US20050107851A1

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Publication number: US20050107851A1
Application number: US10/938,423
Authority: US
Inventors: Luis Taboada; Jackson Streeter
Original assignee: Individual
Current assignee: De Taboada Luis H; Photothera Inc; Pthera LLC
Priority date: 2002-11-01
Filing date: 2004-09-10
Publication date: 2005-05-19
Also published as: US7303578B2; US20050187595A1; US20100105977A1; US10758743B2; US20100010592A1; US20040138727A1; US10857376B2; JP2007504909A; US7309348B2; EP2266663A1; JP4224102B2; CA2537370A1; US20080004565A1; WO2005025672A1; EP1663392A1; US10653889B2; US20100010594A1; US20060253177A1; US20100094384A1

Abstract

A therapy apparatus for treating a patient's brain is provided. The therapy apparatus includes a light source having an output emission area positioned to irradiate a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further includes an element interposed between the light source and the patient's scalp. The element is adapted to inhibit temperature increases at the scalp caused by the light.

Description

CLAIM OF PRIORITY

This application is a continuation-in-part of, and claims priority under 35 U.S.C. § 120 to, U.S. patent application Ser. No. 10/682,379, filed Oct. 9, 2003, which is incorporated in its entirety by reference herein and which is a continuation-in-part of, and claims priority under 35 U.S.C. § 120 to, U.S. patent application Ser. No. 10/287,432, filed Nov. 1, 2002, which is incorporated in its entirety by reference herein. The present application also claims benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/502,147, filed Sep. 11, 2003 and U.S. Provisional Application No. 60/585,055, filed Jul. 2, 2004, both of which are incorporated in their entireties by reference herein. U.S. patent application Ser. No. 10/682,379 also claims benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/442,693, filed Jan. 24, 2003, U.S. Provisional Application No. 60/487,979, filed Jul. 17, 2003, and U.S. Provisional Application No. 60/502,147, filed Sep. 11, 2003, each of which is incorporated in its entirety by reference herein. U.S. patent application Ser. No. 10/287,432 also claims benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 60/336,436, filed Nov. 1, 2001 and U.S. Provisional Application No. 60/369,260, filed Apr. 2, 2002, both of which are incorporated in their entireties by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates in general to phototherapy, and more particularly, to novel apparatuses and methods for phototherapy of brain tissue affected by stroke.

2. Description of the Related Art

Stroke, also called cerebrovascular accident (CVA), is a sudden disruption of blood flow to a discrete area of the brain that is brought on by a clot lodging in an artery supplying that area of that brain, or by a cerebral hemorrhage due to a ruptured aneurysm or a burst artery. The consequence of stroke is a loss of function in the affected brain region and concomitant loss of bodily function in areas of the body controlled by the affected brain region. Depending upon the extent and location of the primary insult in the brain, loss of function varies greatly from mild or severe, and may be temporary or permanent. Lifestyle factors such as smoking, diet, level of physical activity and high cholesterol increase the risk of stroke, and thus stroke is a major cause of human suffering in developed nations. Stroke is the third leading cause of death in most developed nations, including the United States.

Until recently, stroke treatment was restricted to providing basic life support at the time of the stroke, followed by rehabilitation. Recently, new drug therapies have taken the approach of breaking up blood clots or protecting surviving at-risk neurons from further damage.

Thrombolytic therapy includes aspirin or intravenous heparin to prevent further clot formation and to maintain blood flow after an ischemic stroke. Thrombolytic drugs include tissue plasminogen activator (TPA) and genetically engineered versions thereof, and streptokinase. However, streptokinase does not appear to improve the patient's outlook unless administered early (within three hours of stroke). TPA when administered early appears to substantially improve prognosis, but slightly increases the risk of death from hemorrhage. In addition, over half of stroke patients arrive at the hospital more than three hours after a stroke, and even if they arrive quickly, a CT scan must first confirm that the stroke is not hemorrhagic, which delays administration of the drug. Also, patients taking aspirin or other blood thinners and patients with clotting abnormalities should not be given TPA.

Neuroprotective drugs target surviving but endangered neurons in a zone of risk surrounding the area of primary infarct. Such drugs are aimed at slowing down or preventing the death of such neurons, to reduce the extent of brain damage. Certain neuroprotective drugs are anti-excitotoxic, i.e., work to block the excitotoxic effects of excitatory amino acids such as glutamate that cause cell membrane damage under certain conditions. Other drugs such as citicoline work by repairing damaged cell membranes. Lazaroids such as Tirilazed (Freedox) counteract oxidative stress produced by oxygen-free radicals produced during stroke. Other drugs for stroke treatment include agents that block the enzyme known as PARP, and calcium-channel blockers such as nimodipine (Nimotop) that relax the blood vessels to prevent vascular spasms that further limit blood supply. However, the effect of nimodipine is reduced if administered beyond six hours after a stroke and it is not useful for ischemic stroke. In addition, drug therapy includes the risk of adverse side effects and immune responses.

Surgical treatment for stroke includes carotid endarterectomy, which appears to be especially effective for reducing the risk of stroke recurrence for patients exhibiting arterial narrowing of more than 70%. However, endarterectomy is highly invasive, and risk of stroke recurrence increases temporarily after surgery. Experimental stroke therapies include an angiography-type or angioplasty-type procedure using a thin catheter to remove or reduce the blockage from a clot. However, such procedures have extremely limited availability and increase the risk of embolic stroke. Other surgical interventions, such as those to repair an aneurysm before rupture remain controversial because of disagreement over the relative risks of surgery versus leaving the aneurysm untreated.

Against this background, a high level of interest remains in finding new and improved therapeutic apparatuses and methods for the treatment of stroke. In particular, a need remains for relatively inexpensive and non-invasive approaches to treating stroke that also avoid the limitations of drug therapy.

SUMMARY OF THE INVENTION

One embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a light source having an output emission area positioned to irradiate a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises an element interposed between the light source and the patient's scalp. The element is adapted to inhibit temperature increases at the scalp caused by the light.

Another embodiment of the present invention provides a therapy apparatus for treating brain tissue. The therapy apparatus comprises a light source positioned to irradiate at least a portion of a patient's head with light. The light has a wavelength and power density which penetrates the cranium to deliver an efficacious amount of light to brain tissue. The therapy apparatus further comprises a material which inhibits temperature increases of the head.

Another embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a light source adapted to irradiate at least a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises an element adapted to inhibit temperature increases at the scalp. At least a portion of the element is in an optical path of the light from the light source to the scalp.

Another embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a light source adapted to irradiate at least a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises a controller for energizing said light source so as to selectively produce a plurality of different irradiation patterns on the patient's scalp. Each of said irradiation patterns is comprised of at least one illumination area that is small compared to the patient's scalp, and at least one non-illuminated area.

Another embodiment of the present invention provides a method comprising interposing a head element between a light source and the patient's scalp. The element is comprised of a material which, for an efficacious power density at the brain, inhibits temperature increases at the scalp.

Another embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a light source adapted to irradiate at least a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises a biomedical sensor configured to provide real-time feedback information. The therapy apparatus further comprises a controller coupled to the light source and the biomedical sensor. The controller is configured to adjust said light source in response to the real-time feedback information.

Another embodiment of the present invention provides a method of treating brain tissue. The method comprises introducing light of an efficacious power density onto brain tissue by directing light through the scalp of a patient. Directing the light comprises providing a sufficiently large spot size on said scalp to reduce the power density at the scalp below the damage threshold of scalp tissue, while producing sufficient optical power at said scalp to achieve said efficacious power density at said brain tissue.

Another embodiment of the present invention provides a method of treating a patient's brain. The method comprises covering at least a significant portion of the patient's scalp with a light-emitting blanket.

Another embodiment of the present invention provides a method of treating a patient's brain following a stroke. The method comprises applying low-level light therapy to the brain no earlier than several hours following said stroke.

Another embodiment of the present invention provides a method for treating a patient's brain. The method comprises introducing light of an efficacious power density onto a target area of the brain by directing light through the scalp of the patient. The light has a plurality of wavelengths and the efficacious power density is at least 0.01 mW/cm²at the target area.

Another embodiment of the present invention provides a method for treating a patient's brain. The method comprises directing light through the scalp of the patient to a target area of the brain concurrently with applying an electromagnetic field to the brain. The light has an efficacious power density at the target area and the electromagnetic field has an efficacious field strength.

Another embodiment of the present invention provides a method for treating a patient's brain. The method comprises directing an efficacious power density of light through the scalp of the patient to a target area of the brain concurrently with applying an efficacious amount of ultrasonic energy to the brain.

Another embodiment of the present invention provides a method of providing a neuroprotective effect in a patient that had an ischemic event in the brain. The method comprises identifying a patient who has experienced an ischemic event in the brain. The method further comprises estimating the time of the ischemic event. The method further comprises commencing administration of a neuroprotective effective amount of light energy to the brain no less than about two hours following the time of the ischemic event.

Another embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a plurality of light sources. Each light source has an output emission area positioned to irradiate a corresponding portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises an element interposed between the light sources and the patient's scalp. The element inhibits temperature increases at the scalp caused by the light.

