CN116322901A

CN116322901A - Systems and methods for preventing or treating Alzheimer's disease and other neurodegenerative diseases

Info

Publication number: CN116322901A
Application number: CN202180067995.1A
Authority: CN
Inventors: J·K·卢特鲁勒; D·B·昌
Original assignee: Ojai Retinal Technology LLC
Current assignee: Ojai Retinal Technology LLC
Priority date: 2020-08-04
Filing date: 2021-06-07
Publication date: 2023-06-23
Also published as: BR112023001701A2; CA3187662A1; WO2022031362A1; JP2023544080A; EP4185376A4; AU2021321214A1; EP4185376A1

Abstract

A protective treatment system for biological tissue or fluid comprising applying a pulsed energy source to a target tissue or target fluid having or at risk of having a chronic progressive disease to therapeutically or prophylactically treat the target tissue or target fluid. A pulsed energy source having selected energy parameters may be applied to the brain of an individual having or at risk of having alzheimer's disease or other neurodegenerative diseases to prevent or treat the neurodegenerative disease.

Description

Systems and methods for preventing or treating Alzheimer's disease and other neurodegenerative diseases

Technical Field

The present invention relates generally to systems and methods for treating biological tissue. In particular, the present invention relates to systems and methods for preventing or treating alzheimer's disease and other neurodegenerative diseases.

Background

Chronic progressive disease (chronic progressive disease; CPD) is currently and increasingly a health care challenge in the future. There are many such CPDs, including type II diabetes, alzheimer's disease, idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis; IPF), heart disease, and the like. The root cause of many diseases is unknown, either untreated or not optimally treated. Some of these diseases either terminate consistently in a short period of time or constitute a significant public health problem due to increased prevalence due to increased high risk populations and chronicity.

These diseases are not only chronic but also progressive. Chronic progressive disease may have many root causes including age, infection, genetics, multifactorial, and immunity. The progressive nature of these diseases means that they all worsen with age. Although CPD has many different reasons, they have in fundamental common. A common feature of all CPDs is the accumulation of abnormal intracellular proteins. Another common feature of all CPDs is increased cell and organ dysfunction, leading to failure. Yet another common and unified feature of CPD is that cell and organ dysfunction causes and promotes chronic inflammation. These features of all CPDs form a vicious circle, resulting in exacerbations of the disease over time.

Thus, interrupting the cycle is critical to improving the course of the disease. One approach to treating CPD is gene therapy, which requires the identification and repair or replacement of defective genes that lead to disease. However, for some CPDs, the gene defect is unknown. For other CPDs, there may be many potential gene defects leading to the same disease. For example, retinal pigment degeneration may be caused by any of more than 150 different genetic defects. This potential variety of root defects makes gene therapy difficult.

Another approach to treating CPD is drug therapy, which generally seeks to target specific cellular proteins that are thought to be critical to the disease process, to inhibit or enhance their effects. However, since there are an estimated 2000 different protein types in a typical cell, there areThere is 10 ⁶⁸⁰ It is therefore difficult to find successful, safe and clinically effective targeted drug therapies without unacceptable side effects.

Another approach to treating CPD is to use non-specific anti-inflammatory therapies. These include various steroidal and non-steroidal anti-inflammatory agents and immunosuppressant agents. However, anti-inflammatory agents have a number of drawbacks in CPD. They must be used for a long period of time and have limited efficacy because they do not address the root cause of the disease. Side effects and complications of treatment limit their utility due to their mode of action and the need for long-term use. Immunosuppressants have the same limitations as anti-inflammatory agents. However, since they alter the normal function of the immune system in addition to the disease process, they can cause further complications, including other disease syndromes and neoplasias. Radiation therapy, for example using x-ray radiation, is another treatment method for CPD. It has similar effects to the use of anti-inflammatory and immunosuppressant drugs. However, it can also cause more problematic side effects that worsen over time even after treatment is stopped, thus often making the radiation treatment unacceptable if long-term survival is expected.

Another newer approach to treating CPD is to identify and inhibit regulatory proteins. Such management protein therapies attempt to address the problems posed by genetic, pharmaceutical, and anti-inflammatory/immunosuppressive therapies by finding proteins or enzymes that are critical and common to several disease states, regardless of their root cause, and inhibiting them in various ways. Since a single management protein may be central to the development of several disease states (e.g., a variety of and otherwise unrelated cancers), blocking this key protein may have broader therapeutic applications than more disease-targeted therapies. However, if the protein itself is targeted, management of protein therapy also has the general limitations of targeted drug therapy, with the additional problem common to targeted therapy: triggering the compensation mechanism up-regulates results in permanent insensitivity to drug action. Furthermore, if targeting the transcriptional and translational mechanisms that produce proteins, management protein therapy also has the general limitations of gene therapy. Although associated with disease processes, such proteins actually play a critical role in normal physiology throughout, and may cause problems if inhibited either universally or indiscriminately. Thus, such management protein therapies also have the problems associated with targeted drug therapies as described above.

Stem cell transplantation (stem cell transplantation; SCT) is yet another method of treating CPD. SCT attempts to replace dead or dysfunctional tissue with new functional tissue by transplanting stem cells into the tissue or into an area surrounding the tissue. SCT is very complex and expensive with significant risks and adverse therapeutic effects. Despite the public interest, SCT has so far been largely ineffective.

The existing methods for treating CPD described above have limited success and utility, so most CPDs are currently untreated or are only supportive, symptomatic, palliative or ineffective treatments. These treatments have success and utility due to practical limitations including unknown or multiple reasons, cost, time, and non-physiological (unnatural and artificial) modes of action, which by definition superimpose new drugs/interventions on CPD to induce disease states. Accordingly, the ideal treatment of CPD should be physiological independent of the root cause, and thus not only effective but well tolerated without side effects, and be able to break the vicious CPD cycle through multiple point interventions in the cycle (including directly distal to the primary defect) to obtain maximum efficacy.

As mentioned above, alzheimer's disease and other neurodegenerative diseases are chronic progressive diseases. Researchers have been trying to find treatments or cures for Alzheimer's disease and other degenerative diseases for decades, with little success. It is believed that potential disease modifying drugs that may prevent or reverse severe memory impairment, as well as other such patterns of alzheimer's disease and other degenerative diseases, may be ineffective because they have difficulty crossing the blood brain barrier and entering neurons of the brain.

In view of the inability of drugs to slow or reverse cognitive dysfunction in alzheimer's disease and other degenerative diseases to date, other non-drug interventions are necessary. Transcranial stimulation (e.g., by using electromagnetic energy sources (including radio frequency)) has been found to be capable of treating tissue and fluids at the blood brain barrier and beyond and into the tissues of the brain.

Disclosure of Invention

The present invention relates to systems and methods for preventing and treating chronic progressive diseases, including Alzheimer's disease and other degenerative diseases. According to the invention, an individual is determined to have or be at risk of having Alzheimer's disease or other degenerative diseases. A pulsed electromagnetic energy source comprising radio frequency or microwaves having selected energy parameters including wavelength or frequency, duty cycle and pulse train duration is applied to the brain of the individual to prevent or treat the alzheimer's disease or other degenerative disease. The pulsed electromagnetic energy may be directed to one or more of a leaky blood brain barrier, an inflamed portion of the brain, a trash protein of the brain, beta (beta) amyloid of the brain, and/or tangled billows (tau) proteins of the brain.

The pulse energy source parameter may be selected to substantially increase the temperature of the tissue being treated, thereby stimulating heat shock protein activation in the tissue or fluid being treated. The energy parameter is selected to raise the temperature of the target tissue or target fluid to 11 ℃, typically between 6 ℃ and 11 ℃, at least during application of the pulsed energy source to the target tissue or target fluid, to obtain a therapeutic or prophylactic effect. The average temperature rise of the tissue or target fluid is maintained at or below a predetermined level over a period of several minutes so as not to permanently damage the target tissue or target fluid. For example, the average temperature rise of the target tissue or target fluid may be maintained at 6 ℃ or less over a period of several minutes. More often, the average temperature rise of the target tissue or target fluid is maintained at about 1 ℃ or less during several minutes, for example, during a six minute period.

The radio frequency may be between 3 and 6 megahertz (MHz) and have a duty cycle between 2.5% and 5.0%, and a pulse train duration between 0.2 and 0.4 seconds. The radio frequency may be generated using a device having a radius between 2 and 6 millimeters and a coil between 13 and 57 ampere turns.

The pulsed electromagnetic energy parameters may be selected and applied to the brain to induce resonant interactions within biomolecules within and around brain tissue. The pulse energy parameter may be selected and applied to the brain to disrupt the structural integrity of the beta amyloid molecule. In particular, the pulse energy parameter may be selected to interact with pi electron stacking resonances in the beta (beta) amyloid and other biomolecules.

A plurality of spaced apart radio frequency transmitters may be disposed adjacent the head of the individual to be treated. Preferably, the radio frequency fields of the spaced radio frequency transmitters do not overlap. The power level of each emitter may be set so that the specific absorption rate in the brain is between 1.0W/kg and 2.0W/kg. Each transmitter may transmit a radio frequency field at 850 to 950 megahertz every 4 to 5 milliseconds.

The source of radio frequency energy may be applied to the brain at given intervals during a given period of time. For example, the radio frequency may be applied to the brain for an hour of treatment period spaced twice daily. This may occur over days, weeks, or even months.

Other features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, illustrating by way of example the principles of the invention.

Drawings

The accompanying drawings are used to illustrate the invention. In these figures:

FIG. 1 is a schematic view showing a system for generating a pulsed energy source in the form of a laser beam in accordance with the present invention;

FIG. 2 is a schematic view of an optical device for generating a laser geometry according to the present invention;

FIG. 3 is a schematic view illustrating an alternative embodiment of a system for generating a laser beam to treat tissue and fluid in accordance with the present invention;

FIG. 4 is a schematic view illustrating another embodiment of a system for generating a laser beam to treat tissue in accordance with the present invention;

FIG. 5 is a top view of an optical scanning mechanism used in accordance with the present invention;

FIG. 6 is a partially exploded view of the optical scanning mechanism of FIG. 5 showing its various components;

FIG. 7 illustrates a controlled shift in illumination of an exemplary geometric pattern grid laser spot for treating a target tissue in accordance with the present invention;

FIG. 8 is a schematic view showing a controllable scanning of a geometric object having a line form to treat a target tissue in accordance with the present invention;

FIG. 9 is a schematic view similar to FIG. 8 but showing the geometric line or bar rotated to treat an area in accordance with the present invention;

FIGS. 10 and 11 are graphs showing the average power of a laser source as compared to the source radius and pulse train duration of the laser;

FIGS. 12 and 13 are graphs showing that the temperature decay time is dependent on the laser source radius and wavelength;

figures 14 through 17 are graphs showing the peak ampere-turns for different radio frequencies, duty cycles, and coil radii;

FIG. 18 is a graph showing temperature rise decay time versus radio frequency coil radius;

FIGS. 19 and 20 are graphs showing average microwave power versus microwave frequency and pulse train duration;

FIG. 21 is a graph showing temperature decay times for different microwave frequencies;

FIG. 22 is a graph showing average ultrasound source power versus frequency and pulse train duration;

FIGS. 23 and 24 are graphs showing temperature decay times for different ultrasonic frequencies;

FIG. 25 is a graph showing volume of a focal heating zone versus ultrasound frequency;

FIG. 26 is a graph of an equation comparison of temperature versus pulse duration for an ultrasonic energy source;

FIGS. 27 and 28 are graphs showing the magnitude of the logarithm of the HSP activated Arrhenius integral as a function of temperature and pulse duration;

FIG. 29 is a schematic view of a light generating unit having a light pipe extending therefrom that generates a timed pulse sequence in accordance with the present invention;

FIG. 30 is a cross-sectional view of a photo-stimulation delivery device delivering electromagnetic energy to target tissue in accordance with the present invention;

FIG. 31 is a cut-away and schematic view of one end of an endoscope inserted into the nasal cavity and treating tissue therein in accordance with the present invention;

FIG. 32 is a schematic and partial cross-sectional view of a bronchoscope according to the present invention extending through the trachea and into the bronchi of the lung and providing therapy thereto;

FIG. 33 is a schematic view of a colonoscope providing optical stimulation to an intestinal or colonic region of a body according to the present invention;

FIG. 34 is a schematic view of an endoscope inserted into the stomach and providing therapy thereto in accordance with the present invention;

FIG. 35 is a partially cut-away perspective view of a capsule endoscope used in accordance with the present invention;

FIG. 36 is a schematic view of pulsed high intensity focused ultrasound for treating tissue inside a body in accordance with the present invention;

FIG. 37 is a schematic view of providing therapy to a patient's blood flow through an earlobe in accordance with the present invention;

FIG. 38 is a cross-sectional view of a stimulation therapy device of the present invention used in delivering optical stimulation through the earlobe to the blood in accordance with the present invention;

FIG. 39 is a schematic and perspective view of a device for treating multiple areas or the entire body of an individual in accordance with the present invention;

FIG. 40 is a schematic perspective view of a plurality of spaced apart radio frequency emitters disposed adjacent to the head of an individual to be treated; and

fig. 41 is a schematic view showing the emission of electromagnetic energy by the emitter into the head and brain of the individual in accordance with the present invention.

