WO2025090944A1 - Device for interfacing with biological tissue through nasal cavity and applications thereof - Google Patents

Abstract

Provided herein are devices and methods provide for measuring, recording, modulating and/or stimulating electrophysiological signals in biological tissues, including the olfactory bulb. The device may be a nasal cavity device for electrophysiologically interfacing with a biological tissue comprising: a flexible tube having: a proximal end, a distal tip, a tube wall extending from the proximal end to the distal tip, the tube wall having an inner surface and an outer surface, wherein the inner surface defines a principle lumen that extends between the proximal end and the distal tip; an electrophysiological device at least partially disposed on the flexible tube outer surface at or adjacent to the distal tip; and a stabilizer connected to the flexible tube outer surface configured to reliably position at least a portion of the nasal cavity device in a nasal cavity during use.

Description

Device for Interfacing with Biological Tissue through Nasal Cavity and Applications Thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63/545,780, filed October 26, 2023, and 63/557,656, filed February 26, 2024, each of which is hereby incorporated by reference in its entirety.

BACKGROUND OF INVENTION

[0002] Olfactory dysfunction is a common clinical symptom, and it presents at early stages across a number of neurological, neurodegenerative and psychiatric conditions. Most research into the neural underpinnings of smell-related changes in clinical populations has focused on higher cortical regions that are accessible using standard human neuroscience tools such as functional neuroimaging (fMRI). fMRI studies have shown that neurodegenerative diseases alter responses to odors in human olfactory cortical areas, and alter network connectivity between olfactory cortex and the rest of the brain. However, though these higher-order olfactory brain areas do exhibit changes in disease states, whether and how changes in earlier olfactory structures — such as the olfactory sensory neurons and olfactory bulb — occur in clinical populations with olfactory deficits is unknown. Thus, there is an important gap in common understanding of the causes of smell loss as well as the link between smell loss and neurological disease. This gap is mainly due to the deep anatomical locations of these early olfactory structures, which are difficult to record from using standard human neuroscience tools.

[0003] Due to the difficultly in accessing the anatomical locations of the olfactory structures, a significant hindrance in our understanding of olfactory dysfunction in clinical populations is the lack of an objective measure of olfactory function. Existing methods to assess smell include surveys that are based on behavioral ratings from patients. However, there is no objective tool to assess the neural functioning of smell organs in clinical populations. Due to the human olfactory bulb’s anatomical location and small size, attempts to measure signals from the human olfactory bulb using functional neuroimaging have been largely unsuccessful. Although some prior art work using surface electrodes placed near the bridge of the nose have claimed to pick up electrical signals originating in the human olfactory bulb, those methods require an extremely large number of trials, and do not have sufficient signal to noise ratio to allow examination of oscillatory activity at the single trial level. This limits their use as a tool to obtain a full understanding of the oscillatory dynamics of neural activity in the human olfactory bulb, and how these dynamics relate to cognition and behavior in real time. [0004] Accordingly, there is need in the art for devices and methods that are capable of reliably interfacing with the olfactory bulb in order to measure, record, or modulate electrophysiological signals at sufficient signal to noise ratios to allow examination of oscillatory activity at the single trial level.

SUMMARY OF THE INVENTION

[0005] Provided herein are devices and methods which address the aforementioned and other challenges. In particular, nasal cavity device embodiments disclosed herein represent a significant advancement by enabling the establishment of electrical communication with, for example, the olfactory bulb, by placing a nasal cavity device comprising an electrophysiological device within the olfactory cleft adjacent to a subject’s cribriform plate. The devices and methods disclosed herein are designed to measure, record, stimulate, or modulate electrophysiological signals from biological tissues located within or in proximity to the nasal cavity, for example biological tissues that are adjacent or around the nasal cavity, such as the olfactory bulb. Examples of biological tissue that the devices and methods disclosed herein enable measuring, recording, modulating, or stimulating electrophysiological signals to or from (generally referred herein as interfacing) include: the olfactory and respiratory epithelium; trigeminal and olfactory nerves, cranial nerve zero, sympathetic nerves, parasympathetic nerves, olfactory bulb, olfactory tract, ventral brain, limbic brain, or any combination thereof. Importantly, the devices and methods disclosed herein facilitate examination of oscillatory activity at the single trial level, thereby providing a platform to improve the understanding of the oscillatory dynamics of neural activity in the olfactory bulb and how these dynamics relate to cognition and behavior in real time. The devices and methods are compatible with electrically interfacing with biological tissue having a range of distances from the electrophysiological device, from near/adjacent distances to more remote distances.

[0006] Provided are devices comprising: a proximal end, a distal tip, and a tube wall extending from the proximal end to the distal tip, the tube wall having an inner surface and an outer surface, wherein the inner surface defines a principle lumen that extends between the proximal end and the distal tip; an electrophysiological device at least partially disposed on the flexible tube outer surface at or adjacent to the distal tip; a stabilizer connected to the flexible tube outer surface configured to reliably position at least a portion of the nasal cavity device in a nasal cavity during use; wherein the flexible tube is configured to establish electrical communication between the electrophysiological device and the biological tissue; and wherein the electrophysiological device is configured to electrically interface with the biological tissue. [0007] The electrophysiological device may further comprise one or more electrodes configured to: electrically stimulate the biological tissue; record an electrophysiological signal generated by the biological tissue; or electrically stimulate the biological tissue and record an electrical parameter generated by the biological tissue. There may be a single electrode that has a plurality of contact surfaces separated by an electrical insulator. There may be a plurality of individually addressable electrodes separated by an electrical insulator. In this manner, reliable interfacing can be achieved by ensuring there is a relatively large contact area along the device so that even if a portion of the device is not in electrical contact, another portion of the device will be in electrical contact. In an embodiment, the plurality of contact surfaces is characterized in terms of an electrode density, such as the number of electrodes per unit surface area of the tube. That density may range between, for example, 1 electrode per mm² to 1 electrode per cm².

[0008] The devices and methods provided herein are compatible with a range of biological tissues, including but not limited to an olfactory and respiratory epithelium; trigeminal and olfactory nerves, olfactory bulb, olfactory tract, and/or ventral brain. Particularly useful biological tissues include those that are reactive to an electrical parameter, such as current or electrical potential.

[0009] The device may further be configured to be supported inside the nasal cavity of the subject on an olfactory epithelium inferior to a cribriform plate, including with a stabilizer. This placement of the nasal cavity device, for the first time, allows electrical communication between an electrophysiological device and for example, the olfactory bulb of a subject. In addition, this placement enables electrical communication between a nasal cavity device with an electrophysiological device or any one of or combination of the olfactory and respiratory epithelium; trigeminal and olfactory nerves, cranial nerve zero, sympathetic nerves, parasympathetic nerves, olfactory bulb, olfactory tract, ventral brain, or limbic brain.

[0010] The stabilizer may be controllably positionable along the flexible tube outer surface at a user-selected location according to an anatomical paramater and the stabilizer may have size configured to extend between the flexible tube outer surface and an inner surface of the nasal cavity. The stabilizer provides sufficient contact between the flexible tube of the nasal cavity device and the inner walls of the nasal cavity so as to reliably position the electrohpysiological device. The stabilizer may be controllably positioned by any number of means, including by a tensile force exerted between the stabilizer and the underlying flexible tube, such that the stabilizer can translate over the surface, but once positioned in the nasal cavity, will not move. Similarly, a fastener such as an adheisve may be used to ensure the stabilizer does not move during use, or similarly, a fastener such as a rivet or screw secured through the wall of the sinus cavity may be used to ensure the stabilizer does not move during use, particularly in cases of long-term placement and use. For example, for long term placement applications on the order of years, including for wireless devices where it is desired to apply stimulation over years, such a fastener through the sinus cavity of the wall assists in long term and reliable device positioning.

[0011] The stabilizer may further be configured to apply tension upon deployment including spring-based tension or a mechanical material-based tension.

[0012] The stabilizer may comprise a material selected from the group of: a silicone, a urethane, an elastomer, a polymer, or any combination of these. The stabilizer may comprise an absorptive sponge, an inflatible catheter, a flap, a ring, a wedge, or a u-shape stabilizer. Any geometry or shape of the stabilizer is envisioned herein, so long as the geometry is capable of applying tension between the flexible tube of the nasal cavity device and an inner surface of a subject’s nasal cavity upon deployment.

[0013] The stablilizer may comprise an absorptive material comprising dehydrated hydroxylated polyvinyl acetate, synthetic biodegradable fragmenting foam, oxidized nitrocellulose, cotton, non-woven gauze, polyether-polyurethane, medical-grade foam, silicone, polyvinyl acetate, a resorbable oxidized cellulose, a hemostatic matrix, or a thrombin soaked hemostatic device prepared purified porcine skin gelatin. The absorptive material may absorb, for example, nasal fluids or other biological fluid present in the subject. Of course, the devices are also compatible with an externally-applied liquid, such as saline.

[0014] The stabilizer may have a thickness greater than or equal to 0.5 mm and less than or equal to 2.2 mm. The thickness of the stabilizer can be selected based on an individual subject’s nasal anatomy.

[0015] The device may further comprise a removeable rod positioned in the principal lumen, wherein the removable rod has a higher stiffness than the flexible tube for reliable positioning of the electrophysiological device at a location in the nasal cavity. Accordingly, the nasal cavity device may have a rod-inserted configuration for device positioning, to assist the passage of the flexible tube toward the nasal cavity distal region, and a rod-removed configuration during use where, once placed and stabilized with the stabilizer, the rod is unneccesary.

[0016] The removable rod may have a diameter of 0.2 mm to 0.6 mm. The diameter of the removable rod may be selected based on an individual subject’s nasal anatomy as well as the lumen diameter of the tube. [0017] Depending on the application of interest, the device may comprise any of a range of electrophysiological devices. Examples may include an ultrasonic probe, one or more electrodes, a multi-contact electrode, an electrode strip, a directional-contact multi-contact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, including a transcranial magnetic stimulator, a transcranial direct current stimulator, including a low-level laser and a transcranial laser, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these.

[0018] The one or more electrodes or multi-contact electrode may comprise a plurality of electrodes, for example, between 2 to 50 electrode contacts located adjacent to the distal tip. The devices are compatible with any number of electrode contacts, depending on the appliation of interest, and can have a very high number of small contacts, or a relatively low number of relatively larger contacts. Optionally, each electrode contact is individually addressable, including to provide the ability to map an electric field. The multi-contact electrode(s) may extend from the distal tip in a direction toward the proximal end of the flexible tube, so that irrespective of the releative orientation and/or position of the flexible tube, at least some of the electrodes establish a reliable interfacing with biological tissue. Optionally multi-contact electrodes provide, for example, a range of anatomical coverage within the nasal cavity and a range of additional electrophysiological information. A multi-contact electrode of the invention disclosed herein facilitates various options in signal referencing enabling refinement in target signals and improvements in signal-to-noise ratios. The ability to vary electrode size, and thus impedance, provides flexibility in tailoring the desired signal range with attendent benefit for recording or stimulating over a smaller or larger distance.

