PS2 mutations shift APP metabolism, resulting in elevated Aβ42 production. For a recent review on the genetics of AD, see Lippa, J Mol Med 4: 529-536, 1999, which is incorporated herein by reference.
• In spite of these compelling genetic data, it is still unclear whether Aβ generation and amyloid deposition are the primary cause of neuronal death and synaptic loss observed in AD. Moreover, the biochemical events leading to Aβ production, the relationship between APP and the presenilins, and between amyloid and neurofibrillary tangles are poorly understood. Thus, the picture of interactions between the major Alzheimer proteins is very incomplete, and it is clear that a large number of novel proteins are yet to be discovered.
• The diagnosis of Alzheimer's disease at autopsy is definitive. Gross pathological changes are found in the brain, including low weight and generalized atrophy of both the gray and white matter of the cerebral cortex, particularly in the temporal and frontal lobes (Adams & Victor, 1977, Principles of Neurology, pp. 401-407 and Merritt, 1979, A Textbook of Neurology,6th edition, Lea & Febiger, Philadelphia, pp. 484-489, both of which are incorporated herein by reference). The histological changes include neurofibrillary tangle (Kidd, Nature 197: 192-193, 1963; Kidd, Brain 87: 307-320, 1964, both of which are incorporated herein by reference), which consists of a tangled mass of paired helical and straight filaments in the cytoplasm of affected neurons (Oyanagei, Adv. Neurol. Sci. 18: 77-88, 1979 and Grundke-Iqbal et al., Acta Neuropathol. 66: 52-61, 1985, both of which are incorporated herein by reference).
• The diagnosis of Alzheimer's disease during life is more difficult than at autopsy since the diagnosis depends upon inexact clinical observations. In the early and middle stages of the disease, the diagnosis is based on clinical judgment of the attending physician. In the late stages, where the symptoms are more recognizable, clinical diagnosis is more straightforward. But, in any case, before an unequivocal diagnosis can be made, other diseases, with partially overlapping symptoms, must be ruled out. Usually a patient must be evaluated on a number of occasions to document the deterioration in intellectual ability and other signs and symptoms. The necessity for repeated evaluation is costly, generates anxiety, and can be frustrating to patients and their families. Furthermore, the development of an appropriate therapeutic strategy is hampered by the difficulties of rapid diagnosis, particularly in the early stages where early intervention could leave the patient with significant intellectual capacity and a reasonable quality of life. In brief, no unequivocal laboratory test specific for Alzheimer's disease has been reported.
• Alzheimer's disease is associated with degeneration of cholinergic neurons, in the basal forebrain, which play a fundamental role in cognitive functions, including memory (Becker et al., Drug Development Research 12: 163-195, 1988, which is incorporated herein by reference). Progressive, inexorable decline in cholinergic function and cholinergic markers in the brain of Alzheimer's disease patients has been observed in numerous studies, and includes, for example, a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline uptake (Davis, Brain Res. 171: 319-327, 1979 and Hardy et al., Neurochem. Int. 7: 545-563, 1985, which are incorporated herein by reference). Even more, decreased cholinergic function may be an underlying cause of cognitive decline seen in Alzheimer's-disease patients (Kish et al., J. Neurol., Neurosurg., and Psych. 51: 544-548, 1988, which is incorporated herein by reference). Choline acetyltransferase and acetylcholinesterase activities decrease significantly as plaque count rises, and, in demented subjects, the reduction in choline acetyl transferase activity was found to correlate with intellectual impairment (Perry, et al., Brit. Med. J. 25, November 1978, p. 1457, which is incorporated herein by reference).
• Nerve cells produce nerve growth factors, proteins that regulate cell maturation during prenatal development and also play an important role in cell survival, repair, and regeneration during adult life. Because of their significance in cell maintenance and repair, these factors have attracted attention as potential treatments in Alzheimer's disease, stroke, spinal cord injury, and other neurodegenerative conditions. However, nerve growth factors are usually too large to cross the blood-brain barrier (BBB), a protective shield that restricts passage of molecules to the brain.
• The BBB is functionally situated at the brain capillaries endothelium layer and covers a surface area of 12 m2/g of brain parenchyma. The total length of this capillary network is 650 km. The cerebral capillary endothelial cell displays some peculiar morphologic characteristics that form the anatomic basis of the blood-brain barrier. It differs from the peripheral capillary endothelial cell (referring to all non-CNS sites) in a number of ways:
• First, the CNS endothelial cell layer is not fenestrated. Cells are joined by tight junctions composed of 6 to 8 pentalaminar structures. They actively block protein movements, hydrophilic transfer and even ionic diffusion. Thus, there is very little movement of compounds between endothelial cells from the blood to the CNS.
• Second, and in contrast to the peripheral capillary endothelial cell, transcellular movement of molecules through the non-specific mechanism of fluid-phase endocytosis is generally absent. The cerebral vascular endothelial cell possesses a transcellular lipophilic pathway, allowing diffusion of small lipophilic compounds. In addition to this route, specific receptor-mediated transport systems are present for given molecules, like insulin, transferrin, glucose, purines and amino acids. These transport systems are highly selective and asymmetric.
• Third, the CNS endothelial cell displays a net negative charge at its endoluminal side and at the basement membrane. This provides an additional selective mechanism by impeding anionic molecules to cross the membrane.
• Fourth, the cerebral endothelial cell has very few pinocytic vesicles, and these vesicles are not involved in any transport function.
• Fifth, astrocyte foot processes surround the microvascular endothelium and cover more than 95 percent of its surface, therefore interposing between capillaries and cerebral neuropil.
• By virtue of this selective barrier, the CNS can preferentially regulate the extracellular concentration of certain solutes, growth factors and neurotransmitters, keep certain molecules in the CNS and isolate itself from some others, and further isolate itself from sudden systemic homeostatic changes. It is therefore an integral component of the mechanisms involved in the tight regulation of the extra-cellular homeostasis necessary to the normal CNS function. This relatively impermeable barrier has some drawbacks, however, when considering the therapeutic delivery of a molecule to the CNS.
• The delivery of therapeutic molecules across the BBB has proven to be a major obstacle in treating various brain disorders. The normal blood-brain barrier prevents passage of ionized water-soluble compounds with a molecular weight greater than 180 Daltons. Therefore, the BBB is a major impediment to the treatment of CNS diseases as many drugs are unable to reach this organ at therapeutic concentrations. More than 98% of the CNS-targeted drugs do not cross the BBB. Example of such disorders are: primary brain tumors, metastatic brain tumors, AD, addiction, ALS, head injury, Huntington's disease, multiple sclerosis (MS), depression, Cerebral Palsy, schizophrenia, epilepsy, stress and anxiety. Many new neurotherapeutic agents are being discovered, but because of a lack of suitable strategies for drug delivery across the BBB, these agents are ineffective. Such drugs will only become effective if strategies for brain delivery are developed in parallel.
• Apart from molecular parameters, the permeability of the BBB and active transport mechanisms, a major determinant of molecular transport across the BBB is their concentration gradient—between the CNS and the cerebral circulation.
• Additionally, the functioning BBB inhibits clearance of neurotoxic compounds, such as β-Amyloid, tau, PS1, and PS2, from the CNS into the systemic circulation. These neurotoxic compounds are therefore not metabolized and removed from the body to the extent desired, and therefore continue to have undesired effects in the CNS.
• PCT Publication WO 01/85094 and U.S. Patent Application Publication 2004/0015068 to Shalev and Gross, which are assigned to the assignee of the present patent application and are incorporated herein by reference, describe apparatus for modifying a property of a brain of a patient, including electrodes applied to a sphenopalatine ganglion (SPG) or a neural tract originating in or leading to the SPG. A control unit drives the electrodes to apply a current capable of inducing (a) an increase in permeability of a blood-brain barrier (BBB) of the patient, (b) a change in cerebral blood flow of the patient, and/or (c) an inhibition of parasympathetic activity of the SPG.
• PCT Publication WO 04/010923 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes a chemical agent delivery system including a chemical agent supplied to a body of a subject for delivery to a site in a central nervous system of said subject via blood of said subject; and a stimulator for stimulating parasympathetic fibers associated with the sphenopalatine ganglion, thereby to render a blood brain barrier (BBB) of said subject permeable to said chemical agent during at least a portion of the time that said chemical agent is present in said blood.
• PCT Publication WO 04/043218 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes treatment apparatus comprising (a) a stimulation device, adapted to be implanted in a vicinity of a site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject and a neural tract originating in or leading to the SPG; and (b) a connecting element, coupled to the stimulation device, and adapted to be passed through at least a portion of a greater palatine canal of the subject. Also described is a method for implanting a treatment stimulation device in a vicinity of a site of a subject, the method comprising passing the device through a greater palatine foramen of the subject, and bringing the device into contact with the vicinity of the site, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject and a neural tract originating in or leading to the SPG.
• PCT Publication WO 04/044947 to Gross et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for use with an implanted medical device having two conductive elements in contact with tissue of a subject. The apparatus comprises a shunt, electrically coupled between the conductive elements, the shunt adapted to be in a first state when the subject is exposed to a source of radiofrequency (RF) energy, and adapted to be in a second state when the subject is not exposed to the RF energy, the shunt being characterized such that in the first state the shunt has a first impedance, and in the second state the shunt has a second impedance at least two times greater than the first impedance.
• U.S. Patent Application Publication 2003/0176898 and PCT Publication WO 04/043217 to Gross et al., which are assigned to the assignee of the present application and are incorporated herein by reference, describe apparatus for treating a condition of an eye of a subject, comprising a stimulator adapted to stimulate at least one site of the subject, so as to treat the eye condition, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject.
• U.S. Patent Application Publication 2003/0176892 and PCT Publication WO 04/043334 to Shalev, which are assigned to the assignee of the present application and are incorporated herein by reference, describe apparatus for delivering a Non Steroidal Anti-Inflammatory Drug (NSAID) supplied to a body of a subject for delivery to at least a portion of a central nervous system (CNS) of the subject via a systemic blood circulation of the subject, including a stimulator adapted to stimulate at least one site of the subject, so as to cause an increase in passage of the NSAID from the systemic blood circulation across a blood brain barrier (BBB) of the subject to the portion of the CNS, during at least a portion of the time that the NSAID is present in the blood, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject.
• PCT Publication WO 04/045242 to Shalev et al., which is assigned to the assignee of the present application and is incorporated herein by reference, describes apparatus for treating a condition of an ear of a subject, comprising a stimulator adapted to stimulate at least one site of the subject at a level sufficient to treat the ear condition, the site selected from the list consisting of: an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject.
• U.S. Pat. No. 5,756,071 to Mattem et al., which is incorporated herein by reference, describes a method for nasally administering aerosols of therapeutic agents to enhance penetration of the blood brain barrier. The patent describes a metering spray designed for pemasal application, the spray containing at least one sex hormone or at least one metabolic precursor of a sex hormone or at least one derivative of a sex hormone or combinations of these, excepting the precursors of testosterone, or at least one biogenic amine, with the exception of catecholamines.
• U.S. Pat. No. 5,752,515 to Jolesz et al., which is incorporated herein by reference, describes apparatus for image-guided ultrasound delivery of compounds through the blood-brain barrier. Ultrasound is applied to a site in the brain to effect in the tissues and/or fluids at that location a change detectable by imaging. At least a portion of the brain in the vicinity of the selected location is imaged, e.g., via magnetic resonance imaging, to confirm the location of that change. A compound, e.g., a neuropharmaceutical, in the patients bloodstream is delivered to the confirmed location by applying ultrasound to effect opening of the blood-brain barrier at that location and, thereby, to induce uptake of the compound there.
• PCT Publication WO 01/97905 to Ansarinia, which is incorporated herein by reference, describes a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode on or proximate to at least one of the patient's SPG, sphenopalatine nerves, or vidian nerves, and activating the electrode to apply an electrical signal to such nerve. In a further embodiment for treating the same conditions, the electrode used is activated to dispense a medication solution or analgesic to such nerve. The '905 publication also describes surgical techniques for implanting the electrode.
• U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein by reference, describes a method for the suppression or prevention of various medical conditions, including pain, movement disorders, autonomic disorders, and neuropsychiatric disorders. The method includes positioning an electrode adjacent to or around a sinus, the dura adjacent a sinus, or falx cerebri, and activating the electrode to apply an electrical signal to the site. In a further embodiment for treating the same conditions, the electrode dispenses a medication solution or analgesic to the site. The '079 patent also describes surgical techniques for implanting the electrode.
• U.S. Patent Application Publication 2002/0052311 to Solomon et al., which is incorporated herein by reference, describes methods for treating and/or diagnosing neurological conditions of the CNS. Some embodiments include displaying a therapeutic molecule capable of treating the condition on a viral display vehicle and introducing the vehicle into a subject in need thereof by applying the viral display vehicle to an olfactory system of the subject.
• PCT Publication WO 02/094191 to Wisniewski et al., which is incorporated herein by reference, describes techniques for diagnosing Alzheimer's disease in vivo using magnetic resonance imaging. A labeled A-beta peptide or its derivative is injected into the patient to be diagnosed, after which the patient is subjected to magnetic resonance imaging.
• U.S. Pat. No. 5,059,415 to Neuwelt, which is incorporated herein by reference, describes a method for diagnosing and characterizing brain lesions by first chemically modifying the blood-brain barrier (BBB) in order to increase BBB permeability. Thereafter, a chemical agent (e.g., mAb or pAb) is introduced which binds to brain lesions.
• U.S. Pat. No. 4,866,042 to Neuwelt, which is incorporated herein by reference, describes a method for treating genetic and acquired brain disorders by introducing genetic material into the blood stream for delivery to the brain. Prior to delivery, the interendothelial structure of the BBB is chemically altered to permit passage of the genetic material therethrough.
• U.S. Pat. No. 6,117,454 to Kreuter et al., which is incorporated herein by reference, describes a method for delivering drugs and diagnostics across the BBB or blood-nerve barrier by incorporating these agents into nanoparticles which have been fabricated in conventional ways and then coated with an additional surfactant.
• PCT Publication WO 00/73343 to Soreq et al., which is incorporated herein by reference, describes techniques for diagnosing CNS stress, elevated glucocorticoid level, disruption of the blood-brain barrier or Alzheimer's disease, by testing a blood sample using antibodies recognizing acetylcholinesterase or a C-terminal peptide derived from acetylcholinesterase.
• U.S. Pat. No. 5,268,164 to Kozarich et al., which is incorporated herein by reference, describes techniques for using polypeptides called receptor mediated permeabilizers to increase the permeability of the blood-brain barrier to molecules such as therapeutic agents or diagnostic agents.
• U.S. Pat. No. 6,005,004 to Katz et al., which is incorporated herein by reference, describes site-specific biomolecular complexes comprising a therapeutic, prophylactic and diagnostic agent, and an omega-3 fatty acid and derivatives thereof, which complexes are covalently bonded with cationic carriers and permeabilizer peptides for delivery across the BBB and with targeting moieties for uptake by target brain cells.
• U.S. Pat. No. 5,833,988 to Friden, which is incorporated herein by reference, describes a method for delivering a neuropharmaceutical or diagnostic agent across the BBB to the brain. The method comprises administering to the host a therapeutically effective amount of an antibody-neuropharmaceutical or diagnostic agent conjugate wherein the antibody is reactive with a transferrin receptor.
• The following references, which are incorporated herein by reference, may be useful:
• Delepine L, Aubineau P, “Plasma protein extravasation induced in the rat dura mater by stimulation of the parasympathetic sphenopalatine ganglion,” Experimental Neurology, 147, 389-400 (1997)
• Hara H, Zhang Q J, Kuroyanagi T, Kobayashi S, “Parasympathetic cerebrovascular innervation: An anterograde tracing from the sphenopalatine ganglion in the rat,” Neurosurgery, 32, 822-827 (1993)
• Jolliet-Riant P, Tillement JP, “Drug transfer across the blood-brain barrier and improvement of brain delivery,” Fundam. Clin. Pharmacol., 13, 16-25 (1999)
• Kroll RA, Neuwelt EA, “Outwitting the blood brain barrier for therapeutic purposes: Osmotic opening and other means,” Neurosurgery, 42, 1083-1100 (1998)
• Sanders M, Zuurmond WW, “Efficacy of sphenopalatine ganglion blockade in 66 patients suffering from cluster headache: A 12-70 month follow-up evaluation,” Journal of Neurosurgery, 87, 876-880 (1997)
• Syelaz J, Hara H, Pinard E, Mraovitch S, MacKenzie ET, Edvinsson L, “Effects of stimulation of the sphenopalatine ganglion on cortical blood flow in the rat,” Journal of Cerebral Blood Flow and Metabolism,” 8, 875-878 (1988)
• Van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA, “Estimation of blood brain barrier crossing of drugs using molecular size and shape and h bonding descriptors,” Journal of Drug Targeting,” 6, 151-165, (1998)
• Suzuki N, Hardebo JE, Kahrstrom J, Owman C, “Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat,” Journal of Cerebral Blood Flow and Metabolism, 10, 383-391 (1990)
• Suzuki N, Hardebo JE, Kahrstrom J, Owman CH, “Effect on cortical blood flow of electrical stimulation of trigeminal cerebrovascular nerve fibres in the rat,” Acta Physiol. Scand., 138, 307-315 (1990)
• Major A, Silver W, “Odorants presented to the rat nasal cavity increase cortical blood flow,” Chem. Senses, 24, 665-669 (1999)
• Fusco B M, Fiore G, Gallo F, Martelletti P, Giacovazzo M, “‘Capsaicin-sensitive’ sensory neurons in cluster headache: pathophysiological aspects and therapeutic indications,” Headache, 34, 132-137 (1994)
• Lambert G A, Bogduk N, Goadsby PJ, Duckworth JW, Lance JW, “Decreased carotid arterial resistance in cats in response to trigeminal stimulation,” Journal of Neurosurgery, 61, 307-315 (1984)
• Silver W L, “Neural and pharmacological basis for nasal irritation,” in Tucker WG, Leaderer BP, Mølhave L, Cain WS (eds), Sources of Indoor Air Contaminants, Ann. NY Acad. Sci., 641, 152-163 (1992)
• Silver W, “Chemesthesis: the burning questions,” ChemoSense, Vol. 2 No. 1, 1-2 (1999)
• Asaba H, Hosoya K, Takanaga H, Ohtsuki S, Tamura E, Takizawa T, Terasaki T, “Blood-Brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organicanion transporting polypeptide 2,” J. Neurochem. 75(5): 1907-1916 (2000)
• Isakovica AJ, Segalb MB, Milojkovica BA, Dacevica MP, Misirlica ST, Rakicc ML, Redzicb ZB, “The efflux of purine nucleobases and nucleosides from the rat brain,” Neuroscience Letters 318: 65-68 (2002)
• Kakee A, Terasaki T, Sugiyama Y, “Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier,” J. Pharmacol. Exp. Ther. 277: 1550-1559(1996)
• Kakee A, Terasaki T, Sugiyama Y, “Selective brain to blood efflux transport of para-aminohippuric acid across the blood-brain barrier: in vivo evidence by use of the brain efflux index method,” J. Pharmacol. Exp. Ther. 283: 1018-1025 (1997)
• Takasawa K, Terasaki T, Suzuki H, Sugiyama Y, “In vivo evidence for carrier-mediated efflux transport of 39-azido-39-deoxythymidine and 29,39-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system,” J. Pharmacol. Exp. Ther. 281: 369-375 (1997)
• Hosoya K, Sugawara M, Asaba H, Terasaki T, “Blood-brain barrier produces significant efflux of L-aspartic acid, but not D-aspartic acid: in vivo evidence using the brain efflux index method,” J. Neurochem. 73: 1206-1211 (1999)
• Boado R J, “Antisense delivery through the blood brain barrier,” Adv. Drug. Del. Rev. 15: 73-107 (1995)
• Devoghel J C, “Cluster headache and sphenopalatine block,” Acta Anaesthesiol Belg., 32(1): 101-7 (1981)
• Tamano H et al., “Uptake of radioactive elements in rat brain tumor,” RIKEN Review, No. 35 (May 2001)
OBJECTS OF THE INVENTION
• It is an object of some aspects of the present invention to provide improved methods and apparatus for delivery of compounds to the brain, particularly through the BBB.
• It is also an object of some aspects of the present invention to provide such methods and apparatus as can be employed to deliver such compounds through the BBB with a minimally invasive approach.
• It is a further object of some aspects of the present invention to provide such methods and apparatus as can facilitate delivery of large molecular weight compounds through the BBB.
• It is yet a further object of some aspects of the present invention to provide cost-effective methods and apparatus for delivery of compounds through the blood-brain-barrier.
• It is still a further object of some aspects of the present invention to provide improved methods and apparatus for remedying or modifying neurological activities and disorders via delivery of compounds through the blood-brain-barrier.
• It is also a further object of some aspects of the present invention to modulate cerebral blood flow.
• It is an additional object of some aspects of the present invention to provide improved methods and apparatus for treating stroke.
• It is yet an additional object of some aspects of the present invention to provide improved methods and apparatus for treating migraine, cluster and other types of headaches.
• It is still an additional object of some aspects of the present invention to provide improved methods and apparatus for treating and/or preventing neurological diseases (for example, Alzheimer's disease), whose prognosis and evolution of pathological symptoms are influenced by cerebral blood flow.
• It is also an object of some aspects of the present invention to provide implantable apparatus which affects a property of the brain, without actually being implanted in the brain.
• It is a further object of some aspects of the present invention to provide methods which affect a property of the brain without the use of implantable apparatus.
• It is still an additional object of some aspects of the present invention to provide improved methods and apparatus for treating and/or preventing Alzheimer's disease.
• It is also an object of some aspects of the present invention to provide improved methods and apparatus for diagnosing neurological diseases.
• It is a further object of some aspects of the present invention to provide improved methods and apparatus for diagnosing Alzheimer's disease.
• It is yet a further object of some aspects of the present invention to affect a property of the brain by using the neuroexcitatory and/or neuroinhibitory effects of odorants on nerves in the head.
• These and other objects of the invention will become more apparent from the description of preferred embodiments thereof provided hereinbelow.
SUMMARY OF THE INVENTION
• In preferred embodiments of the present invention, an electrical stimulator drives current into the sphenopalatine ganglion (SPG) or into related neuroanatomical structures, including neural tracts originating or reaching the SPG, including outgoing and incoming parasympathetic and sympathetic tracts and other parasympathetic centers. Typically, the stimulator drives the current in order to control and/or modify SPG-related behavior, e.g., in order to induce changes in cerebral blood flow and/or to modulate permeability of the blood-brain barrier (BBB). These embodiments may be used in many medical applications, such as, by way of illustration and not limitation, (a) the treatment of cerebrovascular disorders such as stroke, (b) the treatment of migraine, cluster and other types of headaches, or (c) the facilitation of drug transport across the BBB.
• In the specification of the present patent application, unless indication to the contrary is stated, stimulation of the SPG is to be understood to alternatively or additionally include stimulation of one or more of the following nerves or ganglions:
• • an anterior ethmoidal nerve;
  • a posterior ethmoidal nerve;
  • a communicating branch between the anterior ethmoidal nerve and the SPG (retro orbital branch);
  • a communicating branch between the posterior ethmoidal nerve and the SPG (retro orbital branch)
  • a nerve of the pterygoid canal (also called a vidian nerve), such as a greater superficial
  • a petrosal nerve (a preganglionic parasympathetic nerve) or a lesser deep petrosal nerve (a postganglionic sympathetic nerve);
  • a greater palatine nerve;
  • a lesser palatine nerve;
  • a sphenopalatine nerve;
  • a communicating branch between the maxillary nerve and the sphenopalatine ganglion;
  • a nasopalatine nerve;
  • a posterior nasal nerve;
  • an infraorbital nerve;
  • an otic ganglion;
  • an afferent fiber going into the otic ganglion; and/or
  • an efferent fiber going out of the otic ganglion.
• The SPG is a neuronal center located in the brain behind the nose. It consists of parasympathetic neurons innervating the middle cerebral and anterior cerebral lumens, the facial skin blood vessels, and the lacrimal glands. Activation of this ganglion is believed to cause vasodilation of these vessels. A second effect of such stimulation is the opening of pores in the vessel walls, causing plasma protein extravasation (PPE). This effect allows better transport of molecules from within these blood vessels to surrounding tissue.
• The middle and anterior cerebral arteries provide the majority of the blood supply to the cerebral hemispheres, including the frontal and parietal lobes in their entirety, the insula and the limbic system, and significant portions of the following structures: the temporal lobes, internal capsule, basal ganglia and thalamus. These structures are involved in many of the neurological and psychiatric diseases of the brain, and preferred embodiments of the present invention are directed towards providing improved blood supply and drug delivery to these structures.
• There is also some animal evidence for the presence of SPG-originated parasympathetic innervation in the posterior cerebral and basilar arteries. Consistent with the assumption that this is also the case in humans, many regions of the human brain are within the reach of treatments provided by preferred embodiments of the present invention, as described hereinbelow.
• Currently the SPG is a target of manipulation in clinical medicine, mostly in attempted treatments of severe headaches such as cluster headaches. The ganglion is blocked either on a short-term basis, by applying lidocaine, or permanently, by ablation with a radio frequency probe. In both cases the approach is through the nostrils. In some preferred embodiments of the present invention, similar methods for approaching the SPG are utilized, to enable the electrical stimulation or electrical blocking thereof.
• According to a preferred embodiment of the instant invention, a method and apparatus are provided to enhance delivery of therapeutic molecules across the BBB by stimulation of the SPG and/or its outgoing parasympathetic tracts and/or another parasympathetic center. The apparatus typically stimulates the parasympathetic nerve fibers of the SPG, thereby inducing the middle and anterior cerebral arteries to dilate, and also causing the walls of these cerebral arteries to become more permeable to large molecules. In this manner, the movement of large pharmaceutical molecules from within blood vessels to the cerebral tissue is substantially increased. Preferably, therefore, this method can serve as a neurological drug delivery facilitator, without the sacrifices in molecular weight required by techniques of the prior art. In general, it is believed that substantially all pharmacological treatments aimed at cerebral cells for neurological and psychiatric disorders are amenable for use with these embodiments of the present invention. In particular, these embodiments may be adapted for use in the treatment of disorders such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, anxiety, and any other CNS disorders that are directly or indirectly affected by changes in cerebral blood flow or by BBB permeability changes.
• Advantageously (and even in the absence of BBB permeability changes), patients with these and other disorders are generally helped by the vasodilation secondary to stimulation of the SPG, and the resultant improvement in oxygen supply to neurons and other tissue. For some applications, this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients. For other applications, the treatment is performed on a short-term basis, e.g., to minimize the damage following an acute stroke event and initiate neuronal and therefore functional rehabilitation.
• Blocking of nerve transmission in the SPG or in related neural tracts is used in accordance with some preferred embodiments of the present invention to treat or prevent migraine headaches.
• Alternatively or additionally, the changes induced by electrical stimulation as described hereinabove are achieved by presenting odorants to an air passage of a patient, such as a nasal cavity or the throat. There is animal evidence that some odorants, such as propionic acid, cyclohexanone, and amyl acetate, significantly increase cortical blood flow when presented to the nasal cavity. This has been interpreted by some researchers as evidence that these odorants (e.g., environmental pollutants) may be involved in the formation of various headaches by increasing cerebral blood flow. The temporal profile and other quantitative characteristics of such odorant stimulation are believed by the present inventors to have a mechanism of action that has a neuroanatomical basis overlapping with that of the electrical stimulation of the SPG. Furthermore, experimental animal evidence collected by the inventors and described in U.S.Provisional Patent Application 60/368,657 to Shalev and Gross entitled, “SPG stimulation,” filed Mar. 28, 2002, which is assigned to the assignee of the present invention and is incorporated herein by reference, suggest a correlation between the mechanisms of increasing cerebral blood flow and increased cerebrovascular permeability. It is hypothesized that such increased cerebral blood flow caused by odorants is a result of stimulation of parasympathetic and/or trigeminal fibers. These fibers may mediate cerebral blood flow changes directly, by communicating with the SPG, or by some other mechanism. It is also hypothesized that these odorants stimulate via reflex arcs the SPG or other autonomic neural structures that innervate the cerebrovascular system. Therefore, the inventors hypothesize, odorant “stimulation” may increase cerebral blood flow in general, and cortical blood flow in particular, by some or all of the same mechanisms as electrical stimulation, as described hereinabove. Alternatively, odorants may cause increased cortical blood flow by other mechanisms, such as by entering the blood stream and reaching the affected blood vessels in the brain or by parasympathetic stimulation via the olfactory nerve. In addition to the effect on cerebral blood flow, the introduction of odorants into an air passage is also expected to induce an increase in the permeability of the anterior two thirds of the cerebrovascular system to circulating agents of various sizes, i.e., to increase the permeability of the BBB. Similarly, presenting certain other odorants to an air passage decreases cerebral blood flow and decreases the permeability of the BBB.
• Odorants that may increase or decrease cerebral blood flow and/or the permeability of the BBB include, but are not limited to, propionic acid, cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide, sodium chloride, ammonia, menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol.
• For some applications, delivery across the BBB of a pharmacological agent is enhanced by presenting an odorant to an air passage of a patient, such as a nasal cavity or the throat. Ln the context of the present patent application and in the claims, a pharmacological agent is an agent, for administration to a patient, that is made using pharmacological procedures. Pharmacological agents may thus include, by way of illustration and not limitation, therapeutic agents and agents for facilitating diagnostic procedures.
• According to a preferred embodiment of the instant invention, a method is provided to enhance delivery of therapeutic molecules across the BBB by presenting an odorant to an air passage of a patient, such as a nasal cavity or the throat. In a preferred application, this method serves as a neurological drug delivery facilitator. The odorant is preferably presented using apparatus known in the art, such as aqueous spray nasal inhalers; metered dose nasal inhalers; or air-dilution olfactometers. Alternatively or additionally, the odorant is presented by means of an orally-dissolvable capsule that releases the active odorants upon contact with salivary liquids. The odorants reach the appropriate neural structures and induce vasodilatation, vasoconstriction and/or cerebrovascular permeability changes. Delivery of a drug can be achieved by mixing the drug with the odorant; by intravenously, intraperitoneally, or intramuscularly administering the drug, or by other delivery methods known in the art. For some applications, it is desirable to combine a local analgesic with the odorant in order to diminish any possible sensation of pain or discomfort that may directly or indirectly (e.g., via a reflex arc) accompany the odorant action upon nerves in the head. For example, preventing neural transmission in the neighboring pain fibers may be performed as a “pre-odorant” treatment, by topical administration of capsaicin together with a local analgesic for several days prior to the use of odorant stimulation. In this manner, the odorants typically induce the SPG-related response with a reduced or eliminated sensation of pain or discomfort.
• In general, it is believed that substantially all pharmacological treatments aimed at cerebral cells for neurological and psychiatric disorders are amenable for use with these embodiments of the present invention. In particular, this embodiment may be adapted for use in the treatment of disorders such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, anxiety, obesity, pain, disorders requiring the administration of various growth factors, and other CNS disorders that are directly or indirectly affected by changes in cerebral blood flow or by BBB permeability changes.
• Alternatively or additionally, a method is provided for increasing or reducing cortical blood flow and/or inducing or inhibiting vasodilation (even in the absence of BBB permeability changes) by presenting an odorant to an air passage of a patient, such as a nasal cavity or the throat, for treatment of a condition. Patients with the aforementioned disorders and other disorders are generally helped by vasodilation and the resultant improvement in oxygen supply to neurons and other tissue. For some applications, this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients. For other applications, the treatment is performed on a short-term basis, e.g., to minimize the damage following an acute stroke event and initiate neuronal and therefore functional rehabilitation. Alternatively or additionally, the method provided above can be used for diagnostic purposes or in conjunction with other diagnostic methods and/or apparatus known in the art, in order to enhance diagnostic results, reduce procedure risk, reduce procedure time, or otherwise improve such diagnostic procedures and/or diagnostic results. For example, methods and apparatus described herein may be used to increase the uptake into the brain of a radio-opaque material, in order to facilitate a CT scan.
• Decreasing cerebral blood flow by presenting certain odorants to an air passage is used in accordance with some preferred embodiments of the present invention to treat or prevent various types of headaches, especially with an autonomic nervous system (ANS) etiology, such as migraine and cluster headaches.
• Typically, for any of the odorant presentation applications described herein, a suitable dosage of the odorant is determined for a desired application (e.g., increasing or decreasing BBB permeability, or increasing or decreasing cerebral blood flow). The procedure for determine the suitable dosage is typically performed in accordance with standard drug dosage determination procedures known in the art, e.g., testing a range of very small doses for safety and efficacy, and subsequently increasing the magnitude of the doses as safety remains acceptable and efficacy continues to increase.
• In embodiments of the present invention, at least one “modulation target site” (MTS), as defined hereinbelow, is stimulated in order to facilitate a diagnosis of a condition of a central nervous system (CNS) of a subject. The MTS is typically stimulated by applying electrical, chemical, mechanical and/or odorant stimulation to the site. Such stimulation is configured to increase the permeability of the blood-brain barrier (BBB) in order to increase the transport of (a) a diagnostic agent from the systemic blood circulation of the subject into the CNS, and/or (b) a constituent of the CNS, such as a biochemical agent, from the CNS into the systemic circulation. The electrical, chemical, mechanical and odorant stimulation techniques described herein may facilitate the diagnosis of a number of CNS conditions, including, but not limited to, neurodegenerative conditions (e.g., Alzheimer's disease, Parkinson's Disease, and ALS), neoplastic processes (either primary or metastatic), immune- and autoimmune-related disorders (e.g., HIV and multiple sclerosis), and CNS inflammatory processes.
• In the present patent application, a “modulation target site” (MTS) consists of:
• • a sphenopalatine ganglion (SPG) (also called a pterygopalatine ganglion);
  • an anterior ethmoidal nerve;
  • a posterior ethmoidal nerve;
  • a communicating branch between the anterior ethmoidal nerve and the SPG (retro-orbital branch);
  • a communicating branch between the posterior ethmoidal nerve and the SPG (retro-orbital branch);
  • a nerve of the pterygoid canal (also called a vidian nerve), such as a greater superficial petrosal nerve (a preganglionic parasympathetic nerve) or a lesser deep petrosal nerve (a postganglionic sympathetic nerve);
  • a greater palatine nerve;
  • a lesser palatine nerve;
  • a sphenopalatine nerve;
  • a communicating branch between the maxillary nerve and the sphenopalatine ganglion;
  • a nasopalatine nerve;
  • a posterior nasal nerve;
  • an infraorbital nerve;
  • an otic ganglion;
  • an afferent fiber going into the otic ganglion; and/or
  • an efferent fiber going out of the otic ganglion.
• The stimulation techniques described herein typically enhance delivery of diagnostic and biochemical molecules across the BBB by stimulating the nerve fibers of the MTS, thereby inducing the middle and anterior cerebral arteries to dilate, for example, and also causing the walls of these cerebral arteries to become more permeable to large molecules. In this manner, the movement of large molecules from within blood vessels to the cerebral tissue, and from the cerebral issue to blood vessels, is substantially increased. Without the use of the techniques described herein or functional equivalents thereof, the intact BBB generally blocks or substantially reduces the passage of such molecules.
• In some embodiments of the present invention, stimulation of an MTS is configured to increase the transport of a diagnostic agent across the BBB from the systemic blood circulation into the CNS. Prior to, during, or after such stimulation, the diagnostic agent is administered to a non-CNS tissue of the subject, typically the systemic blood circulation, such as intravenously, and a diagnostic procedure, typically an imaging modality, is then performed directly on the CNS. The diagnostic agent is typically a contrast agent or enhancer, or a tracer, such as a radioisotope. For example, an imaging procedure may be performed by intravenously administering labeled (e.g., radiolabeled) beta-Amyloid monoclonal antibody (mAb) or polyclonal antibody (pAb), stimulating an MTS to transport the tracer across the BBB, and mapping the distribution of the tracer in the brain using Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging.
• These techniques for facilitating the transport of diagnostic agents into the CNS generally increase the accuracy of CNS diagnostic procedures. Such increased accuracy is obtained in part because a greater amount of the agent enters the CNS as a result of the MTS stimulation. Additionally, MTS stimulation allows diagnostic agents having greater molecular weights to cross the BBB, which enables the effective use of a broader range of agents having greater specificity, such as labeled antibodies and cytokines. The greater diagnostic sensitivity of these techniques also may allow the performance of a non-invasive imaging procedure instead of a more invasive procedure, such as sampling of CNS tissue or fluid (e.g., cerebrospinal fluid (CSF) lumbar puncture, brain biopsy).
• In other embodiments of the present invention, stimulation of an MTS is configured to increase the transport of a biochemical agent across the BBB from the CNS to a non-CNS tissue of the subject, such as the systemic blood circulation. Such biochemical agents are typically disease-specific biochemical markers. Prior to stimulation of an MTS to increase BBB permeability, the concentration of such a biochemical agent is typically greater in the CNS than in the systemic circulation, i.e., there is a concentration gradient across the endothelium. Therefore, increasing the permeability of the BBB generally releases the agent into the systemic circulation. Once in the systemic circulation, diagnosis is typically performed by sampling a body fluid, typically blood, and analyzing the whole blood, plasma, or serum.
• These techniques for facilitating the transport of biochemical agents from the CNS into the systemic circulation generally increase the rate of transfer and, consequently, the amount of the agent in the systemic circulation. The diagnostic signal, i.e., the statistical sample size, of the agent in the circulation is thereby increased, generally resulting in increased accuracy of the diagnostic procedure. Additionally, for some CNS conditions, use of these techniques may allow the performance of a minimally-invasive procedure instead of a more invasive procedure, such as sampling of CNS tissue or fluid (e.g., CSF lumbar puncture, brain biopsy).
• In some embodiments of the present invention, stimulation of at least one MTS is achieved by presenting odorants to an air passage of a patient, such as a nasal cavity or the throat, as described herein, so as to facilitate a diagnosis of a CNS condition.
• In some embodiments of the present invention, stimulation of at least one MTS is achieved by applying a neuroexcitatory agent to the MTS. Suitable neuroexcitatory agents include, but are not limited to, acetylcholine and urocholine. For some applications, the MTS is stimulated by applying a neuroinhibitory agent, such as atropine, hexamethonium, or a local anesthetic (e.g., lidocaine).
• In some embodiments of the present invention, stimulation of the MTS is achieved by applying mechanical stimulation to the MTS, e.g., vibration.
• It is to be appreciated that references herein to specific modulation target sites are to be understood as including other modulation target sites, as appropriate.
• It is to be appreciated that, whereas preferred embodiments of the present invention are described with respect to driving current into the SPG or into neural structures directly related thereto, the scope of the present invention includes driving current into other sites in the brain which upon stimulation modulate cerebral blood flow or modulate permeability properties of the BBB, as appropriate for a given application.
• It is also to be appreciated that electrical “stimulation,” as provided by preferred embodiments of the present invention, is meant to include substantially any form of current application to designated tissue, even when the current is configured to block or inhibit the activity of nerves.
• It is further to be appreciated that implantation and stimulation sites, methods of implantation, and parameters of stimulation are described herein by way of illustration and not limitation, and that the scope of the present invention includes other possibilities which would be obvious to someone of ordinary skill in the art who has read the present patent application.
• It is yet further to be appreciated that while preferred embodiments of the invention are generally described herein with respect to electrical transmission of power and electrical stimulation of tissue, other modes of energy transport may be used as well. Such energy includes, but is not limited to, direct or induced electromagnetic energy, radiofrequency (RF) transmission, mechanical vibration, ultrasonic transmission, optical power, and low power laser energy (via, for example, a fiber optic cable).