Detailed Description

The invention as fully illustrated and shown herein resides in methods and systems for providing protective treatment to biological tissue or fluids having or at risk of having chronic progressive disease. In particular, the present invention relates to systems and methods for preventing or treating alzheimer's disease or other neurodegenerative diseases.

According to one embodiment of the invention, the pulsed energy source has an energy parameter comprising wavelength or frequency, duty cycle and pulse train duration, the energy parameter being selected to raise the temperature of the target tissue or target fluid to 11 degrees celsius in a short period of time of a few seconds or less while maintaining the average temperature rise of the tissue or target fluid at or below a predetermined level during a few minutes so as not to permanently damage the target tissue or target fluid. The pulsed energy source is applied to the target tissue or target fluid determined to have or be at risk of having a chronic progressive disease. This determination may be made and performed prophylactically before imaging, serology, immunology, or other abnormalities may be detected. This determination can be accomplished by ascertaining whether the patient is at risk for the chronic progressive disease. Alternatively or additionally, the patient's examination or test results may be abnormal. Specific tests (e.g., genetic tests) may be performed to confirm that the patient is at risk for the chronic progressive disease. In the case of alzheimer's disease or other neurodegenerative diseases, MRI or CAT scan may be performed on the brain, cognitive or memory tests may be administered, genetic factors or genetics (e.g., genetic tests) may be utilized, or an individual may be determined to be at risk of developing alzheimer's disease or another neurodegenerative disease or any other test having the disease.

The mechanism by which the present invention is used to therapeutically or prophylactically treat biological tissue or fluid is believed to be by stimulating heat shock protein activation in the target tissue or target fluid. Heat shock proteins (heat shock protein; HSPs) are ubiquitous in a highly conserved enzyme family found in all cells of all organisms. This can be up to 40% of the total protein present in a given cell. HSPs are active and critical in maintaining normal cellular function and homeostasis. HSPs have many key functions, one of which is to protect cells from any type of lethal injury and repair sub-lethal injury.

While chronic inflammation is pathological and destructive, acute inflammation may be reparative. Acute inflammation may occur in response to acute injury. Common injuries that require repair are often associated with cellular and tissue injuries (e.g., wounds or infections). Depending on the severity of the injury and the functional sensitivity of the tissue, loss of critical function may result despite wound repair. Incomplete repair or sustained or repeated injury may lead to chronic inflammation as in CPD.

Normal health is maintained by continuous monitoring and repair of complex physiological processes of defective proteins and potential threats such as bacteria, viruses and neoplasias. These normal physiological processes and their effects are desirable because good health and function are the result of their normal function. While the normal function of these physiological processes is ideal, such steady-state processes are not always perfectly effective per se. Potential threats and anomalies may escape detection or exceed repair capabilities. Failure to monitor and respond can be caused by a number of reasons, including disease-induced immunosuppression, evasion of detection by hidden antigen stimulation (e.g., as occurs in certain cancers and retroviruses), and morbidity and progression below symptom recognition and activation levels.

HSP is the first step in the acute inflammatory process. Activation of HSPs by threat causes a series of subsequent events leading to improved cellular function, reduced chronic inflammation, and local and systemic repair immune modulation. Efficient HSP activation preserves cell life and normalizes cell function, also known as homotrophy. Abrupt and severe but (to cells) sub-lethal stimulation is the most effective stimulatory factor for homotrophic HSP activation. Slow-going and chronic stimulation is not a potent activator of HSP response. Thus, CPD, which is insidiously developed and performed, does not stimulate the repair response of HSP activation. In some CPDs, such as diabetes and alzheimer's disease, HSP function itself may become abnormal to the point of failure.

However, in general, HSPs normalize cellular function independently of the cause of abnormality by recognizing and repairing abnormal cellular proteins regardless of the cause of abnormality. HSPs have the ability to restore each protein to its correct state or eliminate unrepairable proteins for replacement. Since HSP response is physiological and therefore perfect and has no adverse effects, repair of damaged material regardless of the cause of the damage, the HSP repair response is well suited to the disease process. Therefore, homotrophic HSP activation is a non-specific trigger for disease-specific repair without knowing the cause of protein misfolding and thus cellular dysfunction.

The inventors have found that induction of acute but sub-lethal cellular hyperthermia stimulated HSP activation by electromagnetic radiation without cellular or tissue damage is feasible. Thus, a cascade of physiological repair and co-culture of acute inflammatory responses can be triggered without cell death or tissue damage, without adverse therapeutic effects. Acute inflammation induced without tissue damage can be considered "as if it were" acute inflammation. That is, the homotrophic cell hyperthermia can elicit a complete and only beneficial acute inflammatory response, "as if it were caused by tissue damage, but without tissue damage. The safest and most effective stimulation of heterotrophic HSP activation has been found to be by pulsed electromagnetic radiation (pulsed electromagnetic radiation; PEMR). The pulse allows for a significant increase in the sudden and severity of threat stimulation without killing the target cells, thereby maximizing HSP activation in the heterotrophic healing response. Different types of PEMRs are most suitable for different biological applications, including light, laser, radio waves, and microwaves and ultrasound.

The eye is the most functionally sensitive organ of the body. There are several CPDs affecting the retina, which often share the typical characteristics of CPDs, particularly neurodegenerative diseases. Accordingly, the CPD of the retina can serve as a model of the CPD elsewhere in the body. Clinical experience in a large number of patients has found that PEMR in the form of low intensity/high density sub-threshold diode pulse laser therapy (micropulsed laser treatment; SDM) has proven effective in treating, preventing, slowing, reversing or arresting the progression of each major chronic progressive disease of the retina without regard to the cause. These include diseases of age-related, genetic, metabolic and unknown etiology with widely varying genotypes and phenotypes. Despite the thermal sensitivity of the retina, due to the selection of the operational parameters of the PEMR, the SDM does this without any known adverse therapeutic effects, and is therefore performed with complete safety.

With conventional retinal photocoagulation, the physician must deliberately create retinal lesions as a prerequisite for a therapeutically effective treatment. However, the inventors speculate that treatment with retinal pigment epithelium (retinal pigment epithelium; RPE) cytokine production induced by conventional photocoagulation alters cells from the edge of conventional laser firing that are affected by but not killed by laser irradiation. The inventors created an energy parameter that created a "true subthreshold photocoagulation" that was invisible and included laser treatment that was not identifiable by any known method such as FFA, FAF, retrograde FAF, or even SD-OCT, and that did not absolutely produce retinal damage detectable by any means at the time of treatment or at any time later by any known detection means, but still produced the benefits of conventional retinal photocoagulation. This is discussed in U.S. publication 2016/0346126A1, the contents of which are incorporated herein by reference.

Various parameters are determined to achieve true sub-threshold effective photocoagulation, including providing sufficient power to produce effective treatment, but not so high as to cause tissue damage or destruction. The intensity or power of the 810 nm laser beam at a low duty cycle of between 100 watts and 590 watts per square centimeter has been found to be effective and safe. For an 810 nm micropulse diode laser, a particularly preferred intensity or power of the laser beam is about 250 to 350 watts per square centimeter.

The current power limitations of micropulse diode lasers require a longer irradiation duration, but it is important that the generated heat is dissipated towards the non-irradiated tissue at the edge of the laser spot, so as not to damage or destroy the cells or tissue. It has been found that the radiation beam of an 810 nm diode laser should have an irradiation envelope of 500 ms or less, preferably about 100 to 300 ms. If the micropulse diode laser becomes more powerful, the irradiation duration can be reduced accordingly. It has been found that invisible phototherapy or true subthreshold photocoagulation according to the present invention can be performed at various laser wavelengths, e.g. in the range from 532 nm to 1300 nm. The use of different wavelengths may affect the preferred intensity or power of the laser beam and the duration of the illumination envelope so as not to damage retinal tissue, but still achieve a therapeutic effect. Typically, the laser pulse has a duration of less than 1 millisecond, typically between 50 microseconds and 100 microseconds.

Another parameter of the invention when using a laser is the duty cycle, or the frequency of the pulse train or the length of the thermal relaxation time between successive pulses. It has been found that the use of a duty cycle of 10% or higher increases the risk of lethal cell damage in the retina. Thus, a duty cycle of less than 10% is used and preferably about 5% or less, as this parameter has been shown to provide sufficient thermal rise in treatment that remains below the level at which lethal cell damage would be expected to occur. The smaller the duty cycle, the longer the illumination envelope duration may be. For example, if the duty cycle is less than 5%, the illumination envelope duration may exceed 500 milliseconds in some cases.

Thus, the following key parameters have been found to create harmless, realistic (sublethal to the retina) subthreshold photocoagulation in retinal tissue in accordance with the present invention:

a) A light beam having a wavelength of at least 532 nm and preferably between 532 nm and 1300 nm;

b) A low duty cycle, for example less than 10% and preferably 5% or less;

c) A spot size small enough to minimize heat accumulation and ensure uniform heat distribution within a given laser spot, thereby maximizing heat dissipation; and

d) Sufficient power to produce a retinal laser irradiation of between 18 and 55 times MPE to produce an RPE temperature rise of 7℃ to 14℃ and a power of 100 to 590W/CM ² Retinal irradiance between.

By using these above parameters, a true subthreshold or invisible photocoagulation phototherapy treatment is achieved that is harmless but therapeutically effective, which is achievable, and which has been found to produce the benefits of conventional photocoagulation phototherapy but avoids the drawbacks and complexities of conventional phototherapy. Adverse therapeutic effects are completely eliminated and the functional retina is retained rather than sacrificed. Moreover, the entire retina may be exposed to the pulsed energy source of the present invention to allow for prophylactic and therapeutic treatment of an eye suffering from a retinal disease, in whole rather than in part.

In the retina, the clinical benefit of SDM is produced by photothermal RPE HSP activation that is sub-lethal to RPE. In dysfunctional RPE cells, HSP stimulation by SDM results in normalized cytokine expression and thus improved retinal structure and function. Since normal acting cells do not require repair, HSP stimulation in normal cells often does not have a significant clinical effect. The "pathological selectivity" of the near infrared laser effect (e.g., SDM affects diseased cells but not normal cells of various cell types) is consistent with clinical observations of SDM. This function is critical for early and prophylactic treatment of SDM in eyes with chronic progressive disease and eyes with mild retinal abnormalities and mild dysfunction. Although SDM is safe, the clinical effects of SDM are significant and profound. For example, SDM reduces the rate of progression of diabetic retinopathy by 85% (p=0.0001) and of age-related macular degeneration by 95% (P < 0.0001), improving the optic nerve function of glaucoma (p=0.001) and the visual field of glaucoma and all retinal diseases including retinal pigment degeneration (P < 0.0001).

Referring now to FIG. 1, there is shown a schematic diagram of a system for implementing the method of the present invention. The system, generally indicated by reference numeral 10, includes a laser console 12, such as an 810 nm near infrared micropulse diode laser in the preferred embodiment. The laser generates a laser beam that is passed through an optical device, such as an optical lens or mask, or a plurality of optical lenses and/or masks 14, as desired. The laser projector optics 14 delivers a shaped beam to a coaxial wide area untouched digital optical viewing system/camera 16 to project the laser beam light onto the patient's eye 18, or other biological target tissue or body fluid as described in detail herein. It should be appreciated that block 16 may represent both a laser beam projector and a viewing system/camera, which may actually include two different components in use. The viewing system/camera 16 provides feedback to the display monitor 20, which may also include the necessary computerized hardware, data input and control, etc., to operate the laser 12, the optics 14, and/or the projection/viewing assembly 16.

Referring now to FIG. 2, in one embodiment, a laser beam 22 is passed through a collimator lens 24 and then through a mask 26. In a particularly preferred embodiment, mask 26 includes a diffraction grating. Mask/diffraction grating 26 produces a geometric object, or more typically, a geometric pattern of multiple laser spots or other geometric objects produced simultaneously. This is represented by a plurality of laser beams 28. Alternatively, the plurality of laser spots may be generated by a plurality of optical fiber lines. Both methods of generating laser spots allow for the simultaneous creation of a very large number of laser spots over a very wide treatment field, e.g. consisting of the whole retina. In practice, an extremely high number of laser spots (perhaps hundreds or even thousands or more) may cover the entire fundus and the entire retina, including the macula and fovea, retinal blood vessels, and optic nerves. The aim of the method of the invention is to better ensure complete and complete coverage and treatment of the target area, which may include the retina, without leaving any part of the retina behind by the laser light, thus improving vision.

By using optical features with feature sizes comparable to the wavelength of the laser light employed (e.g. by using diffraction gratings), it is possible to exploit quantum mechanical effects to allow a very large number of laser spots to be applied simultaneously to a very large target area. The individual spots produced by such diffraction gratings all have similar optical geometry to the input beam, with each spot having very little power variation. The result is that multiple laser spots with sufficient irradiance simultaneously produce harmless but effective therapeutic applications over a large target area. Other geometric objects and patterns generated by other diffractive optical elements are also contemplated by the present invention.