[0019] The electrode contacts may each have a length of between 1 pm to 2.5 mm and a center to center distance of between 0.1 mm to 5.0 mm. The electrode contacts may be described in terms of an electrode geometry, including but not limited to, circular, rectangular, square, directional, or a ring or a wire. A ring electrode refers to an electrode that at least partially or completely circumferentially extends around the flexible tube outer surface. In this manner, the importantance of the relative rotational position of the device relative to the nasal passage is avoided. Of course, other electrode geometries are compatible, including for electrodes that have radial spacing so that an electrode is always in proximity to a biological tissue irrespective of how the device is rotated. In addition, directional electrode refers to electrode contacts that covers only part of the surface of the flexible tube outer surface, such that the electrodes are placed facing the biological tissue of interest. The electrode size, and thus impedence, may optionally be selected to optimize signal range, including recording or stimulating over a smaller or larger distance.

[0020] At least one of the electrode contacts may comprise a biocompatible metal or a metal alloy, including: Pt, Ir, Au, Ag, Ni, Cu, Ti, Co, Ni, Mg, Cr, or any combination of these. Electrode materials may be selected to optimize properties for an application including, but not limited to, electrode conductivity, electrode resistance, electrode impedence, and durability.

[0021] At least one of the electrode contacts may comprise at least 80% Pt and up to 20% Ir.

[0022] At least one of the electrode contacts may comprise a biocompatible ceramic, including: aluminum oxide, zirconium oxide, tin oxide, bioglass, or any combination of these.

[0023] At least one of the electrode contacts may comprise carbon, including: graphite, vitreous carbon, vitro-ceramic, or any combination of these.

[0024] The flexible tube may further comprise one or more substance delivery pores extending between the outer and inner surface. Examples of substances that may be useful to provide include chemicals and biologies, including potential therapeutics or other material that can impact the biological tissue, incuding to enhance interfacing between the device and the biological tissue. For example, substances that may be useful include neuromodulators, which may be delivered for the purposes of diagnosis or treatment of a pathology, growth factors for stimulating neurogenesis, anti-inflammatories, immunosuppressants, monoclonal antibodies, and insulin. The devices and methods provided herein are beneficially compatible with any of a range of substances, with the specific substance selected based on the applicatoin of interest.

[0025] The flexible tube may comprise a biocompatible polymer, including: polyurethane, silicone, polyethylene, polyamide, polyether ketone, polyethylene, polyethylene terephthalate, polymethylmethacrylate, polystyrene, polytetrafluorethylene, a synthetic rubber, or any combination of these. Any biocompatible material with sufficient flexibility to conform to an individual subject’s nasal cavity for reliable placement of the nasal cavity device is envisioned and disclosed herein.

[0026] The flexible tube may be characterized by a tube parameter selected from the group consisting of: a wall thickness of between 0.1 mm to 1.0 mm; a Young’s modulus of 0.01 GPa to 100 GPa; a bending stiffness less than or equal to 200 g. Wall thickness may be selected based on the size (e.g., diamter and/or length) of the flexible tube, which may be selected, for example, based on its ability to support a rod or stylus or its ability to contain a drug. Accordingly, the application of interest, including subject tissue geometry, pathology, physiology and desired interfacing (electrical, drug delivery, reci ept of biolgoical fluid, etc.), will at least in part inform tube characteristics. The tube wall may be very thin to help faciliate recording.

[0027] The flexible tube may have a length from the proximal end to the distal tip of between 20 mm to 800 mm. The length of the flexible tube may be selected based on the configuration of the device, e.g., wired or wireless, and the individual subject’s nasal anatomy. The distal tip and regions of the device “adjacent” to the distal tip, may refer to the distal-most 10%, 20%, 30% or 40% of the flexible tube length, and any sub-combinations thereof. Generally, the smaller flexible tube lengths are preferable for wireless configurations, where there is no need for the tube to extend out into the external environment, but instead is positioned entirely wihtin the nasal cavity and is not visible from the outside of the subject.

[0028] The flexible tube may have a radius of 0.5 mm to 1.25 mm, selected based on the individual subject’s nasal anatomy as well as the need to deliver substances and its ability to support a rod or stylus.

[0029] The flexible tube may further comprise a secondary lumen adjacent to the tube outer wall or an inner surface of the tube that defines the tube lumen. The secondary lumen may for example, be used to carry substances for delivery to the nasal cavity through substance delivery pores. Similarly, this pore and secondary lumen aspect may be used to collect biological fluid from the subject, such as for analysis.

[0030] Any of the devices may further comprise a flexible clip disposed on the outer surface of the flexible tube. The flexible clip is used primarily in the wired configuration of the device in order to secure extra nasal wire to the opening of the nasal cavity.

[0031] The electrophysiological device may be operably connected to a controller comprising at least one of a recording system and a modulation system. A controller may be in the form of a computer softward and/or hardware, as known in the art, for electronically controlling the device. In this manner, a user can reliably interface with the biolgoical tissue, including having the ability to stimulate the tissue and/or record an output from the tissue. This operable connection may be hard-wired or may comprise a wireless connection.

[0032] The electrophysiological device may be wired connected to the controller, including via at least least one wire or may be wirelessly connected via a wireless configuration. The wireless connection may further comprise a flexible circuit board supported on the flexible tube outer surface at a separation distance from the flexible tube distal end between 15 mm to 35 mm, with attendent antenna and receiver.

[0033] Any of the devices may further comprise an intranasal antenna comprising a flexible circuit board electronically connected to the electrophysiological device and an extra nasal antenna comprising a radiofrequency transmit coil.

[0034] Also provided herein are methods of electrophysiologically interfacing any of the disclosed devices with a biological tissue of a subject. “Electrophysiologically interfacing” refers to the establishing of a functional connection between biological tissues and an electrophysiological device such as an ultrasonic probe, one or more electrodes, a multi-contact electrode, an electrode strip, a directional-contact multi-contact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, including a transcranial magnetic stimulator, a transcranial direct current stimulator, including a low-level laser and a transcranial laser, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these. The interface allows for the exchange of electrical signals between the electrophysiological device and the biological tissue. The electrophysiological interface may enable the monitoring, recording, modulating, or stimulation of electrical activities within cells or biological tissues, facilitating electrical communication between biological tissues and electrophysiological devices.

[0035] Accordingly, provided herein are methods of electrophysiologically interfacing an electrophysiological device with a biological tissue comprising: placing at least a portion of the electrophysiological device in electrical communication with the biological tissue, wherein the biological tissue is located in a nasal cavity of the subject; interfacing with the biological tissue, wherein the interfacing comprises: applying an electrical stimulation signal to at least a portion of the biological tissue from the electrophysiological device; and/or measuring an electrophysiological parameter from at least a portion of the biological tissue with the electrophysiological device; thereby electrophysiologically interfacing the nasal cavity device with the biological tissue.

[0036] The biological tissue of the subject may comprise at least one of an olfactory and respiratory epithelium; trigeminal and olfactory nerves, cranial nerve zero, sympathetic nerves, parasympathetic nerves, olfactory bulb, olfactory tract, ventral brain, limbic brain, or any combination of these. [0037] The method may comprise placing at least a portion of the nasal cavity device at a base of the subject’s cribriform plate in the subject’s nasal cavity.

[0038] The method may comprise placing the nasal cavity device such that at least a portion of the nasal cavity device is adjacently positioned next to or under the perforations of the cribriform plate, including within 2 mm of the olfactory bulb. For example, a distal portion of the device that is in proximity to a desired target may be adjacently positioned, such as the distal most 2 cm, 1 cm, or 0.5 cm length of the tube.

[0039] The step of placing may further comprise: temporarily stiffening at least a portion of the flexible tube of the nasal cavity device by inserting a removable stiffening tool into the principle lumen to generate a stiffened flexible tube; grasping the stiffened flexible tube with a holder at a location physically separated from the distal end of the stiffened flexible tube; and inserting the nasal cavity device into the nasal cavity by moving the stiffened flexible tube along a nasal septum toward an olfactory cleft until the distal end of the nasal cavity device is placed along an inferior aspect of the cribriform plate and at a top of the olfactory cleft.

[0040] The step of placing may further comprise securing the nasal cavity device between a septal wall and a middle turbinate using the stabilizer at a location where the stabilizer touches a most anterior part of the middle turbinate.

[0041] The step of placing the nasal cavity device may further comprise securing the nasal cavity device to an entry of the nasal cavity using a flexible clip connected to the nasal cavity device.

[0042] The step of placing the nasal cavity device may further comprise removing the removable stiffening tool.

[0043] The method may further comprise the step of using the interfacing step to diagnose a disorder impacting a nose and/or sinuses of the subject, a smell or taste disorder, a neurological disease impacting the olfactory bulb, or a neurological disease impacting a central nervous system of the subject.

[0044] The disorder of the nose and/or sinuses may comprise sinusitis with or without polyps, allergic rhinitis, cerebrospinal fluid leak, deviated septum, fungal sinusitis, and nasal masses; the smell or taste disorder comprises anosmia, ageusia, hyposmia, phantosmia, and congenital anosmia; the neurological disease impacting the olfactory bulb comprises Kallmann syndrome, epilepsy, and olfactory neuroblastoma; and the neurological disease impacting the central nervous system comprises Alzheimer’s Disease, Parkinson’s Disease, Autism, Schizophrenia, or Frontotemporal dementia.

[0045] The method may be used on humans. The method may be used on animals that are not human.

[0046] Without wishing to be bound by any particular theory, there may be discussion herein of beliefs or understandings of underlying principles relating to the devices and methods disclosed herein. It is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, an embodiment of the invention can nonetheless be operative and useful.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIGs. 1A-1E: Schematic, showing (FIG. 1A) side view of a wired nasal cavity device; (FIG. IB) front view of a wired nasal cavity device illustrating a clip; (FIG. 1C) front view of a wireless nasal cavity device; (FIG. ID) side view zoomed in illustrating electrophysiological device contacts; (FIG. IE) top view zoomed illustrating substance delivery pores; and (FIG. IF) cross-sectional schematic of flexible tube showing the principle lumen, secondary lumen adjacent to flexible tube inner surface.