• It is additionally to be appreciated that whereas preferred embodiments of the present invention are described with respect to application of electrical currents to tissue, this is to be understood in the context of the present patent application and in the claims as being substantially equivalent to applying an electrical field, e.g., by creating a voltage drop between two electrodes.
• As used in the present patent application, including the claims, the central nervous system (CNS) is to be understood as consisting of CSF, the brain, and the spinal cord.
• There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • one or more electrodes, adapted to be applied to a site selected from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • a control unit, adapted to drive the one or more electrodes to apply a current to the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the patient.
• There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • one or more electrodes, adapted to be applied to a site selected from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • a control unit, adapted to drive the one or more electrodes to apply a current to the site capable of inducing an increase in cerebral blood flow of the patient.
• There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • one or more electrodes, adapted to be applied to a site selected from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • a control unit, adapted to drive the one or more electrodes to apply a current to the site capable of inducing a decrease in cerebral blood flow of the patient.
• There is still further provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • one or more electrodes, adapted to be applied to a site selected from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • a control unit, adapted to drive the one or more electrodes to apply a current to the site capable of inhibiting parasympathetic activity of the SPG.
• Preferably, the one or more electrodes are adapted for a period of implantation in the patient greater than about one month.
• In a preferred embodiment, the apparatus includes a wire, adapted to connect the control unit to the one or more electrodes, wherein the control unit is adapted to drive the one or more electrodes from a position external to the patient.
• Alternatively or additionally, the control unit is adapted to drive the one or more electrodes by wireless communication from a position external to the patient. In a preferred embodiment, the apparatus includes an electromagnetic coupling, adapted to couple the control unit and the one or more electrodes. Alternatively or additionally, the control unit is adapted to be in electro-optical communication with the one or more electrodes. Further alternatively or additionally, the control unit is adapted to be in electro-acoustic communication with the one or more electrodes. Still further alternatively or additionally, the control unit is adapted to be implanted in a nasal cavity of the patient.
• Preferably, the one or more electrodes are adapted to be implanted in a nasal cavity of the patient. For some applications, at least one of the one or more electrodes includes a flexible electrode, adapted for insertion through a nostril of the patient and to extend therefrom to the site.
• The apparatus preferably includes at least one biosensor, adapted to measure a physiological parameter of the patient and to generate a signal responsive thereto. The control unit, in turn, is preferably adapted to modify a parameter of the applied current responsive to the signal. As appropriate, the biosensor may include one or more of the following:
• • a blood flow sensor.
  • a temperature sensor.
  • a chemical sensor.
  • an ultrasound sensor.
  • transcranial Doppler (TCD) apparatus.
  • laser-Doppler apparatus.
  • a systemic blood pressure sensor.
  • an intracranial blood pressure sensor.
  • a detecting element adapted to be fixed to a cerebral blood vessel, and wherein the control unit is adapted to analyze the signal to detect an indication of a change in blood pressure indicative of a clot.
  • a kinetics sensor (in this case, the control unit is typically adapted to analyze the signal to detect an indication of a change in body disposition of the patient).
  • an electroencephalographic (EEG) sensor.
  • a blood vessel clot detector.
• In a preferred embodiment, the control unit is adapted to configure the current so as to facilitate uptake of a drug through the BBB when the permeability of the BBB is increased.
• Alternatively or additionally, the control unit is adapted to configure the current so as to increase a diameter of a blood vessel and allow an embolus that is located at a site in the blood vessel to move from the site in the blood vessel.
• Further alternatively or additionally, the control unit is adapted to drive the one or more electrodes to apply the current responsive to an indication of stroke.
• Still further alternatively or additionally, the control unit is adapted to drive the one or more electrodes to apply the current responsive to an indication of migraine of the patient.
• There is also provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including:
• • selecting a site from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • applying a current to the site capable of inducing an increase in permeability of a blood-brain barrier (BBB) of the patient.
• There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including:
• • selecting a site from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • applying a current to the site capable of inducing an increase in cerebral blood flow of the patient.
• There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including:
• • selecting a site from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • applying a current to the site capable of inducing a decrease in cerebral blood flow of the patient.
• There is still additionally provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including:
• • selecting a site from a group of sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a neural tract originating in or leading to the SPG; and
  • applying a current to the site capable of inhibiting parasympathetic activity of the SPG.
• For some applications, the one or more electrodes are adapted for a period of implantation in the patient less than about one week.
• There is further provided, in accordance with a preferred embodiment of the present invention, vascular apparatus, including:
• • a detecting element, adapted to be fixed to a blood vessel of a patient and to generate a signal responsive to energy coming from the blood vessel; and
  • a control unit, adapted to analyze the signal so as to determine an indication of an embolus in the blood vessel.
• Preferably, the detecting element includes an energy transmitter and an energy receiver. For example, the energy transmitter may include an ultrasound transmitter or a transmitter of electromagnetic energy.
• There is yet further provided, in accordance with a preferred embodiment of the present invention, a method for detecting, including:
• • fixing a detecting element to a blood vessel of a patient;
  • generate a signal responsive to energy coming from the blood vessel; and
  • analyzing the signal so as to determine an indication of an embolus in the blood vessel.
• There is still further provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is such as to increase conductance of molecules between a systemic blood circulation of the patient and brain tissue of the patient, by way of a blood brain barrier (BBB) of the brain.
• For some applications, the method includes sensing a parameter of the patient and presenting the odorant responsive thereto. The parameter may include an indication of a behavior of the patient, in which case sensing the parameter includes sensing the indication of the behavior of the patient. Alternatively, the parameter may be selected from the list consisting of: a biochemical value of the patient and a physiological value of the patient, in which case sensing the parameter includes sensing the parameter selected from the list. For some applications, sensing the parameter selected from the list includes sensing the parameter using a modality selected from the list consisting of: CT, MRI, PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, light microscopy, and oximetry. Alternatively or additionally, sensing the parameter selected from the list includes measuring a level of the molecules in the patient. For some applications, measuring the level of the molecules includes sampling a body fluid of the patient selected from the list consisting of: blood, plasma, serum, ascites fluid, and urine.
• In an embodiment of the present invention, presenting the odorant to the air passage of the patient includes presenting the odorant, the odorant having been selected for presentation to the air passage because it is such as to increase conductance of the molecules from the systemic blood circulation of the patient through the blood brain barrier (BBB) into brain tissue of the patient, the molecules being selected from the group consisting of: an endogenous agent, a pharmacological agent, a therapeutic agent, and an agent for facilitating a diagnostic procedure.
• In an embodiment, presenting the odorant includes presenting the odorant in a dosage determined to increase the conductance of the molecules. In an embodiment, the method includes administering the molecules for inhalation by the patient.
• In an embodiment, the method includes administering the molecules to the patient in a bolus. In an embodiment, the method includes administering the molecules to the patient in a generally continuous manner.
• In an embodiment, the method includes administering an agent capable of blocking a P-glycoprotein transporter from transporting the molecules from a target site in the brain tissue.
• In an embodiment, the method includes administering the molecules to the systemic blood circulation. For some applications, administering the molecules includes administering the molecules mixed with the odorant. Alternatively or additionally, administering the molecules includes administering the molecules to the systemic blood circulation using a technique selected from the list consisting of: per-oral administration intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, and intramuscular administration.
• In an embodiment, the molecules include the agent for facilitating a diagnostic procedure, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the agent for facilitating the diagnostic procedure. For some applications, the agent for facilitating a diagnostic procedure includes an imaging contrast agent, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the imaging contrast agent. Alternatively or additionally, the agent for facilitating a diagnostic procedure includes a radio-opaque material, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the radio-opaque material. Further alternatively or additionally, the agent for facilitating a diagnostic procedure includes an antibody, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the antibody.
• In an embodiment, presenting the odorant includes selecting the molecules, the molecules being appropriate for treating a disorder of the central nervous system (CNS) of the patient. In an embodiment, the CNS disorder is selected from the list consisting of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, and anxiety, and selecting the molecules includes selecting the molecules, the molecules being appropriate for treating the selected CNS disorder.
• In an embodiment, the method includes regulating a parameter of the odorant presentation. For some applications, regulating the parameter includes regulating a parameter selected from the list consisting of: relative concentrations of two or more ingredients of the odorant, a quantity of the odorant presented, a rate of presentation of the odorant, a pressure of the odorant at presentation, and a temperature of at least a portion of the odorant. In an embodiment, the method includes administering the molecules to the patient during a treatment session that is subsequent to regulating the parameter of the odorant presentation. In an embodiment, the method includes administering the molecules to the patient during a treatment session, and regulating the parameter of the odorant presentation during the same treatment session. For some applications, regulating the parameter of the odorant presentation includes selecting the parameter from a predefined set of parameters for the odorant presentation.
• For some applications, the method includes sensing a parameter of the patient and regulating the parameter of the odorant presentation responsive thereto. The parameter of the patient may include an indication of a behavior of the patient, in which case sensing the parameter of the patient includes sensing the indication of the behavior of the patient Alternatively, the parameter of the patient may be selected from the list consisting of: a biochemical value of the patient and a physiological value of the patient, in which case sensing the parameter of the patient includes sensing the parameter of the patient selected from the list.
• In an embodiment, the molecules include the therapeutic agent, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the therapeutic agent. For some applications, the therapeutic agent includes a neurological drug, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the neurological drug. For some applications, the therapeutic agent includes a protein, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the protein. For some applications, the therapeutic agent includes a polymer, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the polymer. For some applications, the therapeutic agent includes a viral vector, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the viral vector.
• For some applications, the therapeutic agent includes an anti-cancer drug, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the anti-cancer drug. For some applications, the therapeutic agent includes an agent from the list consisting of: glatiramer acetate and interferon beta-1b, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the agent selected from the list. For some applications, the therapeutic agent includes an agent from the list consisting of: an agent for DNA therapy and an agent for RNA therapy, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the agent selected from the list. For some applications, the therapeutic agent includes an agent from the list consisting of:
• • (a) an antisense molecule against type-1 insulin-like growth factor receptor, and (b) ADV-HSV-tk, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the agent selected from the list consisting of the antisense molecule and the ADV-HSV-tk.
• In an embodiment, the method includes administering the molecules in conjunction with presenting the odorant. In an embodiment, administering the molecules in conjunction with presenting the odorant includes administering the molecules at a time determined with respect to a time of presenting the odorant. For some applications, administering the molecules includes administering the molecules at least a predetermined time prior to presenting the odorant. Alternatively, administering the molecules includes administering the molecules at generally the same time as presenting the odorant. Further alternatively, administering the molecules includes administering the molecules at least a predetermined time subsequent to presenting the odorant.
• In an embodiment, the molecules include the pharmacological agent, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the pharmacological agent. For some applications, the pharmacological agent includes a viral vector, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the viral vector. For some applications, the pharmacological agent includes an antibody, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the antibody. For some applications, the antibody is selected from the list consisting of: a toxin-antibody complex, a radiolabeled antibody, and anti-HER2 mAb, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the selected antibody. Alternatively, the antibody is selected from the list consisting of: anti-b-amyloid antibody and anti-amyloid-precursor-protein antibody, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the selected antibody.
• In an embodiment, the molecules include the endogenous agent, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the endogenous agent. For some applications, the endogenous agent includes an endogenous agent substantially unmodified by artificial means, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the endogenous agent that is substantially unmodified by artificial means. Alternatively, the endogenous agent includes an endogenous agent an aspect of which is modified by artificial means, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the endogenous agent the aspect of which is modified by artificial means. Further alternatively, the endogenous agent includes an enzyme, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the enzyme. For some applications, the enzyme includes hexosamimidase, and presenting the odorant includes presenting the odorant, the odorant being such as to increase the conductance of the hexosaminidase.
• In an embodiment, the method includes administering the molecules to a mucous membrane of the patient. For some applications, administering the molecules includes administering the molecules to oral mucosa of the patient. Alternatively, administering the molecules includes administering the molecules to nasal mucosa of the patient.
• For some applications, administering the molecules includes administering the molecules in combination with the odorant. Alternatively, administering the molecules includes administering the molecules separately from the odorant.
• In an embodiment of the present invention, presenting the odorant to the air passage of the patient includes presenting the odorant, the odorant having been selected for presentation to the air passage because it is such as to increase conductance of molecules from the brain tissue of the patient through the blood brain barrier (BBB) into the systemic blood circulation.
• In an embodiment, the method includes sensing a quantity of the molecules from a site outside of the brain of the patient, following initiation of presentation of the odorant. For some applications, sensing the quantity of the molecules includes sensing using a modality selected from the list consisting of: CT, MRI, PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, light microscopy, and oximetry. For some applications, sensing the quantity of the molecules includes sampling a fluid of the patient selected from the list consisting of: blood, plasma, serum, ascites fluid, and urine.
• In an embodiment, the method includes determining a diagnostically-relevant parameter responsive to sensing the quantity of the molecules.
• In an embodiment, the method includes selecting a dosage of the odorant responsive to a disorder of the patient. For some applications, selecting the dosage of the odorant includes determining a dosage of the odorant that increases conductance of the molecules, responsive to presentation of the odorant, to an extent sufficient to treat the disorder at least in part. For some applications, selecting the dosage includes selecting the dosage responsive to the disorder of the patient, the disorder being selected from the list consisting of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, and anxiety.
• In an embodiment, the method includes administering a hyperosmolarity-inducing agent to the patient at a dosage sufficient to augment an increase in conductance of the molecules caused by presentation of the odorant.
• In an embodiment, the method includes inducing a state of dehydration of the patient, of an extent sufficient to augment an increase in conductance of the molecules caused by presentation of the odorant.
• In an embodiment, the method includes administering an agent to the patient that modulates synthesis or metabolism of nitric-oxide (NO) in blood vessels of the brain, at a dosage sufficient to augment an increase in conductance of the molecules caused by presentation of the odorant.
• There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient during or following a stroke event, including presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is capable of inducing an increase in cerebral blood flow of the patient, so as to reduce a pathology associated with the stroke event.
• In an embodiment, presenting the odorant includes presenting the odorant in a dosage determined to increase the cerebral blood flow.
• There is also provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient who suffers from headache attacks, including presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is capable of modifying cerebral blood flow of the patient, so as to reduce a severity of a headache attack of the patient.
• In an embodiment, presenting the odorant includes presenting the odorant in a dosage determined to modify the cerebral blood flow.
• In an embodiment, presenting the odorant includes selecting the odorant, the odorant being capable of decreasing the cerebral blood flow, so as to reduce the severity of the headache attack.
• In an embodiment, the headache attack includes a migraine headache attack of the patient, and presenting the odorant includes presenting to the air passage an odorant that is capable of reducing the cerebral blood flow, so as to reduce the severity of the migraine headache attack. In an embodiment, the headache attack includes a cluster headache attack of the patient, and presenting the odorant includes presenting to the air passage an odorant that is capable of reducing the cerebral blood flow, so as to reduce the severity of the cluster headache attack.
• There is further provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient who suffers from a disorder of the central nervous system (CNS), including presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is capable of modifying cerebral blood flow of the patient, so as to treat the CNS disorder.
• In an embodiment, presenting the odorant includes presenting the odorant in a dosage determined to modify the cerebral blood flow.
• In an embodiment, the CNS disorder is selected from the list consisting of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, and anxiety, and presenting the odorant includes presenting the odorant that is capable of modifying the cerebral blood flow, so as to treat the selected CNS disorder.
• In an embodiment, presenting the odorant includes selecting the odorant, the odorant being capable of decreasing the cerebral blood flow. In an embodiment, presenting the odorant includes selecting the odorant, the odorant being capable of increasing cerebral blood flow of the patient. In an embodiment, presenting the odorant includes selecting the odorant, the odorant being capable of increasing cortical blood flow of the patient.
• There is still further provided, in accordance with a preferred embodiment of the present invention, a method for modifying a property of a brain of a patient, including presenting an odorant to an air passage of the patient, the odorant having been selected for presentation to the air passage because it is such as to decrease conductance of molecules from a systemic blood circulation of the patient through a blood brain barrier (BBB) of the brain into brain tissue of the patient.
• In an embodiment, presenting the odorant includes presenting the odorant in a dosage determined to decrease the conductance of the molecules.
• In an embodiment, the method includes presenting in association with the odorant an analgesic in a dosage configured to reduce a sensation associated with the presenting of the odorant. In an embodiment, presenting the analgesic includes topically presenting the analgesic at a site selected from the list consisting of: a vicinity of one or more nerves in a nasal cavity of the patient, a vicinity of one or more nerves in an oral cavity of the patient, and a vicinity of one or more nerves innervating a face of the patient. In an embodiment, presenting the analgesic includes topically presenting the analgesic in a vicinity of a sphenopalatine ganglion (SPG) of the patient. In an embodiment, presenting the analgesic includes administering the analgesic for inhalation at generally the same time as the presenting of the odorant.
• In an embodiment, the air passage includes a nasal cavity of the patient, and presenting the odorant includes presenting the odorant to the nasal cavity.
• In an embodiment, the air passage includes a throat of the patient, and presenting the odorant includes presenting the odorant to the throat.
• In an embodiment, the odorant is selected from the list consisting of: propionic acid, cyclohexanone, and amyl acetate, and presenting the odorant includes presenting the selected odorant. Alternatively, the odorant is selected from the list consisting of: acetic acid, citric acid, carbon dioxide, sodium chloride, and ammonia, and presenting the odorant includes presenting the selected odorant. Further alternatively, the odorant is selected from the list consisting of: menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol, and presenting the odorant includes presenting the selected odorant.
• In an embodiment, presenting the odorant includes presenting a capsule for placement within a mouth of the patient, the capsule being configured to dissolve upon contact with salivary liquids of the patient, whereupon the odorant is presented to the air passage.
• In an embodiment, the method includes regulating a parameter of the odorant presentation. For some applications, regulating the parameter includes regulating a parameter selected from the list consisting of: relative concentrations of two or more ingredients of the odorant, a quantity of the odorant presented, a rate of presentation of the odorant, a pressure of the odorant at presentation, and a temperature of at least a portion of the odorant. Alternatively or additionally, regulating the parameter of the odorant presentation includes selecting the parameter from a predefined set of parameters for the odorant presentation.
• In an embodiment, the method includes sensing a parameter of the patient and regulating the parameter of the odorant presentation responsive thereto. For some applications, the parameter of the patient includes an indication of a behavior of the patient, and sensing the parameter of the patient includes sensing the indication of the behavior of the patient.
• In an embodiment, the parameter of the patient is selected from the list consisting of: a biochemical value of the patient and a physiological value of the patient, and sensing the parameter of the patient includes sensing the parameter of the patient selected from the list.
• In an embodiment, the method includes sensing a parameter of the patient and presenting the odorant responsive thereto. For some applications, the parameter includes an indication of a behavior of the patient, and sensing the parameter includes sensing the indication of the behavior of the patient. Alternatively, the parameter is selected from the list consisting of: a biochemical value of the patient and a physiological value of the patient, and sensing the parameter includes sensing the parameter selected from the list. For some applications, sensing the parameter selected from the list includes sensing the parameter using a modality selected from the list consisting of: CT, MRI, PET, SPECT, angiography, ophthalmoscopy, fluoroscopy, light microscopy, and oximetry. Alternatively, sensing the parameter selected from the list includes sampling a body fluid of the patient selected from the list consisting of: blood, plasma, serum, ascites fluid, and urine.
• There is additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing conductance of molecules from a systemic blood circulation of the patient through a blood brain barrier (BBB) of the brain into brain tissue of the patient, the molecules being selected from the group consisting of: a pharmacological agent, a therapeutic agent, and an agent for facilitating a diagnostic procedure; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient.
• In an embodiment, the odorant-storage vessel is adapted to store the odorant mixed with the molecules.
• In an embodiment, the molecules include the therapeutic agent, and the odorant is such as to increase the conductance of the therapeutic agent.
• In an embodiment, the therapeutic agent includes a neurological drug, and the odorant is such as to increase the conductance of the neurological drug.
• In an embodiment, the molecules include the agent for facilitating a diagnostic procedure, and the odorant is such as to increase the conductance of the agent for facilitating the diagnostic procedure. For some applications, the agent for facilitating a diagnostic procedure includes a radio-opaque material, and the odorant is such as to increase the conductance of the radio-opaque material.
• In an embodiment, the odorant includes an agent for facilitating treatment of a disorder of the central nervous system (CNS) of the patient. For some applications, the CNS disorder is selected from the list consisting of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, and anxiety, and the odorant includes an agent for facilitating treatment of the selected CNS disorder.
• There is yet additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient during or following a stroke event, including:
• • an odorant-storage vessel;
  • an odorant, for storage within the odorant-storage vessel, the odorant being capable of inducing an increase in cerebral blood flow of the patient; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to reduce a pathology associated with the stroke event.
• There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient who suffers from headache attacks, including:
• • an odorant-storage vessel;
  • an odorant, for storage within the odorant-storage vessel, the odorant being capable of modifying cerebral blood flow of the patient; and
  • an odorant-delivery element, configured to present the odorant to an air passage of the patient, so as to reduce a severity of a headache attack of the patient.
• In an embodiment, the odorant is capable of decreasing the cerebral blood flow.
• In an embodiment, the headache attack includes a migraine headache attack of the patient, and the odorant is capable of reducing the severity of the migraine headache attack. In an embodiment, the headache attack includes a cluster headache attack of the patient, and the odorant is capable of reducing the severity of the cluster headache attack.
• There is still additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient who suffers from a disorder of the central nervous system (CNS), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of modifying cerebral blood flow of the patient; and
  • an odorant-delivery element, configured to present the odorant to an air passage of the patient, so as to treat the CNS disorder.
• In an embodiment, the CNS disorder is selected from the list consisting of: a brain tumor, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, obesity, pain, and anxiety, and the odorant includes an agent for facilitating treatment of the selected CNS disorder.
• In an embodiment, the odorant is capable of decreasing the cerebral blood flow. Alternatively, the odorant is capable of increasing the cerebral blood flow. For some applications, the odorant is capable of increasing cortical blood flow of the patient.
• There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for modifying a property of a brain of a patient, including:
• • an odorant-storage vessel;
  • an odorant, for storage within the odorant-storage vessel, the odorant being capable of decreasing conductance of molecules from a systemic blood circulation of the patient through a blood brain barrier (BBB) of the brain into brain tissue of the patient; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient.
• In an embodiment, the apparatus includes an analgesic for storage within the odorant-storage vessel in a dosage configured to reduce a sensation associated with the presenting of the odorant, and the odorant-delivery element is adapted to present the analgesic to the air passage in association with the odorant.
• In an embodiment, the odorant-storage vessel in combination with the odorant-delivery element includes an aqueous spray nasal inhaler. Alternatively, the odorant-storage vessel in combination with the odorant-delivery element includes a metered dose nasal inhaler. Further alternatively, the odorant-storage vessel in combination with the odorant-delivery element includes an air-dilution olfactometer.
• In an embodiment, the air passage includes a nasal cavity of the patient, and the odorant-delivery element is adapted to present the odorant to the nasal cavity.
• In an embodiment, the air passage includes a throat of the patient, and the odorant-delivery element is adapted to present the odorant to the throat.
• In an embodiment, the odorant includes an agent selected from the list consisting of: propionic acid, cyclohexanone, and amyl acetate. Alternatively, the odorant includes an agent selected from the list consisting of: acetic acid, citric acid, carbon dioxide, sodium chloride, and ammonia. Further alternatively, the odorant includes an agent selected from the list consisting of: menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol.
• In an embodiment, the odorant-storage vessel includes a capsule for placement in a mouth of the patient, and the odorant-delivery element includes a portion of the capsule adapted to dissolve upon contact with salivary liquids of the patient, whereupon the odorant is presented to the air passage of the patient.
• There is also provided, in accordance with a preferred embodiment of the present invention, a method for treating Alzheimer's disease (AD), including stimulating a sphenopalatine ganglion (SPG) of a subject so that the concentration of a substance in a brain of the subject changes.
• In a preferred embodiment, the stimulation causes increased clearance of the substance from the brain. As appropriate, the substance may be one or more of the following:
• • amyloid;
  • tau protein;
  • PS1;
  • PS2;
  • RNA fragments;
  • cytokine;
  • a marker of neuronal death;
  • a marker of neuronal degeneration;
  • a marker of an inflammatory process; and
  • a neurotoxic substance.
• Alternatively or additionally, the substance may include DNA.
• In another preferred embodiment, the stimulation causes increased clearance of the substance from cerebrospinal fluid (CSF). As appropriate, the substance may be one or more of the following:
• • amyloid;
  • tau protein;
  • PS1;
  • PS2;
  • RNA fragments;
  • cytokine;
  • a marker of neuronal death;
  • a marker of neuronal degeneration;
  • a marker of an inflammatory process; and
  • a neurotoxic substance.
• Alternatively or additionally, the substance may include DNA.
• There is additionally provided, in accordance with a preferred embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • supplying a pharmaceutical agent to blood of a subject; and
  • stimulating a sphenopalatine ganglion (SPG) of the subject so that the concentration of the pharmaceutical agent in a brain of the subject increases.
• As appropriate, the pharmaceutical agent may be one or more of the following:
• • a glutamate receptor antagonist;
  • a β-amyloid inhibitor;
  • an NMDA-receptor blocker;
  • a combination of an AD vaccine and an anti-inflammatory drug;
  • a microglial activation modulator;
  • a cholinesterase inhibitor;
  • a stimulant of nerve regeneration;
  • a nerve growth factor;
  • a compound that stimulates production of nerve growth factor;
  • an antioxidant;
  • a hormone;
  • an inhibitor of protein tyrosine phosphatases;
  • medium chain triglycerides;
  • an endogenous protein;
  • a gene therapy agent;
  • an anti-inflammatory drug;
  • a non-steroidal anti-inflammatory drug; and
  • an AD vaccine. More specifically, the AD vaccine may contain antibodies against a specific protein that is characteristic of AD. Still more specifically, the AD vaccine may contain antibodies against P-amyloid and/or antibodies against tau protein.
• Alternatively, the pharmaceutical agent is adapted to have an inhibitory effect on the derivation of β-amyloid from amyloid precursor protein.
• There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including stimulating a sphenopalatine ganglion (SPG) of a subject so that molecular passage increases between a central nervous system (CNS) of the subject and another body compartment of the subject.
• Preferably, the method includes measuring a constituent of the other body compartment. As appropriate, the other body compartment may be one of the following:
• • blood of the subject;
  • plasma of the subject;
  • serum of the subject; and
  • ascites of the subject.
• There is still additionally provided, in accordance with a preferred embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including stimulating a sphenopalatine ganglion (SPG) of a subject so that molecular passage increases between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject.
• Preferably, the method includes measuring a constituent of the other body fluid. More preferably, the method includes correlating an abnormal concentration of the constituent to a pathology of AD. As appropriate, the constituent may be selected from the group consisting of the following: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme.
• Alternatively or additionally, the measurement is performed by sampling a fluid selected from the group consisting of the following: whole blood, plasma, serum, and ascites. Further alternatively or additionally, the measurement is performed by extracting the fluid from tissue of the subject.
• Optionally, the measurement may be performed by measuring more than one constituent. In this case, a diagnostic result may be determined according to the interrelation between concentrations of the constituents.
• There is also provided, in accordance with a preferred embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including stimulating a sphenopalatine ganglion (SPG) of a subject so that molecular passage increases between cerebrospinal fluid (CSF) of the subject and a tissue of the subject.
• Preferably, the method includes measuring a constituent of the tissue. More preferably, the method includes correlating an abnormal concentration of the constituent to a pathology of AD. As appropriate, the constituent may be selected from the group consisting of the following: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme.
• Optionally, the measurement may be performed by measuring more than one constituent. In this case, a diagnostic result may be determined according to the interrelation between concentrations of the constituents.
• There is further provided, in accordance with a preferred embodiment of the present invention, a system for treating Alzheimer's disease (AD), including a stimulator for stimulating the sphenopalatine ganglion (SPG) of a subject, so that the concentration of a substance in a brain of the subject changes.
• There is yet further provided, in accordance with a preferred embodiment of the present invention, a pharmaceutical agent delivery system for treating Alzheimer's disease (AD), including:
• • a pharmaceutical agent supplied to a body of a subject for delivery to a brain of the subject via blood of said subject; and
  • a stimulator for stimulating a sphenopalatine ganglion (SPG) of the subject, so that the concentration of the pharmaceutical agent in the brain increases.
• There is still further provided, in accordance with a preferred embodiment of the present invention, a system for diagnosing Alzheimer's disease (AD), including a stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so that molecular passage increases between a CNS of the subject and another body compartment of the subject.
• There is additionally provided, in accordance with a preferred embodiment of the present invention, a system for diagnosing Alzheimer's disease (AD), including a stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so that molecular passage increases between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject.
• There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a system for diagnosing Alzheimer's disease (AD), including a stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so that molecular passage increases between cerebrospinal fluid (CSF) of the subject and a tissue of the subject.
• There is therefore provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is further provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is still further provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• In an embodiment, stimulating the SPG-related tissue includes directly stimulating the SPG.
• For some applications, the AD-related constituent includes an inflammatory-related constituent, tau protein, PS1, PS2, a DNA fragment, an RNA fragment, a cytokine, a marker of neuronal death or degeneration, a marker of an inflammatory process, a neurotoxic substance, amyloid protein, an amyloid protein selected from the list consisting of: wild amyloid protein and mutated amyloid protein, and/or an amyloid protein selected from the list consisting of: fragmented amyloid protein and whole amyloid protein, and configuring the stimulation includes configuring the stimulation so as to cause the increase in the clearance of the inflammatory-related constituent, tau protein, PS1, PS2, DNA fragment, RNA fragment, cytokine, marker of neuronal death or degeneration, marker of an inflammatory process, neurotoxic substance, amyloid protein, amyloid protein selected from the list consisting of: wild amyloid protein and mutated amyloid protein, and/or amyloid protein selected from the list consisting of: fragmented amyloid protein and whole amyloid protein.
• There is also provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • supplying a pharmaceutical agent to a systemic blood circulation of a subject;
  • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in passage of the pharmaceutical agent from the systemic blood circulation into a central nervous system (CNS) of the subject, so as to treat the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • supplying a pharmaceutical agent to a systemic blood circulation of a subject;
  • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in passage of the pharmaceutical agent from the systemic blood circulation into a central nervous system (CNS) of the subject, so as to treat the AD.
• In an embodiment, supplying the pharmaceutical agent includes administering the pharmaceutical agent to the systemic blood circulation using a technique selected from the list consisting of: per-oral administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, and intramuscular administration.
• For some applications, the pharmaceutical agent includes a glutamate receptor antagonist, an NMDA receptor blocker, an agent having an inhibitory effect on derivation of β-amyloid from amyloid precursor protein, a cholinesterase inhibitor, a stimulant of nerve regeneration, a nerve growth factor, a compound that stimulates production of nerve growth factor, a microglial activation modulator, an antioxidant, a hormone, an inhibitor of protein tyrosine phosphatases, a medium chain triglyceride, a gene therapy agent, a β-amyloid inhibitor, an endogenous protein, an anti-inflammatory agent, a non-steroidal anti-inflammatory drug (NSAID), or a pharmaceutical agent selected from the list consisting of: an AD vaccine, a component of an AD vaccine, and a derivative of an AD vaccine (for example, the selected pharmaceutical agent including (a) an anti-inflammatory drug, (b) antibodies against a specific protein that is characteristic of AD, (c) antibodies against β-amyloid, or (d) antibodies against tau protein), and configuring the stimulation includes configuring the stimulation so as to cause the increase in the passage of the pharmaceutical agent.
• In an embodiment, supplying the pharmaceutical agent includes administering the pharmaceutical agent for inhalation by the subject. For example, administering the pharmaceutical agent for inhalation by the subject may include administering the pharmaceutical agent mixed with the odorant.
• There is still additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• In an embodiment, configuring the stimulation includes configuring the stimulation so as to cause an improvement in a metabolic state of a central nervous system (CNS) of the subject.
• There is also provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• In an embodiment, the method includes measuring a constituent of the other body compartment.
• For some applications, the other body compartment includes a systemic blood circulation of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation. Alternatively or additionally, the other body compartment includes plasma of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma. Further alternatively or additionally, the other body compartment includes serum of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum. Still further alternatively or additionally, the other body compartment is ascites of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.
• There is yet additionally provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• In an embodiment, the method includes measuring a constituent of the other body fluid.
• In an embodiment, the method includes correlating an abnormal concentration of the constituent to a pathology of AD.
• For some applications, the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and measuring the constituent includes measuring the selected constituent. Alternatively or additionally, the other body fluid is selected from the list consisting of: whole blood, plasma, serum, and ascites, and measuring the constituent includes sampling the selected fluid.
• Measuring the constituent typically includes extracting the other body fluid from tissue of the subject, and, for some applications, measuring a plurality of constituents. In an embodiment, the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents.
• There is also provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is further provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• For some applications, the method includes measuring a constituent of the tissue and/or correlating an abnormal concentration of the constituent to a pathology of AD.
• In accordance with an embodiment of the present invention, the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and measuring the constituent includes measuring the selected constituent.
• In an embodiment, measuring the constituent includes measuring a plurality of constituents of the tissue. In this case, for some applications, the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents of the tissue.
• There is still further provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including presenting an odorant to an air passage of a subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • supplying a pharmaceutical agent to a systemic blood circulation of a subject;
  • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in passage of the pharmaceutical agent from the systemic blood circulation into a central nervous system (CNS) of the subject, so as to treat the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • supplying a pharmaceutical agent to a systemic blood circulation of a subject; and
  • presenting an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in passage of the pharmaceutical agent from the systemic blood circulation into a central nervous system (CNS) of the subject, so as to treat the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including:
• • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating Alzheimer's disease (AD), including presenting an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is further provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including presenting an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is still further provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including presenting an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is also provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including:
• • applying an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for diagnosing Alzheimer's disease (AD), including presenting an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• In an embodiment, the method includes presenting in association with the odorant an analgesic in a dosage configured to reduce a sensation associated with the presenting of the odorant. For some applications, the air passage includes a nasal cavity or a throat of the patient, and presenting the odorant includes presenting the odorant to the nasal cavity or the throat.
• For some applications, the odorant is selected from the list consisting of: propionic acid, cyclohexanone, and amyl acetate, and presenting the odorant includes presenting the selected odorant.
• Alternatively or additionally, the odorant is selected from the list consisting of: acetic acid, citric acid, carbon dioxide, sodium chloride, and ammonia, and presenting the odorant includes presenting the selected odorant.
• Further alternatively or additionally, the odorant is selected from the list consisting of: menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol, and presenting the odorant includes presenting the selected odorant.
• In an embodiment, presenting the odorant includes presenting a capsule for placement within a mouth of the patient, the capsule being configured to dissolve upon contact with salivary liquids of the patient, whereupon the odorant is presented to the air passage.
• There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• In an embodiment, the stimulator is adapted to directly stimulate the SPG.
• There is still further provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in passage from a systemic blood circulation of the subject into a central nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in passage from a systemic blood circulation of the subject into a central nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and configure the stimulation so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is still further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject, from a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of a subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in clearance of an AD-related constituent of a central nervous system (CNS) of the subject from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
• • configure the signal so as to cause an increase in passage from a systemic blood circulation of the subject into a central nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in passage from a systemic blood circulation of the subject into a central nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so astotreatthe AD.
• There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to:
• • apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in cerebral blood flow (CBF) of the subject, so as to treat the AD.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is still further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
• There is additionally provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to:
• • apply an electrical signal to at least one site of a subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including a stimulator adapted to present an odorant to an air passage of the subject, the odorant having been selected for presentation to the air passage because it is such as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
• There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing clearance of an AD-related constituent of a central nervous system (CNS) of the subject from cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to treat the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing passage, from a systemic blood circulation of a subject into a central nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to treat the AD.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for treating Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing cerebral blood flow (CBF) of the subject; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to treat the AD.
• There is still further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing molecular passage between a central nervous system (CNS) of the subject and another body compartment of the subject; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to facilitate a diagnosis of the AD.
• There is yet further provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to facilitate a diagnosis of the AD.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for diagnosing Alzheimer's disease (AD), including:
• • an odorant-storage vessel;
  • an odorant for storage within the odorant-storage vessel, the odorant being capable of increasing molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject; and
  • an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to facilitate a diagnosis of the AD.
• In an embodiment, the odorant-storage vessel in combination with the odorant-delivery element includes an aqueous spray nasal inhaler.
• In an embodiment, the odorant-storage vessel in combination with the odorant-delivery element includes a metered dose nasal inhaler.
• In an embodiment, the odorant-storage vessel in combination with the odorant-delivery element includes an air-dilution olfactometer.
• There is also provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a patient, including:
• • stimulating a modulation target site of the patient at a level sufficient to increase permeability of a blood-brain barrier (BBB) of the patient; and
  • administering a diagnostic agent capable of passing through the BBB and into a central nervous system (CNS) of the patient while the permeability of the BBB is increased.
• There is further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a patient, including:
• • stimulating a modulation target site of the patient at a level sufficient to increase permeability of a blood-brain barrier (BBB) of the patient; and
  • receiving a constituent of a central nervous system (CNS) of the patient that passes from the CNS and through the BBB while the permeability of the BBB is increased.
• There is still further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a subject, including:
• • applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG;
  • configuring the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject; and
  • sensing a quantity of the molecules from a site outside of the brain of the subject, following initiation of application of the current.
• For some applications, sensing the quantity of the molecules includes sampling a fluid of the subject selected from the list consisting of: blood, plasma, serum, ascites fluid, and urine.
• For some applications, the method includes determining a diagnostically-relevant parameter responsive to sensing the quantity of the molecules.
• For some applications, the method includes administering a hyperosmolarity-inducing agent to the subject at a dosage sufficient to augment an increase in conductance of the molecules caused by the application of the current. Alternatively or additionally, the method includes inducing a state of dehydration of the subject, of an extent sufficient to augment an increase in conductance of the molecules caused by the application of the current.
• For some applications, the method includes administering an agent to the subject that modulates synthesis or metabolism of nitric-oxide (NO) in blood vessels of the brain, at a dosage sufficient to augment an increase in conductance of the molecules caused by the application of the current.
• For some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period greater than about one month. Alternatively, for some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period less than about one week.
• For some applications, applying the current includes implanting a control unit in a nasal cavity of the subject. For some applications, applying the current includes implanting a control unit at a lower side of a bony palate of the subject. For some applications, applying the current includes implanting one or more electrodes in a nasal cavity of the subject. For some applications, implanting includes inserting a flexible electrode through a nostril of the subject.
• There is also provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the other body compartment.
• For some applications, stimulating the SPG-related tissue includes directly stimulating the SPG.
• For some applications, the other body compartment includes a systemic blood circulation of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation. Alternatively or additionally, the other body compartment includes plasma of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma. Further alternatively or additionally, the other body compartment includes serum of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum. Still further alternatively or additionally, the other body compartment is ascites of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.
• For some applications, the CNS condition includes Parkinson's disease, and configuring the stimulation includes configuring the stimulation so as to facilitate the diagnosis of the Parkinson's disease. For some applications, the CNS condition includes epilepsy, and configuring the stimulation includes configuring the stimulation so as to facilitate the diagnosis of the epilepsy. For some applications, the CNS condition includes amyotrophic lateral sclerosis (ALS), and configuring the stimulation includes configuring the stimulation so as to facilitate the diagnosis of the ALS. For some applications, the CNS condition includes multiple sclerosis (MS), and configuring the stimulation includes configuring the stimulation so as to facilitate the diagnosis of the MS.
• For some applications, stimulating the SPG-related tissue includes implanting an electrode at the site, designated to remain in the subject for a period greater than about one month. Alternatively, for some applications, stimulating the SPG-related tissue includes implanting an electrode at the site, designated to remain in the subject for a period less than about one week.
• For some applications, stimulating the SPG-related tissue includes implanting a control unit in a nasal cavity of the subject. For some applications, stimulating the SPG-related tissue includes implanting a control unit at a lower side of a bony palate of the subject.
• For some applications, the method includes correlating an abnormal concentration of the constituent to a pathology of the CNS condition.
• For some applications, the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and measuring the constituent includes measuring the selected constituent.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the other body fluid.
• For some applications, stimulating the SPG-related tissue includes directly stimulating the SPG.
• For some applications, the method includes correlating an abnormal concentration of the constituent to a pathology of the CNS condition.
• For some applications, the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and measuring the constituent includes measuring the selected constituent.
• For some applications, the other body fluid is selected from the list consisting of: whole blood, plasma, serum, and ascites, and measuring the constituent includes sampling the selected fluid.
• For some applications, measuring the constituent includes extracting the other body fluid from tissue of the subject.
• For some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period greater than about one month. Alternatively, for some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period less than about one week.
• For some applications, applying the current includes implanting a control unit in a nasal cavity of the subject. For some applications, applying the current includes implanting a control unit at a lower side of a bony palate of the subject.
• For some applications, measuring the constituent includes measuring a plurality of constituents. For some applications, the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents.
• There is yet additionally provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the tissue.
• For some applications, stimulating the SPG-related tissue includes directly stimulating the SPG.
• For some applications, the method includes correlating an abnormal concentration of the constituent to a pathology of the CNS condition.
• For some applications, the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and measuring the constituent includes measuring the selected constituent.
• For some applications, measuring the constituent includes measuring a plurality of constituents of the tissue. For some applications, the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents of the tissue.
• There is still additionally provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate a diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the other body compartment.
• There is further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the other body fluid.
• There is yet further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including:
• • applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and
  • configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the CNS condition.
• In an embodiment, the method includes measuring a constituent of the tissue.
• There is still further provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, the method including:
• • stimulating at least one site of the subject by applying an electrical current to the site, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between the anterior ethmoidal nerve and the SPG, a communicating branch between the posterior ethmoidal nerve and the SPG, a nerve of the pterygoid canal of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve of the subject and the SPG, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion, and an efferent fiber going out of the otic ganglion;
  • configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject;
  • taking a sample from the body compartment; and
  • determining a level of a constituent of the sample, so as to facilitate the diagnosis of the CNS condition.
• For some applications, the CNS condition includes a neurodegenerative condition, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the neurodegenerative condition. For some applications, the CNS condition includes a neoplastic process, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the neoplastic process. For some applications, the CNS condition is selected from the list consisting of: an immune-related disorder and an autoimmune-related disorder, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the selected condition. For some applications, the CNS condition includes a CNS inflammatory process, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the CNS inflammatory process.
• In an embodiment, the method includes interpreting a low value of the level as indicative of an increased likelihood that the subject suffers from the CNS condition. For some applications, the method includes interpreting a high value of the level as indicative of a decreased likelihood that the subject suffers from the CNS condition. For some applications, the body compartment includes a systemic blood circulation of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation. Alternatively or additionally, the body compartment includes plasma of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma. Further alternatively or additionally, the body compartment includes serum of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum. Still further alternatively or additionally, the body compartment is ascites of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites. For some applications, the site includes the SPG, and stimulating the site includes stimulating the SPG.
• For some applications, the CNS condition includes Alzheimer's disease, and interpreting the low value includes interpreting the low value as indicative of the increased likelihood that the subject suffers from Alzheimer's disease. For some applications, the constituent includes amyloid-beta peptide, and determining the level of the constituent includes determining the level of the amyloid-beta peptide. Alternatively or additionally, the constituent includes presenilin-1, and determining the level of the constituent includes determining the level of the presenilin-1.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, the method including:
• • stimulating at least one site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between the anterior ethmoidal nerve and the SPG, a communicating branch between the posterior ethmoidal nerve and the SPG, a nerve of the pterygoid canal of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve of the subject and the SPG, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion, and an efferent fiber going out of the otic ganglion;
  • configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject;
  • taking a sample from the body compartment; and
  • determining a level of a constituent of the sample, so as to facilitate the diagnosis of the CNS condition.
• For some applications, the CNS condition includes a neurodegenerative condition, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the neurodegenerative condition. For some applications, the CNS condition includes a neoplastic process, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the neoplastic process. For some applications, the CNS condition is selected from the list consisting of: an immune-related disorder and an autoimmune-related disorder, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the selected condition. For some applications, the CNS condition includes a CNS inflammatory process, and determining the level of the constituent includes determining the level of the constituent so as to facilitate the diagnosis of the CNS inflammatory process.
• In an embodiment, the method includes interpreting a low value of the level as indicative of an increased likelihood that the subject suffers from the CNS condition. For some applications, the method includes interpreting a high value of the level as indicative of a decreased likelihood that the subject suffers from the CNS condition.
• In an embodiment, stimulating includes applying magnetic stimulation to the site. In an embodiment, stimulating includes applying electromagnetic stimulation to the site. In an embodiment, stimulating includes applying chemical stimulation to the site. In an embodiment, stimulating includes applying mechanical stimulation to the site.
• For some applications, the body compartment includes a systemic blood circulation of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation.
• Alternatively or additionally, the body compartment includes plasma of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma. Further alternatively or additionally, the body compartment includes serum of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum. Still further alternatively or additionally, the body compartment is ascites of the subject, and configuring the stimulation includes configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.
• For some applications, the site includes the SPG, and stimulating the site includes stimulating the SPG.
• For some applications, the CNS condition includes Alzheimer's disease, and interpreting the low value includes interpreting the low value as indicative of the increased likelihood that the subject suffers from Alzheimer's disease. For some applications, the constituent includes amyloid-beta peptide, and determining the level of the constituent includes determining the level of the amyloid-beta peptide. Alternatively or additionally, the constituent includes presenilin-1, and determining the level of the constituent includes determining the level of the presenilin-1.
• There is also provided, in accordance with an embodiment of the present invention, a method for treating a condition of a central nervous system (CNS) of a subject, including:
• • applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG;
  • configuring the current to increase clearance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject, so as to treat the CNS condition.
• For some applications, the molecules include a toxin, and configuring the current includes configuring the current to increase the clearance of the toxin from the brain tissue, so as to treat the CNS condition.
• For some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period greater than about one month. Alternatively, for some applications, applying the current includes implanting an electrode at the site, designated to remain in the subject for a period less than about one week.
• For some applications, applying the current includes implanting a control unit in a nasal cavity of the subject. For some applications, applying the current includes implanting a control unit at a lower side of a bony palate of the subject.
• There is further provided, in accordance with an embodiment of the present invention, a method for treating a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• For some applications, stimulating the SPG-related tissue includes directly stimulating the SPG.
• There is still further provided, in accordance with an embodiment of the present invention, a method for treating a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• There is additionally provided, in accordance with an embodiment of the present invention, a method for treating a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• For some applications, stimulating the SPG-related tissue includes directly stimulating the SPG.
• There is yet additionally provided, in accordance with an embodiment of the present invention, a method for treating a condition of a central nervous system (CNS) of a subject, including:
• • stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and
  • configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a subject, including a stimulator adapted to:
• • apply a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG, and
  • configure the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject, so as to facilitate the diagnosis of the condition.
• For some applications, the stimulator is adapted to directly stimulate the SPG.
• In an embodiment, the apparatus is adapted to measure a constituent of the other body compartment.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the other body compartment.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the other body fluid.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the tissue.
• There is additionally provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the other body compartment.
• There is yet additionally provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the other body fluid.
• There is still additionally provided, in accordance with an embodiment of the present invention, apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and
  • configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate the diagnosis of the CNS condition.
• In an embodiment, the apparatus is adapted to measure a constituent of the tissue.
• There is also provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• There is further provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• There is yet further provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• There is still further provided, in accordance with an embodiment of the present invention, apparatus for treating a condition of a central nervous system (CNS) of a subject, including a stimulator adapted to:
• • stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and
  • configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.
• The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
• FIGS. 1A and 1B are schematic pictorial views of a fully implantable stimulator for stimulation of the SPG, in accordance with preferred embodiments of the present invention;
• FIG. 2 is a schematic pictorial view of another stimulator for stimulation of the SPG, in accordance with a preferred embodiment of the present invention;
• FIG. 3 is a schematic block diagram illustrating circuitry for use with the stimulator shown inFIGS. 1A and 1B, in accordance with a preferred embodiment of the present invention;
• FIG. 4 is a schematic block diagram illustrating circuitry for use with the stimulator shown inFIG. 2, in accordance with a preferred embodiment of the present invention;
• FIGS. 5A and 5B are schematic illustrations depicting different modes of operation of stimulators such as those shown inFIGS. 1A, 1B, and2, in accordance with preferred embodiments of the present invention;
• FIG. 6 is a schematic illustration of a mode of operation of the stimulators shown inFIGS. 1A, 1B, and2, synchronized with a drug delivery system, in accordance with a preferred embodiment of the present invention;
• FIG. 7 is a schematic block diagram illustrating circuitry for use with the stimulator shown inFIGS. 1A and 1B, where the stimulator is driven by an external controller and energy source using a modulator and a demodulator, in accordance with a preferred embodiment of the present invention;
• FIG. 8 depicts sample modulator and demodulator functions for use with the circuitry ofFIG. 7, in accordance with a preferred embodiment of the present invention;
• FIGS. 9, 10A, and10B are schematic diagrams illustrating further circuitry for use with implantable stimulators, in accordance with respective preferred embodiments of the present invention;
• FIGS. 11 and 12 are bar graphs showing experimental data collected in accordance with a preferred embodiment of the present invention;
• FIG. 13 is a schematic illustration of a sensor for application to a blood vessel, in accordance with a preferred embodiment of the present invention;
• FIG. 14 is a schematic sectional illustration of a nasal inhaler, for use in presenting an odorant to a subject, in accordance with a preferred embodiment of the present invention;
• FIGS. 15-17 are graphs showing the results from SPG stimulation experiments carried out in accordance with embodiments of the present invention; and
• FIG. 18 is a schematic illustration of an implantable stimulator for stimulation of an MTS, in accordance with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
• FIGS. 1A and 1B are schematic pictorial views of a fully-implantable stimulator4, for stimulation of the sphenopalatine ganglion (SPG)6, a “modulation target site” (MTS), or other parasympathetic site of a patient, in accordance with preferred embodiments of the present invention. InFIGS. 1A and 1B, a humannasal cavity2 is shown. InFIG. 1A,stimulator4 is implanted adjacent toSPG6. InFIG. 1B,stimulator4 is implanted between the hard palate and the mucoperiosteum (not shown) of the roof of the mouth. Branches of parasympathetic neurons coming fromSPG6 extend to the middle cerebral and anterior cerebral arteries (not shown). Preferably, one or more relativelyshort electrodes7 extend fromstimulator4 to contact or to be in a vicinity ofSPG6 or of nerves innervating SPG6 (e.g., postganglionic parasympathetic trunks thereof).
• In the present patent application, a “modulation target site” consists of:
• • a sphenopalatine ganglion (SPG) (also called a pterygopalatine ganglion);
  • an anterior ethmoidal nerve;
  • a posterior ethmoidal nerve;
  • a communicating branch between the anterior ethmoidal nerve and the SPG (retro-orbital branch);
  • a communicating branch between the posterior ethmoidal nerve and the SPG (retro-orbital branch);
  • a nerve of the pterygoid canal (also called a vidian nerve), such as a greater superficial petrosal nerve (a preganglionic parasympathetic nerve) or a lesser deep petrosal nerve (a postganglionic sympathetic nerve);
  • a greater palatine nerve;
  • a lesser palatine nerve;
  • a sphenopalatine nerve;
  • a communicating branch between the maxillary nerve and the sphenopalatine ganglion;
  • a nasopalatine nerve;
  • a posterior nasal nerve;
  • an infraorbital nerve;
  • an otic ganglion;
  • an afferent fiber going into the otic ganglion; and/or
  • an efferent fiber going out of the otic ganglion.
• For some applications,stimulator4 is implanted on top of the bony palate, in the bottom of the nasal cavity. Alternatively or additionally, the stimulator is implanted at the lower side of the bony palate, at the top of the oral cavity. In this instance, one or moreflexible electrodes7 originating in the stimulator are passed through the palatine bone or posterior to the soft palate, so as to be in a position to stimulate the SPG or its parasympathetic tracts, or another MTS. Further alternatively or additionally, the stimulator may be directly attached to the SPG and/or to its postganglionic parasympathetic trunk(s) and/or to another MTS.
• For some applications,stimulator4 is delivered to a desired point withinnasal cavity2 by removably attachingstimulator4 to the distal end of a rigid or slightly flexible introducer rod (not shown) and inserting the rod into one of the patient's nasal passages until the stimulator is properly positioned. As appropriate, the placement process may be facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery (FES) techniques or by any other effective guidance method known in the art, or by combinations of the aforementioned. Preferably, the ambient temperature and/or cerebral blood flow is measured concurrently with insertion. The cerebral blood flow may be measured with, for example, a laser Doppler unit positioned at the patient's forehead or transcranial Doppler measurements. Verification of proper implantation of the electrodes onto the appropriate neural structure may be performed by activating the device, and generally simultaneously monitoring cerebral blood flow.
• The placement process may be performed using techniques described in U.S.Provisional Patent Application 60/426,180 filed Nov. 14, 2002, entitled, “Surgical tools and techniques for stimulation,” or in PCT Publication WO 04/043218 to Gross et al., which are assigned to the assignee of the present patent application and is incorporated herein by reference.
• The passage of certain molecules from cerebral blood vessels into the brain is hindered by the BBB. The endothelium of the capillaries, the plasma membrane of the blood vessels, and the foot processes of the astrocytes all impede uptake by the brain of the molecules. The BBB generally allows only small molecules (e.g., hydrophilic molecules of molecular weight less than about 200 Da, and lipophilic molecules of less than about 500 Da) to pass from the circulation into the brain.
• In accordance with a preferred embodiment of the present invention, parasympathetic activation induced by current fromstimulator4 overcomes the resistance to trans-BBB molecular movement generated by the endothelium of the cerebral capillaries and the plasma membrane. For some applications, therefore,stimulator4 may be used to transiently remove a substantial obstacle to the passage of drugs from the blood to the brain, of diagnostic agents from the systemic blood circulation to the CNS, and/or of biochemical agents from the CNS to the systemic blood circulation. For example, the stimulator may cyclically apply current for about two minutes, and subsequently have a rest period of between about 1 and 20 minutes.
• It is hypothesized that two neurotransmitters play an important role in this change in properties of the BBB—vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). (Acetylcholine may also be involved.) VIP is a short peptide, and NO is a gaseous molecule. VIP is believed to be a major factor in facilitating plasma protein extravasation (PPE), while NO is responsible for vasodilation. For some applications,stimulator4 is adapted to vary parameters of the current applied to the SPG, as appropriate, in order to selectively influence the activity of one or both of these neurotransmitters. For example, stimulation of the parasympathetic nerve at different frequencies can induce differential secretion—low frequencies cause secretion of NO, while high frequencies (e.g., above about 10 Hz) cause secretion of peptides (VIP).
• For other applications, a constant level DC signal, or a slowly varying voltage ramp is applied, in order to block parasympathetic neural activity in affected tissue. Alternatively, similar results can be obtained by stimulating at a rate higher than about 10 Hz, because this tends to exhaust neurotransmitters. Thus,stimulator4 may be configured to induce parasympathetic electrical block, in order to cause vasoconstriction by mimicking the overall effect of chemical block on the SPG. This vasoconstrictive effect may be used, for example, to controllably prevent or reverse the formation of migraine headaches. This technique of electrical treatment of migraines stands in contrast to methods of the prior art, in which pharmacological agents such as lidocaine are applied so as to induce SPG block.
• FIG. 2 is a schematic illustration of astimulator control unit8 positioned external to a patient's body, in accordance with a preferred embodiment of the present invention. At least oneflexible electrode10 preferably extends fromcontrol unit8, through anostril12 of the patient, and to a position within thenasal cavity14 that is adjacent toSPG6.
• It is to be understood that electrodes7 (FIGS. 1A and 1B) and10 may each comprise one or more electrodes, e.g., two electrodes, or an array of microelectrodes. For applications in which stimulator4 comprises a metal housing that can function as an electrode, then typically oneelectrode7 is used, operating in a monopolar mode. Regardless of the total number of electrodes in use, typically only a single or a double electrode extends toSPG6.Other electrodes7 or10 or a metal housing ofstimulator4 are preferably temporarily or permanently implanted in contact with other parts ofnasal cavity2.
• Each ofelectrodes7 and/or10 preferably comprises a suitable conductive material, for example, a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy. For some applications, one or more of the electrodes have lengths ranging from about 1 to 5 mm, and diameters ranging from about 50 to 100 microns. Each electrode is preferably insulated with a physiologically-acceptable material such as polyethylene, polyurethane, or a co-polymer of either of these. The electrodes are preferably spiral in shape, for better contact, and may have a hook shaped distal end for hooking into or near the SPG. Alternatively or additionally, the electrodes may comprise simple wire electrodes, spring-loaded “crocodile” electrodes, or adhesive probes, as appropriate.
• In a preferred embodiment of the invention, each one ofelectrodes7 and/or10 comprises a substantially smooth surface, except that the distal end of each such electrode is configured or treated to have a large surface area. For example, the distal tip may be porous platinized. Alternatively or additionally, at least the tip ofelectrode7 or10, and/or a metal housing ofstimulator4 includes a coating comprising an anti-inflammatory drug, such as beclomethasone sodium phosphate or beclomethasone phosphate. Alternatively, such an anti-inflammatory drug is injected or otherwise applied.
• Typically, a determination regarding whether to use a configuration such as that shown inFIG. 1B or that shown inFIG. 2 is made responsive to a frequency or total number of diagnostic procedures anticipated. When this frequency or total number is high, the preference is for a configuration such as that shown inFIG. 1B, while one-time or infrequent diagnostic procedures indicates for a configuration such as that shown inFIG. 2.
• FIG. 3 is a schematic block diagram illustrating circuitry comprising an implantedunit20 and anexternal unit30, for use withstimulator4, in accordance with a preferred embodiment of the present invention. Implantedunit20 preferably comprises afeedback block22 and one or more sensing orsignal application electrodes24. Implantedunit20 typically also comprises anelectromagnetic coupler26, which receives power and/or sends or receives data signals to or from anelectromagnetic coupler28 inexternal unit30.
• External unit30 preferably comprises amicroprocessor32 which receives an external control signal34 (e.g., from a physician or from the patient), and afeedback signal36 fromfeedback block22.Control signal34 may include, for example, operational parameters such as a schedule of operation, patient parameters such as the patient's weight, or signal parameters, such as desired frequencies or amplitudes of a signal to be applied to the SPG or another MTS. If appropriate,control signal34 can comprise an emergency override signal, entered by the patient or a healthcare provider to terminate stimulation or to modify it in accordance with a predetermined program.Microprocessor32, in turn, preferably processescontrol signal34 andfeedback signal36 so as to determine one or more parameters of the electric current to be applied throughelectrodes24. Responsive to this determination,microprocessor32 typically generates anelectromagnetic control signal42 that is conveyed byelectromagnetic coupler28 toelectromagnetic coupler26.Control signal42 preferably corresponds to a desired current or voltage to be applied byelectrodes24 toSPG6 or another MTS, and, in a preferred embodiment, inductively drives the electrodes. The configuration ofcouplers26 and28 and/or other circuitry inunits20 or30 may determine the intensity, frequency, shape, monophasic or biphasic mode, or DC offset of the signal (e.g., a series of pulses) applied to designated tissue.
• Power formicroprocessor32 is typically supplied by a battery44 or, optionally, another DC power supply. Grounding is provided by battery44 or aseparate ground46. If appropriate,microprocessor32 generates adisplay signal38 that drives adisplay block40 ofexternal unit30. Typically, but not necessarily, the display is activated to show feedback data generated byfeedback block22, or to provide a user interface for the external unit.
• Implantedunit20 is preferably packaged in a case made of titanium, platinum or an epoxy or other suitable biocompatible material. Should the case be made of metal, then the case may serve as a ground electrode and, therefore, stimulation typically is performed in a monopolar mode. Alternatively, should the case be made of biocompatible plastic material, twoelectrodes24 are typically driven to apply current to the SPG or another MTS.
• For some applications, the waveform applied by one or more ofelectrodes24 to designated tissue, such as designated tissue of an MTS (e.g., the SPG) comprises a waveform with an exponential decay, a ramp up or down, a square wave, a sinusoid, a saw tooth, a DC component, or any other shape known in the art to be suitable for application to tissue. Alternatively or additionally, the waveform comprises one or more bursts of short shaped or square pulses—each pulse preferably less than about 1 ms in duration. Generally, appropriate waveforms and parameters thereof are determined during an initial test period ofexternal unit30 and implantedunit20. For some applications, the waveform is dynamically updated according to measured physiological parameters, measured during a period in whichunit20 is stimulating the SPG or another MTS, and/or during a non-activation (i.e., standby) period.
• In the case of migraine treatment, the waveform may take the form of a slowly varying shape, such as a slow saw tooth, or a constant DC level, intended to block outgoing parasympathetic messaging.
• FIG. 4 is a schematic block diagram of circuitry for use, for example, in conjunction with control unit8 (FIG. 2), in accordance with a preferred embodiment of the present invention. Anexternal unit50 comprises a microprocessor52 supplied by abattery54 or another DC power source. Grounding may be provided bybattery54 or by aseparate ground56. Microprocessor52 preferably receives control and feedback signals58 and68 (analogous to signal34 and36 described hereinabove), and generates responsive thereto astimulation signal64 conveyed by one ormore electrodes66 to the SPG, another MTS, or other tissue. Typically, but not necessarily,feedback signal68 comprises electrical feedback measured by one or more ofelectrodes66 and/or feedback from other sensors on or in the patients brain or elsewhere coupled to the patient's body. If appropriate, microprocessor52 generates adisplay signal60 which drives adisplay block62 to output relevant data to the patient or the patient's physician. Typically, some or all ofelectrodes66 are temporarily implanted in the patient (e.g., following a stroke), and are directly driven by wires connecting the external unit to the implanted unit.
• FIG. 5A is a graph schematically illustrating a mode of operation of one or more of the devices shown inFIGS. 1-4, in accordance with a preferred embodiment of the present invention. Preferably, the effect of the applied stimulation is monitored by means of a temperature transducer at the SPG, at another MTS, or elsewhere in the head, e.g., in the nasal cavity. As shown inFIG. 5A for a step (ON/OFF) mode of stimulation, stimulation of the SPG or related tissue, or of another MTS, is initiated at a time T1, and this is reflected by a measurable rise in temperature (due to increased blood flow). Once the temperature rises to a predetermined or dynamically-varying threshold (e.g., 37° C.), stimulation is terminated (time T2), responsive to which the temperature falls. As appropriate, when the temperature drops to a designated or dynamically-determined point, the stimulation is reinitiated (time T3). Preferably, suitable temperatures or other physiological parameters are determined for each patient so as to provide the optimal treatment. If appropriate, control instructions may also be received from the patient, e.g., to initiate stimulation upon the onset of a migraine headache.
• FIG. 5B is a graph schematically illustrating a mode of operation of one or more of the devices shown inFIGS. 1-4, in accordance with another preferred embodiment of the present invention. In this embodiment, the amplitude of the waveform applied to the SPG or another MTS is varied among a continuous set of values (S1), or a discrete set of values (S2), responsive to the measured temperature, in order to achieve the desired performance. It will be appreciated that other feedback parameters measured in the head (e.g., intracranial pressure and/or cerebral blood flow), as well as measured systemic parameters (e.g., heart rate) and subjective patient inputs (e.g., migraine pain=⅗) may be used in conjunction with or separately from temperature measurements, in order to achieve generally optimal performance of the implanted apparatus.
• FIG. 6 is a graph schematically illustrating a mode of operation of one or more of the devices shown inFIGS. 1-4, in accordance with a preferred embodiment of the present invention. In this embodiment, a drug is administered to the patient at a constant rate, e.g., intravenously, prior to the initiation of stimulation of the SPG or another MTS at time T1. Advantageously, this prior generation of heightened concentrations of the drug in the blood tends to provide relatively rapid transfer of the drug across the BBB and into the brain, without unnecessarily prolonging the enhanced permeability of the BBB while waiting for the blood concentration of the drug to reach an appropriate level. Alternatively, for some applications it is desirable to give a single injection of a bolus of the drug shortly before or after initiation of stimulation of the SPG or another MTS. Typically, combined administration and stimulation schedules are determined by the patient's physician based on the biochemical properties of each drug targeted at the brain.
• As used in the specification and in the claims, stimulation of an MTS to facilitate transport of a diagnostic agent from the systemic blood circulation to the CNS, is to be understood as including stimulation prior to, during, and/or after administration of the agent to the systemic circulation. For subjects in whom an MTS stimulator previously was implanted for therapeutic purposes, such implanted stimulator may be used for performing stimulation to facilitate a diagnosis, as described herein.
• FIG. 7 is a schematic block diagram showing circuitry for parasympathetic stimulation, which is particularly useful in combination with the embodiments shown inFIGS. 1A and 1B, in accordance with a preferred embodiment of the present invention. Anexternal unit80 preferably comprises amicroprocessor82 that is powered by abattery84 and/or an AC power source.Microprocessor82 is grounded throughbattery84 or through anoptional ground86.
• In a typical mode of operation, anexternal control signal88 is input tomicroprocessor82, along with afeedback signal108 from one ormore biosensors106, which are typically disposed in a vicinity of an implantedunit100 or elsewhere on or in the patient's body. Responsive tosignals88 and108,microprocessor82 preferably generates adisplay signal89 which drives adisplay90, as described hereinabove. In addition,microprocessor82 preferably processesexternal control signal88 andfeedback signal108, to determine parameters of anoutput signal92, which is modulated by amodulator94. The output therefrom preferably drives a current through anelectromagnetic coupler96, which inductively drives anelectromagnetic coupler98 of implantedunit100. Ademodulator102, coupled toelectromagnetic coupler98, in turn, generates asignal103 which drives at least oneelectrode104 to apply current to the SPG or to other tissue, as appropriate.
• Preferably,biosensor106 comprises implantable or external medical apparatus including, for example, one or more of the following:
• • a blood flow sensor,
  • a temperature sensor,
  • a chemical sensor,
  • an ultrasound sensor,
  • transcranial Doppler (TCD) apparatus, laser-Doppler apparatus,
  • a systemic or intracranial blood pressure sensor (e.g., comprising a piezoelectric crystal fixed to a major cerebral blood vessel, capable of detecting a sudden blood pressure increase indicative of a clot),
  • a kinetics sensor, comprising, for example, an acceleration, velocity, or level sensor (e.g., a mercury switch), for indicating body dispositions such as a sudden change in body attitude (as in collapsing),
  • an electroencephalographic (EEG) sensor comprising EEG electrodes attached to, or implanted in, the patients head, for indicating changes in neurological patterns, such as symptoms of stroke or migraine,
  • a blood vessel clot detector (e.g., as described hereinbelow with reference toFIG. 13), or
  • other monitors of physiological quantities suitable for carrying out the objects of this or other embodiments of the present invention.
• FIG. 8 is a schematic illustration showing operational modes ofmodulator94 and/ordemodulator102, in accordance with a preferred embodiment of the present invention. The amplitude and frequency ofsignal92 inFIG. 7 can have certain values, as represented in the left graph; however, the amplitude and frequency are modulated so thatsignal103 has different characteristics (not necessarily those shown).
• FIG. 9 is a schematic illustration of further apparatus for stimulation of the SPG or another MTS, in accordance with a preferred embodiment of the present invention. In this embodiment, substantially all of the processing and signal generation is performed by circuitry in an implantedunit110 in the patient, and, preferably, communication with acontroller122 in anexternal unit111 is performed only intermittently. The implantedunit110 preferably comprises amicroprocessor112 coupled to abattery114.Microprocessor112 generates asignal116 that travels along at least oneelectrode118 to stimulate the SPG or another MTS. Afeedback signal120 from a biosensor (not shown) and/or fromelectrode118 is received bymicroprocessor112, which is adapted to modify stimulation parameters responsive thereto. Preferably,microprocessor112 andcontroller122 are operative to communicate viaelectromagnetic couplers126 and124, in order to exchange data or to change parameters. Further preferably,battery114 is inductively rechargeable by electromagnetic coupling.