The laser diffraction through mask 26 produces a periodic pattern at a distance from mask 26, as shown by laser beam 28 in fig. 2. A single laser beam 22 is thus formed into a plurality (up to hundreds or even thousands) of individual laser beams 28 to create a desired pattern of spots or other geometric objects. These laser beams 28 may be passed through additional lenses, collimators, etc. 30 and 32 to deliver the laser beams and form the desired pattern on the patient's retina. Such additional lenses, collimators, etc. 30 and 32 may also convert and redirect the laser beam 28 as desired.

Any pattern can be constructed by controlling the shape, spacing, and pattern of the optical mask 26. The pattern and illumination spot can be arbitrarily created and modified as required by the application requirements of the expert in the field of optical engineering. Photolithographic techniques (particularly those developed in the field of semiconductor fabrication) may be used to create simultaneous geometric patterns of spots or other objects.

Although hundreds or even thousands of simultaneous laser spots may be generated and created and formed into a pattern to be applied to tissue, the number of treatment spots or beams that can be used simultaneously in accordance with the present invention is limited due to the requirement that the tissue not be overheated. Each individual laser beam or spot needs to be power efficient at minimum average over the column duration. At the same time, however, the tissue cannot exceed a specific temperature rise without being damaged. For example, for using an 810 nm wavelength laser, when using a 0.04 (4%) duty cycle and a total column duration of 0.3 seconds (300 milliseconds), the number of simultaneous spots generated and used may range from only 1 up to about 100.

The absorption of water increases with increasing wavelength, resulting in heating over a long path length through the vitreous body in front of the retina. For shorter wavelengths (e.g., 577 nanometers), the absorption coefficient of melanin of the RPE may be higher, and thus the laser power may be lower. For example, at 577 nanometers, the power may be reduced by a factor of 4 in order for the present invention to be effective. Accordingly, when 577 nm wavelength lasers are used, there may be only a single laser spot or up to about 400 laser spots while still not damaging or damaging the eye or other tissue. The present invention may use multiple simultaneously generated therapeutic beams or spots, e.g., tens or even hundreds, because the parameters and methods of the present invention create a therapeutically effective but non-destructive and non-permanent lesion treatment.

Fig. 3 schematically illustrates a system for coupling a plurality of light sources to the pattern generating optical subassembly described above. Specifically, this system 10' is similar to the system 10 described above in FIG. 1. The main difference between the alternative system 10' and the earlier described system 10 is that it includes a plurality of laser consoles 12 whose outputs are each input into a fiber coupler 34. The fiber coupler produces a single output that is passed into the laser projector optics 14 as described in the earlier systems. Coupling multiple laser consoles 12 into a single fiber is accomplished by a fiber coupler 34 as known in the art. Other known mechanisms for combining multiple light sources are available and may be substituted for the fiber optic couplers described herein.

In this system 10', the plurality of light sources 12 follow a similar path as described in the earlier system 10, namely collimation, diffraction, re-collimation, and guidance into the retina by a guidance mechanism. In this alternative system 10', the diffractive element acts in a different manner than described earlier, depending on the wavelength of the light passing through, resulting in a slightly varying pattern. The variation is linear with the wavelength of the diffracted light source. In general, the difference in diffraction angles is small enough so that different overlay patterns can be directed along the same optical path through the directing mechanism 16 to the retina 18 for treatment. A small difference in diffraction angle will affect how the guide pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, the sequential shift to achieve complete coverage will be different for each wavelength. This sequence offset may be implemented in two modes. In the first mode, all wavelengths of light are applied simultaneously without the same coverage. An offset guide pattern is used that achieves complete coverage for one of the multiple wavelengths. Thus, while the selected wavelength of light achieves complete coverage of the tissue region to be treated, the application of other wavelengths achieves incomplete or overlapping tissue coverage. The second mode sequentially applies light sources of varying or different wavelengths with appropriate guiding patterns to achieve complete coverage of the tissue for that particular wavelength. This mode precludes the possibility of using multiple wavelengths for simultaneous treatment, but allows the optical method to achieve the same coverage for each wavelength. This avoids incomplete or overlapping coverage for any light wavelength.

These patterns may also be mixed and matched. For example, two wavelengths may be applied simultaneously, one to achieve complete coverage and the other to achieve incomplete or overlapping coverage, followed by sequential application of a third wavelength and achieving complete coverage.

Fig. 4 schematically illustrates another alternative embodiment of the inventive system 10 ". This system 10 "is configured substantially the same as the system 10 shown in fig. 1. The main difference is that it includes multiple pattern generating subassembly channels tuned to specific wavelengths of the light source. A plurality of laser consoles 12 are arranged in parallel, each directly leading to its own laser projector optics 14. The laser projector optics of each

channel

38a, 38b, 38c includes the collimator 24, the mask or diffraction grating 28, and the re-collimators 30, 32-the entire set of optics is tuned for the particular wavelength generated by the respective laser console 12 as described above in connection with fig. 2. The outputs of the sets of optics 14 are then directed to a beam splitter 36 for combining with other wavelengths. As is known to those of ordinary skill in the art, a beam splitter used in reverse may be used to combine multiple beams into a single output.

The combined channel output from the final beam splitter 36c is then directed through the camera 16, which applies a directing mechanism to allow complete coverage of the retina 18.

In system 10", the optical elements of each channel are tuned to produce a precise specific pattern for the wavelength of the channel. Thus, when all channels are combined and properly aligned, a single guide pattern can be used to achieve complete coverage of the retina for all wavelengths.

The system 10 "may use as

many channels

38a, 38b, 38c, etc. as there are wavelengths of light used in the treatment, as well as

beam splitters

36a, 36b, 36c, etc.

The implementation of system 10 "may utilize different symmetries to reduce the number of alignment constraints. For example, the proposed grid pattern is periodic in two dimensions and guided along the two dimensions to achieve complete coverage. Thus, if the pattern of each channel is the same as specified, the actual pattern of each channel will not need to be aligned for the same guide pattern to achieve complete coverage for all wavelengths. Only optical alignment of the channels will be required to achieve efficient combining.

In system 10", the channels begin with light source 12, which may be from an optical fiber as in other embodiments of the pattern generation subassembly. This light source 12 is directed to an optical assembly 14 to collimate, diffract, re-collimate and direct to the beam splitter, which combines the channel with the primary output.

The field of photobiology suggests that different biological effects can be obtained by exposing target tissue to laser light of different wavelengths. The same effect may also be obtained by sequentially applying a plurality of lasers having different or the same wavelengths sequentially at variable intervals and/or with different radiant energies. The present invention contemplates the simultaneous or sequential application of multiple laser, light or radiation wavelengths (or modes) to maximize or tailor the desired therapeutic effect. This approach also minimizes potentially deleterious effects. The optical methods and systems shown and described above provide for simultaneous or sequential application of multiple wavelengths.

Typically, the system of the present invention comprises a guidance system to ensure complete and comprehensive treatment by light stimulation. A fixation/tracking/registration system consisting of a fixation target, a tracking mechanism and operatively linked to the system may be incorporated into the present invention.

In certain preferred embodiments, the geometric patterns of the simultaneous laser spots are sequentially offset to achieve fusion and complete treatment of the target tissue. This is performed in a time-saving manner by arranging a plurality of spots over the target tissue at a time. The pattern of simultaneous spots is sequentially scanned, offset, or redirected as an overall array to cover the entire target tissue during a single treatment.

This may be performed in a controlled manner using the optical scanning mechanism 40. Fig. 5 and 6 show an optical scanning mechanism 40 that may be used in the form of a MEMS mirror having a substrate 42 with electronically actuated

controls

44 and 46 for tilting and moving a mirror 48 when power is applied to and removed from the electronically actuated controls. Applying power to the

controllers

44 and 46 causes the mirror 48 to move, thereby causing the simultaneous pattern of laser spots or other geometric objects reflected thereon to correspondingly move over the target tissue of the patient. This may be performed in an automated manner, for example, by using an electronic software program to adjust the optical scanning mechanism 40 until the target tissue is completely covered or at least a portion of the target tissue in need of treatment is exposed to phototherapy. The optical scanning mechanism may also be a small beam diameter scanning galvanometer system, or similar system, such as that distributed by Thorlabs corporation. Such a system is capable of scanning the laser in a desired offset pattern.

Since the parameters of the present invention determine that the applied radiation energy or laser is not destructive or damaging, the geometric patterns of the laser spots can be overlapped, for example, without damaging the tissue or creating any permanent damage. However, in a particularly preferred embodiment, as shown in fig. 7, the pattern of spots is offset at each shot to form a space between the previous shot, thereby allowing for heat dissipation and preventing the possibility of thermal injury or tissue damage. Thus, as shown in fig. 7, the pattern of the grid shown as an example of 16 spots is shifted each time the irradiation is performed so that the laser spot occupies a different space than the previous irradiation. It should be understood that the schematic use of circles or hollow dots and solid dots is for illustrative purposes only to illustrate the previous and subsequent illumination of the area by the spot pattern according to the present invention. The spacing of the laser spots prevents overheating and damaging the tissue. It will be appreciated that this occurs until the entire target tissue has received phototherapy or until the desired effect is achieved. This may be performed, for example, by a scanning mechanism, such as by applying an electrostatic torque to the micro-machined mirror, as shown in fig. 5 and 6. By using a combination of small laser spots (preventing heat build-up) separated by non-illuminated areas and a grid with a large number of spots on each side, it is possible to treat a large target area with short illumination durations atraumatically and invisibly very quickly.

By rapidly and sequentially repeating the reorientation or deflection of the entire concurrently applied grid array of spots or geometric objects, complete coverage of the target tissue (e.g., human retina) can be achieved rapidly without thermal tissue damage. Depending on the laser parameters and the desired application, this offset may be determined algorithmically to ensure the fastest treatment time and minimum risk of damage due to thermal tissue.

For example, modeling is performed by using Fraunhoffer Approximation as follows. With a 9x9 square mask, a 9 micron aperture radius, a 600 micron aperture pitch, a 890 nm wavelength laser, a 75 mm mask-lens spacing, and a 2.5 mm x2.5 mm secondary mask size, the following parameters will produce a grid of 19 spots per side with a spot size radius of 6 microns at 133 microns. Given the required area side length "a", the output pattern spot "n" for each square side, the spacing "R" between spots, the spot radius "R" and the required square side length "a" for the treatment area, the number of exposures "m" required for treatment (coverage applied with fused small spots) can be given by:

with the above arrangement, the number m of operations for treating different irradiation field regions can be calculated. For example, a 3 mm x3 mm region that is beneficial for treatment would require 98 offset operations, requiring a treatment time of about 30 seconds. Another example is a 3 cm x3 cm area. For such large treatment areas, a larger secondary mask size of 25 mm x25 mm may be used, resulting in a treatment grid of 190 spots per side with a spot size radius of 6 microns, spaced 133 microns. Since the secondary mask size is increased by the same factor as the required treatment area, the number of offset operations of about 98 and thus the treatment time of about 30 seconds is unchanged. A field size of 3 mm would, for example, allow for the treatment of the macula of an entire person in a single irradiation, facilitating the treatment of common blinding conditions such as diabetic macular edema and age-related macular degeneration. Performing a full 98 sequential shifts will ensure complete coverage of the macula.

Of course, the number and size of spots generated in the simultaneous pattern array is variable and variable, so that the number of sequential offset operations required to complete a treatment can be easily adjusted depending on the treatment requirements of a given application.

Moreover, quantum mechanical behavior can be observed by means of small holes employed in the diffraction grating or mask, which allows an arbitrary distribution of the laser input energy. This will allow the generation of multiple spots in any geometry or pattern, for example in a grid pattern, lines or any other desired pattern. Other methods of generating geometry or pattern, such as using a plurality of optical fibers or microlenses, may also be used in the present invention.

Referring now to fig. 8 and 9, instead of using a geometric pattern of small laser spots, the present invention contemplates using other geometric objects or patterns. For example, a single laser line 50 may be created that is formed continuously or by a series of closely spaced spots. The line may be scanned sequentially over the area using an offset optical scanning mechanism, as indicated by the downward arrow in fig. 8. Referring now to fig. 9, the same geometric objects of the rotatable line 50 are shown by arrows, thereby creating a circular phototherapy field. However, a potential negative effect of this approach is that the central region will be repeatedly irradiated and may reach unacceptable temperatures. However, this disadvantage can be overcome by increasing the time between irradiation or forming voids in the line so that the central region is not irradiated.

The power limitations in current micropulse diode lasers require a fairly long irradiation duration. The longer the illumination time, the more important the center-spot heat dissipation capability towards the non-illuminated tissue at the edge of the laser spot. Thus, the micro-pulsed laser beam of an 810 nm diode laser should have an illumination envelope duration of 500 milliseconds or less, and preferably about 300 milliseconds. Of course, if the micropulse diode laser becomes more powerful, the irradiation duration should be reduced accordingly.