Another embodiment of the present invention provides a therapy apparatus for treating brain tissue. The therapy apparatus comprises a plurality of light sources. Each light source is positioned to irradiate at least a corresponding portion of a patient's head with light having a wavelength and power density which penetrates the cranium to deliver an efficacious amount of light to brain tissue. The therapy apparatus further comprises a material which inhibits temperature increases of the head.

Another embodiment of the present invention provides a therapy apparatus for treating a patient's brain. The therapy apparatus comprises a plurality of light sources. Each light source irradiates at least a corresponding portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further comprises a controller for energizing said light sources so as to selectively produce a predetermined irradiation pattern on the patient's scalp.

For purposes of summarizing the present invention, certain aspects, advantages, and novel features of the present invention have been described herein above. It is to be understood, however, that not necessarily all such advantages may be achieved in accordance with any particular embodiment of the present invention. Thus, the present invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other advantages as may be taught or suggested herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a therapy apparatus comprising a cap which fits securely over the patient's head.

FIG. 2 schematically illustrates a fragmentary cross-sectional view taken along the lines2-2 ofFIG. 1, showing one embodiment of a portion of a therapy apparatus comprising an element and its relationship to the scalp and brain.

FIG. 3 schematically illustrates an embodiment with an element comprising a container coupled to an inlet conduit and an outlet conduit for the transport of a flowing material through the element.

FIG. 4A schematically illustrates a fragmentary cross-sectional view taken along the lines2-2 ofFIG. 1, showing another embodiment of a portion of a therapy apparatus comprising an element with a portion contacting the scalp and a portion spaced away from the scalp.

FIG. 4B schematically illustrates a fragmentary cross-sectional view taken along the lines2-2 ofFIG. 1, showing an embodiment of a portion of a therapy apparatus comprising a plurality of light sources and an element with portions contacting the scalp and portions spaced away from the scalp.

FIGS. 5A and 5B schematically illustrate cross-sectional views of two embodiments of the element in accordance withFIG. 4B taken along the line4-4.

FIGS. 6A-6C schematically illustrate an embodiment in which the light sources are spaced away from the scalp.

FIGS. 7A and 7B schematically illustrate the diffusive effect on the light by the element.

FIGS. 8A and 8B schematically illustrate two light beams having different cross-sections impinging a patient's scalp and propagating through the patient's head to irradiate a portion of the patient's brain tissue.

FIG. 9A schematically illustrates a therapy apparatus comprising a cap and a light source comprising a light blanket.

FIGS. 9B and 9C schematically illustrate two embodiments of the light blanket.

FIG. 10 schematically illustrates a therapy apparatus comprising a flexible strap and a housing.

FIG. 11 schematically illustrates a therapy apparatus comprising a handheld probe.

FIG. 12 is a block diagram of a control circuit comprising a programmable controller.

FIG. 13 schematically illustrates a therapy apparatus comprising a light source and a controller.

FIG. 14 schematically illustrates a light source comprising a laser diode and a galvometer with a mirror and a plurality of motors.

FIGS. 15A and 15B schematically illustrate two irradiation patterns that are spatially shifted relative to each other.

FIG. 16 schematically illustrates an exemplary therapy apparatus in accordance with embodiments described herein.

FIG. 17A is a graph of the effects of laser treatment of 7.5mW/cm²for a treatment duration of 2 minutes on a population of rabbits having small clot embolic stroke.

FIG. 17B is a graph of the effects of laser treatment of 25 mW/cm²for a treatment duration of 10 minutes on a population of rabbits having small clot embolic stroke.

FIG. 18 is a graph showing the therapeutic window for laser-induced behavioral improvements after small-clot embolic strokes in rabbits.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Low level light therapy (“LLLT”) or phototherapy involves therapeutic administration of light energy to a patient at lower power outputs than those used for cutting, cauterizing, or ablating biological tissue, resulting in desirable biostimulatory effects while leaving tissue undamaged. In non-invasive phototherapy, it is desirable to apply an efficacious amount of light energy to the internal tissue to be treated using light sources positioned outside the body. (See, e.g., U.S. Pat. No. 6,537,304 to Oron and U.S. patent application Ser. No. 10/353,130, both of which are incorporated in their entireties by reference herein.)

Laser therapy has been shown to be effective in a variety of settings, including treating lymphoedema and muscular trauma, and carpal tunnel syndrome. Recent studies have shown that laser-generated infrared radiation is able to penetrate various tissues, including the brain, and modify function. In addition, laser-generated infrared radiation can induce angiogenesis, modify growth factor (transforming growth factor-β) signaling pathways, and enhance protein synthesis.

However, absorption of the light energy by intervening tissue can limit the amount of light energy delivered to the target tissue site, while heating the intervening tissue. In addition, scattering of the light energy by intervening tissue can limit the power density or energy density delivered to the target tissue site. Brute force attempts to circumvent these effects by increasing the power and/or power density applied to the outside surface of the body can result in damage (e.g., burning) of the intervening tissue.

Non-invasive phototherapy methods are circumscribed by setting selected treatment parameters within specified limits so as to preferably avoid damaging the intervening tissue. A review of the existing scientific literature in this field would cast doubt on whether a set of undamaging, yet efficacious, parameters could be found. However, certain embodiments, as described herein, provide devices and methods which can achieve this goal.

Such embodiments may include selecting a wavelength of light at which the absorption by intervening tissue is below a damaging level. Such embodiments may also include setting the power output of the light source at very low, yet efficacious, power densities (e.g., between approximately 100 μW/cm²to approximately 10 W/cm²) at the target tissue site, and time periods of application of the light energy at a few seconds to minutes to achieve an efficacious energy density at the target tissue site being treated. Other parameters can also be varied in the use of phototherapy. These other parameters contribute to the light energy that is actually delivered to the treated tissue and may play key roles in the efficacy of phototherapy. In certain embodiments, the irradiated portion of the brain can comprise the entire brain.

Element to Inhibit Temperature Increases at the Scalp

FIGS. 1 and 2 schematically illustrate an embodiment of atherapy apparatus10 for treating a patient'sbrain20. Thetherapy apparatus10 comprises alight source40 having anoutput emission area41 positioned to irradiate a portion of thebrain20 with an efficacious power density and wavelength of light. Thetherapy apparatus10 further comprises anelement50 interposed between thelight source40 and the patient'sscalp30. Theelement50 is adapted to inhibit temperature increases at thescalp30 caused by the light.

As used herein, the term “element” is used in its broadest sense, including, but not limited to, as a reference to a constituent or distinct part of a composite device. In certain embodiments, theelement50 is adapted to contact at least a portion of the patient'sscalp30, as schematically illustrated inFIGS. 1-4. In certain such embodiments, theelement50 is in thermal communication with and covers at least a portion of thescalp30. In other embodiments, theelement50 is spaced away from thescalp30 and does not contact thescalp30.

In certain embodiments, the light passes through theelement50 prior to reaching thescalp30 such that theelement50 is in the optical path of light propagating from thelight source40, through thescalp30, through the bones, tissues, and fluids of the head (schematically illustrated inFIG. 1 by the region22), to thebrain20. In certain embodiments, the light passes through a transmissive medium of theelement50, while in other embodiments, the light passes through an aperture of theelement50. As described more fully below, theelement50 may be utilized with various embodiments of thetherapy apparatus10.

In certain embodiments, thelight source40 is disposed on the interior surface of acap60 which fits securely over the patient's head. Thecap60 provides structural integrity for thetherapy apparatus10 and holds thelight source40 andelement50 in place. Exemplary materials for thecap60 include, but are not limited to, metal, plastic, or other materials with appropriate structural integrity. Thecap60 may include aninner lining62 comprising a stretchable fabric or mesh material, such as Lycra or nylon. In certain embodiments, thelight source40 is adapted to be removably attached to thecap60 in a plurality of positions so that theoutput emission area41 of thelight source40 can be advantageously placed in a selected position for treatment of a stroke or CVA in any portion of thebrain20. In other embodiments, thelight source40 can be an integral portion of thecap60.

Thelight source40 illustrated byFIGS. 1 and 2 comprises at least onepower conduit64 coupled to a power source (not shown). In some embodiments, thepower conduit64 comprises an electrical conduit which is adapted to transmit electrical signals and power to an emitter (e.g., laser diode or light-emitting diode). In certain embodiments, thepower conduit64 comprises an optical conduit (e.g., optical waveguide) which transmits optical signals and power to theoutput emission area41 of thelight source40. In certain such embodiments, thelight source40 comprises optical elements (e.g., lenses, diffusers, and/or waveguides) which transmit at least a portion of the optical power received via theoptical conduit64. In still other embodiments, thetherapy apparatus10 contains a power source (e.g., a battery) and thepower conduit64 is substantially internal to thetherapy apparatus10.

In certain embodiments, the patient'sscalp30 comprises hair and skin which cover the patient's skull. In other embodiments, at least a portion of the hair is removed prior to the phototherapy treatment, so that thetherapy apparatus10 substantially contacts the skin of thescalp30.