• FIG. 10A is a schematic illustration of astimulator150, in accordance with a preferred embodiment of the present invention. Preferably, substantially all of the electronic components (including anelectronic circuit158 having a rechargeable energy source) are encapsulated in abiocompatible metal case154. Aninductive coil156 and at least oneelectrode162 are preferably coupled tocircuit158 by means of a feed-throughcoupling160. The inductive coil is preferably isolated by anepoxy coating152, which allows for higher efficiency of the electromagnetic coupling.
• FIG. 10B is a schematic illustration of another configuration of an implantable stimulator, in accordance with a preferred embodiment of the present invention. Preferably, substantially all of the electronic components (including aninductive coil176 and anelectronic circuit178 having a rechargeable energy source) are encapsulated in abiocompatible metal case174. One or more feed-throughs are preferably provided to enable coupling between at least oneelectrode182 and the electronic circuit, as well as betweeninductive coil176 and another inductive coil (not shown) in communication therewith.
• With reference toFIGS. 10A and 10B, the energy source forelectronic circuits158 and178 may comprise, for example, a primary battery, a rechargeable battery, or a super capacitor. For applications in which a rechargeable battery or a super capacitor is used, any kind of energizing means may be used to charge the energy source, such as (but not limited to) standard means for inductive charging or a miniature electromechanical energy converter that converts the kinetics of the patient movement into electrical charge. Alternatively, an external light source (e.g., a simple LED, a laser diode, or any other light source) may be directed at a photovoltaic cell in the electronic circuit. Further alternatively, ultrasound energy is directed onto the implanted unit, and transduced to drive battery charging means.
• FIGS. 11 and 12 are bar graphs showing experimental results obtained during rat experiments performed in accordance with a preferred embodiment of the present invention. A common technique in monitoring bio-distribution of materials in a system includes monitoring the presence and level of radio-labeled tracers. These tracers are unstable isotopes of common elements (e.g., Tc, In, Cr, Ga, and Gd), conjugated to target materials. The chemical properties of the tracer are used as a predictor for the behavior of other materials with similar physiochemical properties, and are selected based on the particular biological mechanisms that are being evaluated. Typically, a patient or experimental animal is placed on a Gamma camera, or target tissue samples can be harvested and placed separately into a well counter. For the purpose of the present set of experiments which were performed, the well counter method was chosen due to its higher sensitivity and spatial resolution. A series of experiments using 99Tc-DTPA (DTPA molecule conjugated to a 99-Technetium isotope) were performed. The molecular weight of 99Tc-DTPA is 458 Da, its lipophilicity is negative, and its electric charge is +1. These parameters are quite similar with pharmacological agents used in standard chemotherapy, such as tamoxifen, etoposide and irinotecan.
• FIGS. 11 and 12 show results obtained using 99Tc-DTPA penetration assays using ordinary brain sampling techniques (FIG. 11) and peeled brain techniques (FIG. 12). The x-axis of each graph represents different experimental runs, and the y-axis of each graph is defined as: [(hemisphere radioactivity)/(hemisphere weight)]/[(total injected radioactivity)/(total animal weight)]. The results obtained demonstrate an average 2.5-fold increase in the penetration of 99Tc-DTPA to the rat brain. It is noted that these results were obtained by unilateral stimulation of the SPG. The inventors believe that bilateral SPG stimulation will approximately double drug penetration, relative to unilateral SPG stimulation.
• In bothFIG. 11 andFIG. 12, some animals were designated as control animals, and other animals were designated as test animals. In each group, the left and right hemispheres were tested separately, and the height of each bar represents, for a given animal and a given hemisphere, the normalized level of radioactivity as defined above. Thus,FIG. 11 shows results from a total of four test hemispheres and four control hemispheres.FIG. 12 shows results from six test hemispheres and fourteen control hemispheres. The juxtaposition of control and test bars in the bar graphs is not meant to imply pairing of control and test hemispheres.
• FIG. 13 is a schematic illustration of acoustic or opticalclot detection apparatus202, for use, for example, in providing feedback to any of the microprocessors or other circuitry described hereinabove, in accordance with a preferred embodiment of the present invention. The detection is preferably performed by coupling to a major blood vessel200 (e.g., the internal carotid artery or aorta) a detecting element comprising an acoustic or optical transmitter/receiver206, and an optional reflectingsurface204. Natural physiological liquids may serve as a mediating fluid between the device and the vessel. Preferably, the transmitter/receiver generates an ultrasound signal or electromagnetic signal which is reflected and returned, and a processor evaluates changes in the returned signal to detect indications of a newly-present clot. Alternatively, a transmitter is placed on side of the vessel and a receiver is placed on the other side of the vessel. In either case, for some applications, more than onesuch apparatus202 are placed on the vessel, in order to improve the probability of successful clot detection for possible estimation of the clot's direction of motion within the vessel, and to lower the false alarm (i.e. false detection) rate.
• FIG. 14 is a schematic sectional illustration of anasal inhaler300, for use in presenting an odorant to a subject, in accordance with a preferred embodiment of the present invention.Nasal inhaler300 preferably comprises apparatus known in the art, such as an aqueous spray nasal inhaler, a metered dose nasal inhaler, or an air-dilution olfactometer. The odorant is stored in an odorant-storage vessel302, and is delivered to a nasal passage using an odorant-delivery element304, such as a nasal piece. Alternatively or additionally, the odorant is presented by means of an orally-dissolvable capsule that releases the active odorants upon contact with salivary liquids. The odorants reach the appropriate neural structures and induce vasodilatation, vasoconstriction and/or cerebrovascular permeability changes.
• FIG. 15 is a graph showing the results of an efflux study, performed in accordance with an embodiment of the present invention. Techniques described in the following two articles, which are incorporated herein by reference, were applied for use with this embodiment:
• Asaba et al., “Blood brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organicanion transporting polypeptide 2.” J. Neurochem. 75, pp. 1907-1916, (2000).
• Isakovic et al., “The efflux of purine nucleobases and nucleosides from the rat brain.” Neuroscience Letters 318, pp. 65-68, (2002).
• Male Wistar rats (280-300 g; Harlan) were used. Six rats were in an experimental group, and six rats were in a control group. A BEI (brain efflux index) study was performed according to the method described in an article by Kakee et al., “Brain efflux index as a novel method of analyzing efflux transport at the blood brain barrier.” J. Pharmacol. Exp. Ther. 277, 1550-1559. (1996), which is incorporated herein by reference. Rats were anesthetized by intraperitoneal administration of Pentobarbital, and then mounted on a stereotaxic frame. A burr hole was made 5.5 mm lateral and 0.2 mm anterior to the bregma, and a fine injection needle was advanced to a depth of 4.5 mm. Then, 0.50 ml of [3H]PNA (150,000 disintegrations per minute (dpm), 0.5′-CCGCTCCG-3′, MW. 2122) dissolved in extracellular fluid (ECF) buffer (122 mM NaCl, 25 mM NaHCO3, 10 mM D-glucose, 3 mM KCl, 1.4 mM CaCl2, 1.2 mM MgSO4, 0.4 mM K2HPO4, 10 mM HEPES, pH 7.4) was administered over 1 min using a 5.0-ml microsyringe (Hamilton, Reno, Nebr., U.S.A.) fitted with a fine needle at a depth of 4.5 mm from the surface of the scalp (that is, in the parietal cortex area 2 (Par2) region). At the end of the experiment (60 min), an aliquot of CSF was collected from the cisterna magna, using techniques described in Kakee et al., 1996. The whole brain was subsequently isolated, and the left cerebrum, right cerebrum, and cerebellum were isolated. After weighing, tissue samples were dissolved in 1 ml of 2 M NaOH at 50° C. for 3 h and then were mixed with 4 ml of scintillation cocktail. The associated radioactivity was measured in a liquid scintillation counter equipped with an appropriate crossover correction of 3H (LS-6500; Beckman, Fullerton, Calif., U.S.A.).
• The SPG stimulation protocol included cycling between on-periods, lasting 90 seconds, and off-periods, lasting for 60 seconds. During each on-period, a 5 volt, 10 Hz signal was applied to the SPG, each pulse having a pulse width of 1 ms. The signal was applied using a concentric bipolar electrode, both poles of the electrode being inserted slightly into the SPG.
• FIG. 15 clearly shows the increased clearance of the injected tracer from the animals that received electrical SPG stimulation, compared to the clearance in the non-stimulated (i.e., control) animals. The error bars represent one standard deviation. No electrodes were inserted into the SPG of the control animals.
• FIG. 16 is a graph showing the results of an experiment performed in accordance with an embodiment of the present invention. Four beagles were in a control (non-stimulated) group, and four beagles were in a stimulated group. No electrodes were applied to the SPG of the animals of the control group. At time zero, a solution of 10 kDa FITC-dextran tracer was administered intravenously, and, at the same time, SPG stimulation was initiated. Administration of the dextran was performed continuously over a 20 minute period, and SPG stimulation continued for 30 minutes (i.e., for 10 minutes after termination of the dextran administration). The SPG stimulation protocol included cycling between on-periods, lasting 90 seconds, and off-periods, lasting for 60 seconds. During each on-period, a 6 volt, 10 Hz signal was applied to the SPG, each pulse having a pulse width of 1 ms. The signal was applied using a concentric bipolar electrode, both poles of the electrode being inserted slightly into the SPG.
• After termination of the SPG stimulation (or equivalent time period in the control group), each animal was sacrificed. Concentrations of dextran in various parts of each beagle's brain were measured. In the control group, concentrations in the left half and the right half were measured separately, such that the control results shown inFIG. 16 represent n=8, from four animals. In the experimental group, four animals were used. For each experimental animal, only one sample was taken from each brain region, ipsilateral to the stimulation (thus n=4).
• FIG. 16 shows results from six brain regions known to be regulated to some extent by the SPG (the frontal cortex, the temporal cortex, frontal white matter, the olfactory bulb, the striatum, and the hippocampus).FIG. 16 also shows dextran concentrations measured in the pons, a portion of the brain regulated by the otic ganglion (and substantially not by the SPG). Notably, the results of this experiment show that dextran concentrations in each of the six regions regulated by the SPG were significantly higher in the SPG-stimulated group than in the control group. The high concentration of the dextran tracer (a large molecule), indicates that BBB permeability was substantially increased as a result of the SPG stimulation, in the brain regions regulated by the SPG. Also notable is the almost exact equivalence between the dextran levels in the pons of the SPG-stimulated animals and in the pons of the control animals. The contrast between:
• • (a) the equivalence of the experimental and control groups, in a non-SPG-regulated brain tissue, and
  • (b) the significant differences between the experimental and control groups in the SPG-regulated brain tissues, is a strong indication that the displayed significant effect of the experimental protocol shown inFIG. 16 is a result of modulating the functioning of the SPG and its control over BBB permeability in certain portions of the brain.
• In addition to the results shown inFIG. 16 and described hereinabove, the inventor additionally assessed the concentration of the dextran tracer in temporal muscle of the animals in the SPG-stimulated group and in the control group. It is noted that temporal muscle, being outside of the brain, has no protection from the BBB. The results show that the dextran concentrations rose to high and essentially equivalent values in the temporal muscle of the animals in both the SPG-stimulated group and the control group. This, in combination with the pons data, shows that SPG stimulation as provided herein only produced a measured effect on brain tissue that is regulated by the SPG.
• FIG. 17 shows results from an experiment which included one hour of continuous SPG stimulation in five rats, in accordance with an embodiment of the present invention. Prior to the initiation of SPG stimulation, cerebral blood flow (CBF) was measured, and this measurement provided a baseline for subsequent CBF measurements. CBF was continuously recorded throughout the hour of SPG stimulation, and continued to be recorded for 30 minutes after the stimulation ceased. SPG stimulation protocols were identical to those described hereinabove with reference toFIG. 15.
• Three bars are shown inFIG. 17. The left bar represents the averageblood flow change 20 minutes after SPG stimulation was initiated. The middle bar shows averageblood flow change 40 minutes after stimulation was initiated, and the right bar shows averageblood flow change 20 minutes after the termination of SPG stimulation. From this figure, it is evident that during SPG stimulation, a CBF increase of around 50% (i.e. 150% of original blood flow level) is measured. This increase in cerebral blood flow is believed to be associated with improved metabolic state of brain tissue supplied by the CBF, as supported by other data collected by the inventor (not shown).
• FIG. 18 is a schematic illustration of animplantable stimulator400 for stimulation of an MTS, in accordance with an embodiment of the present invention.Stimulator400 is preferably implanted adjacent toorbital cavity408 of a subject. At least oneelectrode402 extends from the stimulator to at least one of: an anteriorethmoidal nerve404 and a posteriorethmoidal nerve406, which are modulation target sites.Stimulator400 is preferably implanted through an incision made in the upper edge of the eyelid (not shown).
• In an embodiment of the present invention, an odorant is presented to an air passage of a patient, such as a nasal cavity or the throat, so as to increase transport of a diagnostic agent across the BBB from the systemic blood circulation to the CNS, in order to facilitate a diagnosis of a CNS condition. Alternatively or additionally, an odorant is similarly presented in order to enhance transport of a biochemical agent from the CNS to a non-CNS tissue, such as the systemic blood circulation, in order to facilitate a diagnosis of a CNS condition.
• In an embodiment of the present invention, stimulation of the MTS is achieved by applying a neuroexcitatory agent to the MTS. Suitable neuroexcitatory agents include, but are not limited to acetylcholine and urocholine. For some applications, the MTS is stimulated by applying a neuroinhibitory agent, such as atropine, hexamethonium, or a local anesthetic (e.g., lidocaine).
• In an embodiment of the present invention, stimulation of the MTS is achieved by applying mechanical stimulation to the MTS, e.g., vibration.
• Embodiments of the present invention have many medical applications. For example, chemotherapeutic drugs need to pass into cerebral tissue in order to treat brain tumors. Most of the chemotherapeutic drugs have molecular weights of 200-1200 Da, and thus their transport through the blood-brain barrier (BBB) is highly restricted. To overcome the impedance of the BBB, an intracarotid infusion of high osmotic load has been used in the prior art in order to open the tight junctions of the BBB for a very short period (e.g., 25 minutes), during which the medications are given. This procedure is not simple—it is invasive, requires general anesthesia, requires subsequent intensive care, and is in any case relatively expensive. For these reasons, such intracarotid infusions are used only in very few healthcare facilities, even though some reports claim a substantial improvement in life expectancy in patients receiving chemotherapy in this manner.
• Preferably, embodiments of the present invention which facilitate increased trans-BBB drug delivery, and therefore more efficient chemotherapy, also enable a reduction or elimination of the need for radiotherapy. It is noted that such irradiation of the brain is indicated in the literature to be a significant cause of long-term cognitive and other deficits.
• The better delivery of drugs, as provided in accordance with a preferred embodiment of the present invention, is also a factor in the treatment of other disorders, such as Parkinson's disease, Alzheimer's disease, and other neurological diseases. For some applications, the trans-BBB delivery of various growth factors is facilitated using the techniques described herein. Growth factors are typically large molecules that stimulate the growth of neurons, and may be used to treat degenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Motor Neuron Diseases (e.g., Lou Gehrig's disease).
• Another preferred application of the present invention includes facilitating drug delivery across the BBB in order to treat inflammation in the brain, e.g., for cases of infectious diseases of the brain in immunocompromised patients. Similarly, medications to treat AIDS may be more effectively administered to sites in the brain through the BBB, when appropriate, through the use of methods and apparatus described herein. A further application of some embodiments of the present invention includes the delivery through the BBB of viruses that are agents of gene therapy (e.g., for treating Parkinson's disease). Similarly, methods and apparatus described herein may be used for metabolic disorders of the brain, such as GM2 gangliosidosis.
• Another aspect of some preferred embodiments of the invention relates to the modulation of cerebral blood flow. Roughly 750,000 Americans suffer strokes each year. Stroke is the United States' third leading cause of death, killing about 160,000 Americans every year. More than 3 million people in the United States have survived strokes, of whom more than 2 million suffer crippling paralysis, speech loss and lapses of memory. About 85% of strokes are ischemic, i.e., a blood vessel is occluded and its territory is deprived of oxygen supply. A cerebral region that is totally deprived of blood supply is surrounded by a second region of partial lack of supply, whose vitality is at risk. This second region is one of the main targets of some embodiments of the invention—stimulation of the SPG will dilate its vessels and significantly improve that region's likelihood of survival. If the intervention is given early enough in the event (e.g., a few hours post-stroke), it might help also the core region of the stroke, as the thrombus is not yet organized, and dilation of the vessels may reintroduce blood supply to the tissue. Alternatively, SPG stimulation may allow the clot to move from a big vessel to a small vessel, and thus deprive blood supply only from a much smaller volume of the brain (which would, in any case, have probably been deprived of blood supply had the clot remained in place).
• Population-based studies have shown that about 5% of men and 16% of women suffer migraine attacks. Over 80% of these people suffer some degree of headache-related disability. Parasympathetic block (in contrast to stimulation) is known to cause vasoconstriction. An embodiment of the present invention uses electrical means to induce the vasoconstrictive effect and treat migraine. For example, it may use techniques to block nerve messaging, such as applying a slowly-varying voltage, or in some cases, a constant level DC voltage.
• Alzheimer's disease is becoming a major source of disability and financial load with the increase in life expectancy. In recent years, vascular factors have been considered prominent in the pathophysiology of the disease. Current therapy is generally concentrated along one line—cholinomimetic medications, which can, at most, slow down the deterioration of cognitive function in patients. SPG stimulation, as provided in accordance with a preferred embodiment of the present invention, is believed to increase blood flow and oxygen supply to the brain, and therefore help these patients. For this use, permanent stimulators may be implanted in the nasal cavity, for long-term intermittent stimulation.
• In general, it is believed that substantially all pharmacological treatments aimed at cerebral cells for neurological and psychiatric disorders are amenable for use with these embodiments of the present invention. In particular, this embodiment may be adapted for use in the treatment of disorders such as brain tumors, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress, anxiety, disorders requiring the administration of various growth factors, and other CNS disorders that are directly or indirectly affected by changes in cerebral blood flow or by BBB permeability changes.
• Alternatively or additionally, a method is provided for increasing or reducing cortical blood flow and/or inducing or inhibiting vasodilation (even in the absence of BBB permeability changes) by presenting an odorant to an air passage of a patient, such as a nasal cavity or the throat, for treatment of a condition. Patients with the aforementioned disorders and other disorders are generally helped by vasodilation and the resultant improvement in oxygen supply to neurons and other tissue. For some applications, this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients. For other applications, the treatment is performed on a short-term basis, e.g., to minimize the damage following an acute stroke event and initiate neuronal and therefore functional rehabilitation. Alternatively or additionally, the method provided above can be used for diagnostic purposes or in conjunction with other diagnostic methods and/or apparatus known in the art, in order to enhance diagnostic results, reduce procedure risk, reduce procedure time, or otherwise improve such diagnostic procedures and/or diagnostic results. For example, methods and apparatus described herein may be used to increase the uptake into the brain of a radio-opaque material, in order to facilitate a CT scan.
• In a preferred embodiment of the present invention, stimulation of the SPG may be performed using direct galvanic contact, indirect electromagnetic induction, photonic excitation, chemical excitation, mechanical excitation and other methods or combinations thereof, which are known in the art of neural stimulation. Stimulation of the SPG may be performed directly on the SPG, or the nerves connected directly or indirectly with the SPG, e.g., via reflex arc.
• In a preferred embodiment of the present invention, techniques described herein are applied in combination with methods and apparatus described in PCT Application IL 01/00402, filed May 7, 2001, entitled, “Method and apparatus for stimulating the sphenopalatine ganglion to modify properties of the BBB and cerebral blood flow,” U.S.Provisional Patent Application 60/364,451, filed Mar. 15, 2002, entitled, “Applications of stimulating the sphenopalatine ganglion (SPG),” U.S.Provisional Patent Application 60/368,657, filed Mar. 28, 2002, entitled, “SPG stimulation,” and/or U.S.Provisional Patent Application 60/376,048, filed Apr. 25, 2002, entitled, “Methods and apparatus for modifying properties of the BBB and cerebral circulation by using the neuroexcitatory and/or neuroinhibitory effects of odorants on nerves in the head,” all of which are assigned to the assignee of the present invention and are incorporated herein by reference.
• The better delivery of drugs, as provided in accordance with preferred embodiments of the present invention, is an important factor in the treatment of various disorders, such as Parkinson's disease, Alzheimer's disease, and other neurological diseases. For some applications, the trans-BBB delivery of various growth factors is facilitated using the techniques described herein. Growth factors are typically large molecules that stimulate the growth of neurons, and, in accordance with a preferred embodiment of the present invention, are used to treat degenerative disorders, such as Parkinson's disease, Alzheimer's disease, and Motor Neuron Diseases (e.g., Lou Gehrig's disease).
• Alzheimer's disease is becoming a major source of disability and financial load with the increase in life expectancy. In recent years, vascular factors have been considered prominent in the pathophysiology of the disease. Current therapy is generally concentrated along one line—cholinomimetic medications, which typically, at most, slow down the deterioration of cognitive function in patients. SPG stimulation, as provided in accordance with preferred embodiments of the present invention, typically increases blood flow and oxygen supply to the brain, and therefore help these patients. For this use, permanent stimulators may be implanted in the nasal cavity, for long-term intermittent stimulation. In a preferred embodiment, the delivery of cholinomimetic medications is facilitated by SPG stimulation.
• Apart from molecular parameters, the permeability of the BBB and active transport mechanisms, a major determinant of molecular transport across the BBB is their concentration gradient—between the CNS and the cerebral circulation. In cases where a compound has a higher concentration in the brain than in the cerebral circulation, opening of the BBB, preferably, but not necessarily, using techniques described herein leads to an increased net transport of that compound from the CNS into the circulation. In a preferred embodiment, this technique is used to facilitate a diagnosis, e.g., by enhancing permeability of the BBB, taking a blood sample, and testing the blood sample for increased levels of the compound.
• In a preferred embodiment of the present invention, parasympathetic fibers associated with the SPG are stimulated, preferably by using electrical stimulation and/or odorant presentation techniques described herein, thereby rendering the BBB permeable to certain compounds in the CNS. One or more of such compounds are then analyzed by analyzing the blood of the patient. By testing such compounds that are indicative of the presence of AD, AD is diagnosed. Advantageously, such a testing procedure is minimally invasive. Alternatively or additionally, molecular passage is increased to another body compartment and/or fluid, such as plasma, serum, ascites, or cerebrospinal fluid.
• Moreover, in accordance with a preferred embodiment of the present invention, a controlled, reversible suppression of the impedance of the BBB is useful as a stand-alone treatment, when said suppression facilitates clearance of neurotoxic compounds, such as β-Amyloid, tau, PS1, and PS2, from the CNS into the systemic circulation. Once in the systemic circulation, these neurotoxic compounds may be metabolized and removed from the body with greater ease and with fewer side effects, compared to effects that accompany their presence in the CNS.
• The following examples demonstrate selected therapeutic and diagnostic applications of SPG stimulation in the management of Alzheimer's disease. It should be appreciated by those of skill in the art, that the following examples are set forth for demonstrative purposes. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. The following description relates to specific embodiments for stimulation of the SPG and related neural structures, possible system configurations for the stimulator device, variations or combinations of the therapeutic and diagnostic modalities that accompany SPG stimulation and complementary explanation for the various mechanisms of actions of such a system for AD management. Furthermore, the methods described herein may be either directly, or indirectly applicable for the management of other CNS disorders, such as Parkinson's disease, epilepsy, ALS, MS and more. All references cited herein, including articles, patents, and published patent applications, are incorporated herein by reference.
EXAMPLE 1Therapeutics (Glutamate Inhibitors)
• Excitotoxicity is related to excessive activation of glutamate receptors which results in neuronal cell death. The physiological function of glutamate receptors is the mediation of ligand-gated cation channels with the concomitant influx of calcium, sodium and potassium through this receptor-gated channel. The influx of these cations is essential for maintaining membrane potentials and the plasticity of neurons which in itself plays a pivotal role in cognitive function of the central nervous system (Li, H. B. et al., Behav. Brain Res. 83: 225-228, 1997; Roesler, R. et al., Neurology 50: 1195, 1998; Wheal, H. V. et al., Prog. Neurobiol. 55: 611-640, 1998; Wangen, K et al., Brain Res. 99: 126-130, 1997). Excitotoxicity plays an important role in neuronal cell death following acute insults such as hypoxia, ischemia, stroke and trauma, and it also plays a significant role in neuronal loss in AIDS dementia, epilepsy, focal ischemia (Coyle, J. T. et al., Science 262: 689-695, 1993). Neurodegenerative disorders, such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of a specific population of neurons in the central nervous system. Growing evidence suggests that glutamate-mediated excitotoxicity may be a common pathway which contributes to neuronal cell death in a wide range of neurological disorders (Coyle, J. T. et al., Science 262: 689-695, 1993). The molecular mechanisms of excitotoxicity-mediated neuronal cell death remains obscure. Over-production of free radicals that lead to impairment of mitochondrial function is the most widely held hypothesis (Beal, M. F. et al., Ann. Neurol. 38: 357-366, 1995; Coyle, J. T. et al., Science 262: 689-695, 1993). However, it is unclear in the literature whether the increase of free radicals is the precursor that initiates neuronal degeneration or, rather, a subsequent consequence of neuronal degeneration. Interestingly, administration of antioxidants is reported as having little neuroprotective effect in patients suffering from various neurodegenerative diseases (Shults, C. W. et al., Neurology 50: 793-795, 1998). Thus, some other mechanism(s) must exist for excitotoxicity-induced neuronal cell death.
• A potential treatment modality for AD is the systemic administration of a JNK (c-Jun amino-terminal kinase) or MLK (Mixed lineage kinase) apoptosis inhibitor as a means for preventing AD-related apoptosis of brain cells. However, without the use of the techniques described herein, achieving a therapeutic concentration of such an inhibitor in the CNS may be accompanied by undesired dose-related side effects. Advantageously, the use of techniques described herein for enhancing drug delivery to the CNS typically enables the achievement of therapeutic results at lower dosages, which, in turn, lowers the risk of dose-related side effects.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of such inhibitors is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 2Therapeutics β/γ Secretase Inhibitors
• In a preferred embodiment of the present invention, methods for treatment of Alzheimer's disease target the formation of β-amyloid through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit β or γ secretase activity, either directly or indirectly, are used, in accordance with this embodiment, to control the production of β-amyloid. Advantageously, compounds that specifically target γ secretases, could control the production of β-amyloid. Typically, such inhibition of β or γ secretases reduces production of Aβ, which, in turn, reduces or prevents the neurological disorders associated with Aβ protein.
• Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type I integral membrane protein, termed b amyloid precursor protein (APP). P APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ is derived from cleavage of β APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
• The existence of at least four proteolytic activities has been postulated. They include β secretase(s), generating the N-terminus of Aβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending atposition38,39,40,42, and43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
• Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of AD. First, Aβ is the major protein found in amyloid plaques. Second, Aβ is neurotoxic and may be causally related to neuronal death observed in AD patients. Third, missense DNA mutations at position717 in the770 isoform of P APP can be found in affected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other β APP mutations have been described in familiar forms of AD. Fourth, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human β APP. Fifth, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset AD. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the AD.
• It is hypothesized by the inventors that inhibiting the production of Aβ inhibits neurological degeneration by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment preferred by the inventors is based on drugs that inhibit the formation of Aβ in vivo, administered in combination with techniques for SPG stimulation described herein.
• Methods of treatment preferably target the formation of Aβ through the enzymes involved in the proteolytic processing of P amyloid precursor protein. Compounds that inhibit β or γ secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target γ secretases could control the production of Aβ. Such inhibition of p or γ secretases could thereby reduce production of Aβ, which, in turn, could reduce or prevent the neurological disorders associated with Aβ protein.
• U.S. Patent Application Publication 2002/0055501 to Olson et al. describes pharmaceutical compositions and methods of use of such compounds, which inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.
• The efficacy of administration of pharmaceutical agents that inhibit the processing of amyloid precursor protein into P-amyloid is typically substantially increased when used in conjunction with the techniques of SPG stimulation described herein.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of such compounds targeting production of Aβ is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 3Therapeutics (NMDA-Receptor Blocker)
• U.S. Patent Application Publication 2002/0035145 to Tsai et al., describes a method to treat various neuropsychiatric disorders, including Alzheimer's disease. Their description relates that neuropsychiatric disorders characterized by a deficit in neurotransmission via the NMDA receptor can be alleviated by a compound that acts as an agonist of the glycine site on the NMDA receptor or an inhibitor of glycine uptake. The compound is either a partial agonist such as D-cycloserine, which can be used at a dosage of 105-500 mg, or a full agonist (e.g., D-serine or D-alanine) that is selective for the NMDA receptor (compared to the inhibitory glycine receptor and other receptors), or a glycine uptake inhibitor (e.g., N-methylglycine). They describe methods for treating neuropsychiatric disorders in patients (i.e., humans). Examples of disorders that can be treated by the methods they describe include schizophrenia, Alzheimer's disease, autism, depression, benign forgetfulness, childhood learning disorders, closed head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as suffering from such a neuropsychiatric disorder a pharmaceutical composition that contains a therapeutically-effective amount of an agonist of the glycine site of the NMDA receptor or a glycine uptake inhibitor, which agonist is relatively selective for (a) the glycine site of the NMDA receptor, compared with (b) the inhibitory glycine receptor and other receptors. The pharmaceutical composition may include, for example, (i) a therapeutically effective amount of D-alanine (wherein the pharmaceutical composition is substantially free of D-cycloserine) and/or (ii) a therapeutically effective amount of D-serine, and/or (iii) D-cycloserine in an amount of 105-500 mg, and/or (iv) a therapeutically effective amount of N-methylglycine.
• U.S. Patent Application Publication 2001/0051633 to Bigge et al., describes a subtype-selective NMDA receptor ligands and the use thereof for treating or preventing neuronal loss associated with neurodegenerative diseases including Alzheimer's disease by treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids.
• U.S. Patent Application Publication 2001/0047014 to Alanine et al., describes a compound of theformula 1 its R,R-, S,S-enantiomers and racemic mixtures, also suitable for the treatment of Alzheimer's disease.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of such compounds described in this example (Example 3), and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 4Therapeutics (Cholinesterase Inhibitors)
• U.S. Patent Application Publication 2002/0028834 to Villalobos et al., describes the use of cholinesterase inhibitors for enhancing memory in patients suffering from dementia and Alzheimer's disease. It is known that acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer's patients. By inhibiting acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine in the brain and thus enhance memory. Becker et al., cited hereinabove, report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of three known acetylcholinesterase inhibitors, physostigmine, metrifonate, and tetrahydroaminoacridine.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of such cholinesterase inhibitors is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 5Therapeutics (Direct Stimulation of Neural Regeneration)
• There are continuous efforts to use a Nerve Growth Factor (NGF) as a stimulant of neural regeneration, thus potentially slowing degenerative processes, or even reversing neural damage. (NGF belongs to a large family of neural growth factors, including BDNF, IGF, GDNF and other active stimulants of neural regeneration. However, for the purpose of the present patent application, the term NGF shall be used to represent any such compound, or combinations thereof). Therefore, growth factor therapy for AD is considered a potentially curative approach of disease management. However, such an approach still has to overcome the challenge of administering growth factor in adequate amounts, preferably over a continuous period of time, into the CNS. In the prior art, the BBB is generally considered impermeable to high molecular weight compounds, and thus systemic administration of growth factor, without using the techniques described herein, is not generally considered a treatment option for a patient with a functional BBB.
• Because the BBB is generally considered in the prior art to be impermeable to high molecular weight compounds, invasive methods have been developed to enable NGF to reach a patient's brain. For example, a possible method for AD therapy, currently being tested in clinical trials, uses gene therapy techniques for the in-situ production of growth factors. This method involves brain surgery, where a patient's own cells are genetically modified to produce the NGF. The patient's cells, called “fibroblasts,” are obtained from skin biopsies. The fibroblasts are genetically modified in vitro and are then implanted into either 5 or 10 locations in the patient's brain. The eventual goal of this research effort is to determine whether NGF produced by the cells implanted into the brain can prevent the death of some nerve cells that are affected in Alzheimer's disease, and enhance the function of some remaining brain cells.
• In animal studies, fibroblasts genetically modified to produce NGF have been shown to prevent the death of certain nerve cells in the brain. This effectiveness has been shown in both the rat brain and the monkey brain. The genetically-modified cells prevent cell death after injury, and prevent cell atrophy that is a natural consequence of aging in primates.
• A straightforward approach to circumventing the BBB would be to pierce the meninges and directly administer growth factors into the CNS. This technique, however, has several drawbacks. First, it puts the patient in a continuous risk of inflammatory brain processes. Second, direct infusion into the brain is usually very localized, and therefore its effectiveness is limited to the close vicinity of the administration tip, especially where the active molecule is of high molecular weight, making it less mobile. It is therefore clear that a relatively safe method of transiently opening the BBB to large molecular weight molecules, such as that described herein, could make nerve growth factors a compound of choice for the treatment of AD.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of nerve growth factor is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• U.S. Patent Application Publication 2002/0040052 to Ito et al., describes a method for extending neurites of neurocytes without any side effects, and a method for preventing and/or treating neurodegeneration diseases using compositions having neurite extending effect. This invention is described as being necessary because the more direct method of administering NGF directly suffers from several limitations: “However, an NGF is a protein having a molecular weight of 13000 in the form of monomer and 26000 in the form of dimer, so that it cannot pass through the blood-brain barrier. Therefore, in order to treat disorders of central function, NGFs are required to be administrated intraventricularly. Moreover, it is difficult to prepare NGFs in large quantities. In these respects, there are many problems about the use of NGF itself. As a result, it is very difficult to use NGF itself clinically.”
EXAMPLE 6Therapeutics (Indirect Stimulation of Neural Regeneration)
• One of the characteristics of Alzheimer's disease (AD) is loss of presynaptic markers such as synaptophysin. Synaptophysin decreases in neurodegenerative disorders along with a decline in neurotransmission. Synaptophysin: (i) is a synaptic vesicle-associated integral membrane protein (molecular weight about 38 kDa), (ii) acts as a specific marker for the presynaptic terminal, and (iii) is involved in neuronal transmission (Scheller, R. H., “Membrane Trafficking in the Presynaptic Nerve Terminal,” Neuron 14: 893-897, 1995). A combination of neurotrophic factors is most effective in providing optimal trophic support for compromised neuron functions, including neurotransmission (Rathbone M. P. et al., “AIT-082 as a potential neuroprotective and regenerative agent in stroke and central nervous system injury,” Exp. Opin. Invest. Drugs. 8: 1255-12652, 1999). Multiple neurotrophic factors may synergistically regulate synaptophysin levels in a manner that can lead to increased neurotransmission and improved neuronal function.
• Pharmaceutical agents that increase synaptophysin synthesis and/or secretion, decrease its metabolism, increase its release or improve its effectiveness may also be of benefit in reversing the course of neurological diseases including neurodegenerative diseases, such as Alzheimer's disease, and improve function in neurodevelopmental disorders, such as Down's syndrome. U.S. Patent Application Publication 2002/0040032 to Glasky et al. describes a method of increasing the synthesis and/or secretion of synaptophysin, comprising administering to a patient with a neurological disease or a patient at risk of developing a neurological disease an effective quantity of a purine derivative or analogue, a tetrahydroindolone derivative or analogue, or a pyrimidine derivative or analogue. If the compound is a purine derivative, the purine moiety can be guanine or hypoxanthine.
• Therefore, there exists a need for methods that can stimulate the synthesis and/or secretion of synaptophysin in patients with neurological diseases, including neurodegenerative diseases such as AD and neurodevelopmental disorders such as Down's syndrome, in order to preserve, restore or improve neuronal transmission capability in such patients. Preferably, these methods are combined with methods that enable active compounds to cross the BBB, making combined therapy more efficient. These methods are suitable for use with compounds or pharmaceutical compositions that can stimulate nerve growth or regeneration in patients with neurological diseases, including neurodegenerative diseases such as AD and neurodevelopmental disorders such as Down's syndrome, thus reversing the course of the disease.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of compounds affecting synaptophysin, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• U.S. Patent Application Publication 2002/0019519 to Bingham et al. describes the use of KIAA0551 polypeptides and polynucleotides in the design of protocols for the treatment of various neurological disorders, among which is AD.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of KIAA0551 polypeptides and polynucleotides, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 7Therapeutics (Antioxidants)
• A number of diseases and disorders are thought to be caused by or to be associated with alterations in mitochondrial metabolism and/or inappropriate induction or suppression of mitochondria-related functions leading to apoptosis. These include, by way of example and not limitation, chronic neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD); auto-immune diseases; diabetes mellitus, including Type I and Type II; mitochondria associated diseases, including but not limited to congenital muscular dystrophy with mitochondrial structural abnormalities, fatal infantile myopathy with severe mtDNA depletion and benign “later-onset” myopathy with moderate reduction in mtDNA, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) and MIDD (mitochondrial diabetes and deafness); MERFF (myoclonic epilepsy ragged red fiber syndrome); arthritis; NARP (Neuropathy; Ataxia; Retinitis Pigmentosa); MNGIE (Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy), LHON (Leber's; Hereditary; Optic; Neuropathy), Kearns-Sayre disease; Pearson's Syndrome; PEO (Progressive External Ophthalmoplegia); Wolfram syndrome DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness); Leigh's Syndrome; dystonia; schizophrenia; and hyperproliferative disorders, such as cancer, tumors and psoriasis.
• According to generally accepted theories of mitochondrial function, proper ETC respiratory activity requires maintenance of an electrochemical potential (ATm) in the inner mitochondrial membrane by a coupled chemiosmotic mechanism. Conditions that dissipate or collapse this membrane potential, including but not limited to failure at any step of the ETC, may thus prevent ATP biosynthesis and hinder or halt the production of a vital biochemical energy source. Altered or defective mitochondrial activity may also result in a catastrophic mitochondrial collapse that has been termed “mitochondrial permeability transition” (MPT). In addition, mitochondrial proteins such as cytochrome c and “apoptosis inducing factor” may dissociate or be released from mitochondria due to MPT (or the action of mitochondrial proteins such as Bax), and may induce proteases known as caspases and/or stimulate other events in apoptosis (Murphy, Drug Dev. Res. 46: 18-25, 1999).