In addition to the power limitation, another parameter of the invention is the duty cycle, or frequency of the micropulse train, or length of thermal relaxation time between successive pulses. It has been found that using a 10% duty cycle or higher duty cycle of a micropulse laser adjusted to deliver similar irradiance at similar MPE levels significantly increases the risk of lethal cell damage. However, a duty cycle of less than 10% and preferably 5% or less indicates adequate thermal rise and treatment at MPE cell levels to stimulate a biological response, but remains below the level expected to produce lethal cell damage. However, the lower the duty cycle, the longer the illumination envelope duration increases, and in some cases may exceed 500 milliseconds.

Each micro-pulse lasts a fraction of a millisecond, typically between 50 microseconds and 100 microseconds in duration. Thus, for an illumination envelope duration of 300 to 500 milliseconds, and a duty cycle of less than 5%, there is a significant amount of time between micropulses to allow for thermal relaxation times between successive pulses. Typically, a thermal relaxation time delay of between 1 and 3 milliseconds, preferably about 2 milliseconds, is required between successive pulses. For adequate treatment, the cells are typically irradiated or impacted with a laser between 50 and 200 times, and preferably between 75 and 150 at each location. With a relaxation or interval of 1 to 3 milliseconds, the total time for treating a given region (or in particular the location of the target tissue exposed to the laser spot) according to the above described embodiments averages between 200 and 500 milliseconds. Thermal relaxation times are required to avoid overheating the cells in the site or spot and to prevent damage or destruction of the cells.

The inventors have found that treatment of patients suffering from age-related macular degeneration (AMD) according to the invention may slow down progression or even prevent progression of AMD. Further evidence of this restorative treatment effect is that the inventors have found that treatment can uniquely reduce the risk of vision loss in AMD due to choroidal neovascularization by up to 90%. After treatment according to the present invention, most patients have seen a significant improvement in dynamic intermediate logMAR visual acuity versus comparative visual acuity, with some experiencing better vision. This is believed to act by targeting, maintaining, and "normalizing" (toward normal) the function of the Retinal Pigment Epithelium (RPE).

Although systemic diabetes persists, treatment according to the invention has also been demonstrated to prevent or reverse the manifestation of diabetic retinopathy disease states without treatment-related damage or adverse effects. Studies by the inventors have shown that the restorative effect of treatment can uniquely reduce the risk of progression of diabetic retinopathy by 85%. On this basis, it is assumed that the present invention may function by inducing a return to more normal cellular functions and cytokine expression in RPE cells affected by diabetes, similar to clicking a "reset" button of an electronic device to restore factory defaults.

Based on the above information and studies, SDM treatment can directly affect cytokine expression and Heat Shock Protein (HSP) activation in targeted tissues, particularly the Retinal Pigment Epithelium (RPE) layer. The inventors have noted that holoretinal and holotopic SDMs reduce the rate of progression of many retinal diseases, including severe non-proliferative and proliferative diabetic retinopathy, AMD, DME, and the like. The known therapeutic benefits of treatment in combination with the lack of known adverse therapeutic effects in individuals with these retinal diseases allow for early and prophylactic treatment, free use, and re-treatment to be considered, if necessary. This reset theory also suggests that the present invention is applicable to many different types of RPE mediated retinal diseases. Indeed, the inventors have recently discovered that holotopic treatment can significantly improve retinal function and health, retinal sensitivity, and dynamic logMAR visual acuity as well as comparative visual acuity in dry age-related macular degeneration, retinitis pigmentosa, cone rod retinal degeneration, and Stargardt's disease (no other treatment has been previously found to do so).

Currently, retinal imaging and visual acuity testing guide the management of chronic progressive retinal disease. Since tissue and/or organ structural damage and vision loss are manifestations of advanced disease, the treatments initiated at this time must be intensive, often long-term and expensive, and often fail to improve visual acuity and rarely restore normal vision. Since the present invention has proven to be an effective treatment for several retinal diseases without adverse therapeutic effects, and because of its safety and effectiveness, it is often useful to treat the eye to prophylactically arrest or delay the onset or symptoms of retinal diseases or as a prophylactic treatment for such retinal diseases. Any treatment that improves retinal function and thus health should also reduce disease severity, progression, accidents, and vision loss. By starting treatment early before the pathological structural changes and maintaining the therapeutic benefit by conventional functional guidance re-treatment, structural degeneration and vision loss may thus be delayed, if not prevented. Even a slight decrease in the rate of disease progression may lead to a significant decrease in the long term vision loss and complications. By alleviating the consequences of the major deficiency, the disease process can be alleviated, progression slowed, and complications and vision loss reduced. This is reflected in the inventors' studies, which found that treatment reduced the risk of progression of diabetic retinopathy and vision loss by 85% and AMD by 80%.

According to one embodiment of the invention, a patient (e.g., a patient's eye) is determined to be at risk of developing a disease. This may be performed before imaging anomalies are detectable. Such a determination may be made by ascertaining whether the patient is at risk for chronic progressive disease, such as retinopathy, including diabetes mellitus, age-related macular degeneration or retinitis pigmentosa. Alternatively or additionally, the patient's examination or test results may be abnormal. Specific tests (e.g., physiological tests or genetic tests) may be performed to confirm that the patient is at risk of developing a disease.

When treating or prophylactically protecting retina or other ocular tissue having or at risk of having a chronic progressive disease, a sub-lethal laser beam is generated and creates a true sub-threshold photocoagulation in the retinal tissue, and at least a portion of the retinal tissue is exposed to the generated laser beam without damaging the exposed retina or fovea tissue, thereby providing a prophylactic and protective treatment of the retinal tissue of the eye. The retina being treated may include the fovea, retinal Pigment Epithelium (RPE), choroid, choroidal neovascularization, subretinal fluid, macula, macular edema, parachlorous, and/or perifoveal regions. The laser beam may be directed to only a portion of the retina, or substantially the entire retina and fovea.

Although many therapeutic effects appear to be long-term (if not permanent), clinical observations and laboratory studies indicate that others may fade. Accordingly, the tissue is periodically re-treated to maintain maximum efficacy and therapeutic benefit. This may be performed according to an established plan or when it is determined that the patient's tissue needs to be re-treated, for example by periodically monitoring the patient's vision and/or retinal function or condition.

Although the invention is particularly suited for the treatment of retinal diseases (e.g., diabetic retinopathy and macular edema), it has been found that it can also be used for other diseases. The system and method of the present invention can be implemented with another customized treatment field template using the trabecular meshwork as a target for treating glaucoma. Furthermore, treatment of retinal tissue (as described above) with SDM on eyes with progressive open angle glaucoma has shown an improved key indicator of optic nerve and ganglion cell function, indicating a significant neuroprotective effect of this treatment. The visual field is also improved without adverse therapeutic effects. It is therefore believed that SDM can aid in clinical management of glaucoma by reducing the risk of vision loss Independent of Ocular Pressure (IOP) lowering in accordance with the present invention.

As detailed above, low intensity/high density subthreshold (sublethal) diode micropulse lasers (SDMs) have proven to be effective in treating traditional retinal laser indications such as diabetic macular edema, proliferative diabetic retinopathy, central serous chorioretinopathy, and retinal branch vein occlusion without adverse therapeutic effects. As noted above, the mechanism of retinal laser treatment is sometimes referred to herein as the "reset to default" theory, which assumes that the primary mode of retinal laser action is the sublethal activation of Retinal Pigment Epithelium (RPE) heat shock proteins.

Recent studies by the inventors have also shown that SDM should be neuroprotective in open angle glaucoma. Linear regression analysis showed that the most abnormal values before treatment improved the most after treatment for almost all indicators. In accordance with the present invention, the treatment of full-macula SDM in an eye with progressive Open Angle Glaucoma (OAG) improves key indicators of optic nerve and ganglion cell function, indicating significant neuroprotective effective treatment. The visual field is also improved without adverse therapeutic effects. Thus, generating a micropulse laser beam having the above-described characteristics and parameters and applying the laser beam to the retina and/or foveal tissue of an eye suffering from or at risk of suffering from glaucoma produces a therapeutic effect on the retina and/or foveal tissue exposed to the laser beam without damaging or permanently damaging the retina and/or foveal tissue and also improves the function or condition of the optic nerve and/or retinal ganglion cells of the eye.

Retinal ganglion cells and optic nerves are affected by the health and function of the Retinal Pigment Epithelium (RPE). Retinal homeostasis is maintained by the RPE primarily via a still unintelligible but extremely complex interaction of small proteins secreted by the RPE into the intercellular space, known as "cytokines". Some RPE-derived cytokines, such as pigment epithelium-derived factor (pigment epithelial derived factor; PEDF), are neuroprotective. Retinal laser treatment may alter RPE cytokine expression, including but not limited to increasing PEDF expression. According to the present invention, the effect of SDM is "syntrophic" in the absence of retinal damage, tending to normalize retinal function. By normalizing RPE function, retina autoregulation and cytokine expression is also normalized. This suggests that normalization of retinal cytokine expression may be the root cause of the neuroprotective effects of SDM in OAG.

Although SDM has a significant beneficial effect on chronic progressive retinal diseases, most of these diseases do not have any other beneficial treatment. In this regard, retinal CPD is also similar to CPD elsewhere. Abnormalities in the HSP system have been identified in all CPDs including type II diabetes, alzheimer's disease, idiopathic Pulmonary Fibrosis (IPF), and ischemic heart disease, as well as various cardiomyopathy. Currently, no non-physical therapy is available outside the present invention to stimulate HSP isotrophy in systemic CPD. Experience with SDM associated with ocular disease has shown that properly designed PEMR should effectively and safely treat any CPD that affects any other part of the body. Moreover, SDM experience in otherwise untreated retinal diseases suggests that the beneficial effects of PEMR elsewhere should be important rather than trivial, robust, significant and safe. Like SDM, the effect of PEMR on CPD elsewhere in the body will likely not cure the primary cause of the disease (age, diabetes, genetic defects, etc.), but rather will slow, prevent or reverse the disease process by repairing abnormalities that develop due to the primary disease defect. By periodically re-treating to maintain therapeutic benefit, the progression of the disease process should be reduced, thereby reducing the risk of death and disability.

Since heat shock proteins play a role in responding to a number of abnormal conditions in body tissues other than ocular tissues, it is believed that similar systems and methods may be advantageously used to treat such abnormal conditions, infections, and the like, other than the eye. Thus, the invention also relates to the controlled application of pulsed ultrasound or electromagnetic radiation to treat abnormal conditions, including inflammatory, autoimmune conditions, and cancers accessible by fiber optics and focused electromagnetic/sonic waves through an endoscope or surface probe. For example, cancers on the surface of the prostate with the greatest metastatic threat can be accessed through fiber optics in a proctoscope. Colon tumors can be accessed through fiber optic systems, like those used in colonoscopy.

As indicated above, subthreshold diode-pulsed laser (SDM) light stimulation is effective in stimulating direct repair of slightly misfolded proteins in ocular tissue. In addition to HSP activation, another approach that may occur is that the temperature peaks caused by micropulses in the form of thermal time courses allow water to diffuse inside the protein, and this allows peptide-peptide hydrogen bonding cleavage that prevents the protein from recovering its natural state. Diffusion of water into proteins results in an increase in the number of hydrogen bonds inhibited by a factor of a thousand. It is therefore believed that this process may also be advantageously applied to other diseases.

Laser treatment may induce HSP production or activation and alter cytokine expression. The more sudden and severe the non-lethal cellular stress (e.g., laser irradiation), the more rapid and robust HSP activation. Thus, the burst of repeated low temperature thermal peaks with very high rate of change (about 7 ℃ per 100 microsecond micropulse rise, or 70,000 ℃/sec) produced by each SDM irradiation is particularly effective in stimulating HSP activation, especially compared to non-lethal irradiation with continuous wave lasers for subthreshold treatment (which only replicates low average tissue temperature rise).

In accordance with the systems and methods of the present invention, a pulsed energy source (e.g., laser, ultrasound, ultraviolet, radio frequency, microwave radio frequency, etc.) has an energy parameter selected to induce a thermal time course in the tissue or body fluid to raise the target tissue or body fluid temperature to a sufficient level during a short period of time to achieve a therapeutic effect while maintaining the average tissue temperature below a predetermined level over a long period of time to avoid permanent tissue damage. The creation of this heat schedule is thought to stimulate heat shock protein activation or production and promote protein repair without causing any cellular damage. The parameters of the pulsed energy source and its application to the target tissue or target body fluid are important to create the thermal schedule to obtain a therapeutic effect without causing damage.

The choice of these parameters can be determined by requiring an Arrhenius (Arrhenius) integral for HSP activation of greater than 1 or one. Arrhenius (Arrhenius) integration was used to analyze the effect on biological tissue. See, e.g., the CRC Handbook of Thermal Engineering, frank Kreith edit, springer Science and Business Media (2000). At the same time, the selected parameters must not permanently damage the tissue. Thus, also Arrhenius (Arrhenius) integral for lesions may be used, wherein the resolved Arrhenius (Arrhenius) integral is less than 1 or one.