[0048] FIGs. 2A-2F: Wireless nasal cavity device for placement in the left nostril, showing (FIG. 2A) top view illustrating electrophysiological device contacts and internal nasal antenna and its components (FIG. 2B) side view of wireless nasal cavity device further illustrating a device comprising a stabilizer; and (FIG. 2C) front view of wireless nasal cavity device; and over the nose antenna (left nostril) showing (FIG. 2D) side view; (FIG. 2E) front view; and (FIG. 2F) top view.

[0049] FIG. 3: schematic showing lateral cross-section of an example of a nasal cavity device. Illustrates a removable rod or stylus inserted into the principle lumen of the flexible tube for reliable positioning of the electrophysiological device in a subject’s nasal cavity. FIG. 3 also illustrates one exemplary embodiment, wherein the electrode contact is a ring fitted to the outer surface of the flexible tube, providing a circumferential coverage, with a single wire electrically connecting the electrode contact ring positioned at the electrode tip, including to a similar ring on the electrode tail or to controller, receiver, or the like (not shown).

[0050] FIGs. 4A-4B: schematic showing (FIG. 4A) wireless configuration of the nasal cavity device placed in a model subject’s nasal cavity, and (FIG. 4B) wired configuration of the nasal cavity device placed in a model subject’s nasal cavity. [0051] FIG. 5: Intranasal device placement CTs detail: Sagittal (left) and coronal (right) cross-sections of human nasal cavity with device in place (electrode contacts highlighted in pink). Olfactory bulb is labeled and can be seen in close proximity to electrode (approx. l-2mm).

[0052] FIG. 6: Intranasal device placement CTs Examples: Sagittal CT images showing six different placements of intranasal device in human nasal cavity. Electrode contacts are highlighted as white dots; sponge evident as a white shadow anterior to electrode contacts; securing clip evident at columelia.

[0053] FIG. 7: Example results of nasal cavity electrophysiological recordings: Time/frequency spectrograms showing z-scored power (see color bar), with respiration overlayed (black line): Sniffs containing odor induce (top panel, titled “Odor”) significantly stronger responses than sniff containing air (bottom panel, titled “No Odor”), suggesting that the signal is originating in olfactory structures.

[0054] FIG. 8: CT scan after multicontact device placement.

[0055] FIG. 9: Recorded electrophysiological signal (blue line) and Nasal airflow (black line).

[0056] FIG. 10: Changes in the power of the frequencies with breathing.

[0057] FIG. 11: illustrates a nasal cavity device disposed inside a subject’s nose, and its intracranial recording process.

[0058] FIG. 12: illustrates that odor-evoked gamma oscillations are diminished by anosmia induced by local lidocaine application.

[0059] FIG. 13: illustrates that odor-evoked gamma oscillations are reduced and delayed when odor is delivered through the contralateral nostril.

[0060] FIG. 14: illustrates that two oscillatory modes compete across the sniff cycle during an attentive olfactory task.

DETAILED DESCRIPTION OF THE INVENTION

[0061] In the following description, numerous specific details of the devices, device components and methods of the present invention are set forth in order to provide a thorough explanation of the precise nature of the invention. It will be apparent, however, to those of skill in the art that the invention can be practiced without these specific details. [0062] In general, the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art. The following definitions are provided to clarify their specific use in the context of the invention.

[0063] The term “flexible,” is used broadly herein to refer to a material that has the ability to bend, expand, contract, fold, unfold, or otherwise substantially deform or change shape under an applied force, without adversely impacting the material’s functionality. A material that is more flexible than another is more able to change shape under an applied force without fracture or breaking. For example, a flexible tube refers to a tubular component of the nasal cavity device that is able to bend such that the flexible tube conforms to an individual subject’s nasal cavity anatomy, and that is capable of deforming as the device is fed along the nasal cavity.

[0064] The term “tube,” as used herein, refers to a conduit, pipe, capillary, or open ended structure. In this context, it should be noted that the term tube is not limited to tubes with circular cross-sections, but includes all elongated hollow bodies, for example, also those with polygonal cross-sections, square cross-sections, and oval cross-sections which are suitable for a nasal cavity device are included herein.

[0065] The term “electrophysiological device,” as used herein, refers to an instrument designed to interface with a biological tissue, including to measure, record, modulate, or stimulate electrical activity in biological tissues or cells thereof. As used herein, electrophysiological device also refers to an instrument that may deliver an electrical signal to a biological tissue in the body. More particularly, an electrophysiological device refers to a device that measures or stimulates electrical signals in biological tissues. Non-limiting examples of an electrophysiological device includes for example, an ultrasonic probe, one or more electrodes, a multi-contact electrode, an electrode strip, a directional-contact multi-contact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, including a transcranial magnetic stimulator, a transcranial direct current stimulator, including a low-level laser and a transcranial laser, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these.

[0066] “Electrophysiologically interfacing” refers to the establishing of a functional connection between biological tissues and an electrophysiological device such as an ultrasonic probe, one or more electrodes, a multi-contact electrode, an electrode strip, a directional-contact multi-contact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, including a transcranial magnetic stimulator, a transcranial direct current stimulator, including a low-level laser and a transcranial laser, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these. The interface allows for the exchange of electrical signals between the electrophysiological device and the biological tissue in electrical communication. Electrophysiologically interfacing enables, for example, the monitoring, recording, stimulation, or modulation of electrical activities within cells or biological tissues, facilitating electrical communication between biological tissues and electrophysiological devices.

[0067] The terms “electrical signal,” “electrical parameter,” “electrophysiological signal,” or “electrophysiological parameter” are used interchangeably and as used herein, refer to variations in electrical potential that occur in biological tissues or cells as a result of ion flux or other charged species in the biological tissue or cells. Non-limiting examples of electrical signals produced by a biological tissue include electrical current and electric potential derived from ion flux. The terms electrical signal, electrical parameter, electrophysiological signal, and electrophysiological parameter are used broadly to include any event, occurrence, or phenomenon that can be detected electrically, such as, for example, potential, resistance, capacitance, inductance, other impedance, or current. Preferably, the term electrical signal, electrical parameter, electrophysiological signal or electrophysiological parameter refers to such an event that occurs at a location within the body that can propagate through a biological tissue, and that may be detected or sensed at a location on the biological tissue or near the biological tissue with the instant devices. The terms electrical signal, electrical parameter, electrophysiological signal or electrophysiological parameter may also refer to variations in electrical potential that occur in biological tissue which are modulated, stimulated, or created by the electrophysiological device, such that such a signal is imparted to the biological tissue.

[0068] The term “electrical communication,” is used herein to refer to an electrical continuity, wherein the interface between the two materials is electrically conductive and includes configurations in which there may not be direct physical contact between the two materials, including a physical space between the two materials. The term electrical communication refers to the arrangement of two or more materials or items such that electrons can be transported to, past, through, and/or from one material or item to another. Electrical communication between two materials or items can be direct or indirect through another one or more materials or items. Generally, materials or items in electrical communication are electrically conducting or semiconducting. [0069] The term “biological tissue,” is used broadly herein, and includes any cells, tissue, or organs, including the skin or parts thereof, for example, mucosal tissues, epithelial tissues, and surfaces of the nasal cavity. The biological tissue can be in humans or other types of non-human animals (particularly mammals). Mammalian biological tissues directly or indirectly accessible from the nasal cavity include, for example, the olfactory and respiratory epithelium; trigeminal and olfactory nerves, cranial nerve zero, sympathetic nerves, parasympathetic nerves, olfactory bulb, olfactory tract, ventral brain, limbic brain, or any combination of these are of particular use with the present devices and methods.

[0070] The term “stabilizer,” as used herein refers to a material that stably maintains the positioning of a nasal cavity device of the present invention during use in a subject’s nasal cavity. For example, the stabilizer may be a material that is able to expand upon positioning of the nasal cavity device in a subject’s nasal cavity in order to enable a stable contact area between the nasal cavity device and an inner surface of the subject’s nasal cavity. For example, a stabilizer may be used to secure the nasal cavity device between the subject’s septal wall and middle turbinate. A stabilizer may be a material capable of expansion once the nasal cavity device has been properly placed within the subject’s nasal cavity, preferably at a location between the subject’s nasal wall and optionally the subject’s lower, middle, or superior turbinates, including a sponge-like material. Additionally, the stabilizer may comprise a mechanical device, for example, a spring, a flap, a ring, a wedge, or u-shape, or any configuration of a mechanical device that may applies tension upon deployment, such as a spring-tension, or mechanical material-based tension. Useful materials for a mechanical stabilizer may comprise silicone, urethane, elastomer or other polymer. Useful materials for an absorptive stabilizer may comprise hydroxylated polyvinyl acetate, synthetic biodegradable fragmenting foam, oxidized nitrocellusolse, cotton, non-woven gauze, polyether-polyurethane, polyurethane, medical-grade foam, silicone, polyvinyl acetate, a resorbable oxidized cellulose material (trade name: Surgicel), a thrombin soaked hemostatic device prepared purified porcine skin gelatin (trade name: Gelfoam), or a hemostatic matrix (trade name: Floseal).

[0071] The term “electrode,” refers to an electrically conductive material through which current can flow by electronic movement. An electrode may be formed of a biocompatible material that is electrically conducting. For example, an electrode may be comprised of a metal, a metal alloy, and oxides, and dioxides thereof. For example, a useful metal of the present invention may comprise Pt, Ir, Au, Ag, Ni, Cu, Ti, Co, Ni, Mg, Cr, or any combination of these. In addition, the electrode may comprise a biocompatible ceramic, for example, aluminum oxide, zirconium oxide, tin oxide, or bioglass. The electrode may also comprise carbon, examples of carbon materials useful in the present invention include graphite, vitreous carbon, vitro-ceramic, or doped diamond. An electrode may, for example, comprise a wire, a microwire, a nanowire, an electrode strip or materials embedded in or patterned onto the nasal cavity device of the disclosure herein. Preferably, the electrode has material characteristics that can provide reduced irritation to the patient, such as being flexible, chemically and biologically inert, and that do not overheat during use. The electrode may have a spatial pattern, with a plurality of electrode contacts that are spatially positioned on or through the flexible tube wall.

[0072] The term “biocompatible” refers to the properties of a material or device that allows it to interact with a biological tissue without evoking an adverse response, for example, an adverse immune response, or causing toxicity. A biocompatible material may be integrated into living biological tissues or systems, for example the nasal cavity of a subject, promoting compatibility and functionality of the biocompatible material or device while minimizing inflammation, irritation, or rejection. The use of biocompatible materials to fabricate the devices of the instant invention ensures that the devices can perform their intended functions within, for example, the nasal cavity of a subject.