In certain embodiments, theelement50 is adapted to contact the patient'sscalp30, thereby providing an interface between thetherapy apparatus10 and the patient'sscalp30. In certain such embodiments, theelement50 is coupled to thelight source40 and in other such embodiments, the element is also adapted to conform to thescalp30, as schematically illustrated inFIG. 1. In this way, theelement50 positions theoutput emission area41 of thelight source40 relative to thescalp30. In certain such embodiments, theelement50 is mechanically adjustable so as to adjust the position of thelight source40 relative to thescalp30. By fitting to thescalp30 and holding thelight source40 in place, theelement50 inhibits temperature increases at thescalp30 that would otherwise result from misplacement of thelight source40 relative to thescalp30. In addition, in certain embodiments, theelement50 is mechanically adjustable so as to fit thetherapy apparatus10 to the patient'sscalp30.

In certain embodiments, theelement50 provides a reusable interface between thetherapy apparatus10 and the patient'sscalp30. In such embodiments, theelement50 can be cleaned or sterilized between uses of the therapy apparatus, particularly between uses by different patients. In other embodiments, theelement50 provides a disposable and replaceable interface between thetherapy apparatus10 and the patient'sscalp30. By using pre-sterilized and pre-packaged replaceable interfaces, certain embodiments can advantageously provide sterilized interfaces without undergoing cleaning or sterilization processing immediately before use.

In certain embodiments, theelement50 comprises a container (e.g., a cavity or bag) containing a material (e.g., gel or liquid). The container can be flexible and adapted to conform to the contours of thescalp30. Other exemplary materials contained in the container of theelement50 include, but are not limited to, thermal exchange materials such as glycerol and water. Theelement50 of certain embodiments substantially covers theentire scalp30 of the patient, as schematically illustrated inFIG. 2. In other embodiments, theelement50 only covers a localized portion of thescalp30 in proximity to the irradiated portion of thescalp30.

In certain embodiments, at least a portion of theelement50 is within an optical path of the light from thelight source40 to thescalp30. In such embodiments, theelement50 is substantially optically transmissive at a wavelength of the light emitted by theoutput emission area41 of thelight source40 and is adapted to reduce back reflections of the light. By reducing back reflections, theelement50 increases the amount of light transmitted to thebrain20 and reduces the need to use a higherpower light source40 which may otherwise create temperature increases at thescalp30. In certain such embodiments, theelement50 comprises one or more optical coatings, films, layers, membranes, etc. in the optical path of the transmitted light which are adapted to reduce back reflections.

In certain such embodiments, theelement50 reduces back reflections by fitting to thescalp30 so as to substantially reduce air gaps between thescalp30 and theelement50 in the optical path of the light. The refractive-index mismatches between such an air gap and theelement50 and/or thescalp30 would otherwise result in at least a portion of the light propagating from thelight source40 to thebrain20 to be reflected back towards thelight source40.

In addition, certain embodiments of theelement50 comprise a material having, at a wavelength of light emitted by thelight source40, a refractive index which substantially matches the refractive index of the scalp30 (e.g., about1.3), thereby reducing any index-mismatch-generated back reflections between theelement50 and thescalp30. Examples of materials with refractive indices compatible with embodiments described herein include, but are not limited to, glycerol, water, and silica gels. Exemplary index-matching gels include, but are not limited to, those available from Nye Lubricants, Inc. of Fairhaven, Mass.

In certain embodiments, theelement50 is adapted to cool thescalp30 by removing heat from thescalp30 so as to inhibit temperature increases at thescalp30. In certain such embodiments, theelement50 comprises a reservoir (e.g., a chamber or a conduit) adapted to contain a coolant. The coolant flows through the reservoir near thescalp30. Thescalp30 heats the coolant, which flows away from thescalp30, thereby removing heat from thescalp30 by active cooling. The coolant in certain embodiments circulates between theelement50 and a heat transfer device, such as a chiller, whereby the coolant is heated by thescalp30 and is cooled by the heat transfer device. Exemplary materials for the coolant include, but are not limited to, water or air.

In certain embodiments, theelement50 comprises a container51 (e.g., a flexible bag) coupled to aninlet conduit52 and anoutlet conduit53, as schematically illustrated inFIG. 3. A flowing material (e.g., water, air, or glycerol) can flow into thecontainer51 from theinlet conduit52, absorb heat from thescalp30, and flow out of thecontainer51 through theoutlet conduit53. Certain such embodiments can provide a mechanical fit of thecontainer51 to thescalp30 and sufficient thermal coupling to prevent excessive heating of thescalp30 by the light. In certain embodiments, thecontainer51 can be disposable andreplacement containers51 can be used for subsequent patients.

In still other embodiments, theelement50 comprises a container (e.g., a flexible bag) containing a material which does not flow out of the container but is thermally coupled to thescalp30 so as to remove heat from thescalp30 by passive cooling. Exemplary materials include, but are not limited to, water, glycerol, and gel. In certain such embodiments, the non-flowing material can be pre-cooled (e.g., by placement in a refrigerator) prior to the phototherapy treatment to facilitate cooling of thescalp30.

In certain embodiments, theelement50 is adapted to apply pressure to at least a portion of thescalp30. By applying sufficient pressure, theelement50 can blanch the portion of thescalp30 by forcing at least some blood out the optical path of the light energy. The blood removal resulting from the pressure applied by theelement50 to thescalp30 decreases the corresponding absorption of the light energy by blood in thescalp30. As a result, temperature increases due to absorption of the light energy by blood at thescalp30 are reduced. As a further result, the fraction of the light energy transmitted to the subdermal target tissue of thebrain20 is increased.

FIGS. 4A and 4B schematically illustrate embodiments of theelement50 adapted to facilitate the blanching of thescalp30. In the cross-sectional view of a portion of thetherapy apparatus10 schematically illustrated inFIG. 4A,certain element portions72 contact the patient'sscalp30 andother element portions74 are spaced away from thescalp30. Theelement portions72 contacting thescalp30 provide an optical path for light to propagate from thelight source40 to thescalp30. Theelement portions72 contacting thescalp30 also apply pressure to thescalp30, thereby forcing blood out from beneath theelement portion72.FIG. 4B schematically illustrates a similar view of an embodiment in which thelight source40 comprises a plurality of

light sources

40a,40b,40c.

FIG. 5A schematically illustrates one embodiment of the cross-section along the line4-4 ofFIG. 4B. Theelement portions72 contacting thescalp30 comprise ridges extending along one direction, and theelement portions74 spaced away from thescalp30 comprise troughs extending along the same direction. In certain embodiments, the ridges are substantially parallel to one another and the troughs are substantially parallel to one another.FIG. 5B schematically illustrates another embodiment of the cross-section along the line4-4 ofFIG. 4B. Theelement portions72 contacting thescalp30 comprise a plurality of projections in the form of a grid or array. More specifically, theportions72 are rectangular and are separated byelement portions74 spaced away from thescalp30, which form troughs extending in two substantially perpendicular directions. Theportions72 of theelement50 contacting thescalp30 can be a substantial fraction of the total area of theelement50 or of thescalp30.

FIGS. 6A-6C schematically illustrate an embodiment in which thelight sources40 are spaced away from thescalp30. In certain such embodiments, the light emitted by thelight sources40 propagates from thelight sources40 through thescalp30 to thebrain20 and disperses in a direction generally parallel to thescalp30, as shown inFIG. 6A. Thelight sources40 are preferably spaced sufficiently far apart from one another such that the light emitted from eachlight source40 overlaps with the light emitted from the neighboringlight sources40 at thebrain20.FIG. 6B schematically illustrates this overlap as the overlap ofcircular spots42 at a reference depth at or below the surface of thebrain20.FIG. 6C schematically illustrates this overlap as a graph of the power density at the reference depth of thebrain20 along the line L-L ofFIGS. 6A and 6B. Summing the power densities from the neighboring light sources40 (shown as a dashed line inFIG. 6C) serves to provide a more uniform light distribution at the tissue to be treated. In such embodiments, the summed power density is preferably less than a damage threshold of thebrain20 and above an efficacy threshold.

In certain embodiments, theelement50 is adapted to diffuse the light prior to reaching thescalp30.FIGS. 7A and 7B schematically illustrate the diffusive effect on the light by theelement50. An exemplary energy density profile of the light emitted by alight source40, as illustrated byFIG. 7A, is peaked at a particular emission angle. After being diffused by theelement50, as illustrated byFIG. 7B, the energy density profile of the light does not have a substantial peak at any particular emission angle, but is substantially evenly distributed among a range of emission angles. By diffusing the light emitted by thelight source40, theelement50 distributes the light energy substantially evenly over the area to be illuminated, thereby inhibiting “hot spots” which would otherwise create temperature increases at thescalp30. In addition, by diffusing the light prior to its reaching thescalp30, theelement50 can effectively increase the spot size of the light impinging thescalp30, thereby advantageously lowering the power density at thescalp30, as described more fully below. In addition, in embodiments with multiplelight sources40, theelement50 can diffuse the light to alter the total light output distribution to reduce inhomogeneities.