Alternatively, FDA/FCC limits on energy deposition and temperature rise per gram of tissue measured during a period of minutes are met to avoid permanent tissue damage. FDA/FCC requirements for energy deposition and temperature rise are widely used and can be referenced, for example, at www.fda.gov/medialdevices/devicedogicalband/guida ncedocuments/ucm073817.Htm# attacha for electromagnetic sources, and Anastosio and P.Larivero, edited Emerg Imaging technologies.CRC Press (2012), for ultrasound sources.

In general, a tissue temperature rise between 6 ℃ and 11 ℃ over a short period of time (e.g., seconds or fractions of a second) may form a therapeutic effect, for example, by activating heat shock proteins, but maintaining the average tissue temperature below a predetermined temperature (e.g., 6 ℃ and even 1 ℃ or less in certain cases) for a long period of time (e.g., during minutes, e.g., 6 minutes) will not permanently damage the tissue.

As described above, the energy source to be applied to the target tissue will have energy and operating parameters that must be determined and selected to obtain a therapeutic effect without permanently damaging the tissue. For example, in the case of using a beam energy source (e.g., a laser beam), the laser wavelength, duty cycle, and total pulse train duration parameters must be considered. Other parameters that may be considered include the radius of the laser source and the average laser power. Adjusting or selecting one of these parameters may affect at least one other parameter.

Figures 10 and 11 show graphs of average power in watts compared to laser source radius (between 0.1 cm and 0.4 cm) and pulse train duration (between 0.1 and 0.6 seconds). Fig. 10 shows a wavelength of 880 nanometers, while fig. 11 has a wavelength of 1000 nanometers. It can be seen that in these figures, the required power decreases monotonically with decreasing radius of the source, with increasing total column duration, and with decreasing wavelength. The preferred parameter for the radius of the laser source is 1 mm to 4 mm. For a wavelength of 880 nanometers, the minimum power value is 0.55 watts with a laser source radius of 1 millimeter and a total pulse duration of 600 milliseconds. The maximum power value for 880 nm wavelength was 52.6 watts when the laser source radius was 4 mm and the total pulse train duration was 100 ms. However, when a laser having a wavelength of 1000 nm is selected, the minimum power value is 0.77 watts in the case of a laser source radius of 1 mm and a total pulse train duration of 600 ms, and the maximum power value is 73.6 watts when the laser source radius is 4 mm and the total pulse train duration is 100 ms. The corresponding peak power during a single pulse is obtained by dividing the average power by the duty cycle.

The volume of the tissue region to be heated is determined by the wavelength, the absorption length in the tissue of interest, and the beam width. The total pulse duration and the average laser power determine the total energy delivered to heat the tissue, and the duty cycle of the pulse train gives the peak power associated with the average laser power. Preferably, the pulse energy source energy parameters are selected to absorb about 20 to 40 joules of energy per cubic centimeter of target tissue.

In the thin melanin layer in the retinal pigment epithelium, the absorption length is very small. In other parts of the body, the absorption length is generally not so small. The penetration depth and skin trend is in the range of 0.5 mm to 3.5 mm in wavelengths ranging from 400 nm to 2000 nm. Penetration depth into human mucous tissue is in the range of 0.5 mm to 6.8 mm. Accordingly, the heating volume will be limited to the outer or inner surface where the radiation source is disposed, the depth being equal to the penetration depth and the lateral dimension being equal to the lateral dimension of the radiation source. Since diseased tissue near the outer surface or near the internally accessible surface is treated with a beam energy source, a source radius between 1 millimeter and 4 millimeters and operating a wavelength of 880 nanometers produces a penetration depth of about 2.5 millimeters, and a wavelength of 1000 nanometers produces a penetration depth of about 3.5 millimeters.

It has been determined that within a short period of time (e.g., less than 1 second), the target tissue can be heated up to about 11 ℃ to produce the therapeutic effect of the present invention while maintaining the target tissue average temperature at a lower temperature range (e.g., less than 6 ℃ or even 1 ℃ or less) during a long period of time (e.g., minutes). The duty cycle and the total pulse train duration are selected to provide a time interval during which heat can be dissipated. A duty cycle of less than 10% and preferably between 2.5% and 5% has been found to be effective with a total pulse duration of between 100 milliseconds and 600 milliseconds. Fig. 12 and 13 show the time for a laser source having a radius between 0.1 cm and 0.4 cm to decay from 10 ℃ to 1 ℃ with a wavelength of 880 nm in fig. 12 and 1000 nm in fig. 13. It can be seen that when using a wavelength of 880 nanometers, the decay time is shorter, but both wavelengths are within acceptable requirements and operating parameters to obtain the benefits of the present invention without causing permanent tissue damage.

It has been found that during total irradiation, the average temperature rise of the desired target region increases by at least 6 ℃ and up to 11 ℃, and preferably about 10 ℃, resulting in HSP activation. The control of target tissue temperature is determined by selecting the source and target parameters such that the Arrhenius integral for HSP activation is greater than 1 while ensuring compliance with conservative FDA/FCC requirements to avoid injury or damage to the Arrhenius integral is less than 1.

To meet the conservative FDA/FCC limits to avoid permanent tissue damage, the average temperature rise of the target tissue during any 6 minutes is 1℃or less for the beam and other electromagnetic radiation sources. Fig. 12 and 13 above show typical decay times required to heat the target from a temperature rise of about 10 c to 1 c by thermal diffusion, as can be seen from fig. 12, when the wavelength is 880 nm and the source diameter is 1 mm, the temperature decay time is 16 seconds. When the source diameter was 4 mm, the temperature decay time was 107 seconds. As shown in fig. 13, when the wavelength is 1000 nm, the temperature decay time is 18 seconds when the source diameter is 1 mm, and 136 seconds when the source diameter is 4 mm. This is entirely within the time that the average temperature rise is maintained during the course of several minutes (e.g., 6 minutes or less). Although the temperature of the target tissue is raised (e.g., to about 10 ℃) quickly (e.g., within a fraction of a second) during application of the energy source to the tissue, the lower duty cycle provides a longer period of time between pulses of energy applied to the tissue and the shorter pulse train duration ensures adequate temperature diffusion and decay over a shorter period of time including a few minutes (e.g., 6 minutes or less) so that there is no permanent tissue damage.

The parameters of the energy sources (including microwave, infrared laser, radio frequency and ultrasound) are different because the absorption properties of tissue are different for these different types of energy sources. Tissue moisture content can vary from tissue type to tissue type, however, under normal or near normal conditions, consistency of tissue properties can be observed, allowing for disclosure of tissue parameters that are widely used by clinicians to design treatments. The following is a table showing the properties of electromagnetic waves in biological media, table 1 relates to muscle, skin and tissue with high water content, and table 2 relates to fat, bone and tissue with low water content.

Table 1 properties of electromagnetic waves in biological media: muscle, skin and tissue with high water content

Table 2 properties of electromagnetic waves in biological media: fat, bone and tissue with low water content

The absorption length of radio frequency in body tissue is long compared to the body dimensions. Thus, the heating zone is determined by the size of the coil as a source of radio frequency energy, rather than by the absorption length. At a long distance r from the coil, the (near) magnetic field of the coil is 1/r ³ Is reduced. At smaller distances, the electric and magnetic fields may be represented by vector magnetic potentials, which may be represented in a closed form by respective first and second types of elliptic integrals. Heating only occurs in an area that is comparable in size to the coil source itself. Accordingly, if it is desired to preferentially heat an area characterized by a radius, the source coil will be selected to have a similar radius. Due to 1/r of magnetic field ³ Falling, outside the hemispherical region of radius, the heating falls rapidly. Since it is recommended to use radio frequencies that only access diseased tissue from the outside or from the lumen, it is reasonable to consider coil radii between about 2 and 6 millimeters.

The radius of the source coil and the ampere turns (NI) in the source coil give the magnitude and spatial extent of the magnetic field, and radio frequency is a factor that relates the magnitude of the electric field to the magnitude of the magnetic field. Heating is proportional to the product of conductivity and the square of the electric field. For target tissue of interest at or near the outer surface, the electrical conductivity is that of skin and mucous tissue. The duty cycle of the pulse train and the total train duration of the pulse train are factors that influence how much total energy is delivered to the tissue.

Preferred parameters of the radio frequency energy source have been determined to be a coil radius between 2 and 6 millimeters, a radio frequency in the range of 3 to 6MHz, a total pulse train duration of 0.2 to 0.4 seconds, and a duty cycle between 2.5% and 5%. Figures 14 to 17 show how the number of ampere turns varies with these parameters to give a rise in temperature that yields an Arrhenius integral of about 1 or one for HSP activation. Referring to fig. 14, for an RF frequency of 6MHz, a pulse train duration between 0.2 and 0.4 seconds, a coil radius between 0.2 and 0.6 cm, and a 5% duty cycle, the peak ampere-turns (NI) is 13 at a 0.6 cm coil radius and 20 at a 0.2 cm coil radius. For a 3MHz frequency, as shown in fig. 15, the peak ampere-turns is 26 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 cm and the duty cycle is 5%. However, for the same 5% duty cycle, the peak ampere-turns is 40 when the coil radius is 0.2 cm and the pulse train duration is 0.2 seconds. A duty cycle of 2.5% is used in figures 16 and 17. As shown in fig. 16, 18 ampere-turns are produced for a 6MHz radio frequency having a coil radius of 0.6 cm and a pulse train duration of 0.4 seconds, and 29 ampere-turns are produced when the coil radius is only 0.2 cm and the pulse train duration is 0.2 seconds. Referring to fig. 17, in the case of a duty cycle of 2.5% and a radio frequency of 3MHz, the peak ampere-turns are 36 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 cm, and 57 ampere-turns when the pulse train duration is 0.2 seconds and the coil radius is 0.2 cm.

The time (in seconds) for the temperature rise to decay from about 10 ℃ to about 1 ℃ for a coil radius between 0.2 cm and 0.6 cm for the rf energy source is shown in fig. 18. The temperature decay time was about 37 seconds when the radio frequency coil radius was 0.2 cm and about 233 seconds when the radio frequency coil radius was 0.5 cm. When the radio frequency coil radius is 0.6 cm, the decay time is about 336 seconds, which is still within the acceptable decay time range, but at the upper end of the range.

Microwaves are another source of electromagnetic energy that may be used in accordance with the present invention. The frequency of the microwaves determines the tissue penetration distance. The gain of a tapered microwave horn is compared to the microwave wavelength, indicating that in these cases energy is radiated mainly in a narrow forward load. Typically, the microwave source used in accordance with the present invention has a linear dimension on the order of centimeters or less, so that the source is smaller than the wavelength, in which case the microwave source may be approximated as a dipole antenna. Such a small microwave source is easier to insert into the internal body cavity and can also be used to radiate the external surface. In this case, the heating zone may be approximated as a hemisphere with a radius equal to the absorption length of microwaves in the body tissue being treated. When microwaves are used to treat tissue near the outer surface or surfaces accessible from the lumen, frequencies in the range of 10 to 20GHz are used, with corresponding penetration distances of only between about 2 and 4 millimeters.

The temperature rise of the tissue using the microwave energy source is determined by the average power of the microwaves and the total pulse train duration. The duty cycle of the pulse train determines the peak power of the individual pulses in the pulse train. When a radius of less than about 1 cm of source is employed, and frequencies between 10 and 20GHz are typically used, pulse train durations of 0.2 and 0.6 seconds are preferred.

The required power decreases monotonically with column duration and with increasing microwave frequency. For a frequency of 10GHz, the average power is 18 watts when the pulse train duration is 0.6 seconds, and 52 watts when the pulse train duration is 0.2 seconds. For 20GHz microwave frequency, an average power of 8 watts is used when the pulse train is 0.6 seconds, and may be 26 watts when the pulse train duration is only 0.2 seconds. The corresponding peak power is simply obtained by dividing the average power by the duty cycle.

Referring now to fig. 19, the average microwave power (in watts) of a microwave having a frequency of 10GHz and a pulse train duration of between 0.2 seconds and 0.6 seconds is graphically displayed. Fig. 20 is a similar graph but showing the average microwave power for microwaves having a frequency of 20 GHz. It will thus be seen that the average microwave source power varies with the total column duration and the microwave frequency. However, the control conditions were such that the Arrhenius (Arrhenius) integral for HSP activation in the heating zone was about 1.

Referring to FIG. 21, a graph shows the time (in seconds) for the temperature to decay from about 10deg.C to 1deg.C compared to the microwave frequency between 58MHz and 20000 MHz. The minimum and maximum temperature decay for the preferred microwave frequency range is 8 seconds when the microwave frequency is 20GHz and 16 seconds when the microwave frequency is 10 GHz.

The use of ultrasound as an energy source enables heating of surface tissue, as well as tissue of varying depth in the body (including relatively deep tissue). The absorption length of ultrasound in the body is quite long, as it is demonstrated by its widespread use in imaging. Accordingly, ultrasound can be focused at a target region deep within the body, with heating of the focused ultrasound beam focused primarily at the approximately cylindrical focal region of the beam. The volume of the heating zone is determined by the focal waist of the airy disk and the length of the focal waist region, i.e. the confocal parameter. Multiple beams from sources at different angles may also be used, with heating occurring at overlapping focal regions.