[0073] The term “absorptive,” as used herein refers to a material that has the ability to accumulate liquid into the interior or void spaces within the material. For example, when placed in the nasal cavity of a subject, the dehydrated absorptive sponge has the ability to accumulate fluid into its interior or void spaces in order to expand and form a temporary, but reliable, connection between the subject’s nasal wall and the flexible tube of the nasal cavity device, to ensure reliable placement.

[0074] The term “dehydrated,” as used herein when defining a material, such as a dehydrated absorptive sponge, refers to a material that has undergone a dehydration process. A dehydrated material, such as a dehydrated absorptive sponge, has a water content that is preferably less than 5 %.

[0075] In an embodiment, a composition or compound of the invention, such as an alloy or precursor to an alloy, is isolated or substantially purified. In an embodiment, an isolated or purified compound is at least partially isolated or substantially purified as would be understood in the art. In an embodiment, a substantially purified composition, compound or formulation of the invention has a chemical purity of 95%, optionally for some applications 99%, optionally for some applications 99.9%, optionally for some applications 99.99%, and optionally for some applications 99.999% pure. [0076] The invention can be further understood by the following non-limiting examples.

[0077] Example 1: Exemplary nasal cavity device embodiments

[0078] FIGs. 1A-3 are schematic illustrations of various embodiments of the nasal cavity devices disclosed herein for electrophysiologically interfacing with a biological tissue, for example a biological tissue of the nasal cavity. For example, the devices and methods disclosed herein facilitate the measurement, recording, or modulation/stimulation of electrical signals from or to the brain and respiratory system through the nasal cavity. Preferably, the nasal cavity devices disclosed herein provide a way to measure, record, modulate, or stimulate signals from or to the olfactory bulb of a subject by allowing for placement of the nasal cavity device within the nasal cavity wherein an electrophysiological device disposed on at least a portion of the outer surface of the nasal cavity device is placed at the base of a subject’s cribriform plate within about 2 mm of the subject’s olfactory bulb. This preferred placement provides an electrophysiological device in electrical communication with, for example, the subject’s olfactory bulb.

[0079] FIGs. 1A-2F schematically illustrates the various components of embodiments of the nasal cavity device 90 for measuring, recording, modulating, or stimulating electrical signals of a biological tissue with an electrophysiological device disposed on a portion of the nasal cavity device. Exemplary illustrated components include a flexible tube 100 having a proximal end 120 and a distal tip 110 (FIG. 1A). A tube wall 175 extends from the proximal end 120 to the distal tip 110. The tube wall 175 has an inner surface 160 and an outer surface 155 wherein the inner surface 160 defines a principle lumen 170 (FIG. IF). The flexible tube may optionally be fabricated from polyurethane. The nasal cavity device further comprises an electrophysiological device 140 for measuring, recording, or modulating an electrophysiological signal of a subject’s biological tissue located in the subject’s nasal cavity. The electrophysiological device 140 may be any device capable of measuring, recording, modulating, or stimulating an electrophysiological signal of biological tissue. For example, the electrophysiological device may be an ultrasonic probe, one or more electrodes 125, an optical stimulator, or any combination of those (FIGs. 1A and ID) The one or more electrodes may comprise one or more electrode contacts 145 (FIG. ID). For example, an electrophysiological device 140 may comprise one or more electrodes 125 comprising 2 to 20 individually addressable electrode contacts 145.

[0080] Also illustrated is a stabilizer 150 connected to the flexible tube outer surface 155 configured to reliably position at least a portion of the nasal cavity device in a subject’s nasal cavity during use (FIG. 1A). Preferably, the stabilizer 150 comprises a dehydrated absorptive sponge or an inflatable catheter. The dehydrated absorptive sponge may optionally comprise hydroxylated polyvinyl acetate. The flexible tube 100 is configured to establish electrical communication between the electrophysiological device 140 at least partially disposed on the flexible tube outer surface 155 and a subject’s biological tissue, preferably a biological tissue located within or adjacent to the nasal cavity. The flexible tube may further comprise one or more substance delivery pores 135 (FIG. IE) for medications, drugs, neuromodulators, odors, hormones, insulin, growth factors, anti-inflammatories, immunosuppressants, monoclonal antibodies.

[0081] In an embodiment, the device comprises a wired configuration (FIG. 1A-1B; FIG. 4B). In the wired configuration, the nasal cavity device may further comprise a clip 115 disposed on the outer surface of the flexible tube. The clip 115 may be a flexible clip and it may optionally be fabricated from plastic or metal. The clip 115 is placed 50 to 100 mm from the distal tip of the tube.

[0082] In another embodiment, the device comprises a wireless configuration (FIG. 1C; FIG. 2A-2F; FIG. 4A). In the wireless configuration, the nasal cavity device may further comprise an extra nasal antenna 220 optionally comprising a 13.56 MHz radiofrequency transmit coil with a diameter of 25 mm to 55 mm. In the wireless configuration, the nasal cavity device may also further comprise an intranasal antenna 210 further comprising a flexible circuit board 200.

[0083] Also illustrated in FIG. IF is a cross sectional schematic of the flexible tube of the nasal cavity device 90. The cross sectional schematic illustrates the tube wall 185 which extends from the proximal end 110 to the distal tip 120. The tube wall 185 has an inner surface 160 and an outer surface 155 wherein the inner surface defines a principle lumen 170 that extends between the proximal end and the distal tip. Also illustrated is a secondary lumen 176 adjacent to the tube outer wall surface and extending there along. Also illustrated in FIG. 3 is an exemplary preferred embodiment of the present invention. A removable rod or stylus 190 is inserted into the principle lumen 170 of the flexible tube 100 for reliable positioning of the electrophysiological device in a subject’s nasal cavity.

[0084] Also illustrated in FIG. 3 is a schematic showing lateral cross-section of an example of a nasal cavity device. Illustrated is a removable rod or stylus 190 inserted into the principle lumen 170 of the flexible tube for reliable positioning of the electrophysiological device, for example, an electrode contact 145 in a subject’s nasal cavity. FIG. 3 also illustrates an exemplary embodiment wherein an electrode contact 145 is a ring fitted to the surface of the flexible tube, providing a circumferential coverage. A wire 212, provides electrical communication with the electrode at the wire distal end. The wire proximal end may connect directly to controllers or acquisition equipment. The wire proximal end may connect to a similar ring electrode at an electrode tail (e.g., in the proximal direction from the electrode ring illustrated in FIG. 3). The contact may also be an electrically-conductive plate, such as a metal plate), placed over part of the tube surface, with a wire extending through and down the tube. The basic configuration is for an electrically conductive element, exemplified as a wire, that connects the electrode contact to a tail contact by extending through the tube wall and longitudinally traversing the tube lumen toward the proximal end. In this manner, the wire can traverse the wall of the flexible tube and provide electrical connection to signal acquisition and/or signal generation equipment, such as a power source, computer and memory.

[0085] Example 2: Exemplary nasal cavity device for measuring, recording, and modulating brain and respiratory activity through the nasal cavity

[0086] Disclosed herein is a tool for measuring, recording, and modulating brain and respiratory activity through the nasal cavity, with wired and wireless configurations.

[0087] In an exemplary embodiment, the device is an apparatus comprising a multi-contact electrode, a sponge-based stabilizer, a sponge-based placement marker, a stylus-based placement system, a delivery lumen, and a modulation component, designed to be placed in the nasal cavity at various locations including the lower, middle, and superior turbinates, and the olfactory cleft, such that it can measure, record, and modulate brain and respiratory signals, including signals from the olfactory and respiratory epithelium; the trigeminal and olfactory nerves, and from the olfactory bulb, olfactory tract, and ventral brain; in both hard-wired and wireless configurations. This device can be used for research, including measuring, recording and modulating respiratory and olfactory function, and states of consciousness, and for clinical purposes, including diagnosis, treatment, and prevention of brain, consciousness, olfactory, respiratory, and nasal pathologies.

[0088] Wired Embodiment: In an embodiment, the nasal cavity device comprises a series of electrode contacts made of an 80% platinum and 20% iridium alloy optionally 100% platinum, or optionally other metals and alloys and materials that have design characteristics that optimize electrical recording and/or stimulation exposed to nasal mucosa on an outer flexible tube having a proximal end, a principal lumen extending to the proximal end, and at least one radial aperture through the wall communicating with the lumen as well as a secondary lumen adjacent to the tube outer-wall surface and extending there along. A removable 0.2 mm to 0.6 mm rod optionally made of stainless steel or optionally made of other metals and alloys and materials that have design characteristics that optimize electrode placement will be inserted into the 0.3 mm to 0.7 mm lumen. A compressed, dehydrated sponge composed of hydroxylated polyvinyl acetate is attached to the outer side of the tube 15 mm to 35 mm from the distal tip. A flexible plastic or metal clip is placed 50 mm to 100mm from the distal tip of the tube. The proximal part of the electrode comprises nickel-chromium contacts that are connected to the recording system with an adaptor.

[0089] Flexible tube: The flexible tube may optionally be made of polyurethane or other materials that have design characteristics that optimize the placement and shaping. The distal to proximal length of the tube is 20 mm to 800 mm. The outer radius of the tube is 0.5 mm to 1.25 mm. The radius of the internal lumen is 0.3 mm to 0.7 mm.

[0090] Electrode contacts: Distal electrode contacts may comprise an 80% platinum and 20% iridium alloy, optionally 100% platinum, or optionally other metals and alloys and materials that have design characteristics that optimize the electrical recording and/or stimulation. Each contact is 0.1 pm to 2.5 mm in length with a radius of 0.5 to 1.5 mm, with nickel-chromium wires in polyurethane tubing leading to nickel-chromium tail contacts. Each electrode may have a plurality of contacts placed at the 4 to 60 mm distal part of the electrode. Center to center distance of the distal contacts is 0.1 mm to 5.0 mm.

[0091] Sponge: Optionally, a compressed, dehydrated trapezoid or square sponge optionally composed of hydroxylated polyvinyl acetate is attached to the outer side of the tube 15 mm to 35 mm from the distal tip. The location of the sponge is customizable based on the individual anatomy. The thickness of the dehydrated sponge is 0.8 mm to 2.2 mm. The size of the dehydrated sponge is about 7mm square or about 7X2X8X6 mm right square.

[0092] Internal lumen: Each flexible tube has a principal lumen extending to the proximal end, and at least one radial aperture through the wall communicating with the lumen as well as a secondary lumen adjacent to the tube distal outer- wall surface. The radius of the lumen is 0.3 mm to 0.7 mm.

[0093] Internal lumen stylus: Optionally, a removable 0.2 mm to 0.6 mm rod made of stainless steel or other metals and alloys and materials that have design characteristics that optimize electrode placement are inserted into the 0.3 to 0.7 mm lumen.