In certain embodiments, theelement50 provides sufficient diffusion of the light such that the power density of the light is less than a maximum tolerable level of thescalp30 andbrain20. In certain other embodiments, theelement50 provides sufficient diffusion of the light such that the power density of the light equals a therapeutic value at the target tissue. Theelement50 can comprise exemplary diffusers including, but are not limited to, holographic diffusers such as those available from Physical Optics Corp. of Torrance, Calif. and Display Optics P/N SN1333 from Reflexite Corp. of Avon, Conn.

Power Density

Phototherapy for the treatment of stroke is based in part on the discovery that power density (i.e., power per unit area or number of photons per unit area per unit time) and energy density (i.e., energy per unit area or number of photons per unit area) of the light energy applied to tissue appear to be significant factors in determining the relative efficacy of low level phototherapy. This discovery is particularly applicable with respect to treating and saving surviving but endangered neurons in a zone of danger surrounding the primary infarct after a stroke or cerebrovascular accident (CVA). Preferred methods described herein are based at least in part on the finding that, given a selected wavelength of light energy, it is the power density and/or the energy density of the light delivered to tissue (as opposed to the total power or total energy delivered to the tissue) that appears to be important factors in determining the relative efficacy of phototherapy.

Without being bound by theory, it is believed that light energy delivered within a certain range of power densities and energy densities provides the desired biostimulative effect on the intracellular environment, such that proper function is returned to previously nonfunctioning or poorly functioning mitochondria in at-risk neurons. The biostimulative effect may include interactions with chromophores within the target tissue, which facilitate production of ATP thereby feeding energy to injured cells which have experienced decreased blood flow due to the stroke. Because strokes correspond to blockages or other interruptions of blood flow to portions of the brain, it is thought that any effects of increasing blood flow by phototherapy are of less importance in the efficacy of phototherapy for stroke victims. Further information regarding the role of power density and exposure time is described by Hans H. F. I. van Breugel and P. R. Dop Bär in “Power Density and Exposure Time of He—Ne Laser Irradiation Are More Important Than Total Energy Dose in Photo-Biomodulation of Human Fibroblasts In Vitro,” Lasers in Surgery and Medicine,Volume 12, pp. 528-537 (1992), which is incorporated in its entirety by reference herein.

The significance of the power density used in phototherapy has ramifications with regard to the devices and methods used in phototherapy of brain tissue, as schematically illustrated byFIGS. 8A and 8B, which show the effects of scattering by intervening tissue. Further information regarding the scattering of light by tissue is provided by V. Tuchin in “Tissue Optics: Light Scattering Methods and Instruments for Medical Diagnosis,” SPIE Press (2000), Bellingham, Wash., pp. 3-11, which is incorporated in its entirety by reference herein.

FIG. 8A schematically illustrates alight beam80 impinging aportion90 of a patient'sscalp30 and propagating through the patient's head to irradiate aportion100 of the patient'sbrain tissue20. In the exemplary embodiment ofFIG. 8A, thelight beam80 impinging thescalp30 is collimated and has a circular cross-section with a radius of 2 cm and a cross-sectional area of approximately 12.5 cm². For comparison purposes,FIG. 8B schematically illustrates alight beam82 having a significantly smaller cross-section impinging asmaller portion92 of thescalp30 to irradiate aportion102 of thebrain tissue20. Thelight beam82 impinging thescalp30 inFIG. 8B is collimated and has a circular cross-section with a radius of 1 cm and a cross-sectional area of approximately 3.1 cm². The collimations, cross-sections, and radii of the light beams80,82 illustrated inFIGS. 8A and 8B are exemplary; other light beams with other parameters are also compatible with embodiments described herein. In particular, similar considerations apply to focussed beams or diverging beams, as they are similarly scattered by the intervening tissue.

As shown inFIGS. 8A and 8B, the cross-sections of the light beams80,82 become larger while propagating through the head due to scattering from interactions with tissue of the head. Assuming that the angle of dispersion is 15 degrees and theirradiated brain tissue20 is 2.5 cm below thescalp30, the resulting area of theportion100 ofbrain tissue20 irradiated by thelight beam80 inFIG. 8A is approximately 22.4 cm². Similarly, the resulting area of theportion102 ofbrain tissue20 irradiated by thelight beam82 inFIG. 8B is approximately 8.8 cm².

Irradiating theportion100 of thebrain tissue20 with a power density of 10 mW/cm²corresponds to a total power within theportion100 of approximately 224 mW (10mW/cm²×22.4 cm²). Assuming only approximately 5% of thelight beam80 is transmitted between thescalp30 and thebrain tissue20, theincident light beam80 at thescalp30 will have a total power of approximately 4480 mW (224 mW/0.05) and a power density of approximately 358 mW/cm²(4480 mW/12.5 cm²). Similarly, irradiating theportion102 of thebrain tissue20 with a power density of 10 mW/cm²corresponds to a total power within theportion102 of approximately 88 mW (10 mW/cm×8.8 cm²), and with the same 5% transmittance, theincident light beam82 at thescalp30 will have a total power of approximately 1760 mW (88 mW/0.05) and a power density of approximately 568 mW/cm²(1760 mW/3.1 cm²). These calculations are summarized in Table 1.

	TABLE 1


	2cm Spot Size	1 cm Spot Size
	(FIG. 8A)	(FIG. 8B)

Scalp:
Area	12.5 cm²	3.1 cm²
Total power	4480 mW	1760 mW
Power density	358 mW/cm²	568 mW/cm²
Brain:
Area	22.4 cm²	8.8 cm²
Total power	224 mW	88mW
Power density
10 mW/cm²	10 mW/cm²

These exemplary calculations illustrate that to obtain a desired power density at thebrain20, higher total power at thescalp30 can be used in conjunction with a larger spot size at thescalp30. Thus, by increasing the spot size at thescalp30, a desired power density at thebrain20 can be achieved with lower power densities at thescalp30 which can reduce the possibility of overheating thescalp30. In certain embodiments, the light can be directed through an aperture to define the illumination of thescalp30 to a selected smaller area.

Light Source

In certain embodiments, a singlelight source40 is used as a light generator to generate light, while in other embodiments, a plurality oflight sources40 are used as a light generator to generate light. Thelight source40 preferably generates light in the visible to near-infrared wavelength range. In certain embodiments, thelight source40 comprises one or more laser diodes, which each provide coherent light. In embodiments in which the light from thelight source40 is coherent, the emitted light may produce “speckling” due to coherent interference of the light. This speckling comprises intensity spikes which are created by constructive interference and can occur in proximity to the target tissue being treated. For example, while the average power density may be approximately 10 mW/cm², the power density of one such intensity spike in proximity to the brain tissue to be treated may be approximately 300 mW/cm². In certain embodiments, this increased power density due to speckling can improve the efficacy of treatments using coherent light over those using incoherent light for illumination of deeper tissues.

In other embodiments, thelight source40 provides incoherent light. Exemplarylight sources40 of incoherent light include, but are not limited to, incandescent lamps or light-emitting diodes. A heat sink can be used with the light source40 (for either coherent or incoherent sources) to remove heat from thelight source40 and to inhibit temperature increases at thescalp30.

In certain embodiments, thelight source40 generates light which is substantially monochromatic (i.e., light having one wavelength, or light having a narrow band of wavelengths). So that the amount of light transmitted to the brain is maximized, the wavelength of the light is selected in certain embodiments to be at or near a transmission peak (or at or near an absorption minimum) for the intervening tissue. In certain such embodiments, the wavelength corresponds to a peak in the transmission spectrum of tissue at about 820 nanometers. In other embodiments, the wavelength of the light is preferably between about 630 nanometers and about 1064 nanometers, more preferably between about 780 nanometers and about 840 nanometers, and most preferably includes wavelengths of about 785, 790, 795, 800, 805, 810, 815, 820, 825, or 830 nanometers. An intermediate wavelength in a range between approximately 730 nanometers and approximately 750 nanometers (e.g., about 739 nanometers) appears to be suitable for penetrating the skull, although other wavelengths are also suitable and may be used.

In other embodiments, thelight source40 generates light having a plurality of wavelengths. In certain such embodiments, each wavelength is selected so as to work with one or more chromophores within the target tissue. Without being bound by theory, it is believed that irradiation of chromophores increases the production of ATP in the target tissue, thereby producing beneficial effects. In certain embodiments, thelight source40 is adapted to generate light having a first wavelength concurrently with light having a second wavelength. In certain other embodiments, thelight source40 is adapted to generate light having a first wavelength sequentially with light having a second wavelength.

In certain embodiments, thelight source40 includes at least one continuously emitting GaAlAs laser diode having a wavelength of about 830 nanometers. In another embodiment, thelight source40 comprises a laser source having a wavelength of about 808 nanometers. In still other embodiments, thelight source40 includes at least one vertical cavity surface-emitting laser (VCSEL) diode. Otherlight sources40 compatible with embodiments described herein include, but are not limited to, light-emitting diodes (LEDs) and filtered lamps.