For ultrasound, the relevant parameters for determining tissue temperature when given the focal length and diameter of an ultrasound transducer are the frequency of ultrasound, the total column duration, and the transducer power. The frequency, focal length, and diameter determine the volume of the focal zone in which the ultrasonic energy is concentrated. The focal volume comprises a target volume of the treated tissue. Transducers having a diameter of about 5 cm and a focal length of about 10 cm are readily available. An advantageous focal spot size is obtained when the ultrasound frequency is between 1 and 5MHz and the total column duration is 0.1 to 0.5 seconds. For example, for a focal length of 10 cm and a transducer diameter of 5 cm, the focal volume is 0.02 cubic cm at 5MHz and 2.36 cubic cm at 1 MHz.

Referring now to fig. 22, the average source power (in watts) versus frequency (between 1MHz and 5 MHz) and pulse train duration (between 0.1 and 0.5 seconds) are graphically shown. Assume a transducer focal length of 10 cm and a source diameter of 5 cm. The power required to give an Arrhenius integral for HSP activation of about 1 decreases monotonically with increasing frequency and with increasing total column duration. Given the preferred parameters, the minimum power for a 1GHz frequency and a pulse train duration of 0.5 seconds is 5.72 watts, while the maximum power for a 1GHz frequency and a pulse train duration of 0.1 seconds is 28.6 watts. For a 5GHz frequency, 0.046 watts is required for a pulse train duration of 0.5 seconds, with 0.23 watts being required for a pulse train duration of 0.1 seconds. The corresponding peak power during a single pulse is simply obtained by dividing by the duty cycle.

Fig. 23 shows the time (in seconds) for the temperature to diffuse or decay from 10 ℃ to 6 ℃ when the ultrasound frequency is between 1 and 5 MHz. Fig. 24 shows the time (in seconds) for the attenuation of the ultrasonic frequency from about 10 ℃ to about 1 ℃ from 1 to 5 MHz. For a preferred focal length of 10 cm and a transducer diameter of 5 cm, the maximum temperature decay time is 366 seconds when the ultrasonic frequency is 1MHz and the minimum temperature decay is 15 seconds when the microwave frequency is 5 MHz. For test times of several minutes, when the FDA only requires a temperature rise of less than 6 ℃, a decay time of 366 seconds at 1MHz is allowed to reach a temperature rise of 1 ℃ during several minutes. As can be seen from fig. 23 and 24, the decay time of the temperature rise at 6 ℃ is about 70 times smaller than the temperature rise at 1 ℃.

Fig. 25 shows the volume (in cubic centimeters) of the focal heating zone compared to ultrasonic frequencies between 1 and 5 MHz. Considering ultrasonic frequencies between 1 and 5MHz, the respective focal spot sizes for these frequencies range from 3.7 mm to 0.6 mm, and the focal spot zone lengths range from 5.6 cm to 1.2 cm. The corresponding treatment volume varies between about 2.4 cubic centimeters and 0.02 cubic centimeters.

Examples of parameters giving a desired HSP activation Arrhenius (Arrhenius) integral greater than 1 and a lesion Arrhenius (Arrhenius) integral less than 1 are total ultrasound power between 5.8 and 17 watts, pulse duration of 0.5 seconds, interval between pulses of 5 seconds, total pulse number 10 in total pulse stream time of 50 seconds. The target treatment volume will be about 1 millimeter on one side. By applying ultrasound in a plurality of simultaneously applied adjacent but spaced apart columns, a large treatment volume can be treated with an ultrasound system like a laser diffraction optical system. The plurality of focused ultrasound beams converge on a very small therapeutic target within the body, which allows for minimal heating, except for overlapping beams at the target. This region will be heated and stimulate HSP activation and promote protein repair through transient high temperature peaks. However, given the pulsing pattern of the present invention and the smaller area treated at any given time, the treatment meets FDA/FCC requirements for a long term (minutes) average temperature rise of < 1K. An important distinction of the present invention from existing therapeutic heat treatments for pain and muscle strain is the lack of high T peaks in the prior art, which are required to effectively activate HSP's and promote protein repair to provide healing at the cellular level.

Pulse train energy delivery patterns have distinct advantages over single pulse or progressive energy delivery patterns in terms of salvage HSP activation and promotion of protein repair. There are two considerations that make up this advantage:

first, a great advantage of HSP activation and protein repair in PEMR energy delivery modes comes from the peak temperatures that produce on the order of 10 ℃. Such a large temperature rise has a large impact on Arrhenius (Arrhenius) integration, which quantifies the number of activated HSPs and the rate of water diffusion into the protein that promotes protein repair. This is because temperature constitutes an index with an amplifying effect.

It is important that the temperature rise not remain high (10 ℃ or higher) for long periods of time, as that would violate FDA and FCC requirements that the average temperature rise must be less than 1 ℃ (or 6 ° in the case of ultrasound) during a period of several minutes.

SDM or other PEMR energy delivery modes uniquely meet both of these considerations by judicious choice of power, pulse time, pulse interval, and volume of the target region to be treated. The volume of the treatment zone is incorporated because the temperature must decay relatively rapidly from its high value on the order of 10 ℃ so that the long term average temperature rise does not exceed the long term FDA/FCC limit (6 ℃ for ultrasonic frequencies and 1 ℃ or less for electromagnetic radiation energy sources).

For a region with a linear dimension L, the time taken for the peak temperature to decay e-times in tissue is about L ² 16D, wherein d= 0.00143cm ² The heat diffusion coefficient is typical per second. For example, if l=1 mm, the decay time is about 0.4 seconds. Accordingly, for a 1 mm area on one side, a column of 10 pulses each of 0.5 seconds duration with 5 seconds spacing between pulses, the desired instantaneous high temperature rise can be achieved while still not exceeding the average long term temperature rise of 1 ℃. This is further demonstrated below.

The limitation of the heating volume is why RF electromagnetic radiation is not a good choice for treating deep areas of the body as ultrasound does. Long skin depths (penetration distances) and ohmic heating along the entire skin depth result in large heating volumes whose thermal inertia does not allow high peak temperatures to be reached to activate HSP and promote protein repair, nor does it allow rapid temperature decay to meet long-term FDA and FCC limitations of average temperature rise.

Ultrasound has been used to therapeutically heat areas of the body to relieve pain and muscle strain. However, this heating does not follow the protocol of the present invention and does not have a temperature peak responsible for the excitation of HSPs.

Thus, consider a set of focused ultrasound beams that are directed at a target region deep within the body. To simplify the math, it is assumed that the beams are replaced by a single source with a spherical surface shape focused on the center of the sphere. The absorption length of ultrasound can be quite long. Table 3 below shows typical absorption coefficients of ultrasound at 1 MHz. The absorption coefficient is approximately proportional to the frequency.

TABLE 3 typical absorption coefficient of 1MHz ultrasound in body tissue

Given that the geometrical change of the incident radiation due to focusing is dominated by any change due to attenuation, the intensity of the incident ultrasound at a distance r from the focus can be approximately written as:

I(r)＝P/(4πr ² ) [1]

where P represents the total ultrasonic power.

The temperature rise at the end of the short pulse duration tp at r is then

dT(t _p )＝Pαt _p /(4πC _v r ² ) [2]

Wherein alpha is the absorption coefficient and C _v Is specific heat capacity. This continues until r is reached where t _p Becomes comparable to r or reaches the diffraction limit of the focused beam. For smaller r, the temperature rise is substantially independent of r. For exampleIt is assumed that the diffraction limit is reached at a smaller radial distance than the radial distance determined by the thermal diffusion. Then

r _dif ＝(4Dt _p ) ^1/2 [3]

Wherein D is the thermal diffusivity and r < r for _dif At t _p Is the temperature rise of

dT(r _dif ，t _p )＝3Pα/(8πC _v D) when r＜r _dif [4]

Thus, at the end of the pulse, we can write the following for the temperature rise:

dT _p (r)＝{Pαt _p /(4πC _v }[(6/r _dif ² )U{r _dif -r)+(1/r ² )U(r-r _dif )] [5]

when the greens function is applied for thermal diffusion

G(r，t)＝(4ΩDt) ^-3/2 exp[-r ² /(4Dt)] [6]

For this initial temperature distribution we find that the temperature dT (t) at the focal point r=0 at time t is

dT(t)＝[dT _o /{(1/2)+(π ^1/2 /6)}][(1/2)(t _p /t) ^3/2 +(π ^1/2 /6)(t _p /t)] [7]

And is also provided with

dT _o ＝3Pα/(8πC _v D) [8]

The following formula provides a good approximation of formula (7):

dT(t)≈dT _o (t _p /t) ^3/2 [9]

as can be seen in FIG. 26, the plot is for dT (t)/dT at the target treatment region _o Comparison of formulas (7) and (9). The bottom curve is an approximation of equation (9).

The Arrhenius (Arrhenius) integral for N pulse trains can now be estimated by the temperature rise given by equation (9). In the case of the formula (I) of this kind,

dT _N (t)＝∑dT(t-nt _I ) [11]

wherein dT (t-nt) _I ) Is represented by formula (9), t is represented by t-nt _I Substitute and t _I Representing pulseInterval between punches.

Arrhenius (Arrhenius) integration can be approximated by dividing the integration interval into a portion where the temperature peak occurs and a portion where the temperature peak does not exist. The sum of contributions at the temperature peaks can be simplified by applying the end point formula of laplace through integration over the temperature peaks. Furthermore, the integration over the part where the peak is not present can be simplified by noting that the off-peak temperature rise reaches the gradual value very rapidly, so that a good approximation is obtained by replacing the change time rise with the gradual value. When these approximations are performed, the formula (10) becomes:

Ω＝AN[{t _p (2k _B T _o ² /(3EdTo)}exp[-(E/k _B )1/(T _o +dT _o +dT _N (Nt _I ))]+exp[-(E/k _B )1/(T _o +dT _N (Nt _l ))]] [12]

Wherein, the liquid crystal display device comprises a liquid crystal display device,

dT _N (Nt _I )≈2.5dT _o (t _p /t _I ) ^3/2 [13]

(2.5 in the formula (13) is produced in the form of (N-N) ^-3/2 And is the magnitude of the harmonic number (N, 3/2) for a typical N of interest

It is interesting to compare this formula with the formula for SDM applied to the retina. The first term is very similar to the term of peak contribution in the retinal case, except that the effective peak spacing is reduced 3 times for this three-dimensional convergence case. Including dT _N (Nt _I ) The second term of (2) is much smaller than in the case of the retina. The background temperature rise is comparable in magnitude to the peak temperature rise. But here, in the case of convergence beam, the background temperature rise is small (t _p /t _I ) ^3/2 Is a ratio of (2). This points to the importance of peak contributions to activating or generating HSPs and promoting protein repair, since background temperature rises similar to those in the case of continuous ultrasound heating are negligible compared to peak contributions. At the end of the pulse train, even this low background temperature rise rapidly disappears by thermal diffusion.

FIGS. 27 and 28 show the time for pulse duration t _p =0.5 seconds, pulse interval t _I =10 secondsAnd total pulse number n=10, amplitude of logarithm of Arrhenius (Arrhenius) integral for injury and for HSP activation or generation is plotted against dT _o And changes from variation to variation. For pulse duration t _p =0.5 seconds, pulse interval t _I 10 seconds, and a total number of ultrasound pulses n=10, the logarithm of the Arrhenius integral for injury and for HSP activation (formula 12) is related to the temperature rise dT from a single pulse _o (in degrees kelvin) changes. Fig. 27 shows a sample with Arrhenius constant a=8.71x10 ³³ sec ^-1 E=3.55x10 ^-12 Logarithm of damage score for ergs. Fig. 28 shows a sample with an Arrhenius constant a=1.24x10 ²⁷ 8ec ^-1 E=2.66x10 ^-12 The HSP of ergs activates the log of the integral. The graphs in FIGS. 27 and 28 show up to dT. Exceeding 11.3k omega _damage Only exceeds 1, but Ω _hsp Greater than 1 throughout the interval shown is a condition required for cell repair without damage.

Formula (8) shows when α=0.1 cm ^-1 dT of 11.5K is obtained with a total ultrasonic power of 5.8 watts _o . This is easy to achieve. If alpha is increased by a factor of 2 or 3, the resulting power is still easy to achieve. The volume of the region of increased temperature is constant (i.e., corresponding to r=r _d ＝(4Dt _p ) ^1/2 Is 0.00064 cubic centimeters. This corresponds to a cube with one side of 0.86 mm.

This simple example demonstrates that focused ultrasound should be available to stimulate reparative HSP deep in the body by readily available equipment.

To expedite treatment of larger internal volumes, SAPRA systems may be used.

The pulsed energy source may be directed to an exterior of the body adjacent to the target tissue or with a blood supply proximate to a surface of the exterior of the body. Alternatively, a device may be inserted into the body cavity to apply a pulsed energy source to the target tissue. Whether the energy source is applied to the exterior of the body or the interior of the body and what type of device is used depends on the energy source selected and used to treat the target tissue.