[0094] Wireless Embodiment [0095] The device optionally comprises a plurality of electrode contacts made of an 80% platinum and 20% iridium alloy optionally 100% platinum, optionally other metals and alloys and materials configured to optimize electrical recording and/or stimulation exposed to nasal mucosa on an outer flexible tube having a proximal end. The electrode contacts have a form factor configured to facilitate electrical interfacing. For example, the contact material should be able to conform around the tube (e.g., bend) and have a minimal profile extending out past the tube surface. For example, extending a step distance from the underlying flexible tube outer surface that is less than 5 mm, less than 2 mm, less than 1 mm, less than 100 pm and less than 10 pm, so long as the interfacing is not adversely impacted. Shape and form of contact are relevant as they influence impedance and area of interface (recording/stimulating area). Shape and form may be selected depending on the particular application of interest.

[0096] Optionally, a removable 0.2 to 0.6 mm rod optionally made of stainless steel or other metals and alloys and materials that have design characteristics that optimize electrode placement is inserted into the 0.3 mm to 0.7 mm lumen. Optionally, a compressed, dehydrated sponge composed of hydroxylated polyvinyl acetate is attached to the outer side of the tube 15 mm to 35 mm from the distal tip. A flexible printed circuit board (PCB) and receiving coils are attached to the outer side of the tube 15 mm to 35 mm from the distal tip facing the frontal wall of the nasal cavity. The removable rod material may be selected to balance its stiffness and flexibility for insertion of the nasal cavity device. Stiffness may selected such that the removable rod provides maneuverability of the nasal cavity device within the nasal passage while also having a flexibility that may enable the user to bend the removable rod into a shape such that the removable rod retains that shape. For example, the user may desire to place a small (~15 degree) bend approximately 3 cm from the distal end in order to help guide the place of the tube with precision

[0097] Intra Nasal antenna: Optionally, a 12-tum coil is fabricated on a flexible 0.26 mm polyimide substrate. Optionally, the chip is wire-bonded on the PCB, which is responsible for continuous power harvesting and demodulating the incoming data. The construction of the implant may include the following components: (1) Customized chip, (2) Silver Epoxy, (3) Cuf electrodes (PerenniaFLEX Model 304, LivaNova PLC, London, United Kingdom), (4) Flexible polyimide PCB, (5) 22 pF capacitor (AVX Corporation, 04026D226MAT2A), (6) light-emitting diode (LED) chip (Kingbright,APT1608LZGCK), (7) 47 k resistor (Rohm

Semiconductor, ESR01MZPJ473), (8) 10 pF capacitor (AVX Corporation, 04026D106MAT2 A), (9) 47 pF capacitor (Murata Electronics, GCM1555C1H470FA16D). [0098] Extra nasal antenna: Optionally, a 13.56 MHz radiofrequency transmit coil is fabricated using a 1.6 mm FR4 substrate with six turns on each side. Optionally, the radiofrequency transmit coil has a diameter of 25 mm to 55 mm and measured quality factor (Qt) is 39. On the receiver side, for maximum current delivery, the inductor is resonated with a high- quality factor (Q> 200) 47 pF capacitor. Unlike the transmitter coil, the inductance cannot be directly measured due to the high parasitic inductance of probes and the relatively small size of the receiver coil. The frequency at which minimum power is required to turn on the LED is the resonance frequency of the coil.

[0099] Electrode contacts: Distal contacts optionally comprise 80% platinum and 20% iridium alloy, optionally 100% platinum, or optionally other metals and alloys and materials that have design characteristics that optimize the electrical recording and/or stimulation. Each contact can be 0.1 pm to 2.5 mm in length with a radius of 0.5 mm to 1.5 mm, with nickel-chromium wires in polyurethane tubing leading to the PCB and coils. Each electrode may have 2 to 50 contacts placed at the 4 to 60 mm distal part of the electrode. Center to center distance of the distal contacts is 0.1 mm to 5.0 mm.

[0100] Sponge: Optionally, a compressed, dehydrated trapezoid or square sponge composed of hydroxylated polyvinyl acetate is attached to the outer side of the tube 15 mm to 35 mm from the distal tip. The location of the sponge is customizable based on the individual anatomy. The thickness of the dehydrated sponge is 0.8 mm to 2.2 mm. Optionally, the size of the dehydrated sponge will be 7mm square or 7X2X8X6 mm right square.

[0101] Internal lumen: Each flexible tube has a principal lumen extending to the proximal end, and at least one radial aperture through the wall communicating with the lumen as well as a secondary lumen adjacent to the tube distal outer- wall surface. The radius of the principle lumen is 0.3 mm to 0.7 mm.

[0102] Internal lumen stylus: Optionally, a removable 0.2 to 0.6 mm rod optionally made of stainless steel or optionally other metals and alloys and materials that have design characteristics that optimize electrode placement are inserted into the 0.3 mm 0.7 mm lumen.

[0103] Example 3: Exemplary method for measuring, recording, and modulating brain and respiratory activity through the nasal cavity

[0104] Disclosed herein is a method and device for measuring, recording, and modulating brain and respiratory activity through the nasal cavity, with wired and wireless configurations. [0105] The human olfactory bulb is vastly under- studied. Due to its anatomical location and small size, attempts to measure signals from the human olfactory bulb using functional neuroimaging have been largely unsuccessful. Recent work using surface electrodes placed near the bridge of the nose have claimed to pick up electrical signals originating in the human bulb, however, these methods require an extremely large number of trials, and do not have sufficient signal to noise ratio to allow examination of oscillatory activity at the single trial level. This limits their use as a tool to obtain a full understanding of the oscillatory dynamics of neural activity in the olfactory bulb, and how these dynamics relate to cognition and behavior in real time.

[0106] Here, we developed a novel approach to measuring electrophysiological signals from the human olfactory bulb using a flexible multi-contact electrode placed at the base of the cribriform plate inside the nasal cavity. Using this approach, we are able to obtain recordings from an electrode that is optionally less than 2 mm away from the human bulb, separated only by the thinnest part of the skull. Our findings suggest that oscillatory activity in the human olfactory bulb is dominated by beta and gamma frequencies. Consistent with rodent work showing that olfactory bulb beta and gamma oscillations are generated by the same circuit, our data suggest that beta and gamma oscillations in the human olfactory bulb compete, defining distinct neural states that switch back and forth depending on cognitive state, sensory input, and breathing rhythms. This method provides novel insights for basic research into the mechanisms of the olfactory system, but also provides:

[0107] 1. a method for recording olfactory brain signals from the olfactory epithelium, olfactory bulb and brain

[0108] 2. a method for delivering electrical, optical or mechanical stimulation into the human olfactory epithelium, olfactory bulb and brain

[0109] 3. a diagnostic method for disease, including especially those with neurological, psychiatric, nasal or olfactory symptoms

[0110] 4. a treatment method for disease, including especially those with neurological, psychiatric, nasal or olfactory symptoms

[0111] Also provided is a method for using in recording and modulating olfactory epithelium and olfactory bulb electrophysiological signals by placing a recording and stimulating device for example, such a tool may be an ultrasonic probe, a multi-contact electrode, an optical stimulator, or similar device such that the device is wired or wireless and such that the device may record and stimulate or record only or stimulate only within the nasal cavity inside the olfactory cleft to be placed on the inferior aspect of the cribriform plate. Such a device is then connected to an electrophysiological data acquisition and stimulation system, or equivalent system appropriate for the device signal type. Through the use of this method's device placement and connection to a recording/stimulating system, this method can be used to:

[0112] 1. record electrophysiological signals from the olfactory epithelium, and separately and simultaneously from the olfactory bulb, in order to precisely and accurately assess the electrophysiological activity therein,

[0113] 2. deliver electrical stimulation to the olfactory epithelium, and separately and simultaneously to the olfactory bulb,

[0114] 3. use such recordings and/or stimulation in the pursuit of research including neuroscientific research on the human olfactory system, human sensory processing and neural activity in the human brain,

[0115] 4. use such recordings and/or stimulation in the pursuit of diagnosis of diseases including and especially such diseases with neurological, psychiatric, nasal or olfactory symptoms,

[0116] 5. use such recordings and/or stimulation in the pursuit of treatment of diseases including and especially such diseases with neurological, psychiatric, nasal or olfactory symptoms,

[0117] 6. use such recordings and/or stimulation in the pursuit of modulation of diseases including and especially such diseases with neurological, psychiatric, nasal or olfactory symptoms,

[0118] 7. use such recordings and/or stimulation in the pursuit of separately quantifying peripherally and centrally originating signals in the human olfactory bulb.

[0119] Example 4: An exemplary method for placing a nasal cavity device in subject’s nasal cavity

[0120] Step 1 : Place the device inside the nasal cavity on the olfactory epithelium inferior to the human cribriform plate. This is done by first using a stiffening tool, typically a stylus to hold the device wire-rigid, excepting the distal end (approximately 3 cm), grasping the device with forceps approximately 10 cm from the distal end, and typically with the aid of a nasal endoscope to visually assess the progress of placement, insert the device into the nasal cavity moving along the nasal septum toward the olfactory cleft such that the distal end of the device is placed along the inferior aspect of the cribriform plate at the top of the olfactory cleft such that the recording/ stimulating aspects of the device lay under the perforations of the cribriform plate.

[0121] Step 2: Secure the device between the septal wall and the middle turbinate using an absorbent sponge or inflatable catheter attached to the device at the point where it touches the most anterior part of the middle turbinate. Secure the device to the entry of the nasal cavity using a clip or similar device which grasps the nasal septum at the nostrils.

[0122] Step 3: Connect the device to the data acquisition or stimulation system.

[0123] Example 5: Intracranial Recording Process and Relevant Results

[0124] As shown in Fig. 11, a depth electrode designed for intracranial recordings was repurposed and placed at the top of the nasal cavity below the cribriform plate. Placement was conducted by an ENT surgeon using a camera-guided endoscope. The proper position of the electrode just below the cribriform plate was verified by a low-res CT scan of the nasal cavity, as shown in the two right panels of FIG. 11, and re-verified after the experiment to confirm that the electrode did not move. Electrophysiological data were recorded using a Neuralynx acquisition system with a sampling rate of 2000Hz. Nasal airflow was recorded with a piezoelectric pressure sensor attached to a nasal cannula at the nares. Odors were delivered by a 12-channel computer- controlled air-dilution olfactometer.

[0125] FIG. 12 shows that odor-evoked gamma oscillations are diminished by anosmia induced by local lidocaine application.