Thelight source40 is capable of emitting light energy at a power sufficient to achieve a predetermined power density at the subdermal target tissue (e.g., at a depth of approximately 2 centimeters from the dura). It is presently believed that phototherapy of tissue is most effective when irradiating the target tissue with power densities of light of at least about 0.01 mW/cm²and up to about 1 W/cm²at the level of the tissue. In various embodiments, the subsurface power density is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, or 90 mW/cm², respectively, depending on the desired clinical performance. In certain embodiments, the subsurface power density at the target tissue is preferably about 0.01 mW/cm²to about 100 mW/cm², more preferably about 0.01 mW/cm²to about 50 mW/cm², and most preferably about 2 mW/cm²to about 20 mW/cm². It is believed that these subsurface power densities are especially effective at producing the desired biostimulative effects on the tissue being treated.

Taking into account the attenuation of energy as it propagates from the skin surface, through body tissue, bone, and fluids, to the subdermal target tissue, surface power densities preferably between about 10 mW/cm²to about 10 W/cm², or more preferably between about 100 mW/cm²to about 500 mW/cm², will typically be used to attain the selected power densities at the subdermal target tissue. To achieve such surface power densities, thelight source40 is preferably capable of emitting light energy having a total power output of at least about 25 mW to about 100 W. In various embodiments, the total power output is limited to be no more than about 30, 50, 75, 100, 150, 200, 250, 300, 400, or 500 mW, respectively. In certain embodiments, thelight source40 comprises a plurality of sources used in combination to provide the total power output. The actual power output of thelight source40 is preferably controllably variable. In this way, the power of the light energy emitted can be adjusted in accordance with a selected power density at the subdermal tissue being treated.

Certain embodiments utilize alight source40 that includes only a single laser diode that is capable of providing about 25 mW to about 100 W of total power output at the skin surface. In certain such embodiments, the laser diode can be optically coupled to thescalp30 via an optical fiber or can be configured to provide a sufficiently large spot size to avoid power densities which would burn or otherwise damage thescalp30. In other embodiments, thelight source40 utilizes a plurality of sources (e.g., laser diodes) arranged in a grid or array that together are capable of providing at least about 25 mW to about 100 W of total power output at the skin surface. Thelight source40 of other embodiments may also comprise sources having power capacities outside of these limits.

FIG. 9A schematically illustrates another embodiment of thetherapy apparatus10 which comprises thecap60 and a light source comprising a light-emittingblanket110.FIG. 9B schematically illustrates an embodiment of theblanket110 comprising a flexible substrate111 (e.g., flexible circuit board), apower conduit interface112, and a sheet formed byoptical fibers114 positioned in a fan-like configuration.FIG. 9C schematically illustrates an embodiment of theblanket110 comprising a flexible substrate111, apower conduit interface112, and a sheet formed byoptical fibers114 woven into a mesh. Theblanket110 is preferably positioned within thecap60 so as to cover an area of thescalp30 corresponding to a portion of thebrain20 to be treated.

In certain such embodiments, thepower conduit interface112 is adapted to be coupled to anoptical fiber conduit64 which provides optical power to theblanket110. Theoptical power interface112 of certain embodiments comprises a beam splitter or other optical device which distributes the incoming optical power among the variousoptical fibers114. In other embodiments, thepower conduit interface112 is adapted to be coupled to an electrical conduit which provides electrical power to theblanket110. In certain such embodiments, thepower conduit interface112 comprises one or more laser diodes, the output of which is distributed among the variousoptical fibers114 of theblanket110. In certain other embodiments, theblanket110 comprises an electroluminescent sheet which responds to electrical signals from thepower conduit interface112 by emitting light. In such embodiments, thepower conduit interface112 comprises circuitry adapted to distribute the electrical signals to appropriate portions of the electroluminescent sheet.

The side of theblanket110 nearer thescalp30 is preferably provided with a light scattering surface, such as a roughened surface to increase the amount of light scattered out of theblanket110 towards thescalp30. The side of theblanket110 further from thescalp30 is preferably covered by a reflective coating so that light emitted away from thescalp30 is reflected back towards thescalp30. This configuration is similar to configurations used for the “back illumination” of liquid-crystal displays (LCDs). Other configurations of theblanket110 are compatible with embodiments described herein.

In certain embodiments, thelight source40 generates light which cause eye damage if viewed by an individual. In such embodiments, theapparatus50 can be configured to provide eye protection so as to avoid viewing of the light by individuals. For example, opaque materials can be appropriately placed to block the light from being viewed directly. In addition, interlocks can be provided so that thelight source40 is not activated unless theapparatus50 is in place, or other appropriate safety measures are taken.

Light Delivery Apparatuses

The phototherapy methods for the treatment of stroke described herein may be practiced and described using, for example, a low level laser therapy apparatus such as that shown and described in U.S. Pat. No. 6,214,035, U.S. Pat. No. 6,267,780, U.S. Pat. No. 6,273,905 and U.S. Pat. No. 6,290,714, which are all incorporated in their entirety by reference herein, as are the references incorporated by reference therein.

Another suitable phototherapy apparatus in accordance with embodiments described here is illustrated inFIG. 10. The illustratedtherapy apparatus10 includes alight source40, anelement50, and aflexible strap120 adapted for securing thetherapy apparatus10 over an area of the patient's head. Thelight source40 can be disposed on thestrap120 itself, or in ahousing122 coupled to thestrap120. Thelight source40 preferably comprises a plurality of

diodes

40a,40b,etc. capable of emitting light energy having a wavelength in the visible to near-infrared wavelength range. Theelement50 is adapted to be positioned between thelight source40 and the patient'sscalp30.

Thetherapy apparatus10 further includes a power supply (not shown) operatively coupled to thelight source40, and aprogrammable controller126 operatively coupled to thelight source40 and to the power supply. Theprogrammable controller126 is configured to control thelight source40 so as to deliver a predetermined power density to thebrain tissue20. In certain embodiments, as schematically illustrated inFIG. 10, thelight source40 comprises theprogrammable controller126. In other embodiments theprogrammable controller126 is a separate component of thetherapy apparatus10.

In certain embodiments, thestrap120 comprises a loop of elastomeric material sized appropriately to fit snugly onto the patient'sscalp30. In other embodiments, thestrap120 comprises an elastomeric material to which is secured any suitable securing means130, such as mating Velcro strips, buckles, snaps, hooks, buttons, ties, or the like. The precise configuration of thestrap120 is subject only to the limitation that thestrap120 is capable of maintaining thelight source40 in a selected position so that light energy emitted by thelight source40 is directed towards the targetedbrain tissue20.

In the exemplary embodiment illustrated inFIG. 10, thehousing122 comprises a layer of flexible plastic or fabric that is secured to thestrap120. In other embodiments, thehousing122 comprises a plate or an enlarged portion of thestrap120. Various strap configurations and spatial distributions of thelight sources40 are compatible with embodiments described herein so that thetherapy apparatus10 can treat selected portions of brain tissue.

In still other embodiments, thetherapy apparatus10 for delivering the light energy includes ahandheld probe140, as schematically illustrated inFIG. 11. Theprobe140 includes alight source40 and anelement50 as described herein.

FIG. 12 is a block diagram of acontrol circuit200 comprising aprogrammable controller126 according to embodiments described herein. Thecontrol circuit200 is configured to adjust the power of the light energy emitted by thelight source40 to generate a predetermined surface power density at thescalp30 corresponding to a predetermined energy delivery profile, such as a predetermined subsurface power density, to the target area of thebrain20.

In certain embodiments, theprogrammable controller126 comprises alogic circuit210, aclock212 coupled to thelogic circuit210, and aninterface214 coupled to thelogic circuit210. Theclock212 of certain embodiments provides a timing signal to thelogic circuit210 so that thelogic circuit210 can monitor and control timing intervals of the applied light. Examples of timing intervals include, but are not limited to, total treatment times, pulsewidth times for pulses of applied light, and time intervals between pulses of applied light. In certain embodiments, thelight sources40 can be selectively turned on and off to reduce the thermal load on thescalp30 and to deliver a selected power density to particular areas of thebrain20.

Theinterface214 of certain embodiments provides signals to thelogic circuit210 which thelogic circuit210 uses to control the applied light. Theinterface214 can comprise a user interface or an interface to a sensor monitoring at least one parameter of the treatment. In certain such embodiments, theprogrammable controller126 is responsive to signals from the sensor to preferably adjust the treatment parameters to optimize the measured response. Theprogrammable controller126 can thus provide closed-loop monitoring and adjustment of various treatment parameters to optimize the phototherapy. The signals provided by theinterface214 from a user are indicative of parameters that may include, but are not limited to, patient characteristics (e.g., skin type, fat percentage), selected applied power densities, target time intervals, and power density/timing profiles for the applied light.

In certain embodiments, thelogic circuit210 is coupled to alight source driver220. Thelight source driver220 is coupled to apower supply230, which in certain embodiments comprises a battery and in other embodiments comprises an alternating current source. Thelight source driver220 is also coupled to thelight source40. Thelogic circuit210 is responsive to the signal from theclock212 and to user input from theuser interface214 to transmit a control signal to thelight source driver220. In response to the control signal from thelogic circuit210, thelight source driver220 adjust and controls the power applied to thelight sources40. Other control circuits besides thecontrol circuit200 ofFIG. 12 are compatible with embodiments described herein.