The optical stimulus according to the present invention can be effectively delivered to the interior surface area or tissue of the body through the use of an endoscope (e.g., bronchoscope, proctoscope, colonoscope, etc.). Various endoscopes consist essentially of a flexible tube that itself contains one or more inner tubes. Typically, one of the inner tubes includes a light pipe or multimode optical fiber that guides light along the endoscope to illuminate the region of interest and to enable the physician to see the object at the illuminated end. Another inner tube may be composed of a wire that carries electrical current to enable the physician to cauterize the illuminated tissue. Yet another inner tube may be composed of a biopsy tool that enables a physician to cut and preserve any irradiated tissue.

In the present invention, one of these inner tubes is used as an electromagnetic radiation tube, such as a multimode fiber, to transmit SDM or other pulses of electromagnetic radiation, which are fed into the endoscope at the end held by the physician. Referring now to fig. 29, a light generating unit 10 (e.g., a laser having a desired wavelength and/or frequency) is configured to generate electromagnetic radiation (e.g., laser light) in a controlled, pulsed manner that is delivered through a light pipe 52 to a distal end (shown in fig. 30) of an endoscope 54 that is inserted into the body and that laser or other radiation 56 is delivered to a target tissue 58 to be treated.

The light generating unit 10 of fig. 29 may comprise a light generating unit as described above with reference to fig. 1 to 6. However, the delivery device or assembly may include an endoscope, bronchoscope, and pass the generated laser beam through light pipe 52. The system may comprise a laser beam projector or delivery device (e.g. an endoscope) and the viewing system/camera will comprise two different components when in use. The viewing system/camera may provide feedback to a display monitor that may also include the necessary computerized hardware, data input and control to operate the optics, the delivered laser or other pulsed energy source, and/or the projection/viewing components. Moreover, an offsetable pattern may be generated, as described above. Of course, the laser generating systems of FIGS. 1-6 are exemplary, and other devices and systems may be used to generate a laser or other pulsed electromagnetic radiation source that may be operatively passed through a projector device, such as the endoscope or light pipe shown in FIGS. 29 and 30, etc.

Other forms of electromagnetic radiation may also be generated and used, including ultraviolet waves, microwaves, other radio frequency waves, and lasers at predetermined wavelengths. Moreover, ultrasound can also be generated and used to create a thermal time course temperature peak in the target tissue that is sufficient to activate or produce heat shock proteins in cells of the target tissue without damaging the target tissue itself. To this end, a pulsed ultrasound or electromagnetic radiation energy source is typically provided and applied to the target tissue by transiently elevating the target tissue temperature (e.g., between 6 ℃ and 11 ℃) while only 6 ℃ or 1 ℃ or less over a prolonged period (e.g., over a period of several minutes).

For deep tissues not near the internal bore, the light pipe is not an efficient way to deliver pulsed energy. In this case, pulsed low frequency electromagnetic energy or preferably pulsed ultrasound may be used to induce a series of temperature peaks in the target tissue.

Thus, in accordance with the present invention, a pulsed ultrasonic or electromagnetic radiation source is applied to a target tissue or fluid to stimulate HSP production or activation and promote protein repair in living animal tissue. Generally, the electromagnetic radiation may be ultraviolet waves, microwaves, other radio frequency waves, lasers at predetermined wavelengths, and the like. On the other hand, if electromagnetic energy is to be used for deep tissue targets away from the natural orifice, the absorption length will be limited to the wavelength of the microwave or radio frequency wave, depending on the depth of the target tissue. However, ultrasound is preferred over long wavelength electromagnetic radiation for deep tissue targets away from natural holes.

Ultrasound or electromagnetic radiation is pulsed to create thermal time courses in tissue that stimulate HSP production or activation and promote protein repair without damage to the cells and tissue being treated. The area and/or volume of tissue being treated is also controlled and minimized to peak temperatures on the order of a few degrees (e.g., about 10 ℃) while maintaining long term temperature rise below FDA regulatory limits (e.g., 1 ℃). It has been found that if too large an area or volume of tissue is treated, the increased temperature of the tissue does not spread sufficiently rapidly to meet FDA requirements. However, limiting the area and/or volume of tissue being treated and creating a pulsed energy source achieves the goal of the present invention to stimulate HSP activation or production by heating or otherwise stressing cells and tissue while allowing the treated cells and tissue to dissipate any excess heat generated to within acceptable limits.

It is believed that stimulation of HSP production in accordance with the invention may be effective in treating various tissue abnormalities, afflictions, and even infections. For example, viruses that cause colds primarily affect small portions of the respiratory epithelium in the nasal passages and nasopharynx. Similar to the retina, the respiratory epithelium is a thin and transparent tissue. Referring to fig. 31, a cross-sectional view of a human head 60 is shown with an endoscope 54 inserted into a nasal cavity 62 and energy 56 (e.g., laser light, etc.) directed to tissue 58 to be treated within the nasal cavity 62. The tissue 58 to be treated may be located within the nasal cavity 62, including the nasal passages, as well as the nasopharynx.

To ensure absorption of laser energy or other energy sources, the wavelength may be tuned to the Infrared (IR) absorption peak of the water, or an adjuvant dye may be used to act as a photosensitizer. In this case, the treatment will then consist of the following procedure: the adjuvant is drunk or topically applied, waiting for a few minutes for the adjuvant to penetrate the surface tissue, and then providing a laser or other energy source 56 to the target tissue 58 for a few seconds, for example, through optical fibers in the endoscope 54, as shown in fig. 31. For patient comfort, the endoscope 54 may be inserted after the local anesthetic is applied. This process may be repeated periodically, for example, on the order of a day, if necessary.

The treatment will raise the intracellular temperature and this temperature increase will be antiviral in itself, as will the fever response to the viral infection. In addition, the treatment will thermally stimulate the activation or production of heat shock proteins and promote protein repair without damaging the cells and tissues being treated. As described above, specific heat shock proteins have been found to play an important role in the immune response as well as in targeting the health of cells and tissues. The energy source may be a monochromatic laser (e.g., 810 nm wavelength laser) provided in a similar manner as described in the above-referenced patent application, but provided by an endoscope or the like, as shown in fig. 31. The adjuvant dye will be selected to increase laser absorption. While this includes the particular preferred method and embodiment of carrying out the invention, it should be understood that other types of energy and delivery means may be used in accordance with the invention to achieve the same objectives.

Referring now to fig. 32, there are similar situations for other diseases in which the primary target is the epithelium of the upper respiratory tree, in a portion greater than about 3.3 millimeters in diameter, i.e., the upper six passages of the upper respiratory tree. A thin layer of mucus separates the targeted epithelial cells from the airway lumen, i.e., in this layer, antigen-antibody interactions occur, resulting in inactivation of viruses (e.g., cold and influenza).

With continued reference to fig. 32, flexible light pipe 52 of bronchoscope 54 is inserted through throat and trachea 66 through mouth 64 of the individual into bronchi 68 of the respiratory tree. Here, a laser or other energy source 56 is provided and delivered to the tissue in this region of the uppermost portion to treat the tissue and region in the same manner as described above with respect to fig. 32. It is contemplated that the wavelength of the laser or other energy will be selected to match the IR absorption peak of the water residing in the mucus to heat the tissue and stimulate HSP activation or production and promote protein repair, with its attendant additional benefits.

Referring now to fig. 33, a colonoscope 54 has its flexible light pipe 52 inserted into the anus and rectum 70 and into the large or

small intestine

72, 74 to deliver a selected laser or other energy source 56 to the area and tissue to be treated, as shown. This can be used to help treat colon cancer as well as other gastrointestinal problems.

In general, the procedure may be performed like a colonoscopy, in that to clean up all of the bowel, the patient would lie on his side and the physician would insert the long, thin light pipe portion 52 of the colonoscope 54 into the rectum and move it into the region of the colon, large intestine 72 or small intestine 74 to the region to be treated. The physician can observe the path of the inserted flexible member 52 through the monitor and even the tissue at the end of the colonoscope 54 located in the intestine to view the area to be treated. By using one of the other optical fibers or light pipes, the distal end 76 of the endoscope will be directed to the tissue to be treated and the laser or other radiation source 56 will be delivered through one of the light pipes of the colonoscope 54 to treat the area of tissue to be treated, as described above, to stimulate HSP activation or production in the tissue 58.

Referring now to fig. 34, in another example, the present invention may be advantageously used in the gastrointestinal tract, such as the condition of the Gastrointestinal (GI) tract, often referred to as "leaky gut" syndrome, marked by inflammation or other metabolic dysfunction. Since, like the retina, the gastrointestinal tract is susceptible to metabolic dysfunction, it is expected that it will respond well to the treatment of the present invention. This may be performed by subthreshold, diode micropulse laser (SDM) treatment as described above, or by other energy sources and devices described herein and known in the art.

With continued reference to fig. 34, a flexible light pipe 52, such as an endoscope, is inserted through the patient's mouth 64, through the throat and tracheal region 66 and into the stomach 78, wherein its distal end 64 is directed toward the tissue 58 to be treated and a laser or other energy source 56 is directed to the tissue 58. Those skilled in the art will appreciate that a colonoscope may also be used and inserted through the rectum 70 and into the stomach 78 or any tissue between the stomach and rectum.

Chromophore pigments or other light absorbing materials (e.g., metal nanoparticles) may be delivered orally to gastrointestinal tissue if necessary to enable absorption of radiation. For example, if unfocused 810 nm radiation from a laser diode or LED were to be used, the pigment would have an absorption peak at or near 810 nm. Alternatively, the wavelength of the energy source may be tuned to a slightly longer wavelength at the absorption peak of the water, thereby eliminating the need for an externally applied chromophore.

The present invention also contemplates the use of a capsule endoscope 80, such as that shown in fig. 35, to provide a source of radiation and energy in accordance with the present invention. Such capsules have a relatively small size (e.g., about 1 inch long) for swallowing by a patient. As the capsule or pill 80 is swallowed and enters the stomach and passes through the gastrointestinal tract, the capsule or pill 80 may receive power and signals (e.g., via the antenna 82) when in place, thereby activating the energy source 84 (e.g., laser diode and associated circuitry), and a suitable lens 86 focuses the generated laser light or radiation through the radiolucent cover 88 and onto the tissue to be treated. It should be appreciated that the position of capsule endoscope 80 may be determined by various means, such as external imaging, signal tracking, or even by a miniature camera with lights through which a physician views images of the gastrointestinal tract through which pill or capsule 80 is passing. The capsule or pill 80 may have its own power source (e.g., by means of a battery), or be externally powered by an antenna to cause a laser diode 84 or other energy generating source to create the desired wavelength and pulse energy source to treat the tissue and region to be treated.

As with retinal treatments in previous applications, the pulsed radiation is used to take advantage of the micropulse temperature peaks and related safety, and the power can be adjusted to render the treatment completely harmless to the tissue. This may include adjusting peak power, pulse time, and repetition rate to give peak temperature rise on the order of 10 ℃ while maintaining long term temperature rise below FDA regulatory limits of 1 ℃. If bolus form 80 delivery is used, power may be provided to the device by a small rechargeable battery or by wireless inductive excitation, etc. The heating/stressing tissue will stimulate HSP activation or production and promote protein repair, with its additional benefits.

From the above examples, the techniques of the present invention are limited to treatment of conditions at near body surfaces or at interior surfaces readily accessible by fiber optic or other optical delivery devices. The reason why the application of SDM or PEMR to activate HSP activity is limited to the near-surface or optically accessible region of the body is that the absorption length of IR or visible radiation in the body is very short. However, conditions deeper within the tissue or body may benefit from the present invention. Accordingly, the present invention contemplates the use of ultrasound and/or Radio Frequency (RF) and even shorter wavelength Electromagnetic (EM) radiation, such as microwaves, which have a longer absorption length in body tissue. Pulsed ultrasound is often preferred over RF electromagnetic radiation to activate salvage HSP activity in abnormal tissues that are inaccessible to surface SDM and the like. Pulsed ultrasonic sources may also be used for anomalies at or near the surface.

Referring now to fig. 36, a specific region deep in the body can be specifically targeted using ultrasound, microwave or radio frequency, by using one or more beams focused on the target site, respectively. Pulsed heating will thus be mainly only in the targeted area where the beams are focused and overlap.

As shown in fig. 36, an ultrasound transducer 90 or the like generates a plurality of ultrasound beams 92 that are coupled to the skin by means of an acoustic-impedance-matching glue and penetrate the skin 94 as well as through intact tissue in front of the focal point of the beams 92 to a target organ 96 (e.g. the liver as shown), and in particular to a target tissue 98 to be treated, where the ultrasound beams 92 are focused. As described above, pulsed heating will therefore only overlap the targeted focal zone 98 at the focused beam 92. The tissue in front of and behind the focal zone 98 will not be significantly heated or affected.

The present invention contemplates treating not only surface or near surface tissue, such as by using a laser, but also blood disorders, as well as other bodily fluid disorders (e.g., sepsis), by using, for example, focused ultrasound, radio frequency, or microwave beams, etc. As indicated above, focused ultrasound therapy can be applied to both surfaces and deep body tissue, and in this case to treat blood. However, SDM and similar PEMR treatments, which are typically limited to surface or near surface treatment of epithelial cells or the like, are also contemplated for use in treating blood or fluid disorders in areas accessible to blood or fluid through thinner layers of tissue (e.g., earlobes).