• Defective mitochondrial activity may alternatively or additionally result in the generation of highly-reactive free radicals that have the potential of damaging cells and tissues. These free radicals may include reactive oxygen species (ROS) such as superoxide, peroxynitrite and hydroxyl radicals, and potentially other reactive species that may be toxic to cells. For example, oxygen free radical induced lipid peroxidation is a well established pathogenetic mechanism in central nervous system (CNS) injury such as that found in a number of degenerative diseases, and in ischemia (i.e., stroke). (Mitochondrial participation in the apoptotic cascade is believed to also be a key event in the pathogenesis of neuronal death.)
• There are, moreover, at least two deleterious consequences of exposure to reactive free radicals arising from mitochondrial dysfunction that adversely impact the mitochondria themselves. First, free radical mediated damage may inactivate one or more of the myriad proteins of the ETC. Second, free radical mediated damage may result in catastrophic mitochondrial collapse that has been termed “transition permeability.” According to generally accepted theories of mitochondrial function, proper ETC respiratory activity requires maintenance of an electrochemical potential in the inner mitochondrial membrane by a coupled chemiosmotic mechanism. Free radical oxidative activity may dissipate this membrane potential, thereby preventing ATP biosynthesis and/or triggering mitochondrial events in the apoptotic cascade.
• There is evidence that defects in oxidative phosphorylation within the mitochondria are at least a partial cause of sporadic AD. The enzyme cytochrome c oxidase (COX), which makes up part of the mitochondrial electron transport chain (ETC), is present in normal amounts in AD patients; however, the catalytic activity of this enzyme in AD patients and in the brains of AD patients at autopsy has been found to be abnormally low. This suggests that the COX in AD patients is defective, leading to decreased catalytic activity that in some fashion causes or contributes to the symptoms that are characteristic of AD.
• One hallmark pathology of AD is the death of selected neuronal populations in discrete regions of the brain. Cell death in AD is presumed to be apoptotic because signs of programmed cell death (PCD) are seen and indicators of active gliosis and necrosis are not found (Smale et al., Exp. Neurolog. 133: 225-230, 1995; Cotman et al., Molec. Neurobiol. 10: 19-45, 1995). The consequences of cell death in AD, neuronal and synaptic loss, are closely associated with the clinical diagnosis of AD and are highly correlated with the degree of dementia in AD (DeKosky et al., Ann. Neurology 2757-464, 1990).
• Mitochondrial dysfunction is thought to be critical in the cascade of events leading to apoptosis in various cell types (Kroemer et al., FASEB J 9: 1277-1287, 1995), and may be a cause of apoptotic cell death in neurons of the AD brain. Altered mitochondrial physiology may be among the earliest events in PCD (Zamzami et al., J. Exp. Med. 182: 367-77, 1995; Zamzami et al., J. Exp. Med. 181: 1661-72, 1995) and elevated reactive oxygen species (ROS) levels that result from such altered mitochondrial function may initiate the apoptotic cascade (Ausserer et al., Mol. Cell. Biol. 14: 5032-42, 1994). In several cell types, including neurons, reduction in the mitochondrial membrane potential (δψm) precedes the nuclear DNA degradation that accompanies apoptosis. In cell-free systems, mitochondrial, but not nuclear, enriched fractions are capable of inducing nuclear apoptosis (Newmeyer et al., Cell 70: 353-64, 1994). Perturbation of mitochondrial respiratory activity leading to altered cellular metabolic states, such as elevated intracellular ROS, may occur in mitochondria associated diseases and may further induce pathogenetic events via apoptotic mechanisms.
• Oxidatively-stressed mitochondria may release a pre-formed soluble factor that can induce chromosomal condensation, an event preceding apoptosis (Marchetti et al., Cancer Res. 56: 2033-38, 1996). In addition, members of the Bcl-2 family of anti-apoptosis gene products are located within the outer mitochondrial membrane (Monaghan et al., J. Histochem. Cytochem. 40: 1819-25, 1992) and these proteins appear to protect membranes from oxidative stress (Korsmeyer et al, Biochim. Biophys. Act. 1271: 63, 1995). Localization of Bcl-2 to this membrane appears to be indispensable for modulation of apoptosis (Nguyen et al., J. Biol. Chem. 269: 16521-24, 1994). Thus, changes in mitochondrial physiology may be important mediators of apoptosis. To the extent that apoptotic cell death is a prominent feature of neuronal loss in AD, mitochondrial dysfunction may be critical to the progression of this disease and may also be a contributing factor in other mitochondria associated diseases.
• Focal defects in energy metabolism in the mitochondria, with accompanying increases in oxidative stress, may be associated with AD. It is well-established that energy metabolism is impaired in AD brain (Palmer et al., Brain Res. 645: 338-42, 1994; Pappolla et al., Am. J. Pathol. 140: 621-28, 1992; Jeandel et al., Gerontol. 35: 275, 1989; Balazs et al., Neurochem. Res. 19: 1131-37, 1994; Mecocci et al., Ann. Neurol. 36: 747-751, 1994; Gsell et al., J. Neurochem. 64: 1216-23, 1995). For example, regionally specific deficits in energy metabolism in AD brains have been reported in a number of positron emission tomography studies (Kuhl, et al., J. Cereb. Blood Flow Metab. 7: S406, 1987; Grady, et al., J. Clin. Exp. Neuropsychol. 10: 576-96, 1988; Haxby et al., Arch. Neurol. 4: 753-60, 1990; Azari et al., J. Cereb. Blood Flow Metab. 13: 438-47, 1993). Metabolic defects in the temporoparietal neocortex of AD patients apparently presage cognitive decline by several years. Skin fibroblasts from AD patients display decreased glucose utilization and increased oxidation of glucose, leading to the formation of glycosylation end products (Yan et al., Proc. Nat. Acad. Sci. U.S.A. 91: 7787-91, 1994). Cortical tissue from postmortem AD brain shows decreased activity of the mitochondrial enzymes pyruvate dehydrogenase (Sheu et al., Ann. Neurol. 17: 444-49, 1985) and α-ketoglutarate dehydrogenase (Mastrogiacomo et al., J. Neurochem. 6: 2007-2014, 1994), which are both key enzymes in energy metabolism. Functional magnetic resonance spectroscopy studies have shown increased levels of inorganic phosphate relative to phosphocreatine in AD brain, suggesting an accumulation of precursors that arises from decreased ATP production by mitochondria (Pettegrew et al., Neurobiol. of Aging 15: 117-32, 1994; Pettigrew et al., Neurobiol. of Aging 16: 973-75, 1995). In addition, the levels of pyruvate, but not of glucose or lactate, are reported to be increased in the cerebrospinal fluid of AD patients, consistent with defects in cerebral mitochondrial electron transport chain (ETC) activity (Pametti et al., Neurosci. Lett 199: 231-33, 1995).
• Signs of oxidative injury are prominent features of AD pathology and, as noted above, reactive oxygen species (ROS) are critical mediators of neuronal degeneration. Indeed, studies at autopsy show that markers of protein, DNA and lipid peroxidation are increased in AD brain (Palmer et al., Brain Res. 645: 338-42, 1994; Pappolla et al., Am. J. Pathol. 140: 621-28, 1992; Jeandel et al., Gerontol. 35: 275-82, 1989; Balazs et al., Arch. Neurol. 4: 864, 1994; Mecocci et al., Ann. Neurol. 36: 747-751, 1994; Smith et al., Proc. Nat. Acad. Sci. U.S.A. 88: 10540-10543, 1991). In hippocampal tissue from AD but not from controls, carbonyl formation indicative of protein oxidation is increased in neuronal cytoplasm, and nuclei of neurons and glia (Smith et al., Nature 382: 120-21, 1996). Neurofibrillary tangles also appear to be prominent sites of protein oxidation (Schweers et al., Proc. Nat. Acad. Sci. U.S.A. 92: 8463, 1995; Blass et al., Arch. Veurol. 4: 864, 1990). Under stressed and non-stressed conditions incubation of cortical tissue from AD brains taken at autopsy demonstrate increased free radical production relative to non-AD controls. In addition, the activities of critical antioxidant enzymes, particularly catalase, are reduced in AD (Gsell et al., J. Neurochem. 64: 1216-23, 1995), suggesting that the AD brain is vulnerable to increased ROS production. Thus, oxidative stress may contribute significantly to the pathology of mitochondria associated diseases such as AD, where mitochondrial dysfunction and/or elevated ROS may be present.
• Increasing evidence points to the fundamental role of mitochondrial dysfunction in chronic neurodegenerative diseases (Beal, Biochim. Biophys. Acta 1366: 211-223, 1998), and recent studies implicate mitochondria for regulating the events that lead to necrotic and apoptotic cell death (Susin et al., Biochim. Biophys. Acta 1366: 151-168, 1998). Stressed (by, e.g., free radicals, high intracellular calcium, loss of ATP, among others) mitochondria may release pre-formed soluble factors that can initiate apoptosis through an interaction with apoptosomes (Marchetti et al., Cancer Res. 56: 2033-38, 1996; Li et al., Cell 91: 479-89, 1997). Release of preformed soluble factors by stressed mitochondria, like cytochrome c, may occur as a consequence of a number of events. In any event, it is thought that the magnitude of stress (ROS, intracellular calcium levels, etc.) influences the changes in mitochondrial physiology that ultimately determine whether cell death occurs via a necrotic or apoptotic pathway. To the extent that apoptotic cell death is a prominent feature of degenerative diseases, mitochondrial dysfunction may be a critical factor in disease progression.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of antioxidant compounds, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 8Therapeutics (β-Amyloid Inhibitors)
• U.S. Patent Application Publication 2002/0042420 to Briem et. al., describes a method to prepare compounds which may be capable of interfering (preferably in an inhibitory capacity) in the process of the formation of Aβ or its release from cells, or of reducing the activity of Aβ by inhibiting it. Their description has the further objective of preparing compounds which can be used effectively for the prevention or treatment of Alzheimer's disease.
• U.S. Patent Application Publication 2002/0025955 to Han et al., describes the potential use of lactams that inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby potentially acting to prevent the formation of neurological deposits of amyloid protein.
• U.S. Patent Application Publication 2002/0022621 to Chaturvedula et al., describes a series of arylacetamidoalanyl derivatives of benzodiazepinones, which are inhibitors of β-amyloid peptide production and may be useful in the treatment of Alzheimer's disease and other conditions characterized by aberrant extract cellular deposition of amyloid.
• U.S. Patent Application Publication 2001/0020097 to Audia et al., describes compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, may have utility in treating Alzheimer's disease both prophylactically and therapeutically. Introduction of the compounds into the brain, for therapeutic purposes, or out of the brain, for diagnostic purposes, may require crossing the BBB.
• U.S. Pat. No. 6,211,235 to Wu et al., describes compounds which inhibit p-amyloid peptide release and/or its synthesis, and, accordingly, may have utility in treating Alzheimer's disease. It also describes pharmaceutical compositions comprising a compound which may inhibit β-amyloid peptide release and/or its synthesis when introduced either directly or indirectly into the brain. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. No. 5,011,472 to Aebischer et al. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the BBB. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which may transiently open the BBB to some extent.
• However, without using the techniques described herein, no general method is known to controllably open the BBB for the efficient delivery of large-molecular weight pharmaceutical compounds, or compounds with high plasma protein binding.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of the compounds described in this example (Example 8), and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 9Therapeutics (β-Amyloidpolymerization Inhibitors)
• Bernd Bohrmann et al. reported (J Biol Chem, Vol. 274, Issue 23, 15990-15995, Jun. 4, 1999) that certain plasma proteins, at physiological concentrations, are potent inhibitors of β-amyloid peptide polymerization. These proteins are also present in cerebrospinal fluid, but at low concentrations having little or no effect on P-amyloid. Thirteen proteins representing more than 90% of the protein content in plasma and cerebrospinal fluid were studied. Quantitatively, albumin was the most important protein, representing 60% of the total amyloid inhibitory activity, followed by α-1-antitrypsin and immunoglobulins A and G. Albumin suppressed amyloid formation by binding to the oligomeric or polymeric beta-amyloid, blocking a further addition of peptide.
• The results of Bohrmann et al. suggest that several endogenous proteins are negative regulators of amyloid formation. Plasma contains at least 300 times more amyloid inhibitory activity than cerebrospinal fluid. These findings may provide one explanation as to why β-amyloid deposits are not found in peripheral tissues but are only found in the central nervous system. Moreover, the data suggest that some drugs that display an affinity for albumin may enhance P-amyloid formation and promote the development of AD.
• Increased penetration of plasma proteins into the CNS may, on the other hand, have an inhibitory effect on P-amyloid polymerization, consequently slowing, or reversing, AD progression.
• In a preferred embodiment of the present invention, the permeability of the BBB is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB, in order to permit P-amyloid polymerization inhibitors naturally occurring in the blood, particularly albumin, to pass from the blood into the CNS.
EXAMPLE 10Therapeutics (Microglial Activation Modulators)
• Acute and chronic brain injuries can activate resident microglia (resident macrophage-like cells found in the central nervous system) as well as recruit peripheral immune cells to injured brain regions that can exacerbate neuronal damage. Inflammatory processes can induce cell death by (a) the release of proteases and free radicals that induce lipid peroxidation, (b) direct cytotoxic effects or (c) the phagocytosis of sublethally-injured neurons. The attenuation of microglia and peripheral immune cell activation has been correlated with significant neuronal protection in pre-clinical studies of ischemia, traumatic brain injury, spinal cord injury and Alzheimer's disease. U.S. Patent Application Publication 20020022650 to Posmantur et al. describes methods of modulating or inhibiting microglia activation comprising the administration of a compound capable of inhibiting 5-LOX, FLAβ, attenuating degradation of IκBa or inhibiting nuclear translocation of the NF-KB active complex for the treatment of various disorders associated with excessive production of inflammatory mediators in the brain, among which is Alzheimer's disease.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of the compounds described in this example (Example 10), and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 11Therapeutics (NSAID)
• Studies support an inverse relationship between anti-inflammatory medications used for treating patients with rheumatoid arthritis and an associated low prevalence of Alzheimer's disease (Rich, J. B. et al., Neurology 45: 51-55, 1995). Controlled studies of twin pairs having Alzheimer's disease onset greater than 3 years apart provide additional support that prior treatment with anti-inflammatory medications serves a protective role in Alzheimer's disease (Breitner, J. C. S. et al., Neurology 44: 227-232, 1994). Specifically, controlled double-blinded studies have found that the anti-inflammatory agent “indomethacin” administered orally has a therapeutic benefit for mild to moderately cognitively-impaired Alzheimer's disease patients, and treatment with indomethacin during early stages of the disease has a retarding effect on disease progression compared to the placebo treated control group. (Rogers, J. et al., Neurology 43: 1609-1612, 1993). Alzheimer's patients with moderate cognitive impairment treated with indomethacin also exhibit a reduction in cognitive decline. However, patients treated with oral indomethacin developed drug related adverse effects that required their treatment to be discontinued and their removal from the study.
• U.S. Patent Application Publication 2001/0027309 to Elsberry describes a method for treating Alzheimer's disease, comprising delivering indomethacin or nonsteroidal anti-inflammatory drugs (NSAIDs) having cyclooxygenase inhibitor action directly to the hippocampus or the lateral ventricle through an implanted catheter.
• It may also be advantageous to allow NSAID and other anti-inflammatory drugs into the CNS in combination with immunological (vaccine) treatment of AD. A vaccine, made by Elan Corporation (Dublin, Ireland) and known by its code name AN-1792, was tested in a clinical trial. In the trial, twelve volunteers were reported to have fallen seriously ill with brain inflammation, forcing the vaccine's manufacturer to halt the trial and raising doubts about the product's clinical potential. The AN-1792 vaccine had generated unusually intense enthusiasm among scientists and patient advocates during the past two years, as experiments in mice suggested it could halt the progression of Alzheimer's and perhaps even cure the deadly disease.
• In general, NSAIDs are known to be very extensively protein bound (>99%). This characteristic makes the penetration of NSAID into the CNS very scarce, since they are usually bound to plasma proteins having molecular weights of around 70 kDa.
• Therefore, allowing macromolecules into the CNS is expected to allow the introduction of anti-inflammatory drugs. These, on their own, or in conjunction with immunological or other therapeutic approaches, can serve as an effective treatment for AD.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of NSAIDs and other anti-inflammatory agents, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• In another preferred embodiment of the present invention, the administration of a vaccine is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 12Therapeutics (Vaccine)
• U.S. Patent Application Publication 2002/0009445 to Du et al., discusses the use of an anti-Aβ antibody for diagnosing and/or treating amyloid associated diseases, especially Alzheimer's disease. They indicate that naturally-occurring Aβ antibodies exist in biologically relevant fluids, i.e., CSF and plasma, and that levels of these antibodies differ between normal age-matched healthy controls and AD patients. Based on these findings it was concluded and then supported by experiments that these antibodies can be used for diagnosis and treatment of amyloid associated diseases and especially of Alzheimer's disease. In the context of this application, the terms “anti-Aβ antibodies” and “Aβ antibodies” are used interchangeably to designate the antibody of their invention. An embodiment of their diagnostic method uses lumbar CSF samples, on which Aβ antibody levels were determined utilizing an ELISA assay in which the Aβ peptide was used as the capture ligand.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of anti-Aβ antibodies, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 13Therapeutics (Other Approaches)
• U.S. Patent Application Publication 2002/0022593 to Yue describes a method of treating neurodegenerative dysfunctions and aging symptoms by administering a therapeutically-effective amount of relaxin (a polypeptide hormone, whose molecular weight is between 5,700 to 6,500 Da) to a patient. Neurodegenerative dysfunctions potentially amenable to treatment with relaxin include Alzheimer's, attention deficit disorder, Parkinson's, and others. The aforementioned method is based on the recognition that some of the symptoms associated with aging and/or neurodegenerative dysfunctions can be alleviated by relaxin, and may in fact be caused by a decrease of relaxin in the bloodstream. This lack of relaxin in the blood stream may be congenital or the result of another mechanism which suppresses the normal production or action of relaxin.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of relaxin, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• U.S. Patent Application Publication 2002/0019412 to Andersen et al., describes novel inhibitors of Protein Tyrosine Phosphatases (PTPase's) such as PTPIB, CD45, SHP-1, SHP-2, PTPa, LAR and HePTP or the like, for treatment of various systemic and CNS-related disorders, including Alzheimer's disease.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of PTPase's, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• U.S. Patent Application Publication 2002/0006959 to Henderson describes a method of potentially treating or preventing dementia of Alzheimer's type, or other loss of cognitive function caused by reduced neuronal metabolism, comprising administering an effective amount of medium chain triglycerides to a patient in need thereof.
• In a preferred embodiment of the present invention, the therapeutic or prophylactic administration of medium chain triglycerides, and/or the diagnostic use thereof, is enhanced by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
EXAMPLE 14Diagnostics
• Accurate diagnosis of AD during life is highly desirable. However, clinical evaluation is at best only about 80% accurate. Therefore, there exists a need to identify specific biochemical markers of AD. So far, analysis of blood or cerebrospinal fluid (CSF) has not yielded a biochemical marker of sufficient diagnostic value (Blass et al., 1998), although detectable differences are reported in the levels of certain proteins (Motter et al., Ann. Neurol. 38, 643-648, 1995).
• Although recent reports of using positron-emission tomography (PET) (Reiman, E. M., et al., New Eng. J. Med., 334: 752-758, 1996), determining the genotype of an individual's ApoE, or measuring the levels of β-amyloid protein in cerebral spinal fluid may be promising, diagnosis of AD is currently confirmed only upon autopsy to determine the presence of P-amyloid senile plaques.
• Moreover, recent studies have shown that damage to CNS neurons due to Alzheimer's disease begins years before clinical symptoms are evident (Reiman, E. M. et al., New Eng. J. Med., 334: 752-758, 1996), suggesting that therapy could begin in the pre-symptomatic phase of the disease if a sensitive diagnostic test and targeted therapies were available. There exists a great need to determine the physiological mechanisms involved with the disease and for an accurate and easy to perform assay to evaluate the risk of developing Alzheimer's disease.
• U.S. Patent Application Publication 2002/0042121 to Riesner et al., describes a method for the diagnostic detection of diseases associated with protein depositions (pathological protein depositions) by measuring an association of substructures of the pathological protein depositions, structures forming pathological protein depositions, structures corresponding to pathological protein depositions and/or pathological protein depositions as a probe or a target.
• U.S. Patent Application Publication 2002/0028462 to Tanzi et al., describes a diagnostic method for AD based on genotyping the Alpha-2-Macroglobulin locus. A statistically-significant correlation was found between inheritance of particular alleles of the Alpha-2-Macroglobulin gene and the occurrence of AD. The diagnostic method involves the isolation of nucleic acid from an individual and subsequent genotyping by means such as sequencing or restriction fragment length polymorphism analysis. The invention also describes a means for genotype analysis through protein isotyping Alpha-2-Macroglobulin variant proteins. Finally, kits for nucleic acid analysis or protein analysis are described.
• U.S. Patent Application Publication 2002/0022242 to Small et al., describes a method for the diagnosis of AD in a patient by detecting the presence of BuChE with an altered glycosylation pattern in an appropriate body fluid sample. It has been established that on average approximately 93.6% of the BuChE in the CSF of AD patients binds to Concanavalin (Con A). All embodiments of this method are described as using either CSF or brain tissue as the sample, thereby adding a risk factor to the diagnostic procedure.
• U.S. Patent Application Publication 2002/0019519 to Bingham et al., describes the use of KIAA0551 polypeptides and polynucleotides in the design of protocols for the treatment of and also for diagnostics assays of AD.
• U.S. Patent Application Publication 2001/0044126 to Holtzman et al., describes a diagnostic method for identifying individuals at risk for developing Alzheimer's disease, which relies on elevated levels of the ratio of Aβ₄₀/Aβ₄₂associated with lipoproteins in the cerebrospinal fluid of individuals at risk as compared to this ratio in the overall population. It is based on the assessment that the lipoprotein fraction of CSF in such individuals has such increased ratios.
• U.S. Patent Application Publication 2002/0019016 to Vanmechelen et al., describes a method for the differential diagnosis of an individual suffering from AD versus an individual suffering from another neurological disease (dementia with Lewy bodies, Parkinson's disease without dementia, multi-system atrophy and/or progressive supranuclear palsy), where phospho-tau is used as a neurological marker, the level of which is measured in a CSF sample.
• U.S. Patent Application Publication 2002/0009445 to Du et al., cited and summarized hereinabove, describes the use of an anti-Aβ antibody for diagnosing and/or treating amyloid associated diseases, especially Alzheimer's disease.
• U.S. Patent Application Publication 2002/0006627 to Reitz et al., describes a method for diagnosing Alzheimer's disease involving analysis of a test sample in such a way that β-amyloid_{1-42 or Aβ}3pE is completely or nearly completely (i.e., thoroughly) dissociated from binding proteins prior to the analysis of the levels of β-amyloid_1-42or Aβ3pE.
• U.S. Patent Application Publication 2002/0002270 to Zinkowski et al., describes a preparation comprising Alzheimer's disease antigen (A68), as well as methods of obtaining this purified antigen (Ag), and methods using the purified Ag, for instance, for diagnosing Alzheimer's Disease, and also describes treatments of these Ags that enhance their reactivity with autoantibodies directed against A68. These treatments include treatment with hypericin, free fatty acids, and/or hydroxynonenal or other advanced glycation end products.
• U.S. Patent Application Publication 2001/0026916 to Ginsberg et al., describes a method of identifying senile plaques, neurofibrillary tangles and neuropil threads in brain tissue which comprises contacting brain tissue with a fluorescent dye capable of intercalating selectively into nucleic acids and detecting any fluorescence in the brain tissue indicative of senile plaques, neurofibrillary tangles and neuropil threads in the brain tissue.
• U.S. Pat. No. 6,238,892 to Mercken et al., describes the use of a monoclonal antibody which forms an immunological complex with a phosphorylated epitope of an antigen belonging to human abnormally phosphorylated tau protein. The tau protein can be obtained from a brain homogenate, itself isolated from the cerebral cortex of a patient having Alzheimer's disease. Methods for in-vivo diagnosis of AD using the latter mAb, should preferably employ techniques that leaves the meninges intact. Such methods are described in this patent as being yet undeveloped.
• The '892 patent provides an overview of tau (complete references have been provided):
• Tau is a microtubule-associated protein which is synthesized in the neurons (Kosik, K. S. et al., Ann. Neurol. 26, 352-361, 1989) of several species, including humans, and which is abundantly present in the axonal compartment of these neurons (Binder, L. I. et al., J Cell Biol., 101: 1371-1378, 1985). Functionally the tau protein is involved in the polymerization of tubulin (Weingarten, M. D. et al., Proc. Natl. Acad. Sci. U.S.A. 72, 1868-1862, 1975) and presumably in reducing microtubule instability (Bre, M. H. et al., Cell Motil. Cytoskeleton 15, 88-98, 1990).
• Tau protein is also the major constituent of paired helical filaments (PHF), characteristic structures found as neurofibrillary tangles in tissue sections of the brain of Alzheimer patients (Greenberg, S. et al., Proc. Natl. Acad. Sci. U.S.A., 87, 5827-5831, 1990; Lee, V. M.-Y. et al., Science, 251, 675-678, 1991). The protein exists as a family of different isoforms of which 4 to 6 isoforms are found in normal adult brain but only 1 isoform is detected in fetal brain (Goedert, M. et al.,Neuron 3, 519-526, 1989). The diversity of the isoforms is generated from a single gene by alternative mRNA splicing (Himmler, A., Mol. Cell. Biol., 9, 1389-1396, 1989). The most striking feature of tau protein as predicted from molecular cloning is a stretch of 31 or 32 amino acids occurring in the carboxy-terminal part of the molecule that is repeated 3 or 4 times. Additional diversity is generated through 29 or 58 amino acid long insertions in the NH2-terminal part of the molecules (Goedert, M. et al.,Neuron 3, 519-526, 1989).
• Tau variants of 64 and 69 kDa, which are abnormally phosphorylated as revealed by the decrease in their molecular mass observed after alkaline phosphatase treatment, have been detected exclusively in brain areas showing neurofibrillary tangles and senile plaques (Flament, S. et al., A., J. Neurol. Sci. 92, 133-141, 1989; Flament, S. et al., Brain Res. 516, 15-19, 1990; and Flament, S. et al., Nature 346, 6279, 1990). The sites of phosphorylation by 4 different kinases have been mapped in the C-terminal microtubule-binding half of tau and it could be shown that the action of a calcium calmodulin-dependent kinase on bacterially expressed tau resulted in a phosphorylation of Ser(405) which induced a lower electrophoretical mobility (Steiner, B. et al., TheEMBO Journal 9, 3539-3544, 1990).
• Several antibodies are reported that show reactivity to human tau either because they are directed to nonspecific phosphorylated epitopes present on neurofilament and subsequently shown to cross-react with normal and abnormally phosphorylated tau (Nukina, N. et al., Proc. Natl. Acad. Sci. U.S.A. 84, 3415-3419, 1987; Ksiezak-Reding et al., Proc. Natl. Acad. Sci. U.S.A., 84, 3410-3414, 1987) or because they recognized specific epitopes on normal and abnormally phosphorylated tau.
• The Alz50 monoclonal antibody (Wolozin, B. L. et al., Science 232, 648-650, 1986; Nukina et al., Neurosci. Lett 87, 240-246, 1988) recognizing a phosphate-independent epitope present on tau variants of bovine origin and of normal and abnormally phosphorylated tau from human origin (Ksiezak-Reding, H. et al., J. Biol. Chem., 263, 7943-7947, 1988, Flament, S. et al., Brain Res. 516, 15-19, 1990; and Flament, S. et al., Nature 346, 6279, 1990) belongs to the latter class of antibodies. The epitope recognized by this monoclonal is specifically expressed in the somatodendritic domain of degenerating cortical neurons during Alzheimer disease (Delacourte, A. et al., Acta Neuropathol. 80, 111-117, 1990).
• The Alz50 epitope has recently been mapped to the NH2-terminal part of the tau molecule (Ksiezak-Reding, H. et al., J. Neurosci. Res., 25, 412-419, 1990; Goedert, M. et al., Neurosci. Lett., 126, 149-154, 1991). Due to its cross-reactivity with normal tau, this antibody is only able to discriminate normal from abnormally phosphorylated tau by the use of Western blotting detection of brain homogenates or by ammonium sulfate-concentrated CSF, or also by using a sandwich immunoassay on brain homogenates (Ghanbari et al., J. Clin. Laboratory Anal. 4, 189-192, 1990; Wolozin, B. et al, Ann. Neurol. 22, 521-526, 1987; European PatentApplication Publication EP 0 444 856 to Ghanbari et al.). A CSF-based assay using antibodies directed against PHF was first described by Mehta et al., The Lancet, Jul. 35, 1985, but shows considerable overlap between Alzheimer CSF and CSF from controls. The epitope recognized by this antibody was identified as part of ubiquitin (Perry et al., J. Neurochem. 52, 1523-1528, 1989).
• Other monoclonal antibodies have been developed to recognize tau protein. For instance, monoclonal antibody 5E2 was raised by immunization with human fetal heat-stable microtubule-associated proteins and recognizes an epitope spanning amino acids 156-175 which is present in normal and abnormally phosphorylated tau (Kosik, K. S. et al., Neuron., 1, 817-825, 1988).
• Other antibodies such astau 1 and several others were raised by immunization with bovine tau, bovine heat-stable microtubule-associated protein, or rat brain extracts (Binder, L. I. et al., J. Cell Biol. 101, 1371-1378, 1985; Kosik, K. S. et al., Neuron., 1, 817-825, 1988), and most of the antibodies recognize the normal and the abnormally phosphorylated tau (Ksiezak-Reding, H. et al., J. Neurosci. Res., 25, 412-419, 1990).
• An antibody named “423”, raised against the core of PHF, reacted specifically with a 9.5 and 12-kDa fragment of the tau protein, localized in the repetitive elements of tau, but recognized neither normal human tau nor the abnormally phosphorylated tau in Alzheimer's brain (Wischik, C. H. et al., Proc. Natl. Acad. Sci. U.S.A., 85, 4884-4888, 1988). This antibody has been used to discriminate Alzheimer PHF pathology from normal controls in brain homogenates (Harrington, C. R. et al., J. Immunol. Methods 134, 261-271, 1990; PCT Publication WO89/03993 to Wischik et al.).
• Thus far, none of all the antibodies described heretofore has had an absolute specificity for the abnormally phosphorylated tau either by immunohistology, Western blotting, or ELISA. Quantitative measurements of normal and abnormally phosphorylated tau have until now only been able to detect tau in brain homogenates, in brain extracts containing PHF, or in concentrated CSF samples after Western blotting (Ghanbari H. A. et al., J. Clin. Laboratory Anal. 4, 189-192, 1990; Harrington C. R. et al., J. Immunol. Methods 134, 261-271, 1990, Wisniewski, H. M. et al.,Biological Markers of Alzheimer's Disease, Boller, Katzman, Rascol, Signoret & Christian eds., 23-29, 1989; Wolozin, B. et al., Ann. Neurol. 22, 521-526, 1987).
• U.S. Patent Application Publication 2001/0018191 to Mercken et al., describes monoclonal antibodies which are described as specifically able to detect only abnormally-phosphorylated tau present in brain tissue sections, in brain extracts, or in body fluids such as cerebrospinal fluid. It is required that a method for bypassing the BBB be employed in order to introduce the monoclonal antibodies into the CNS.
• U.S. Patent Application Publication 2001/0014670 to Balin et al., describes a method of treating Alzheimer's disease in a mammal comprising administering to the mammal an anti-microbial agent having anti-Chlamydia pneumoniaeactivity. The description also relates to a method of diagnosing Alzheimer's disease in a mammal comprising measuring the serum anti-Chlamydia pneumoniaeantibody titer in a patient suspected of having Alzheimer's disease. It is required that a method for bypassing the BBB be employed in order to communicate the therapeutic compounds, antibodies, into the CNS, or to be able to evaluate presence of diagnostic agents (e.g.C. Pneumoniae) in a minimally invasive method.
• U.S. Pat. No. 6,287,793 to Schenk et al., describes methods for the identification of key diagnostic antibodies, antigens, diagnostic kits and methods for diagnosis for AD, where the diagnostic procedure uses a biological fluid from a subject—most preferred are plasma and CSF sample.
• Inducing changes in BBB permeability, as provided by preferred embodiments of the present invention, is useful for detecting acetylcholinesterase in human patients. Loss of acetylcholinesterase in humans is associated with brain disorders, such as dementia and epilepsy, muscle disorders, and disorders of the digestive system. The methods of some embodiments of the present invention are particularly useful for detecting acetylcholinesterase in the brain of a patient suspected of suffering from a dementia, such as Alzheimer's disease, thereby allowing the diagnosis, estimating the severity of, and monitoring the progression of the dementia. Certain brain disorders and dementia, including Alzheimer's disease, are known to be accompanied by a decrease in acetylcholinesterase concentration in the brain. Thus, monitoring the concentration of acetylcholinesterase in the brain of a patient suspected of suffering from a brain disorder or dementia typically allows diagnosis of the disorder or dementia, monitoring its progression, and/or estimating its severity. Advantageously, this diagnosis and monitoring is simply performed, for example, by stimulating the SPG using techniques described herein, and, simultaneously or shortly thereafter, extracting a blood sample using standard lab techniques. Since the increase in BBB permeability allows the acetylcholinesterase to pass therethrough, it is quickly in the systemic bloodstream and detectable in the blood sample. It is to be understood that other compounds of diagnostic value can be extracted using essentially the same technique.
• The methods of some embodiments of the present invention can be used to provide a brain image that shows the distribution and relative concentrations of acetylcholinesterase (or other compounds of diagnostic value) in a patient's brain, thereby allowing diagnosis, estimating the severity of, and analysis of the progression of a disorder or dementia in a patient. The methods of some embodiments of the invention can therefore be used to diagnosis, estimate the severity, and monitor the progression of any dementia, known or to be discovered, that is accompanied by a detectable change in concentration of acetylcholinesterase or other compounds of diagnostic value in the brain. In a preferred embodiment, a molecule such as an antibody which is attracted to acetylcholinesterase is injected, swallowed, or otherwise introduced systemically, and its passage into the CNS is facilitated by techniques described herein for increasing permeability of the BBB. Imaging techniques which are able to detect the introduced molecule are then utilized to determine the locations or quantities of acetylcholinesterase or other diagnostic compounds to which the molecule is attached.
• Some of the diagnostic techniques mentioned above indicate to the inventors that there is a need for performing diagnostic tests on certain bio-chemical characteristics of the CSF by using a simple blood test. Other diagnostic techniques mentioned above indicate to the inventors that there is a need for increasing the permeability of the BBB using techniques described herein in order to facilitate the passage of diagnostic molecules into the CNS, where the molecules can be detected, such as by imaging. Diagnostic procedures, which are on one hand highly accurate and on the other minimally invasive, typically substantially improve the management of AD, when applied in accordance with a preferred embodiment of the present invention. In a preferred embodiment of the present invention, the diagnostic techniques described in this example (Example 14) are enhanced and/or enabled by stimulation of the SPG and/or its related neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
• The stimulation techniques described herein may facilitate the diagnosis of a number of CNS conditions, including, but not limited to, the following conditions:
• • neurodegenerative conditions, such as Alzheimer's disease, Parkinson's Disease, ALS, age-associated cognitive decline, progressive supranuclear palsy, vascular (i.e., multi-infarct) dementia, Lewy body dementia, Huntington's Disease, Down's syndrome, normal pressure hydrocephalus, corticobasal ganglionic degeneration, multisystem atrophy, head trauma, Creutzfeld-Jacob disease, viral encephalitis and hypothyroidism, a degenerative disorder associated with learning, memory or cognitive dysfunction, cerebral senility, multi-infarct dementia and senile dementia, and electric shock induced amnesia or amnesia;
  • neoplastic processes (either primary or metastatic), such as neuroectodermal tumors, malignant astrocytomas, and glioblastomas;
  • immune- and autoimmune-related disorders, such as HIV and multiple sclerosis; and
  • CNS inflammatory processes.
• The stimulation techniques described herein may facilitate the imaging of various aspects of the CNS, including biochemical aspects (e.g., GGM in late onset Tay-Sachs disease, dopamine in Parkinson's Disease), morphological aspects (e.g., ventricular dimensions in hydrocephalus), and functional aspects (e.g., glucose utilization in brain tumors).
• In an embodiment of the present invention, stimulation of an MTS is configured to increase the transport of a diagnostic agent across the BBB from a non-CNS tissue, such as the systemic blood circulation, into the CNS. The diagnostic agent is typically administered to the systemic blood circulation, such as intravenously, and a diagnostic procedure, typically an imaging modality, is then performed directly on the CNS. For some applications, the diagnostic agent comprises a tracer agent, such as an imaging contrast agent, for example, a Magnetic Resonance Imaging (MRI) contrast agent, a Single Photon Emission Computed Tomography (SPECT) radioisotope, a Positron Emission Tomography (PET) radioisotope, an ultrasound contrast enhancer, or an X-ray contrast agent (e.g., for a Computerized Tomography (CT) or angiography imaging sequence).
• In an embodiment, the tracer is configured to be disease-specific, typically by conjugation to a biochemical agent for enhancing certain properties or constituents of the CNS (or another physiological compartment). The conjugation is performed either before administration of the agent to the patient, or the conjugation occurs within the systemic circulation, the CNS, or another physiological compartment. Examples of such constituents include selected proteins, cells, biotoxins, pathological tissue, or other biochemical entities that may aid in diagnosis of a CNS condition, such as, for example, the HER2 protein that is overexpressed on the outer membrane of malignant tumors, or certain interleukins, the receptors of which are abundant on the surface membranes of certain types of cancerous cells. In these applications, the tracer may comprise a disease-specific (endogenous or exogenous) biochemical entity, or may comprise a biochemical entity that relates to a broad group of pathological states (e.g., a probe for inflammatory markers).
• For some applications, such diagnostic agents are conjugated to the following types of biochemical agents:
• • Antibodies to proteins which are indicative of neoplastic processes, such as beta-Amyloid monoclonal antibody (mAb) or polyclonal antibody (pAb), and anti-HER2 mAb; and/or
  • Interleukins (cytokines whose amino acid structure is known), such as IL-1-IL18, TNF, IL-1 beta, IL-1ra, and TNF beta. This groups of macromolecules consists of both pro-inflammatory (e.g., IL-6, IL-8) and anti-inflammatory (e.g., IL-4, IL-10) proteins that affect the growth, proliferation, differentiation, regeneration, and secretion of various immuno-active cells (e.g., B, T, CD4+ cells) and also the processes of hematopoiesis and lymphopoiesis. Some of these macromolecules are also produced by immune cells, such as B cells, T cells, macrophages, and acute-phase response proteins. Some of these cytokines are overexpressed by malignant cell lines, as well as in cases of inflammation (e.g., adult T cell leukemia cell lines and Epstein-Barr virus transformed B cells). Such cytokines therefore generally represent diagnostic targets for neoplastic processes.
• In an embodiment of the present invention, stimulation of an MTS is configured to increase the transport of a biochemical agent across the BBB from the CNS to a non-CNS tissue, such as the systemic blood circulation. Such biochemical agents are typically disease-specific biochemical markers. Prior to stimulation of an MTS to increase BBB permeability, the concentration of such a biochemical agent is typically greater in the CNS than in the systemic circulation, i.e., there is a concentration gradient across the endothelium. Therefore, increasing the permeability of the BBB, typically acutely, generally releases the agent into the systemic circulation. Once in the systemic circulation, diagnosis is typically performed by sampling a body tissue or fluid, typically blood, and analyzing the whole blood, plasma, or serum. Analysis is typically performed using a biochemical assay or another analytical procedure, such as imaging, in order to qualitatively or quantitatively probe the presence of the biochemical agent of interest, a metabolite thereof, or a chemical or biological derivative thereof.
• Diagnostic assay modalities typically applicable to the techniques described herein include, but are not limited to, High Purity Liquid Chromatography (HPLC), SMAC, Enzyme Linked Immuno-Sorbent Assay (ELISA), electrophoresis, gel filtration, UV spectrophotometry, HPLC/fluorescence, Fluorescence Polarization Immunoassay (FPIA), HPLC/UV, Gas Chromatography/GC/EC, capillary electrophoresis, mobility shift combination assay, bioluminescent assay, flow immunoassay, Polymerase Chain Reaction (PCR) ELISA, gamma counter, beta counter, chemiluminescence immunoassay (e.g., chemiluminescent ELISA), Dissociated Enhanced Lanthanide Fluorescence Immunoassay (DELFIA), Enzyme Immunoassay (EIA), Fluorescence Immunoassay (FIA), Immunoradiometric Assay (IRMA), Radioimmunoassay (RIA), and Scintillation Proximity Assay (SPA).
• Imaging modalities typically applicable to the techniques described herein include, but are not limited to, PET, SPECT, CT, MRI, magnetic resonance spectroscopy (MRS), Functional Magnetic Resonance Imaging (fMRI), Proton MRSI, Single-voxel proton MRS, Multi-nuclear MRS, gamma camera, and beta camera.
• For some applications, techniques for transporting diagnostic agents from the systemic circulation to the CNS are used to transport one or more of the following radioisotopes for facilitating nuclear imaging modalities, such as PET, SPECT, and gamma cameras: 7Be, 22Na, 46Sc, 48V, 51Cr, 54Mn, 56Co, 65Zn, 75Se, 83Rb, 85Sr, 88Zr, 95 mTc, 103Ru, and 99Rh. These techniques may also be used for transporting one or more of the following diagnostic agents for facilitating PET: 18F-FDG, 18F-FUdR, 11C-MET, 11C-TYR, 15C-O2, 15C-O, H215O, 82Rb, 11C-5-HTP, 11C-L-DOPA, 11C-L-DEP, U-5-HIAA, 99 mTc, 201T1, 111In-Oncoscint, and 1502. These techniques may also be used for transporting one or more of the following diagnostic agents for facilitating SPECT: I-123 ligands (e.g., I-123-IMP, Iodine-123-QNB, Iodine-123-Iodine labeled ligands IBZM and IBZP), Tc-99m ligands (e.g., Tc-99m-hexamethyl propylamine oxime, Tc-Technetium-99m-bicisate), and Xenon-133 ligands.
• The techniques described herein may also be used to transport the diagnostic agents and types of diagnostic agents shown in the following table. Although the agents are categorized by typical diagnostic aims for which they are generally appropriate, the techniques described herein are not limited to facilitating transport for these diagnostic aims.