In certain embodiments, thelogic circuit110 is responsive to signals from a sensor monitoring at least one parameter of the treatment to control the applied light. For example, certain embodiments comprise a temperature sensor thermally coupled to thescalp30 to provide information regarding the temperature of thescalp30 to thelogic circuit210. In such embodiments, thelogic circuit210 is responsive to the information from the temperature sensor to transmit a control signal to thelight source driver220 so as to adjust the parameters of the applied light to maintain the scalp temperature below a predetermined level. Other embodiments include exemplary biomedical sensors including, but not limited to, a blood flow sensor, a blood gas (e.g., oxygenation) sensor, an ATP production sensor, or a cellular activity sensor. Such biomedical sensors can provide real-time feedback information to thelogic circuit210. In certain such embodiments, thelogic circuit110 is responsive to signals from the sensors to preferably adjust the parameters of the applied light to optimize the measured response. Thelogic circuit110 can thus provide closed-loop monitoring and adjustment of various parameters of the applied light to optimize the phototherapy.

In certain embodiments, as schematically illustrated inFIG. 13, thetherapy apparatus310 comprises alight source340 adapted to irradiate a portion of the patient'sbrain20 with an efficacious power density and wavelength of light. Thetherapy apparatus310 further comprises acontroller360 for energizing saidlight source340, so as to selectively produce a plurality of different irradiation patterns on the patient'sscalp30. Each of the irradiation patterns is comprised of a least one illuminated area that is small compared to the patient'sscalp30, and at least one non-illuminated area.

In certain embodiments, thelight source340 includes an apparatus for adjusting the emitted light to irradiate different portions of thescalp30. In certain such embodiments, the apparatus physically moves thelight source40 relative to thescalp30. In other embodiments, the apparatus does not move thelight source40, but redirects the emitted light to different portions of thescalp30. In an exemplary embodiment, as schematically, illustrated inFIG. 14, thelight source340 comprises alaser diode342 and agalvometer344, both of which are electrically coupled to thecontroller360. Thegalvometer344 comprises amirror346 mounted onto anassembly348 which is adjustable by a plurality ofmotors350. Light emitted by thelaser diode342 is directed toward themirror346 and is reflected to selected portions of the patient'sscalp30 by selectively moving themirror346 and selectively activating thelaser diode342. In certain embodiments, thetherapy apparatus310 comprises anelement50 adapted to inhibit temperature increases at thescalp30 as described herein.

FIG. 15A schematically illustrates anirradiation pattern370 in accordance with embodiments described herein. Theirradiation pattern370 comprises at least oneilluminated area372 and at least onenon-illuminated area374. In certain embodiments, theirradiation pattern370 is generated by scanning themirror346 so that the light impinges the patient'sscalp30 in the illuminatedarea372 but not in thenon-illuminated area374. Certain embodiments modify the illuminatedarea372 and thenon-illuminated area374 as a function of time.

This selective irradiation can be used to reduce the thermal load on particular locations of thescalp30 by moving the light from one illuminatedarea372 to another. For example, by irradiating thescalp30 with theirradiation pattern370 schematically illustrated inFIG. 15A, theilluminated areas372 of thescalp30 are heated by interaction with the light, and thenon-illuminated areas374 are not heated. By subsequently irradiating thescalp30 with thecomplementary irradiation pattern370′ schematically illustrated inFIG. 15B, the previouslynon-illuminated areas374 are now illuminatedareas372′, and the previously illuminatedareas372 are nownon-illuminated areas374′. A comparison of the illuminatedareas372 of theirradiation pattern370 ofFIG. 15A with the illuminatedarea372′ of theirradiation pattern370′ ofFIG. 15B shows that the

illuminated areas

372,372′ do not significantly overlap one another. In this way, the thermal load at thescalp30 due to the absorption of the light can be distributed across thescalp30, thereby avoiding unduly heating one or more portions of thescalp30.

FIG. 16 schematically illustrates anothertherapy apparatus400 in accordance with embodiments described herein. Thetherapy apparatus400 comprises a plurality oflight sources410 in ahousing420. Eachlight source410 has an output emission area positioned to irradiate a corresponding portion of thebrain20 with an efficacious power density and wavelength of light. In certain embodiments, these portions overlap such that the portion of thebrain20 irradiated by two or morelight sources410 overlap one another at least in part. As described herein, thelight sources410 can be activated by a controller (not shown) in concert or separately to produce a predetermined irradiation pattern.

Thetherapy apparatus400 ofFIG. 16 further comprises acap430 interposed between thelight sources410 and the patient'sscalp30, such that light passes through thecap430 prior to reaching thescalp30. In certain embodiments, thecap430 is substantially optically transmissive at the wavelength and reduces back reflections of the light. Thecap430 of certain embodiments fits to thescalp30 so as to substantially reduce air gaps between thescalp30 and thecap430. In certain embodiments, thecap430 comprises a material having a refractive index which substantially matches a refractive index of thescalp30. In certain embodiments, thecap430 comprises a material having a refractive index which substantially matches a refractive index of the skin and/or hair of thescalp30.

In the embodiment schematically illustrated byFIG. 16, thecap430 is wearable over the patient'sscalp30. In certain such embodiments, the patient wears thecap430 and is in a reclining position so as to place his head in proximity to thelight sources410. Thecap430 is adapted to inhibit temperature increases at thescalp30 caused by the light from thelight sources410, as described herein (e.g., by cooling thescalp30, by blanching a portion of thescalp30, by diffusing the light prior to reaching the scalp30).

Methods of Light Delivery

Preferred methods of phototherapy are based at least in part on the finding described above that, for a selected wavelength, the power density (light intensity or power per unit area, in W/cm²) or the energy density (energy per unit area, in J/cm², or power density multiplied by the exposure time) of the light energy delivered to tissue is an important factor in determining the relative efficacy of the phototherapy, and efficacy is not as directly related to the total power or the total energy delivered to the tissue. In the methods described herein, power density or energy density as delivered to a portion of the patient'sbrain20, which can include the area of infarct after a stroke, appears to be important factors in using phototherapy to treat and save surviving but endangered neurons in a zone of danger surrounding the infarcted area. Certain embodiments apply optimal power densities or energy densities to the intended target tissue, within acceptable margins of error.

In certain embodiments, the apparatus and methods of phototherapy described herein increase the cerebral blood flow of the patient. In certain such embodiments, the cerebral blood flow is increased by 10%, 15%, 20%, or 25% immediately post-irradiation, as compared to immediately prior to irradiation.

In certain embodiments, the apparatus and methods of phototherapy described herein are used to treat strokes or other sources of neurodegeneration. As used herein, the term “neurodegeneration” refers to the process of cell destruction resulting from primary destructive events such as stroke or CVA, as well as from secondary, delayed and progressive destructive mechanisms that are invoked by cells due to the occurrence of the primary destructive event. Primary destructive events include disease processes or physical injury or insult, including stroke, but also include other diseases and conditions such as multiple sclerosis, anylotrophic lateral sclerosis, heat stroke, epilepsy, Alzheimer's disease, dementia resulting from other causes such as AIDS, cerebral ischemia including focal cerebral ischemia, and physical trauma such as crush or compression injury in the CNS, including a crush or compression injury of the brain, spinal cord, nerves or retina, or any acute injury or insult producing neurodegeneration. Secondary destructive mechanisms include any mechanism that leads to the generation and release of neurotoxic molecules, including apoptosis, depletion of cellular energy stores because of changes in mitochondrial membrane permeability, release or failure in the reuptake of excessive glutamate, reperfusion injury, and activity of cytokines and inflammation. Both primary and secondary mechanisms contribute to forming a “zone of danger” for neurons, wherein the neurons in the zone have at least temporarily survived the primary destructive event, but are at risk of dying due to processes having delayed effect.

As used herein, the term “neuroprotection” refers to a therapeutic strategy for slowing or preventing the otherwise irreversible loss of neurons due to neurodegeneration after a primary destructive event, whether the neurodegeneration loss is due to disease mechanisms associated with the primary destructive event or secondary destructive mechanisms.

The term “cognitive function” as used herein refers to cognition and cognitive or mental processes or functions, including those relating to knowing, thinking, learning, perception, memory (including immediate, recent, or remote memory), and judging. Symptoms of loss of cognitive function can also include changes in personality, mood, and behavior of the patient. Diseases or conditions affecting cognitive function include Alzheimer's disease, dementia, AIDS or HIV infection, Cruetzfeldt-Jakob disease, head trauma (including single-event trauma and long-term trauma such as multiple concussions or other traumas which may result from athletic injury), Lewy body disease, Pick's disease, Parkinson's disease, Huntington's disease, drug or alcohol abuse, brain tumors, hydrocephalus, kidney or liver disease, stroke, depression, and other mental diseases which cause disruption in cognitive function, and neurodegeneration.

The term “motor function” as used herein refers to those bodily functions relating to muscular movements, primarily conscious muscular movements, including motor coordination, performance of simple and complex motor acts, and the like.

The term “neurologic function” as used herein includes both cognitive function and motor function.

The terms “cognitive enhancement” and “motor enhancement” as used herein refer to the improving or heightening of congnitive function and motor function, respectively.

The term “neurologic enhancement” as used herein includes both cognitive enhancement and motor enhancement.