[0126] In particular, the participant performed 120 trials of an odor detection task, which is shown in FIG. 12. Following the 20th trial, lidocaine was applied inside the nasal cavity, at the olfactory cleft. This resulted in unilateral anosmia when odors were presented to the ipsilateral nostril. Odor detection trials were continued during the temporary anosmia. Smell perception returned after the 80th trial. This experiment confirmed that the responses observed in the present invention were not driven by motion artifact during sniffing. Moreover, this confirmed that the responses observed relied on a smell percept and not other cognitive aspects of the task.

[0127] FIG. 13 shows that odor-evoked gamma oscillations are reduced and delayed when odor is delivered through the contralateral nostril. [0128] To validate the origin of the recorded signal from the ipsilateral olfactory bulb, odors were presented to either the ipsilateral or contralateral nostril. As shown in FIG. 13, compared to ipsilateral odors, responses to contralaterally presented odors were reduced in the high gamma range, and significantly delayed in the gamma range (T statistic= -2.5,df= 129 , P-value < 0.01) (~ 130ms), as shown in FIG. 13 right upper panel. Similarly, odor-induced decreases in beta power were significantly delayed when odors were presented contralaterally (T statistic= -5.8, df= 129 , P-value < 0.001), as shown in FIG. 13 right lower panel. These results suggest the signals observed in the present invention are originating in the ipsilateral olfactory bulb, and are unlikely to be volume conducted from the brain.

[0129] As shown in FIG. 14, two oscillatory modes compete across the sniff cycle during an attentive olfactory task.

[0130] In particular, the spectral density shows a prominent bump at -25-50 Hz. A Hilbertbased spectrogram analysis revealed that this bump is comprised of two distinct oscillations, a slower (-25-34) and faster (~35-50Hz) rhythm (figure below). Oscillations in the human olfactory bulb are dominated by one of these two oscillatory modes at any given time. Examination of the ratio of each band relative to the whole spectrum showed that oscillations in these two bands were significantly negatively correlated, supporting the idea that they comprise distinct oscillatory modes, or neural states of the human bulb.

[0131] Certain exemplary aspects and embodiments

[0132] Various aspects are contemplated and disclosed herein, several of which are set forth in the paragraphs below. It is explicitly contemplated and disclosed that any aspect or portion thereof can be combined to form an aspect. Moreover, the terms “any preceding aspect” and “any one of the preceding aspects” means any aspect that appears prior to the aspect that contains such phrase (for example, the sentence “Aspect 15: the device or method of any of the preceding Aspects, wherein the removable rod has a higher stiffness than . . .” means that any Aspect prior to Aspect 15 is referenced, including letter versions). For example, it is contemplated and disclosed that, optionally, any method or system of any of the below aspects may be useful with or combined with any other aspect provided below. Further, for example, it is contemplated and disclosed that any embodiment or aspect described above may, optionally, be combined with any of the below listed aspects or any portion(s) thereof.

[0133] Aspect 1 : a nasal cavity device for electrophysiologically interfacing with a biological tissue of a subject comprising: a flexible tube having: a proximal end, a distal tip, and a tube wall extending from the proximal end to the distal tip, the tube wall having an inner surface and an outer surface, wherein the inner surface defines a principle lumen that extends between the proximal end and the distal tip; an electrophysiological device at least partially disposed on the flexible tube outer surface at or adjacent to the distal tip; a stabilizer connected to the flexible tube outer surface configured to reliably position at least a portion of the nasal cavity device in a nasal cavity during use; wherein the flexible tube is configured to establish electrical communication between the electrophysiological device and the biological tissue; and wherein the electrophysiological device is configured to electrically interface with the biological tissue.

[0134] Aspect 2: a method of electrophysiologically interfacing a nasal cavity device with a biological tissue of a subject, said method comprising the steps of: placing at least a portion of the electrophysiological device in electrical communication with the biological tissue, wherein the biological tissue is located in a nasal cavity of the subject; interfacing with the biological tissue, wherein the interfacing comprises: applying an electrical stimulation signal to at least a portion of the biological tissue from the electrophysiological device; and/or measuring an electrophysiological parameter from at least a portion of the biological tissue with the electrophysiological device; thereby electrophysiologically interfacing the nasal cavity device with the biological tissue.

[0135] Aspect 3 : the device or method of any of the preceding Aspects, wherein the electrophysiological device comprises one or more electrodes configured to: electrically stimulate the biological tissue; record an electrical parameter generated by the biological tissue; or electrically stimulate the biological tissue and record an electrical parameter generated by the biological tissue.

[0136] Aspect 4: the device or method of any of the preceding Aspects, wherein the biological tissue is optionally the olfactory epithelium, optionally the respiratory epithelium, optionally the trigeminal nerves, optionally the olfactory nerves, optionally cranial nerve zero, optionally the sympathetic nerves, optionally the parasympathetic nerves, optionally the olfactory bulb, optionally the olfactory tract, optionally the ventral brain, optionally the limbic and optionally any combination of these.

[0137] Aspect 5: the device or method of any one of the preceding Aspects, wherein the nasal cavity device is optionally configured to be supported inside the nasal cavity of a subject on an olfactory epithelium inferior to the cribriform plate. [0138] Aspect 6: the device or method of any one of the preceding Aspects, wherein the stabilizer is controllably positionable along the flexible tube outer surface at a user-selected location according to an anatomical parameter.

[0139] Aspect 7: the device or method of any one of the preceding Aspects, wherein the stabilizer has a size configured to extend between the flexible tube outer surface and an inner surface of the nasal cavity.

[0140] Aspect 8: The device or method of any one of the preceding Aspects, wherein the stabilizer is configured to apply tension upon deployment including spring-based tension or a mechanical material-based tension.

[0141] Aspect 9: The device or method of any one of the preceding Aspects, wherein the stabilizer comprises a material selected from the group of: a silicone, a urethane, an elastomer, a polymer, or any combination of these.

[0142] Aspect 10: The device or method of any one of the preceding Aspects, wherein the stabilizer comprises an absorptive sponge, an inflatible catheter, a flap, a ring, a wedge, or a u- shape stabilizer.

[0143] Aspect 11 : The device or method of any one of the preceding Aspects,, wherein the stablilizer is an absorptive material comprising dehydrated hydroxylated polyvinyl acetate, synthetic biodegradable fragmenting fowm, oxidized nitrocellulose, cotton, non-woven gauze, polyether-polyurethane, medical-grade foam, a resorbable oxidized cellulose, a hemostatic matrix, or a thrombin soaked hemostatic device prepared purified porcine skin gelatin.

[0144] Aspect 12: the device or method of any one of the preceding Aspects, wherein the dehydrated absorptive sponge has thickness greater than or equal to 0.5 mm and less than or equal to 2.2 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.55 mm and less than or equal to 2.15 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.6 mm and less than 2.1 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.65 mm and less than 2.05 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.70 mm and less than 2.0 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.75 mm and less than or equal to 1.95 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.8 mm and less than or equal to 1.9 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.85 mm and less than or equal to 1.85 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.9 mm and less than or equal to 1.8 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 0.95 mm and less than or equal to 1.75 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 1.0 mm and less than or equal to 1.7 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 1.05 mm and less than or equal to 1.65 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 1.10 mm and less than or equal to 1.6 mm. Optionally, the dehydrated absorptive sponge has a thickness greater than or equal to 1.15 mm and less than or equal to 1.55 mm. Optionally, the absorptive sponge has a thickness greater than or equal to 1.20 mm and less than or equal to 1.50 mm. Optionally, the absorptive sponge has a thickness greater than or equal to 1.25 mm and less than or equal to 1.50 mm. Optionally, the absorptive sponge has a thickness greater than or equal to 1.30 mm and less than or equal to 1.45 mm. Optionally, the absorptive sponge has a thickness greater than or equal to 1.35 mm and less than or equal to 1.40 mm. Any range and value therebetween 0.5 mm and 2.2 mm is explicitly contemplated and disclosed herein.

[0145] Aspect 13: the device or method of any one of the preceding Aspects, wherein the stabilizer is located 15 mm to 35 mm the distal tip. Optionally, the dehydrated absorptive sponge is a square or trapezoid. Optionally, the size of the square is less than or equal to 7 mm square and the size of the trapezoid is less than or equal to 7x2x8x6 mm square.

[0146] Aspect 14: the device or method of any of the preceding Aspects, wherein the nasal cavity device further comprises a removable rod positioned in the principle lumen.

[0147] Aspect 15: the device or method of any of the preceding Aspects, wherein the removable rod has a higher stiffness than the flexible tube for reliable positioning of the electrophysiological device at a location in the nasal cavity.

[0148] Aspect 16: the device or method of any of the preceding Aspects, wherein the removable rod has a diameter of 0.2 mm to 0.6 mm. Optionally, the removable rod has a diameter of 0.25 mm to 0.55 mm. Optionally, the removable rod has a diameter of 0.3 mm to 0.5 mm. Optionally, the removable rod has a diameter of 0.35 mm to 0.5 mm. Optionally, the removable rod has a diameter of 0.35 mm to 0. 45 mm. Optionally, the removable rod has a diameter of about 0.5 mm. Any range and value therebetween 0.2 mm and 0.6 mm is explicitly contemplated and disclosed herein.

[0149] Aspect 17: the device or method of any of the preceding Aspects, wherein the removable rod comprises stainless steel, a metal, a metal alloy, or a plastic. [0150] Aspect 19: the device or method of any of the preceding Aspects, wherein the electrophysiological device is selected from the group consisting of an an ultrasonic probe, one or more electrodes, a multi-contact electrode, an electrode strip, a directional-contact multicontact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, a transcranial direct current stimulator, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these.

[0151] Aspect 20: the device or method of any of the preceding Aspects, wherein the one or more electrodes comprises between 1 to 50 electrode contacts. Optionally, the one or more electrodes comprises 5 to 45 electrode contacts. Optionally, the one or more electrodes comprises 10 to 40 electrode contacts. Optionally, the one or more electrodes comprises 15 to 35 electrode contacts. Optionally, the one or more electrodes comprises 20 to 30 electrode contacts. Optionally, the one or more electrodes comprises 25 electrode contacts. Any range and value therebetween 1 to 50 is explicitly contemplated and disclosed herein.