  Cell proliferation	11C-TdR,18F-3′FLT,124I-IUdR,76Br-
  	FbrAU
  Angiogenesis
  Blood flow	15O-water,99mTc-sestamibi,201Tl-
  	thallium,133Xe-saline
  Blood volume	15O— or11C-carbon monoxide-labeled
  Capillary permeability	erythrocytes (RBCs),99mTc-RBCs
  	82Rb,68Ga-DTPA,68Ga-transferrin,
  	18F—,123I—,131I—,124I— or
  	99mTc-labeled albumin
  Oxygen metabolism	15O (oxygen)
  Hypoxia	18F-fluoromisonidazole,61Cu— or64Cu-
  	ATSM,18F-EF1,18F-EF5
  Transporter up-regulation
  Amino acid transporters	11C-methionine,18F-FET,18F-FACBC
  Nucleoside transporters	11C-FMAU
  Choline transporter	18F-fluorocholine
  Glucose transporter	11C-3OMG,18F-FDG
  Cell surface receptors/
  antigens (endothelial cells
  and tumor cells)
  Transferrin receptors	67Ga-transferrin,111In-DTPA transferrin
  EGF receptor (radiolabeled	chelate
  antibody or peptide)
  Benzodiazepine receptor	iodinated-PK11195
  Other cell surface receptors/
  antigens (e.g., Flt1 and Flk1/
  KDR receptors for VEGF)
  Cell matrix antigens	Integrins (RGD- and other radiolabeled
  	peptides)