As used herein, the term “neuroprotective-effective” as used herein refers to a characteristic of an amount of light energy, wherein the amount is a power density of the light energy measured in mW/cm². A neuroprotective-effective amount of light energy achieves the goal of preventing, avoiding, reducing, or eliminating neurodegeneration, which should result in cognitive enhancement and/or motor enhancement.

The term “neurologic function enhancement effective” as used herein refers to a characteristic of an amount of light energy, wherein the amount is a power density of the light energy measured in mW/cm². The amount of light energy achieves the goal of neuroprotection, motor enhancement, and/or cognitive enhancement.

Thus, a method for the treatment of stroke or for the enhancement of neurologic function in a patient in need of such treatment involves delivering a neurologic function enhancement effective amount or a neuroprotective-effective amount of light energy having a wavelength in the visible to near-infrared wavelength range to a target area of the patient'sbrain20. In certain embodiments, the target area of the patient'sbrain20 includes the area of infarct, i.e. to neurons within the “zone of danger.” In other embodiments, the target area includes portions of thebrain20 not within the zone of danger. Without being bound by theory, it is believed that irradiation of healthy tissue in proximity to the zone of danger increases the production of ATP and copper ions in the healthy tissue and which then migrate to the injured cells within the region surrounding the infarct, thereby producing beneficial effects. Additional information regarding the biomedical mechanisms or reactions involved in phototherapy is provided by Tiina I. Karu in “Mechanisms of Low-Power Laser Light Action on Cellular Level”, Proceedings of SPIE Vol. 4159 (2000), Effects of Low-Power Light on Biological Systems V, Ed. Rachel Lubart, pp. 1-17, which is incorporated in its entirety by reference herein.

In certain embodiments, delivering the neuroprotective amount of light energy includes selecting a surface power density of the light energy at thescalp30 corresponding to the predetermined power density at the target area of thebrain20. As described above, light propagating through tissue is scattered and absorbed by the tissue. Calculations of the power density to be applied to thescalp30 so as to deliver a predetermined power density to the selected target area of thebrain20 preferably take into account the attenuation of the light energy as it propagates through the skin and other tissues, such as bone and brain tissue. Factors known to affect the attenuation of light propagating to thebrain20 from thescalp30 include, but are not limited to, skin pigmentation, the presence and color of hair over the area to be treated, amount of fat tissue, the presence of bruised tissue, skull thickness, and the location of the target area of thebrain20, particularly the depth of the area relative to the surface of thescalp30. For example, to obtain a desired power density of 50 mW/cm²in thebrain20 at a depth of 3 cm below the surface of thescalp30, phototherapy may utilize an applied power density of 500 mW/cm². The higher the level of skin pigmentation, the higher the power density applied to thescalp30 to deliver a predetermined power density of light energy to a subsurface site of thebrain20.

In certain embodiments, treating a patient suffering from the effects of stroke comprises placing thetherapy apparatus10 in contact with thescalp30 and adjacent the target area of the patient'sbrain20. The target area of the patient'sbrain20 can be previously identified such as by using standard medical imaging techniques. In certain embodiments, treatment further includes calculating a surface power density at thescalp30 which corresponds to a preselected power density at the target area of the patient'sbrain20. The calculation of certain embodiments includes factors that affect the penetration of the light energy and thus the power density at the target area. These factors include, but are not limited to, the thickness of the patient's skull, type of hair and hair coloration, skin coloration and pigmentation, patient's age, patient's gender, and the distance to the target area within thebrain20. The power density and other parameters of the applied light are then adjusted according to the results of the calculation.

The power density selected to be applied to the target area of the patient'sbrain20 depends on a number of factors, including, but not limited to, the wavelength of the applied light, the type of CVA (ischemic or hemorrhagic), and the patient's clinical condition, including the extent of the affected brain area. The power density of light energy to be delivered to the target area of the patient'sbrain20 may also be adjusted to be combined with any other therapeutic agent or agents, especially pharmaceutical neuroprotective agents, to achieve the desired biological effect. In such embodiments, the selected power density can also depend on the additional therapeutic agent or agents chosen.

In preferred embodiments, the treatment proceeds continuously for a period of about 10 seconds to about 2 hours, more preferably for a period of about 1 to about 10 minutes, and most preferably for a period of about 1 to 5 minutes. In other embodiments, the light energy is preferably delivered for at least one treatment period of at least about five minutes, and more preferably for at least one treatment period of at least ten minutes. The light energy can be pulsed during the treatment period or the light energy can be continuously applied during the treatment period.

In certain embodiments, the treatment may be terminated after one treatment period, while in other embodiments, the treatment may be repeated for at least two treatment periods. The time between subsequent treatment periods is preferably at least about five minutes, more preferably at least about 1 to 2 days, and most preferably at least about one week. In certain embodiments in which treatment is performed over the course of multiple days, theapparatus10 is wearable over multiple concurrent days (e.g., embodiments ofFIGS. 1, 3,9A,10, and13). The length of treatment time and frequency of treatment periods can depend on several factors, including the functional recovery of the patient and the results of imaging analysis of the infarct. In certain embodiments, one or more treatment parameters can be adjusted in response to a feedback signal from a device (e.g., magnetic resonance imaging) monitoring the patient.

During the treatment, the light energy may be continuously provided, or it may be pulsed. If the light is pulsed, the pulses are preferably at least about 10 nanosecond long and occur at a frequency of up to about 100 kHz. Continuous wave light may also be used.

The thrombolytic therapies currently in use for treatment of stroke are typically begun within a few hours of the stroke. However, many hours often pass before a person who has suffered a stroke receives medical treatment, so the short time limit for initiating thrombolytic therapy excludes many patients from treatment. In contrast, phototherapy treatment of stroke appears to be more effective if treatment begins no earlier than several hours after the ischemic event has occurred. Consequently, the present methods of phototherapy may be used to treat a greater percentage of stroke patients.

In certain embodiments, a method provides a neuroprotective effect in a patient that had an ischemic event in the brain. The method comprises identifying a patient who has experienced an ischemic event in the brain. The method further comprises estimating the time of the ischemic event. The method further comprises commencing administration of a neuroprotective effective amount of light energy to the brain. The administration of the light energy is commenced no less than about two hours following the time of the ischemic event. In certain embodiments, phototherapy treatment can be efficaciously performed preferably within 24 hours after the ischemic event occurs, and more preferably no earlier than two hours following the ischemic event, still more preferably no earlier than three hours following the ischemic event, and most preferably no earlier than five hours following the ischemic event. In certain embodiments, one or more of the treatment parameters can be varied depending on the amount of time that has elapsed since the ischemic event.

Without being bound by theory, it is believed that the benefit in delaying treatment occurs because of the time needed for induction of ATP production, and/or the possible induction of angiogenesis in the region surrounding the infarct. Thus, in accordance with one preferred embodiment, the phototherapy for the treatment of stroke occurs preferably about 6 to 24 hours after the onset of stroke symptoms, more preferably about 12 to 24 hours after the onset of symptoms. It is believed, however, that if treatment begins after about 2 days, its effectiveness will be greatly reduced.

In certain embodiments, the phototherapy is combined with other types of treatments for an improved therapeutic effect. Treatment can comprise directing light through the scalp of the patient to a target area of the brain concurrently with applying an electromagnetic field to the brain. In such embodiments, the light has an efficacious power density at the target area and the electromagnetic field has an efficacious field strength. For example, theapparatus50 can also include systems for electromagnetic treatment, e.g., as described in U.S. Pat. No. 6,042,531 issued to Holcomb, which is incorporated in its entirety by reference herein. In certain embodiments, the electromagnetic field comprises a magnetic field, while in other embodiments, the electromagnetic field comprises a radio-frequency (RF) field. As another example, treatment can comprise directing an efficacious power density of light through the scalp of the patient to a target area of the brain concurrently with applying an efficacious amount of ultrasonic energy to the brain. Such a system can include systems for ultrasonic treatment, e.g., as described in U.S. Pat. No. 5,054,470 issued to Fry et al., which is incorporated in its entirety by reference herein.

PHOTOTHERAPY EXAMPLESExample 1

An in vitro experiment was done to demonstrate one effect of phototherapy on neurons, namely the effect on ATP production. Normal Human Neural Progenitor (NHNP) cells were obtained cryopreserved through Clonetics of Baltimore, Md., catalog #CC-2599. The NHNP cells were thawed and cultured on polyethyleneimine (PEI) with reagents provided with the cells, following the manufacturers' instructions. The cells were plated into 96 well plates (black plastic with clear bottoms, Becton Dickinson of Franklin Lakes, N.J.) as spheroids and allowed to differentiate into mature neurons over a period of two weeks.

A Photo Dosing Assembly (PDA) was used to provide precisely metered doses of laser light to the NHNP cells in the 96 well plates. The PDA included a Nikon Diaphot inverted microscope (Nikon of Melville, N.Y.) with a LUDL motorized x,y,z stage (Ludl Electronic Products of Hawthorne, N.Y.). An 808 nanometer laser was routed into the rear epi-fluorescent port on the microscope using a custom designed adapter and a fiber optic cable. Diffusing lenses were mounted in the path of the beam to create a “speckled” pattern, which was intended to mimic in vivo conditions after a laser beam passed through human skin. The beam diverged to a 25 millimeter diameter circle when it reached the bottom of the 96 well plates. This dimension was chosen so that a cluster of four adjacent wells could be lased at the same time. Cells were plated in a pattern such that a total of 12 clusters could be lased per 96 well plate. Stage positioning was controlled by a Silicon Graphics workstation and laser timing was performed by hand using a digital timer. The measured power density passing through the plate for the NHNP cells was 50 mW/cm².