[0152] Aspect 21 : the device or method of any of the preceding Aspects, wherein the electrode contacts each have a length of 0.1 pm to 2.5 mm. Optionally, the electrode contacts each have a length of 1.0 pm to 2.4 mm. Optionally, the electrode contacts each have a length of 100 pm to 2.3 mm. Optionally, the electrode contacts each have a length of 200 pm to 2.2 mm. Optionally, the electrode contacts each have a length of 300 pm to 2.1 mm. Optionally, the electrode contacts each have a length of 400 pm to 2 mm. Optionally, the electrode contacts each have a length of 500 pm to 1.9 mm. Optionally, the electrode contacts each have a length of 600 pm to 1.8 mm. Optionally, the electrode contacts each have a length of 700 pm to 1.7 mm. Optionally, the electrode contacts each have a length of 800 pm to 1.6 mm. Optionally, the electrode contacts each have a length of 900 pm to 1.5 mm. Optionally, the electrode contacts each have a length of 1.0 mm to 1.4 mm. Optionally, the electrode contacts each have a length of 1.1 mm to 1.3 mm. Optionally, the electrode contacts each have a length of about 1.2 mm. Any range and value therebetween; 0.1 pm to 2.5 mm is explicitly contemplated and disclosed herein.

[0153] Aspect 22: the device or method of any of the preceding Aspects, wherein the electrode contacts each have a center to center distance of 0.1 mm to 5.0 mm. Optionally, the electrode contacts each have a center to center distance of 0.3 mm to 4.8 mm. Optionally, the electrode contacts each have a center to center distance of 0.5 mm to 4.6 mm. Optionally, the electrode contacts each have a center to center distance of 0.7 mm to 4.4 mm. Optionally, the electrode contacts each have a center to center distance of 0.9 mm to 4.2 mm. Optionally, the electrode contacts each have a center to center distance of 1.1 mm to 2.6 mm. Optionally, the electrode contacts each have a center to center distance of 1.3 mm to 4.0 mm. Optionally, the electrode contacts each have a center to center distance of 1.5 mm to 3.8 mm. Optionally, the electrode contacts each have a center to center distance of 1.7 mm to 3.6 mm. Optionally, the electrode contacts each have a center to center distance of 1.9 mm to 3.4 mm. Optionally, the electrode contacts each have a center to center distance of 2.1 mm to 3.2 mm. Optionally, the electrode contacts each have a center to center distance of 2.3 mm to 3.0 mm. Optionally, the electrode contacts each have a center to center distance of 2.5 mm to 2.8 mm. Optionally, the electrode contacts each have a center to center distance of about 2.6 mm. Any range and value therebetween 0.1 mm to 5.0 mm is explicitly contemplated and disclosed herein.

[0154] Aspect 23 : the device or method of any of the preceding Aspects, wherein at least one of the electrode contacts comprises a biocompatible metal or a metal alloy. Optionally, the metal or metal alloy comprises Pt, Ir, Au, Ag, Ni, Cu, Ti, Co, Ni, Mg, Cr, or any combination of these.

[0155] Aspect 24: the device or method of any of the preceding Aspects, wherein at least one of the electrode contacts comprises a biocompatible ceramic, including: aluminum oxide, zirconium oxide, tin oxide, bioglass, or any combination of these.

[0156] Aspect 25: the device or method of any of the preceding Aspects: wherein at least one of the elctrode contacts comprises carbon, including: graphite, vitreous carbon, vitro-ceramic, or any combination of these.

[0157] Aspect 26: the device or method of any of the preceding Aspects, wherein at least one of the electrode contacts comprises at least 80% Pt and up to 20% Ir. Optionally, at least one of the electrode contacts comprises at least 85% Pt and up to 15% Ir. Optionally, at least one of the electrode contacts comprises at least 90% Pt and up to 10% Ir. Optionally, at least one of the electrode contacts comprises at least 95% Pt and 5% Ir. Optionally, at least one of the electrode contacts comprises 100% Pt. Optionally, at least one of the electrode contacts comprises at least 70% Pt and up to 30% Ir. Optionally, at least one of the electrode contacts comprises at least 60% Pt and up to 40% Ir. Optionally, at least one of the electrode contacts comprises at least 50% Pt and up to 50% Ir. Any range and value 50% to 100% Pt and 0% to 50% Ir is explicitly contemplated and disclosed herein.

[0158] Aspect 27: the device or method of any of the preceding Aspects, wherein the flexible tube further comprises one or more substance delivery pores extending between the outer and inner surface. [0159] Aspect 28: the device or method of any of the preceding Aspects, wherein the flexible tube comprises a polymer, including polyurethane, silicone, polyethylene, polyamide, polyether ketone, polyethylene, polyethylene terephthalate, polymethylmethacrylate, polystyrene, polytetrafluorethylene, a synthetic rubber, or any combination of these.

[0160] Aspect 29: the device or method of any of the preceding Aspects, wherein the flexible tube is characterized by a tube parameter selected from the group consisting of: a wall thickness ofbetween O. l mm to 1.0 mm; a Young’s modulus of O.Ol GPa to 100 GPa; a bending stiffness less than or equal to 200 g.

[0161] Aspect 30: the device or method of any of the preceding Aspects, wherein the flexible tube has a length from proximal end to distal tip of between 20 mm to 800 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 100 mm to 750 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 150 mm to 700 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 200 mm to 650 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 250 mm to 600 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 300 mm to 550 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 350 mm to 500 mm. Optionally, the flexible tube has a length from proximal end to distal tip of between 400 mm to 450 mm. Any range and value therebetween 20 mm to 800 mm is explicitly contemplated and disclosed herein.

[0162] Aspect 31 : the device or method of any of the preceding Aspects, wherein the flexible tube has a radius of 0.5 mm to 1.25 mm. Optionally, the flexible tube has a radius of 0.6 mm to 1.15 mm. Optionally the flexible tube has a radius of 0.7 mm to 1.05 mm. Optionally, the flexible tube has a radius of 0.8 mm to 0.95 mm. Optionally, the flexible tube has a radius of about 0.9 mm. Optionally, the flexible tube has a radius of about 2.0 mm. Any range and value 0.5 mm to 1.25 mm is explicitly contemplated and disclosed herein.

[0163] Aspect 32: the device or method of any of the preceding Aspects, wherein the flexible tube further comprises a secondary lumen adjacent to the tube outer wall.

[0164] Aspect 33 : the device or method of any of the preceding Aspects, further comprising a flexible clip disposed on the outer surface of the flexible tube.

[0165] Aspect 34: the device or method of any of the preceding Aspects, wherein the electrophysiological device is operably connected to a controller comprising at least one of a recording system and a modulation system. [0166] Aspect 35: the device or method of any of the preceding Aspects, wherein the electrophysiological device is connected to the controller via at least one wire.

[0167] Aspect 36: the device or method of any of the preceding Aspects, wherein the electrophysiological device is connected to the controller via a wireless configuration comprising an extra nasal antenna supported on the flexible tube outer surface at a separation distance from the flexible tube distal end between 15 mm to 35 mm.

[0168] Aspect 37: the device or method of any of the preceding Aspects, further comprising an intra nasal antenna comprising a flexible circuit board electronically connected to the electrophysiological device and an extra nasal antenna comprising a radiofrequency transmit coil.

[0169] Aspect 36: the device or method of any of any of the preceding Aspects, wherein the intra nasal antenna is a 12 turn coil fabricated on a flexible polyamide substrate.

[0170] Aspect 39: the device or method of any of the preceding Aspects, wherein the nasal cavity device is placed at a base of the subject’s cribriform plate in the subject’s nasal cavity.

[0171] Aspect 40: the device or method of any of the preceding Aspects, wherein at least a portion of the nasal cavity device is adjacently positioned next to or under perforations of the cribriform plate including within 5 mm of the olfactory bulb. Optionally, the nasal cavity device is adjacently positioned next to or under perforations of the cribriform plate including within 4 mm of the olfactory bulb. Optionally, the nasal cavity device is adjacently positioned next to or under perforations of the cribriform plate including within 3 mm of the olfactory bulb. Preferably, the nasal cavity device is adjacently positioned next to or under perforations of the cribriform including within 2mm of the olfactory bulb.

[0172] Aspect 41 : the device or method of any of the preceding Aspects, wherein the step of placing further comprises: temporarily stiffening at least a portion of the flexible tube of the nasal cavity device by inserting a removable stiffening tool into the principle lumen to generate a stiffened flexible tube; grasping the stiffened flexible tube with a holder at a location physically separated from the distal end of the stiffened flexible tube; and inserting the nasal cavity device into the nasal cavity by moving the stiffened flexible tube along a nasal septum toward an olfactory cleft until the distal end of the nasal cavity device is placed along an inferior aspect of the cribriform plate and at a top of the olfactory cleft.

[0173] Aspect 42: the device or method of any of the preceding Aspects, wherein the step of placing further comprises securing the nasal cavity device between a septal wall and a middle turbinate using the stabilizer at a location where the stabilizer touches a most anterior part of the middle turbinate.

[0174] Aspect 43 : the device or method of any of the preceding Aspects, wherein the step of placing the nasal cavity device further comprises securing the nasal further comprises securing the nasal cavity device to an entry of the nasal cavity using a flexible clip connected to the nasal cavity device.

[0175] Aspect 44: the device or method of any of the preceding Aspects, wherein the step of placing the nasal cavity device further comprises removing the removable stiffening tool.

[0176] Aspect 45: the device or method of any of the preceding Aspects, further comprising the step of using the interfacing step to diagnose a disorder impacting a nose and/or sinuses of the subject and/or sinuses of the subject, a smell or taste disorder, a neurological disease impacting the olfactory bulb, or a neurological disease impacting a central nervous system of the subject.

[0177] Aspect 46: the device or method of any of the preceding Aspects, wherein the disorder of the nose and/or sinuses comprises sinusitis with or without polyps, allergic rhinitis, cerebrospinal fluid leak, deviated septum, fungal sinusitis, and nasal masses; the smell or taste disorder comprises anosmia, ageusia, hyposmia, phantosmia, and congenital anosmia; the neurological disease impacting the olfactory bulb comprises Kallmann syndrome, epilepsy, and olfactory neuroblastoma; and the neurological disease impacting the central nervous system comprises Alzheimer’s Disease, Parkinson’s Disease, Autism, or Frontotemporal dementia.

STATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS

[0178] All references throughout this application, for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material; are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (for example, a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference).

[0179] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, exemplary embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the present invention and it will be apparent to one skilled in the art that the present invention may be carried out using a large number of variations of the devices, device components, methods steps set forth in the present description. As will be obvious to one of skill in the art, methods and devices useful for the present methods can include a large number of optional composition and processing elements and steps.

[0180] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising", "including", and "having" can be used interchangeably. The expression “of any of claims XX- YY” (wherein XX and YY refer to claim numbers) is intended to provide a multiple dependent claim in the alternative form, and in some embodiments is interchangeable with the expression “as in any one of claims XX- YY.”

[0181] When a group of substituents is disclosed herein, it is understood that all individual members of that group and all subgroups, are disclosed separately. When a Markush group or other grouping is used herein, all individual members of the group and all combinations and subcombinations possible of the group are intended to be individually included in the disclosure.