• For some applications, techniques for transporting diagnostic agents from the systemic circulation to the CNS are used to transport one or more of the following contrast agents for facilitating MRI: gadolinium chelates (e.g., Gd-DTPA, Gd-DOTAβ, Gd-EOB-DTPA), manganese chelates, paramagnetic iron oxide particles (e.g., polydisperse iron oxide particles, with a partial dextran coat, or ultrasmall superparamagnetic iron oxide-USPIO), and hyperpolarized gases (e.g.,³He¹²⁹Xe).
• For some applications, techniques for transporting diagnostic agents from the systemic circulation to the CNS are used to transport one or more of the following contrast agents for facilitating ultrasound imaging: polymer microbubbles, microscopic bubbles (e.g., Imavist™), investigational agent PB127-filled (polylactide/albumin) or nitrogen-filled microspheres, and iron oxide particles called ferumoxtran.
• For some applications, techniques for transporting diagnostic agents from the systemic circulation to the CNS are used to transport one or more of the following contrast agents for facilitating CT: radiopaque tracers (e.g., dysprosium-, iodine- and gadolinium-based contrast agents) and stable xenon gas.
• For some applications, techniques for transporting diagnostic agents from the systemic circulation to the CNS are used to transport diagnostic agents for facilitating optical intrinsic signal (OIS) imaging.
• For some applications, the stimulation techniques described herein are used to facilitate diagnosis of Alzheimer's disease or other conditions of the CNS in conjunction with techniques described in the following patents. It should be appreciated by those of skill in the art that the following techniques are set forth for demonstrative purposes. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
• U.S. Pat. No. 4,666,829 to Glenner et al., which is incorporated herein by reference, describes a polypeptide and fragments thereof that may be used to produce antibodies useful in a diagnostic test for Alzheimer's disease. Nucleotide probes corresponding to portions of the polypeptide are also described as useful for diagnostic purposes. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used in conjunction with techniques described in the '829 patent.
• U.S. Pat. No. 4,874,694 to Gandy et al., which is incorporated herein by reference, describes a diagnostic method for neurological and psychiatric disorders, utilizing the cerebrospinal fluid incubated in the presence of 32-P labeled ATP and an appropriate protein kinase. After termination of the reaction, a sample is applied to gels for electrophoresis. Subsequent autoradiography results in a disease-specific protein pattern that can be used for diagnosis of disorders such as Alzheimer disease, Huntington disease, Parkinson disease, dystonia ataxia, schizophrenia, epilepsy brain tumors, brain irradiation, head trauma, and acute and chronic encephalitic and vascular disease. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '694 patent.
• U.S. Pat. No. 6,358,681 to Ginsberg et al., which is incorporated herein by reference, describes methods for detecting RNA in brain tissue in order to diagnose Alzheimer's disease. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '681 patent.
• U.S. Pat. No. 6,329,531 to Turner et al., which is incorporated herein by reference, describes the use of optical diagnostic agents in in vivo and in vitro diagnosis of neurodegenerative diseases such as Alzheimer's disease by means of near infra-red radiation (NIR radiation) as a contrasting agent in fluoresecence and transillumination diagnosis in the NIR range. Diagnostic agents containing such components are also described. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used in conjunction with techniques described in the '531 patent.
• U.S. Pat. No. 6,287,793 to Schenk et al., which is incorporated herein by reference, describes methods for identifying key diagnostic antibodies and antigens characteristic of a disease state of interest, such as Alzheimer's disease.
• U.S. Pat. No. 6,210,895 to Schipper et al., which is incorporated herein by reference, describes a method for predicting the onset of, diagnosing, and/or prognosticating dementing diseases. The method comprises determining the concentration of heme oxygenase-1 (HO-1) and/or a nucleotide sequence encoding HO-1 in tissue obtained from a patient, and comparing said concentration with the corresponding concentration of HO-1 and/or an HO-1 encoding nucleotide sequence in corresponding tissue obtained from at least one control person. The tissue is typically plasma, lymphocytes, cerebrospinal fluid or fibroblasts. The method is described as being useful where the dementing disease is any of Alzheimer's disease, Age-Associated Cognitive Decline, Progressive Supranuclear Palsy, Vascular (i.e., multi-infarct) Dementia, Lewy Body Dementia, Huntington's Disease, Down's syndrome, normal pressure hydrocephalus, corticobasal ganglionic degeneration, multisystem atrophy, head trauma, Creutzfeldt-Jacob disease, viral encephalitis and hypothyroidism. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '895 patent.
• U.S. Pat. No. 6,200,768 to Mandelkow et al., which is incorporated herein by reference, describes (a) epitopes of the protein which are specifically occurring in a phosphorylated state in tau protein from Alzheimer paired helical filaments, (b) protein kinases which are responsible for the phosphorylation of the amino acids of the tau protein giving rise to said epitopes, and (c) antibodies specific for said epitopes. The patent also describes pharmaceutical compositions for the treatment or prevention of Alzheimer's disease, diagnostic compositions and methods for the detection of Alzheimer's disease, and the use of said epitopes for the generation of antibodies specifically detecting Alzheimer tau protein. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '768 patent. For some applications, these techniques facilitate increased release of said epitopes of the phosphorylated tau into the systemic circulation, after which a body fluid is analyzed for the presence of the epitopes or chemical/biological derivatives thereof.
• U.S. Pat. No. 6,132,977 to Thompson et al., which is incorporated herein by reference, describes methods for the immunological identification and quantitation of SNAβ-25 in a biological fluid, especially cerebrospinal fluid and amniotic fluid. The quantitated levels of SNAβ-25 serve as a diagnostic marker for some mental illnesses such as major depression, Alzheimer's disease and schizophrenia. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '977 patent, in order to release the SNAβ-25 into the systemic circulation and thereafter analyze body fluid for epitopes and/or chemical/biological derivatives thereof.
• U.S. Pat. No. 6,114,175 to Klunk et al., which is incorporated herein by reference, describes methods using amyloid binding compounds which are non-azo derivatives of Chrysamine G, to identify Alzheimer's brain in vivo and to diagnose other pathological conditions characterized by amyloidosis, such as Down's Syndrome. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '175 patent.
• Other patents describe methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-beta peptide levels in a CSF sample of the patient. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used in conjunction with these methods, in order to increase the permeability of the BBB to transport labeled (e.g., radiolabeled) amyloid-beta mAb or pAb into the CNS and thereafter perform imaging to assess the amount of amyloid-beta peptide. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with these methods. After transport across the BBB has been facilitated, high levels of amyloid-beta peptide in body fluid are considered inconsistent with a diagnosis of Alzheimer's disease, while low levels may indicate a rationale for further inquiries, and may also indicate an increased probability of Alzheimer's disease.
• U.S. Pat. No. 6,130,048 to Nixon, which is incorporated herein by reference, describes a method for diagnosing Alzheimer's disease by measuring the level of a lysosomal hydrolase or lysosomal protease inhibitor in a patient's cerebrospinal fluid. Also described are methods for measuring the progression of the disease and for screening therapeutic compositions for treating the disease. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '048 patent.
• U.S. Pat. No. 6,087,118 to Aronson et al., which is incorporated herein by reference, describes a method for diagnosing Alzheimer's disease using human blood platelets, wherein the presence or absence of functioning calcium-dependent potassium channels in blood platelets are determined by employing potassium channel blockers such as apamin or charybdotoxin, the absence of functioning calcium-dependent potassium channels indicating a positive diagnosis for Alzheimer's disease. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '118 patent. It is hypothesized by the inventor of the present invention that increasing the permeability of the BBB increases the interaction between the intra-cephalic environment and the systemic circulation, thereby increasing the efficacy and statistical accuracy of the method described in the '118 patent.
• U.S. Pat. No. 6,071,705 to Wands et al., which is incorporated herein by reference, describes a method for detecting and diagnosing neurological disease or dysfunction, such as Alzheimer's disease and Down's Syndrome, using antibodies against a neurological form of Pancreatic Thread Protein (nPTP), such antibodies including monoclonal antibodies, a combination of those monoclonal antibodies, or nucleic acid probes. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used in conjunction with techniques described in the '705 patent, in order to increase the permeability of the BBB to transport labeled (e.g., radiolabeled) antibodies of nPTP into the CNS and thereafter perform imaging to assess the amount of nPTP bound to the labeled antibodies. Alternatively or additionally, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '705 patent, in order to increase the release of nPTP into the systemic circulation and thereafter sample a body fluid and analyze it for the presence of nPTP.
• U.S. Pat. No. 6,001,331 to Caprathe et al., which is incorporated herein by reference, describes a method of imaging amyloid deposits, and radiolabeled compounds useful in imaging amyloid deposits. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used in conjunction with techniques described in the '331 patent, in order to increase the delivery of the radiolabeled compounds into the CNS, thereby enhancing the contrast of the plaque.
• U.S. Pat. No. 5,985,581 to Nixon et al., which is incorporated herein by reference, describes a method of diagnosing Alzheimer's disease utilizing presenilin-1, whose level is found to be substantially decreased in Alzheimer's patients. A CSF sample (ventricular or lumbar) is taken, and the level of presenilin-1 is measured using an immunoassay that uses antibodies to presenilin-1, to a fragment thereof, or to a specific amino acid sequence. In an embodiment of the present invention, the antibodies, antibody fragments, or specific amino acid sequence described in the '581 patent are labeled (e.g., radiolabeled) to facilitate a subsequent imaging procedure for assessing the amount of bound presenilin-1. The stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used to deliver the labeled compounds to the CNS. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '581 patent, in order to increase the penetration of the abovementioned proteins from the CNS into the systemic circulation and thereafter analyze a body fluid using the methods and/or diagnostic kits described in the '581 patent. Levels of the protein that are higher than a threshold value may indicate the absence of Alzheimer's disease.
• U.S. Pat. No. 5,981,194 to Jefferies et al., which is incorporated herein by reference, describes methods for using p97 and iron-binding proteins as diagnostic and therapeutic agents, including for the diagnosis of Alzheimer's disease. The methods are based on evidence that Alzheimer's patients have elevated levels of elevated levels of p97 in their serum and cerebrospinal fluid and that p97 levels increase with duration of the disease. The levels of p97 in patient samples may thus be used to diagnose and to monitor the progression of the disease and the efficacy of therapeutic treatments for Alzheimer's disease. Evidence is also presented that microglial cells associated with senile plaques in Alzheimer's disease express p97 and transferrin receptor. Therefore, p97 and transferrin receptor can be used in the diagnosis of Alzheimer's Disease. The finding that microglial cells which deposit the amyloid protein have a high level of proteins which operate in procurement of iron also suggests methods of treatment of Alzheimer's disease based on depletion of iron from these cells using substances such as p97, transferrin, and iron chelators, for example, lactoferrin, ferritin, and ovotransferrin. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '194 patent. The use of these techniques in combination typically enhances the accuracy of diagnosis of Alzheimer's disease.
• U.S. Pat. No. 5,849,600 to Nixon et al., which is incorporated herein by reference, describes a method for diagnosing Alzheimer's disease in a human patient by measuring the amount of p33 present in a biological sample, such as a ventricular or lumbar CSF sample, or brain tissue homogenate. In an embodiment of the present invention, the stimulation techniques described herein are used to facilitate transport of a labeled (e.g., radiolabeled) anti-p33 mAb or pAb from the systemic circulation to the CNS. An imaging procedure is subsequently performed to evaluate the amount of p33 protein in the CNS. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '600 patent, in order to increase the penetration of the abovementioned protein from the CNS into the systemic circulation. Thereafter a body fluid is analyzed using the methods and/or diagnostic kits described in the '600 patent. Levels of the protein that are higher than a threshold value may indicate the presence of Alzheimer's disease.
• U.S. Pat. No. 5,833,988 to Friden, which is incorporated herein by reference, describes a method for delivering a neuropharmaceutical or diagnostic agent across the BBB to the brain. The method comprises administering to the host a therapeutically effective amount of an antibody-neuropharmaceutical or diagnostic agent conjugate wherein the antibody is reactive with a transferrin receptor. In an embodiment of the present invention, the stimulation techniques described herein are used to facilitate transport of an agent described in the '988 patent from the systemic circulation to the CNS. An imaging procedure is subsequently performed to evaluate the amount of a ligand of the agent in the CNS.
• U.S. Pat. No. 5,830,670 to de la Monte et al., which is incorporated herein by reference, describes a method for diagnosing Alzheimer's disease, neuroectodermal tumors, malignant astrocytomas, and glioblastomas, by identifying recombinant hosts and vectors which contain the genes coding for neuronal thread proteins (NTPs) associated with these conditions. Specific targeted NTPs have molecular weights of about 8 kDa, about 14 kDa, about 17 kDa, about 21 kDa, about 26 kDa or about 42 kDa. In an embodiment of the present invention, the stimulation techniques described herein are used to facilitate transport of a labeled (e.g., radiolabeled) antibody against an NTP from the systemic circulation to the CNS. An imaging procedure is subsequently performed to evaluate the amount of the NTP in the CNS. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of biochemical agents from the CNS to the systemic blood circulation are used in conjunction with techniques described in the '670 patent, in order to increase the penetration of the abovementioned protein from the CNS into the systemic circulation. Thereafter in vivo or in vitro analysis of body fluid is performed, typically using a diagnostic kit. Levels of the protein that are higher than a threshold value may indicate the presence of Alzheimer's disease or other conditions described in the '670 patent.
• In an embodiment of the present invention, stimulation techniques described herein are used to facilitate a diagnosis of brain tumors (primary and secondary (metastatic) neoplasms in the brain). Such stimulation typically facilitates the transfer from the systemic circulation to the CNS of a labeled (e.g., radiolabeled) diagnostic agent, which may be specific for the neoplasm to be diagnosed, for a group of neoplasms, or generally for a pathologic state in the CNS.
• For example, these stimulation techniques may be used to diagnosis gliomas. Gliomas often overexpress a receptor for interleukin 13 (IL-13). Because interleukins have large molecular sizes (typically, ten of kilodaltons), they generally penetrate the CNS poorly under a wide range of physiological conditions. In conjunction with administration of labeled IL-13 into the systemic circulation, an MTS is stimulated, allowing the IL-13 to pass into the CNS, where the IL-13 typically concentrates in tumor locations. Such concentration is detected using an imaging procedure. This approach typically represents a relatively low-risk and highly disease-specific approach to diagnosing such tumors.
• Another example is the use of labeled (e.g., radiolabeled) anti-HER2 mAb or pAb for imaging of breast cancer metastases in the brain. HER2 is a protein over-expressed on the malignant cell outer membrane in a significant percentage of patients with breast cancer. The permeability of the BBB is increased using the stimulation techniques described herein, in conjunction with administration of labeled anti-HER2 mAb or mAb and performance of an imaging procedure. This approach typically represents a relatively low-risk and highly disease-specific approach to diagnosing such metastases.
• In an embodiment, methods are used for aiding the diagnosis of brain tumors or screening for brain tumors. Typically, these methods include using labeled interleukins, anti-cancer-cells mAb/pAb or other possible markers of neoplasms in conjunction with an imaging procedures. In an embodiment of the present invention, stimulation techniques described herein for facilitating transport of diagnostic agents from the systemic blood circulation to the CNS are used to transport labeled (e.g., radiolabeled) amyloid-beta mAb or pAb into the CNS, and a subsequent imaging procedure is performed.
• In an embodiment of the present invention, the stimulation techniques described herein are used to facilitate increased release of disease-related agents (e.g., proteins, DNA fragments, etc.) from the CNS into the systemic circulation and body tissues. To diagnose brain tumors, these techniques are used to facilitate the transport of markers of the central malignant process (e.g. glioma) from the CNS to the systemic circulation, where they are detected using a suitable bioassay.
• For some applications, the diagnostic techniques described herein are used at more than one point in time in order to indicate the possible progression of the CNS condition being diagnosed.
• Some existing and proposed diagnostic techniques use a sample of CSF for biochemical analysis. In an embodiment of the present invention, stimulation techniques described herein are used to increase transport of biochemical markers from the CSF to the systemic circulation as an alternative to direct sampling of the CSF.
• “Diagnosis,” as used in the present patent application, including the claims, is to be understood as comprising the art or act of recognizing the presence of disease from its signs or symptoms, deciding as to the character (e.g., stage) of a disease, screening for disease, and/or predicting the onset of disease. Diagnosis may be performed in vivo or in vitro, as appropriate. Diagnosis may comprise a combination of diagnostic procedures. For example, the permeability of the BBB may be increased in combination with taking a blood sample and analyzing it for the presence of a biochemical marker of a CNS neoplastic process, and performing PET imaging for a mAb or pAb to a protein that is indicative of a neoplastic process.
• Whereas some embodiments of the present invention are described herein with respect to enhancing permeability of the BBB so as to facilitate passage of molecules from the systemic circulation to brain tissue of a patient, this is by way of illustration and not limitation. In other embodiments, analogous techniques are utilized so as to facilitate enhanced clearance of molecules from brain tissue to the systemic circulation. For some applications, this enhanced clearance is utilized to facilitate a diagnostic procedure, for example by means of an imaging modality or a blood sample taken during or subsequent to increased BBB permeability. For other applications, the enhanced clearance of molecules is a goal in and of itself, for example in order to facilitate clearance of toxins from the brain.
• Techniques described in this application may be practiced in combination with methods and apparatus described in one or more of the following patent applications, which are assigned to the assignee of the present patent application and are incorporated herein by reference:
• • PCT Publication WO 01/85094, filed May 7, 2001, entitled, “Method and apparatus for stimulating the sphenopalatine ganglion to modify properties of the BBB and cerebral blood flow,” and U.S. Patent Application Publication 2004/0015068 to Shalev and Gross
  • U.S.Provisional Patent Application 60/364,451, filed Mar. 15, 2002, entitled, “Applications of stimulating the sphenopalatine ganglion (SPG)”
  • U.S.Provisional Patent Application 60/368,657, filed Mar. 28, 2002, entitled, “SPG Stimulation”
  • U.S.Provisional Patent Application 60/376,048, filed Apr. 25, 2002, entitled, “Methods and apparatus for modifying properties of the BBB and cerebral circulation by using the neuroexcitatory and/or neuroinhibitory effects of odorants on nerves in the head”
  • U.S.Provisional Patent Application 60/388,931, filed Jun. 14, 2002, entitled “Methods and systems for management of Alzheimer's disease”
  • U.S.Provisional Patent Application 60/400,167, filed Jul. 31, 2002, entitled, “Delivering compounds to the brain by modifying properties of the BBB and cerebral circulation,” and PCT Publication WO 04/010923 to Gross et al.
  • U.S.Provisional Patent Application 60/426,180, filed Nov. 14, 2002, entitled, “Surgical tools and techniques for sphenopalatine ganglion stimulation,” and PCT Publication WO 04/043218 to Gross et al.
  • U.S.Provisional Patent Application 60/426,182, filed Nov. 14, 2002, entitled, “Stimulation circuitry and control of electronic medical device,” and PCT Publication WO 04/044947 to Gross et al.
  • U.S. patent application Ser. No. 10/294,310, filed Nov. 14, 2002, entitled, “SPG stimulation for treating eye pathologies,” and PCT Publication WO 04/043217 to Gross et al.
  • U.S. patent application Ser. No. 10/294,343, filed Nov. 14, 2002, entitled, “Administration of anti-inflammatory drugs into the CNS,” and PCT Publication WO 04/043334 to Shalev
  • U.S.Provisional Patent Application 60/426,181, filed Nov. 14, 2002, entitled, “Stimulation for treating ear pathologies,” and PCT Publication WO 04/045242 to Shalev et al.
  • U.S.Provisional Patent Application 60/448,807, filed Feb. 20, 2003, entitled, “Stimulation for treating autoimmune-related disorders of the CNS”
  • U.S.Provisional Patent Application 60/461,232 to Gross et al., filed Apr. 8, 2003, entitled, “Treating abnormal conditions of the mind and body by modifying properties of the blood-brain barrier and cephalic blood flow”.
• In particular, techniques of electrical signal application described in the above list of patent applications may be used together with or instead of odorant presentation. Thus, applications described herein which utilize odorant presentation may instead use electrical signal application to achieve generally similar results to those achieved through odorant presentation.
• It is to be understood that the term “blood brain barrier (BBB),” as used in the context of the present patent application and in the claims, applies to the barrier between the systemic circulation and the brain, as well as to the barrier between the systemic circulation and a tumor in the brain (sometimes referred to as the “blood tumor barrier”).
• It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description. For example, elements which are shown in a figure to be housed within one integral unit may, for some applications, be disposed in a plurality of distinct units. Similarly, apparatus for communication and power transmission which are shown to be coupled in a wireless fashion may be, alternatively, coupled in a wired fashion, and apparatus for communication and power transmission which are shown to be coupled in a wired fashion may be, alternatively, coupled in a wireless fashion. In addition, it is to be understood that the scope of the present invention includes apparatus for carrying out methods described and/or claimed herein, and also includes methods corresponding to apparatus described and/or claimed herein.