Two independent assays were used to measure the effects of 808 nanometer laser light on the NHNP cells. The first was the CellTiter-Glo Luminescent Cell Viability Assay (Promega of Madison, Wis.). This assay generates a “glow-type” luminescent signal produced by a luciferase reaction with cellular ATP. The CellTiter-Glo reagent is added in an amount equal to the volume of media in the well and results in cell lysis followed by a sustained luminescent reaction that was measured using a Reporter luminometer (Turner Biosystems of Sunnyvale, Calif.). Amounts of ATP present in the NHNP cells were quantified in Relative Luminescent Units (RLUs) by the luminometer.

The second assay used was the alamarBlue assay (Biosource of Camarillo, Calif.). The internal environment of a proliferating cell is more reduced than that of a non-proliferating cell. Specifically, the ratios of NADPH/NADP, FADH/FAD, FMNH/FMN and NADH/NAD, increase during proliferation. Laser irradiation is also thought to have an effect on these ratios. Compounds such as alamarBlue are reduced by these metabolic intermediates and can be used to monitor cellular states. The oxidization of alamarBlue is accompanied by a measurable shift in color. In its unoxidized state, alamarBlue appears blue; when oxidized, the color changes to red. To quantify this shift, a 340PC microplate reading spectrophotometer (Molecular Devices of Sunnyvale, Calif.) was used to measure the absorbance of a well containing NHNP cells, media and alamarBlue diluted 10% v/v. The absorbance of each well was measured at 570 nanometers and 600 nanometers and the percent reduction of alamarBlue was calculated using an equation provided by the manufacturer.

The two metrics described above, (RLUs and % Reduction) were then used to compare NHNP culture wells that had been lased with 50 mW/cm²at a wavelength of 808 nanometers. For the CellTiter-Glo assay, 20 wells were lased for 1 second and compared to an unlased control group of 20 wells. The CellTiter-Glo reagent was added 10 minutes after lasing completed and the plate was read after the cells had lysed and the luciferase reaction had stabilized. The average RLUs measured for the control wells was 3808±3394 while the laser group showed a two-fold increase in ATP content to 7513±6109. The standard deviations were somewhat high due to the relatively small number of NHNP cells in the wells (approximately 100 per well from visual observation), but a student's unpaired t-test was performed on the data with a resulting p-value of 0.02 indicating that the two-fold change is statistically significant.

The alamarBlue assay was performed with a higher cell density and a lasing time of 5 seconds. The plating density (calculated to be between 7,500-26,000 cells per well based on the certificate of analysis provided by the manufacturer) was difficult to determine since some of the cells had remained in the spheroids and had not completely differentiated. Wells from the same plate can still be compared though, since plating conditions were identical. The alamarblue was added immediately after lasing and the absorbance was measured 9.5 hours later. The average measured values for percent reduction were 22% ±7.3% for the 8 lased wells and 12.4%±5.9% for the 3 unlased control wells (p-value=0.076). These alamarBlue results support the earlier findings in that they show a similar positive effect of the laser treatment on the cells.

Increases in cellular ATP concentration and a more reduced state within the cell are both related to cellular metabolism and are considered to be indications that the cell is viable and healthy. These results are novel and significant in that they show the positive effects of laser irradiation on cellular metabolism in in-vitro neuronal cell cultures.

Example 2

In a second example, transcranial laser therapy was investigated using a low-energy infrared laser to treat behavioral deficits in a rabbit small clot embolic stroke model (RSCEM). This example is described in more detail by P. A. Lapchak et al., “Transcranial Infrared Laser Therapy Improves Clinical Rating Scores After Embolic Strokes in Rabbits,” Stroke, Vol. 35, pp. 1985-1988 (2004), which is incorporated in its entirety by reference herein.

RSCEM was produced by injection of blood clots into the cerebral vasculature of anethestized male New Zealand White rabbits, resulting in ischemia-induced behavioral deficits that can be measured quantitatively with a dichotomous rating scale. In the absence of treatment, small numbers of microclots caused no grossly apparent neurologic dysfunction while large numbers of microclots invariably caused encephalopathy or death. Behaviorally normal rabbits did not have any signs of impairment, whereas behaviorally abnormal rabbits had loss of balance, head leans, circling, seizure-type activity, or limb paralysis.

For laser treatment, a laser probe was placed in direct contact with the skin. The laser probe comprised a low-energy laser (wavelength of 808±5 nanometers) fitted with an OZ Optics Ltd. fiber-optic cable and a laser probe with a diameter of approximately 2 centimeters. Instrument design studies showed that these specifications would allow for laser penetration of the rabbit skull and brain to a depth of 2.5 to 3 centimeters, and that the laser beam would encompass the majority of the brain if placed on the skin surface posterior to bregma on the midline. Although the surface skin temperature below the probe was elevated by up to 3° C., the focal brain temperature directly under the laser probe was increased by 0.8° C. to 1.8° C. during the 10-minute laser treatment using the 25 mW/cm²energy setting. Focal brain temperature returned to normal within 60 minutes of laser treatment.

The quantitative relationship between clot dose and behavioral or neurological deficits was evaluated using logistic (S-shaped) curves fitted by computer to the quantal dose-response data. These parameters are measures of the amount of microclots (in mg) that produced neurologic dysfunction in 50% of a group of animals (P₅₀). A separate curve was generated for each treatment condition, with a statistically significant increase in the P₅₀value compared with control being indicative of a behavioral improvement. The data were analyzed using the t test, which included the Bonferroni correction when appropriate.

To determine if laser treatment altered physiological variables, 14 rabbits were randomly divided into 2 groups, a control group and a laser-treated group (25 mW/cm²for 10 minutes). Blood glucose levels were measured for all embolized rabbits using a Bayer Elite XL 3901B Glucometer, and body temperature was measured using a Braun Thermoscan Type 6013 digital thermometer. Within 60 minutes of embolization, there was an increase in blood glucose levels in both the control group and the laser-treated group that was maintained for the 2 hours post-embolization observation time. Blood glucose levels returned to control levels by 24 hours, regardless of the extent of stroke-induced behavioral deficits. Laser treatment did not significantly affect glucose levels at any time. Neither embolization nor laser treatment significantly affected body temperature in either group of rabbits.

FIG. 17A is a graph for the percentage of the population which was either abnormal or dead as a function of the clot weight in milligrams for laser treatment of 7.5 mW/cm²for a treatment duration of 2 minutes. As shown byFIG. 17A, the control curve (dotted line) has a P₅₀value of 0.97±0.19 mg (n=23). Such laser treatment initiated 3 hours after the stroke significantly improved behavioral performance, with the P₅₀value increased to 2.21±0.54 mg (n=28, *P=0/05) (solid line). The effect was durable and was measurable 3 weeks after embolization. However, the same setting did not improve behavior if there was a long delay (24 hours) after embolization (dashed line) (P₅₀=1.23±0.15 mg, n=32).

FIG. 17B is a graph for the percentage of the population which was either abnormal or dead as a function of the clot weight in milligrams for laser treatment of 25 mW/cm2 for a treatment duration of 10 minutes. As shown byFIG. 17B, the control curve (dotted line) has a P₅₀value of 1.10±0.17 mg (n=27). Such laser treatment initiated 1 (dashed line) or 6 (solid line) hours after embolization also significantly increased behavioral performance, with the P₅₀value increased to 2.02±0.46 mg (n=18, *P<0.05) and 2.98±0.65 mg (n=26, *P<0.05), respectively.

FIG. 18 is a graph showing the therapeutic window for laser-induced behavioral improvements after small-clot embolic strokes in rabbits. Results are shown as clinical rating score P₅₀(mg clot) given as mean±SEM for the number of rabbits per time point (number in brackets) for laser treatment initiated 1, 3, 6, or 24 hours after embolization as shown on the x-axis. The horizontal line represents the mean of the control P₅₀values (*P<0.05).

The results in the RSCEM showed that laser treatment significantly improved behavioral rating scores after embolic strokes in rabbits without affecting body temperature and blood glucose levels. In addition, laser treatment was effective when initiated up to 6 hours after strokes, which is later than any other previously effective single therapy in the same preclinical stroke model. Moreover, the effect was durable and was measurable up to 21 days after embolization. The magnitudes of laser-induced improvement in rabbits are similar to previously tested thrombollytics (alteplase, tenecteplase, and microplasmin) and neuroprotective compounds (NXY-059), which are undergoing clinical development.

The explanations and illustrations presented herein are intended to acquaint others skilled in the art with the invention, its principles, and its practical application. Those skilled in the art may adapt and apply the invention in its numerous forms, as may be best suited to the requirements of a particular use. Accordingly, the specific embodiments of the present invention as set forth are not intended as being exhaustive or limiting of the invention.