[0182] Every device, system, formulation, combination of components, or method described or exemplified herein can be used to practice the invention, unless otherwise stated.

[0183] Whenever a range is given in the specification, for example, a temperature range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the claims herein.

[0184] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their publication or filing date and it is intended that this information can be employed herein, if needed, to exclude specific embodiments that are in the prior art. For example, when composition of matter are claimed, it should be understood that compounds known and available in the art prior to Applicant's invention, including compounds for which an enabling disclosure is provided in the references cited herein, are not intended to be included in the composition of matter claims herein.

[0185] As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of' does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0186] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

We claim:

1. A nasal cavity device for electrophysiologically interfacing with a biological tissue of a subject comprising: a flexible tube having: a proximal end, a distal tip, a tube wall extending from the proximal end to the distal tip, the tube wall having an inner surface and an outer surface, wherein the inner surface defines a principle lumen that extends between the proximal end and the distal tip; an electrophysiological device at least partially disposed on the flexible tube outer surface at and/or adjacent to the distal tip; a stabilizer connected to the flexible tube outer surface configured to reliably position at least a portion of the nasal cavity device in a nasal cavity during use; wherein the flexible tube is configured to establish electrical communication between the electrophysiologial device and the biological tissue; and wherein the electrophysiological device is configured to electrically interface with the biological tissue.

2. The nasal cavity device of claim 1, wherein the electrophysiological device comprises one or more electrodes configured to: electrically stimulate the biological tissue; record an electrophysiological signal generated by the biological tissue; or electrically stimulate the biological tissue and record an electrical parameter generated by the biological tissue.

3. The nasal cavity device of any one of claims 1-2, wherein the biological tissue is selected from the group consisting of an olfactory and respiratory epithelium; trigeminal and olfactory nerves; olfactory bulb; olfactory tract; and ventral brain.

4. The nasal cavity device of any one of claims 1-3, wherein the nasal cavity device is configured to be supported inside the nasal cavity of the subject on an olfactory epithelium inferior to a cribriform plate.

5. The nasal cavity device of any one of claims 1-4, wherein the stabilizer is controllably positionable along the flexible tube outer surface at a user-selected location according to an anatomical paramater; and the stabilizer has a size configured to extend between the flexible tube outer surface and an inner surface of the nasal cavity.

6. The nasal cavity device of any one of claims 1-5, wherein the stabilizer is configured to apply tension upon deployment including a spring-based tension or a mechanical material-based tension.

7. The nasal cavity device of any one of claims 1-6, wherein the stabilizer comprises a material selected from the group of: a silicone, a urethane, an elastomer, a polymer, or any combination of these.

8. The nasal cavity device of any one of claims 1-7, wherein the stabilizer comprises an absorptive sponge, an inflatible catheter, a flap, a ring, a wedge, or a u-shape stabilizer.

9. The nasal cavity device of claims 1-8, wherein the stablilizer is an absorptive material comprising dehydrated hydroxylated polyvinyl acetate, synthetic biodegradable fragmenting fowm, oxidized nitrocellulose, cotton, non-woven gauze, polyether-polyurethane, medicalgrade foam, silicone, polyvinyl acetate, a resorbable oxidized cellulose, a hemostatic matrix, or a thrombin soaked hemostatic device prepared purified porcine skin gelatin.

10. The nasal cavity device of claims 1-9, wherein the stabilizer has a thickness greater than or equal to 0.5 mm and less than or equal to 2.2 mm.

11. The nasal cavity device of any one of claims 1-10, further comprising a removeable rod positioned in the principal lumen, wherein the removable rod has a higher stiffness than the flexible tube for reliable positioning of the electrophysiological device at a location in the nasal cavity, the nasal cavity device having a rod-inserted configuration for device positioning and a rod-removed configuration during use.

12. The nasal cavity device of claim 11, wherein the removable rod has a diameter of 0.2 mm to 0.6 mm.

13. The nasal cavity device of any one of claims 1-12, wherein the electrophysiological device is selected from the group consisting of: an ultrasonic probe, one or more electrodes, a multicontact electrode, an electrode strip, a directional-contact multi-contact electrode, an optical stimulator, a mechanical stimulator, a laser stimulator, an ultrasound stimulator, a magnetic stimulator, a transcranial direct current stimulator, a transacranial alternating current stimulator, a fiber-optic probe, a magetnoencehpalographic probe, or and any combination of these.

14. The nasal cavity device of any one of claims 1-13, wherein the one or more electrodes comprises between 2 to 50 electrode contacts located adjacent to and extending from the distal tip, wherein each electrode contact is individually addressable.

15. The nasal cavity device of claim 14, wherein the electrode contacts each have a length 0.1 pm to 2.5 mm and a center to center distance of 0.1 mm to 5.0 mm.

16. The nasal cavity device of any one of claims 11-15, wherein at least one of the electrode contacts comprises a biocompatible metal or a metal alloy, including: Pt, Ir, Au, Ag, Ni, Cu, Ti, Co, Ni, Mg, Cr, or any combination of these.

17. The nasal cavity device of claim 16, wherein at least one of the electrode contacts comprises at least 80% Pt and up to 20% Ir.

18. The nasal cavity device of claims 1-17, wherein at least one of the electrode contacts comprises a biocompatible ceramic, including: aluminum oxide, zirconium oxide, tin oxide, bioglass, or any combination of these.

19. The nasal cavity device of any one of claims 1-18, wherein at least one of the elctrode contacts comprises carbon, including: graphite, vitreous carbon, vitro-ceramic, or any combination of these.

20. The nasal cavity device of any one of claims 1-19, wherein the flexible tube further comprises one or more substance delivery pores extending between the outer and inner surface.

21. The nasal cavity device of any one of claims 1-20, wherein the flexible tube comprises a biocompatible polymer, including: polyurethane, silicone, polyethylene, polyamide, polyetherketone, polyethylene, polyethylene terephthalate, polymethylmethacrylate, polystyrene, polytetrafluorethylene, a synthetic rubber, or any combination of these.

22. The nasal cavity device of claim 1, wherein the flexible tube is characterized by a tube parameter selected from the group consisting of: a wall thickness of between 0.1 mm to 1.0 mm; a Young’s modulus of 0.01 GPa to 100 GPa; a bending stiffness less than or equal to 200 g.

23. The nasal cavity device of any one of claims 1-22, wherein the flexible tube has a length from the proximal end to the distal tip of between 20 mm to 800 mm.

24. The nasal cavity device of any one of claims 1-23, wherein the flexible tube has a radius of 0.5 mm to 1.25 mm.

25. The nasal cavity device of any one of claims 1-24, wherein the flexible tube further comprises a secondary lumen adjacent to the tube outer wall.

26. The nasal cavity device of any one of claims 1-25, further comprising a flexible clip disposed on the outer surface of the flexible tube.

27. The nasal cavity device of any one of claims 1-26, wherein the electrophysiological device is operably connected to a controller comprising at least one of a recording system and a modulation system.

28. The nasal cavity device of claim 27, wherein the electrophysiological device is connected to the controller via at least one wire.

29. The nasal cavity device of claim 28, wherein the electrophysiological device is connected to the controller via a wireless configuration comprising a flexible circuit board supported on the flexible tube outer surface at a separation distance from the flexible tube distal end between 15 mm to 35 mm.

30. The nasal cavity device of claim 29, further comprising an intra nasal antenna comprising a flexible circuit board electronically connected to the electrophysiological device and an extra nasal antenna comprising a radiofrequency transmit coil.

31. A method of electrophy siologically interfacing a nasal cavity device of any one of claims 1- 30 with a biological tissue of a subject, said method comprising the steps of: placing at least a portion of the electrophysiological device in electrical communication with the biological tissue, wherien the biological tissue is located in a nasal cavity of the subject; interfacing with the biological tisuse, werein the interfacing comprises: applying an electrical stimulation signal to at least a portion of the biological tissue from the electrophysiological device; and/or measuring an electricophysiological parameter from at least a portion of the biological tissue with the electrophysiological device; thereby electrophysiologically interfacing the nasal caivty device with the biological tissue.

32. The method of claim 31, wherein the biological tissue of the subject comprises at least one of an olfactory and respiratory epithelium; trigeminal and olfactory nerves, cranial nerve zero, sympathetic nerves, parasympathetic nerves, olfactory bulb, olfactory tract, ventral brain, limbic brain, or any combination of these.

33. The method of any one of claims 31-32, wherein at least a portion of the nasal cavity device is placed at a base of the subject’s cribriform plate in the subject’s nasal cavity.

34. The method of an one of claims 32-33, wherein at least a portion of the nasal cavity device is adjacently positioned next to or under the perforations of the cribriform plate, including within 2 mm of the olfactory bulb.

35. The method of any one of claims 31-34, wherein the step of placing further comprises: temporarily stiffening at least a portion of the flexible tube of the nasal cavity device by inserting a removable stiffening tool into the principle lumen to generate a stiffened flexible tube; grasping the stiffened flexible tube with a holder at a location physically separated from the distal end of the stiffened flexible tube; and inserting the nasal cavity device into the nasal cavity by moving the stiffened flexible tube along a nasal septum toward an olfactory cleft until the distal end of the nasal cavity device is placed along an inferior aspect of the cribriform plate and at a top of the olfactory cleft.

36. The method of any one of claims 31-35, wherein the step of placing further comprises securing the nasal cavity device between a septal wall and a middle turbinate using the stabilizer at a location where the stabilizer touches a most anterior part of the middle turbinate.

37. The method of any one of claims 31-36, wherein the step of placing the nasal cavity device further comprises securing the nasal cavity device to an entry of the nasal cavity using a flexible clip connected to the nasal cavity device.

38. The method of any one of claims 35-37, wherein the step of placing the nasal cavity device further comprises removing the removable stiffening tool.

39. The method of any one of claims 31-38, further comprising the step of using the interfacing step to diagnose a disorder impacting a nose and/or sinuses of the subject, a smell or taste disorder, a neurological disease impacting the olfactory bulb, or a neurological disease impacting a central nervous system of the subject.

40. The method of claim 39, wherein the disorder of the nose and/or sinuses comprises sinusitis with or without polyps, allergic rhinitis, cerebrospinal fluid leak, deviated septum, fungal sinusitis, and nasal masses; the smell or taste disorder comprises anosmia, ageusia, hyposmia, phantosmia, and congenital anosmia; the neurological disease impacting the olfactory bulb comprises Kallmann syndrome, epilepsy, and olfactory neuroblastoma; and the neurological disease impacting the central nervous system comprises Alzheimer’s Disease, Parkinson’s Disease, Autism, Schizophrenia, or Frontotemporal dementia.