Claims (129)

1. A method for facilitating a diagnosis of a condition of a subject, comprising:

applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG;

configuring the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject; and

sensing a quantity of the molecules from a site outside of the brain of the subject, following initiation of application of the current.

2. The method according toclaim 1, wherein sensing the quantity of the molecules comprises sampling a fluid of the subject selected from the list consisting of: blood, plasma, serum, ascites fluid, and urine.

3. The method according toclaim 1, comprising determining a diagnostically-relevant parameter responsive to sensing the quantity of the molecules.

4. The method according toclaim 1, comprising administering a hyperosmolarity-inducing agent to the subject at a dosage sufficient to augment an increase in conductance of the molecules caused by the application of the current.

5. The method according toclaim 1, comprising inducing a state of dehydration of the subject, of an extent sufficient to augment an increase in conductance of the molecules caused by the application of the current.

6. The method according toclaim 1, comprising administering an agent to the subject that modulates synthesis or metabolism of nitric-oxide (NO) in blood vessels of the brain, at a dosage sufficient to augment an increase in conductance of the molecules caused by the application of the current.

7. The method according toclaim 1, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period greater than about one month.

8. The method according toclaim 1, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period less than about one week.

9. The method according toclaim 1, wherein applying the current comprises implanting a control unit in a nasal cavity of the subject.

10. The method according toclaim 1, wherein applying the current comprises implanting a control unit at a lower side of a bony palate of the subject.

11. The method according toclaim 1, wherein applying the current comprises implanting one or more electrodes in a nasal cavity of the subject.

12. The method according toclaim 11, wherein implanting comprises inserting a flexible electrode through a nostril of the subject.

13. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.

14. The method according toclaim 13, comprising measuring a constituent of the other body compartment.

15. The method according toclaim 14, wherein stimulating the SPG-related tissue comprises directly stimulating the SPG.

16. The method accordingclaim 14, wherein the other body compartment includes a systemic blood circulation of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation.

17. The method according toclaim 14, wherein the other body compartment includes plasma of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma.

18. The method according toclaim 14, wherein the other body compartment includes serum of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum.

19. The method according toclaim 14, wherein the other body compartment is ascites of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.

20. The method according toclaim 14, wherein the CNS condition includes Parkinson's disease, and wherein configuring the stimulation comprises configuring the stimulation so as to facilitate the diagnosis of the Parkinson's disease.

21. The method according toclaim 14, wherein the CNS condition includes epilepsy, and wherein configuring the stimulation comprises configuring the stimulation so as to facilitate the diagnosis of the epilepsy.

22. The method according toclaim 14, wherein the CNS condition includes amyotrophic lateral sclerosis (ALS), and wherein configuring the stimulation comprises configuring the stimulation so as to facilitate the diagnosis of the ALS.

23. The method according toclaim 14, wherein the CNS condition includes multiple sclerosis (MS), and wherein configuring the stimulation comprises configuring the stimulation so as to facilitate the diagnosis of the MS.

24. The method according toclaim 14, wherein stimulating the SPG-related tissue comprises implanting an electrode at the site, designated to remain in the subject for a period greater than about one month.

25. The method according toclaim 14, wherein stimulating the SPG-related tissue comprises implanting an electrode at the site, designated to remain in the subject for a period less than about one week.

26. The method according toclaim 14, wherein stimulating the SPG-related tissue comprises implanting a control unit in a nasal cavity of the subject.

27. The method according toclaim 14, wherein stimulating the SPG-related tissue comprises implanting a control unit at a lower side of a bony palate of the subject.

28. The method according toclaim 14, comprising correlating an abnormal concentration of the constituent to a pathology of the CNS condition.

29. The method according toclaim 14, wherein the constituent is selected from the group consisting of: a protein, a honnone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and wherein measuring the constituent comprises measuring the selected constituent.

30. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.

31. The method according toclaim 30, comprising measuring a constituent of the other body fluid.

32. The method according toclaim 31, wherein stimulating the SPG-related tissue comprises directly stimulating the SPG.

33. The method according toclaim 31, comprising correlating an abnormal concentration of the constituent to a pathology of the CNS condition.

34. The method according toclaim 31, wherein the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and wherein measuring the constituent comprises measuring the selected constituent.

35. The method according toclaim 31, wherein the other body fluid is selected from the list consisting of: whole blood, plasma, serum, and ascites, and wherein measuring the constituent comprises sampling the selected fluid.

36. The method according toclaim 31, wherein measuring the constituent comprises extracting the other body fluid from tissue of the subject.

37. The method according toclaim 31, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period greater than about one month.

38. The method according toclaim 31, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period less than about one week.

39. The method according toclaim 31, wherein applying the current comprises implanting a control unit in a nasal cavity of the subject.

40. The method according toclaim 31, wherein applying the current comprises implanting a control unit at a lower side of a bony palate of the subject.

41. The method according toclaim 31, wherein measuring the constituent comprises measuring a plurality of constituents.

42. The method according toclaim 41, comprising determining a diagnostic result according to the interrelation between concentrations of the constituents.

43. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the CNS condition.

44. The method accordingclaim 43, comprising measuring a constituent of the tissue.

45. The method according toclaim 44, wherein stimulating the SPG-related tissue comprises directly stimulating the SPG.

46. The method according toclaim 44, comprising correlating an abnormal concentration of the constituent to a pathology of the CNS condition.

47. The method according toclaim 44, wherein the constituent is selected from the group consisting of: a protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an enzyme, and wherein measuring the constituent comprises measuring the selected constituent.

48. The method according toclaim 44, wherein measuring the constituent comprises measuring a plurality of constituents of the tissue.

49. The method according toclaim 48, comprising determining a diagnostic result according to the interrelation between concentrations of the constituents of the tissue.

50. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and

configuring the signal so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate a diagnosis of the CNS condition.

51. The method accordingclaim 50, comprising measuring a constituent of the other body compartment.

52. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and

configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the CNS condition.

53. The method accordingclaim 52, comprising measuring a constituent of the other body fluid.

54. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising:

applying an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject; and

configuring the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the CNS condition.

55. The method accordingclaim 54, comprising measuring a constituent of the tissue.

56. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, the method comprising:

stimulating at least one site of the subject by applying an electrical current to the site, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between the anterior ethmoidal nerve and the SPG, a communicating branch between the posterior ethmoidal nerve and the SPG, a nerve of the pterygoid canal of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve of the subject and the SPG, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion, and an efferent fiber going out of the otic ganglion;

configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject;

taking a sample from the body compartment; and

determining a level of a constituent of the sample, so as to facilitate the diagnosis of the CNS condition.

57. The method according toclaim 56, wherein the CNS condition includes a neurodegenerative condition, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the neurodegenerative condition.

58. The method according toclaim 56, wherein the CNS condition includes a neoplastic process, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the neoplastic process.

59. The method according toclaim 56, wherein the CNS condition is selected from the list consisting of: an immune-related disorder and an autoimmune-related disorder, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the selected condition.

60. The method according toclaim 56, wherein the CNS condition includes a CNS inflammatory process, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the CNS inflammatory process.

61. The method according toclaim 56, comprising interpreting a low value of the level as indicative of an increased likelihood that the subject suffers from the CNS condition.

62. The method according toclaim 61, comprising interpreting a high value of the level as indicative of a decreased likelihood that the subject suffers from the CNS condition.

63. The method according toclaim 61, wherein the body compartment includes a systemic blood circulation of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation.

64. The method according toclaim 61, wherein the body compartment includes plasma of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma.

65. The method according toclaim 61, wherein the body compartment includes serum of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum.

66. The method according toclaim 61, wherein the body compartment is ascites of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.

67. The method according toclaim 61, wherein the site includes the SPG, and wherein stimulating the site comprises stimulating the SPG.

68. The method according toclaim 61 wherein the CNS condition includes Alzheimer's disease, and wherein interpreting the low value comprises interpreting the low value as indicative of the increased likelihood that the subject suffers from Alzheimer's disease.

69. The method according toclaim 68, wherein the constituent includes amyloid-beta peptide, and wherein determining the level of the constituent comprises determining the level of the amyloid-beta peptide.

70. The method according toclaim 68, wherein the constituent includes presenilin-1, and wherein determining the level of the constituent comprises determining the level of the presenilin-1.

71. A method for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, the method comprising:

stimulating at least one site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between the anterior ethmoidal nerve and the SPG, a communicating branch between the posterior ethmoidal nerve and the SPG, a nerve of the pterygoid canal of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve of the subject and the SPG, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion, and an efferent fiber going out of the otic ganglion;

configuring the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject;

taking a sample from the body compartment; and

determining a level of a constituent of the sample, so as to facilitate the diagnosis of the CNS condition.

72. The method according toclaim 71, wherein the CNS condition includes a neurodegenerative condition, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the neurodegenerative condition.

73. The method according toclaim 71, wherein the CNS condition includes a neoplastic process, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the neoplastic process.

74. The method according toclaim 71, wherein the CNS condition is selected from the list consisting of: an immune-related disorder and an autoimmune-related disorder, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the selected condition.

75. The method according toclaim 71, wherein the CNS condition includes a CNS inflammatory process, and wherein determining the level of the constituent comprises determining the level of the constituent so as to facilitate the diagnosis of the CNS inflammatory process.

76. The method according toclaim 71, comprising interpreting a low value of the level as indicative of an increased likelihood that the subject suffers from the CNS condition.

77. The method according toclaim 76, comprising interpreting a high value of the level as indicative of a decreased likelihood that the subject suffers from the CNS condition.

78. The method according toclaim 76, wherein stimulating comprises applying magnetic stimulation to the site.

79. The method according toclaim 76, wherein stimulating comprises applying electromagnetic stimulation to the site.

80. The method according toclaim 76, wherein stimulating comprises applying chemical stimulation to the site.

81. The method according toclaim 76, wherein stimulating comprises applying mechanical stimulation to the site.

82. The method according toclaim 76, wherein the body compartment includes a systemic blood circulation of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the systemic blood circulation.

83. The method according toclaim 76, wherein the body compartment includes plasma of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the plasma.

84. The method according toclaim 76, wherein the body compartment includes serum of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the serum.

85. The method according toclaim 76, wherein the body compartment is ascites of the subject, and wherein configuring the stimulation comprises configuring the stimulation so as to cause the increase in molecular passage between the CNS and the ascites.

86. The method according toclaim 76, wherein the site includes the SPG, and wherein stimulating the site comprises stimulating the SPG.

87. The method according toclaim 76, wherein the CNS condition includes Alzheimer's disease, and wherein interpreting the low value comprises interpreting the low value as indicative of the increased likelihood that the subject suffers from Alzheimer's disease.

88. The method according toclaim 87, wherein the constituent includes amyloid-beta peptide, and wherein determining the level of the constituent comprises determining the level of the amyloid-beta peptide.

89. The method according toclaim 87, wherein the constituent includes presenilin-1, and wherein determining the level of the constituent comprises determining the level of the presenilin-1.

90. A method for treating a condition of a central nervous system (CNS) of a subject, comprising:

applying a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG;

configuring the current to increase clearance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject, so as to treat the CNS condition.

91. The method according toclaim 90, wherein the molecules include a toxin, and wherein configuring the current comprises configuring the current to increase the clearance of the toxin from the brain tissue, so as to treat the CNS condition.

92. The method according toclaim 90, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period greater than about one month.

93. The method according toclaim 90, wherein applying the current comprises implanting an electrode at the site, designated to remain in the subject for a period less than about one week.

94. The method according toclaim 90, wherein applying the current comprises implanting a control unit in a nasal cavity of the subject.

95. The method according toclaim 90, wherein applying the current comprises implanting a control unit at a lower side of a bony palate of the subject.

96. A method for treating a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

97. The method according toclaim 96, wherein stimulating the SPG-related tissue comprises directly stimulating the SPG.

98. A method for treating a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from:

an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

99. A method for treating a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

100. The method according toclaim 99, wherein stimulating the SPG-related tissue comprises directly stimulating the SPG.

101. A method for treating a condition of a central nervous system (CNS) of a subject, comprising:

stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from:

an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG; and

configuring the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

102. Apparatus for facilitating a diagnosis of a condition of a subject, comprising a stimulator adapted to:

apply a current to a site of the subject selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, and a neural tract originating in or leading to the SPG, and

configure the current to increase conductance of molecules from brain tissue of the subject through a blood brain barrier (BBB) of the subject into a systemic blood circulation of the subject, so as to facilitate the diagnosis of the condition.

103. The apparatus according toclaim 102, wherein the stimulator is adapted to directly stimulate the SPG.

104. The apparatus according toclaim 102, wherein the apparatus is adapted to measure a constituent of the other body compartment.

105. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.

106. The apparatus according toclaim 105, wherein the stimulator is adapted to directly stimulate the SPG.

107. The apparatus according toclaim 105, wherein the apparatus is adapted to measure a constituent of the other body compartment.

108. The apparatus according toclaim 107, wherein the other body compartment includes a systemic blood circulation of the subject, and wherein the apparatus is adapted to measure the constituent of the systemic blood circulation.

109. The apparatus according toclaim 107, wherein the other body compartment includes plasma of the subject, and wherein the apparatus is adapted to measure the constituent of the plasma.

110. The apparatus according toclaim 107, wherein the other body compartment includes serum of the subject, and wherein the apparatus is adapted to measure the constituent of the serum.

111. The apparatus according toclaim 107, wherein the other body compartment is ascites of the subject, and wherein the apparatus is adapted to measure the constituent of the ascites.

112. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.

113. The apparatus according toclaim 112, wherein the stimulator is adapted to directly stimulate the SPG.

114. The apparatus according toclaim 112, wherein the apparatus is adapted to measure a constituent of the other body fluid.

115. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and configure the stimulation so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate the diagnosis of the CNS condition.

116. The apparatus according toclaim 115, wherein the apparatus is adapted to directly stimulate the SPG.

117. The apparatus according toclaim 115, wherein the apparatus is adapted to measure a constituent of the tissue.

118. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and configure the signal so as to cause an increase in molecular passage between the CNS and another body compartment of the subject, so as to facilitate the diagnosis of the CNS condition.

119. The apparatus according toclaim 118, wherein the apparatus is adapted to measure a constituent of the other body compartment.

120. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and

configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate the diagnosis of the CNS condition.

121. The apparatus according toclaim 120, wherein the apparatus is adapted to measure a constituent of the other body fluid.

122. Apparatus for facilitating a diagnosis of a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

apply an electrical signal to at least one site of the subject, the site selected from the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a communicating branch between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a communicating branch between a posterior ethmoidal nerve and a retro-orbital branch of an SPG of the subject, a greater palatine nerve of the subject, a lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a communicating branch between a maxillary nerve and an SPG of the subject, a nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an infraorbital nerve of the subject, an otic ganglion of the subject, an afferent fiber going into the otic ganglion of the subject, an efferent fiber going out of the otic ganglion of the subject, a vidian nerve of the subject, a greater superficial petrosal nerve of the subject, and a lesser deep petrosal nerve of the subject, and

configure the signal so as to cause an increase in molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate the diagnosis of the CNS condition.

123. The apparatus according toclaim 122, wherein the apparatus is adapted to measure a constituent of the tissue.

124. Apparatus for treating a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

125. The apparatus according toclaim 124, wherein the stimulator is adapted to directly stimulate the SPG.

126. Apparatus for treating a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from a brain of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

127. Apparatus for treating a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by applying an electrical signal to the SPG-related tissue, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

128. The apparatus according toclaim 127, wherein the stimulator is adapted to directly stimulate the SPG.

129. Apparatus for treating a condition of a central nervous system (CNS) of a subject, comprising a stimulator adapted to:

stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by presenting an odorant to an air passage of the subject, the SPG-related tissue selected from: an SPG of the subject and nerve fibers of the subject which are directly anatomically connected to the SPG, and

configure the stimulation so as to cause an increase in clearance of a neurotoxic compound from cerebrospinal fluid (CSF) of the subject through a blood brain barrier (BBB) of the subject to a systemic blood circulation of the subject, so as to treat the CNS condition.

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