Referring now to fig. 37 and 38, treatment of hematological disorders simply requires the delivery of SDM or other electromagnetic radiation or ultrasound pulses to the earlobe 100, wherein the SDM or other source of radiant energy may pass through the earlobe tissue and into the blood passing through the earlobe. It should be appreciated that this approach may also occur in other areas of the body where blood flow is high and/or near the tissue surface (e.g., the interior of a fingertip, mouth, or throat, etc.).

Referring again to fig. 37 and 38, the earlobe 100 is shown adjacent to a holding device 102 configured to transmit SDM radiation, etc. This may be, for example, by means of one or more laser diodes 104, which will transmit to the earlobe 100 at a desired pulse and a desired frequency of the pulse train. For example, power may be provided by the lamp driver 106. Alternatively, the lamp driver 106 may be an actual laser source, which is transmitted to the earlobe 100 by suitable optical and electronic means. The holding device 102 will only be used to hold the patient's earlobe and limit radiation to the patient's earlobe 100. This may be by means of mirrors, reflectors, diffusers etc. This may be controlled by a control computer 108 which will operate via a keyboard 110 or the like. If desired, the system may also include a display and speaker 112, for example if the procedure is to be performed by an operator at a distance from the patient.

As described above, while fig. 37 and 38 show treatment of body fluids (i.e., blood) by an easily accessible external ear lobe 100 for exemplary purposes, it should be appreciated that the pulsed energy source of the present invention may be applied to other external areas of the body, internal areas of the body, and use various energy sources (including laser, radio frequency, microwave, and ultrasound). Moreover, the present invention is not limited to treatment of blood and blood diseases, but may also be applied to other body fluids (e.g., lymph fluid) and the like. The type of body fluid being treated may dictate the area where treatment occurs, such as when treating lymph, applying an energy source in the armpit, tonsils, etc.

Although not specifically described above, it should be appreciated that different diseases or underlying diseases may be treated in different areas of the body, depending on the disease and target tissue to be treated for therapeutic purposes or for prophylactic or protective treatment. For example, IPF may be treated locally via bronchoscopic application by PEMR infrared laser. Since the heart is close to the bronchial tree and the lungs, heart diseases can also be treated by bronchoscopy. Alternatively, as noted above, due to the small infrared absorption length, PEMR radio frequency, ultrasound or microwaves can be used to treat the heart, lungs, etc. An additional advantage would be that the bronchoscope would not need to be inserted into the patient's lungs, resulting in discomfort.

Again, the type of treatment selected and the course and parameters of operation may vary depending on the location of the chronic progressive disease. For example, alzheimer's disease can be treated by applying radio frequency or microwaves to the brain. A person suffering from or at risk of suffering from cancer may according to the invention apply a source of energy to the relevant organs or regions of the body, whether it is tissue or blood (not typically cancer itself, since activation of HSP's in cancer cells may enhance survival and growth of cancer; rather components of the immune system are treated to enhance their effectiveness against cancer). Even mental conditions (e.g. depression) may be treated according to the present invention.

The present invention also contemplates that the time course, possible power, and other energy and operating parameters may need to be varied depending on the tissue, organ or region of the body to be treated. For example, for idiopathic pulmonary fibrosis and other pulmonary diseases, such parameters may need to be changed because convective airflow may cool lung tissue. Allowing an individual to exhale and hold his breath for a few seconds can also change these energy parameters, as the inflated lung has a conductivity of 0.2S/m, while the deflated lung has a conductivity of twice (0.41S/m), and the absorption length is inversely proportional to the square root of the conductivity. An important aspect is that the tissue or body fluid is heated to about 11 ℃ quickly while maintaining a lower temperature (e.g., below 6 ℃ or even 1 ℃) during several minutes (e.g., 6 minutes). This would provide therapeutic benefits (e.g., activating HSPs) without damaging body fluids, cells, and tissues.

Referring now to fig. 39, the present invention contemplates that some diseases or risks of diseases may require treatment of multiple areas of the body. For example, diabetes can be treated by applying microwaves, radio frequency, etc. to many areas of the body, and possibly the whole body. In addition, individuals may have or may be at risk of having a variety of chronic progressive diseases, which may require treatment of different areas of the body. Moreover, since the course of treatment according to the invention appears to have only beneficial therapeutic and protective results without permanently damaging or destroying cells or tissues, the whole body can be treated as healthy cells and tissues will not be negatively affected by the application of the pulse energy source applied according to the invention, while those that are damaged will benefit.

Accordingly, with continued reference to fig. 39, the present invention contemplates a device 114 that may hold and/or support the entire body 116, such as by a platform 118 upon which an individual is lying. However, it should be understood that the individual may be in a different position, e.g. standing, and does not necessarily need to lie down. The device 114 will include a pulse energy emitter 120 that can emit a pulse energy source having the parameters described above to treat various types of tissues, organs, body fluids, etc. of an individual. This may be, for example, by means of microwaves, radio Frequency (RF) and/or ultrasound, or even a light source for treating bodily fluids outside the body of an individual or adjacent to such surfaces. The fluid, related organ or other tissue may be treated accordingly. Indeed, as described above, to treat the entire body, the emitter 120 may be moved progressively or in a predetermined manner (e.g., along the track 122) to different regions of the body, thereby treating the desired target tissue or target body fluid region and/or the entire body more quickly by heating those regions to a predetermined temperature while maintaining a predetermined lower temperature for a longer period of time. The entire body treatment may be the sum of the local treatments. This would be a way to treat diabetes and other similar diseases affecting the whole body or multiple areas of the body, for example. For example, this may also be a system and method for the protective and prophylactic treatment of the entire body of an individual (e.g., on a periodic basis).

The proposed treatment using electromagnetic or ultrasound pulse trains has two main advantages over previous treatments containing a single short or sustained (long) pulse. First, a short (preferably sub-second) single pulse in this column activates a cell reset mechanism such as HSP activation that has a greater response rate constant than those operating on a longer scale (minutes or hours). Second, repeated pulses in treatment provide large thermal peaks (of the order of 10000) that allow the repair system of the cell to overcome the activation energy barrier separating the dysfunctional cell state from the desired functional state faster. Lower applied average power and total applied energy may be used to achieve the desired therapeutic goal in the sense that the end result is a "reduced therapeutic threshold".

The present invention has also been found to be useful in the prevention or treatment of neurodegenerative diseases including Alzheimer's disease. The individual is determined to have, or be at risk of having, a neurodegenerative disease (e.g., alzheimer's disease). This may be determined by, for example, genetic testing, cognitive testing, blood or cerebrospinal fluid testing, genetic assays, or any other feasible test that may lead a medical professional to determine that an individual has, or is at risk of having, a neurodegenerative disease.

Providing and applying pulsed electromagnetic energy, typically radio frequency or microwave, having selected energy parameters (including wavelength or frequency, duty cycle, and pulse train duration) to the brain of the individual to prevent or treat the neurodegenerative disease. The pulsed electromagnetic energy may be directed to one or more of the leaky blood brain barrier, the inflamed portion of the brain, the waste proteins of the brain, beta amyloid proteins of the brain, or tangled wave (tau) proteins of the brain, or any other portion of the brain, brain tissue, or cerebrospinal fluid, etc., to provide a treatment. The energy and application parameters may be selected to form thermal interactions, or resonant interactions, with such tissues, proteins, or other molecules.

The pulse energy may be applied to the brain tissue of the individual by means 114 shown in fig. 39, which will selectively apply the pulse energy only to the brain or region of interest of the patient 116. Other means or means of applying the pulse energy are also contemplated by the present invention, such as, for example, a plurality of spaced apart emitters 124 disposed adjacent the head 126 of the individual to be treated, as shown in fig. 40 and 41. The present invention contemplates the use of a single electromagnetic emitter that will emit electromagnetic energy (e.g., radio frequency or microwave energy) through the head of the individual to the brain of the individual and move the emitter as desired.

However, a "headgear" 130 with array-type transmitters 124 interconnected by electrical leads 128 that may be placed over or on the head of an individual is particularly convenient because it is easy to wear and places the transmitters 124 in close proximity to the brain 136. The headgear 130 shown in fig. 40 has eight emitters 124, but the number, size, and configuration may be adjusted as desired. Preferably, the emitters 124 are sufficiently spaced apart from one another such that electromagnetic energy 134 emitted by the emitters 124 does not overlap. The configuration of the emitters 124 in the headgear 130 shown in fig. 40 and 41 may be used to treat substantially the entire brain of an individual. However, it may be more desirable to treat only a portion of the brain, so a different configuration of headgear with a different number of emitters may be used, or some of the emitters 124 may be deactivated if necessary.

The power and control device 132 may be operably connected to the headgear 130 and/or the transmitter 124. The control box 132 may provide the power required by the transmitter 124 to transmit its electromagnetic waves, and may also include electronics to control the strength, timing, etc. of the transmitter 124. It should be appreciated that the size of the control box 132 may vary depending on power and control requirements. When the transmitter 124 is to transmit a larger frequency and/or power, the control and power device 132 may be slightly larger and substantially non-portable. However, in other cases, the power and control device 132 may be very small and may be carried by the user to allow the user to be mobile during treatment.

According to one embodiment of the invention, the pulse energy parameter is selected to increase the temperature of the tissue being treated sufficiently to stimulate heat shock protein activation in the tissue or fluid being treated. For example, the pulse energy may include a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5.0%, and a pulse train duration between 0.2 and 0.4 seconds. The radio frequency may be generated by using a coil having a radius of between 2 mm and 6 mm. The coil may have an ampere-turns between 13 and 45. By such parameters, the pulse energy will raise the temperature of the tissue being treated sufficiently to stimulate activation of heat shock proteins in the tissue or fluid being treated, resulting in protein or cell repair to provide an effective treatment.

Recently, non-invasive electromagnetic therapy, particularly transcranial electromagnetic therapy (transcranial electromagnetic treatment; TEMT), has been found to have statistically significant improvements in cognition enhancement in individuals, alterations in cerebral spinal fluid and blood markers of alzheimer's disease, and evidence of enhanced cerebral connectivity.

In accordance with the treatment, a headgear 130 having a plurality of electromagnetic energy coils 124 (e.g., radio frequency coils) is placed over the head of the individual, and each transmitter emits a radio frequency field (particularly 915 megahertz) between 850 and 950 megahertz every 4 to 5 milliseconds (e.g., every 4.6 milliseconds) to provide a pulse repetition frequency of 217 hertz. As shown in fig. 41, the transmitter coils 124 are spaced far enough apart that their fields 134 extend through the individual's skull and into brain tissue 136, but the fields do not substantially overlap, or preferably do not overlap. The power level of each transmitter is set so that the specific absorption rate (specific absorption rate; SAR) in the brain is between 1.0 and 2.0W/kg. The pulse energy is applied to the brain of the individual for a plurality of daily intervals of treatment. For example, the patient may be treated for a duration of one hour in the morning and another hour in the afternoon. Such treatments may be applied in this manner over a long period of time, including weeks or even months. For example, the treatment may be for 60 days.

Various tests before and after treatment have shown statistically significant improvement in individuals. These include cognitive tests, human billows (tau) (p-billows (tau)) and total billows (tau) assays, human amyloid beta (beta) assays, and PET and functional MRI scans of the brain. Treatment showed statistically significant improvement in ADAS-COG, increased cerebrospinal fluid levels of amyloid beta (beta) and decreased levels of cerebrospinal fluid p-taw (tau) protein/amyloid beta (beta) ratio, as well as decreased levels of oligomeric amyloid beta (beta) in plasma. It has also been found that glucose utilization in the brain is enhanced and functional connectivity is increased.

The power delivered to the brain by the rf transmitter is very low and may not significantly increase brain tissue temperature. As a rough estimate of the expected temperature rise, consider the balance between SAR of 1.0W/kg delivered to brain tissue by an electromagnetic field and the heat removed by blood flow to the brain. About 15% of cardiac output is supplied to the brain: in adults, this corresponds to 750 milliliters per minute. This corresponds to a cerebral blood flow of 50 ml per 100 g/min. The blood flow of 50 ml per 100 g/min corresponds to a residence time of about 2 minutes. This is the time Δt that the SAR has the opportunity to raise the temperature.

The temperature increase Δt during this period is approximately given by:

C _v dT/dt＝SARρ [14]

that is to say

ΔT＝SARρ(Δt/C _v ) [15]

Where ρ represents the density.

The specific heat capacity of brain tissue is 3630 joules/kg/degree celsius, while the specific heat capacity of water is 4178 joules/kg/degree celsius and ρ is about 1 gram/cc.

Thus, the formula [15] gives:

ΔT≈0.03℃ [16]

the temperature rise is indeed very small, much less than that required for activation of the heat shock protein in the above examples.

Despite the low field strength and power, the pulsed electromagnetic field is able to enter the brain as shown below.

The skin depth δ of the electromagnetic field with angular frequency ω into the medium with electrical conductivity σ and magnetic permeability μ is:

δ＝[2/μωσ] ^1/2 [17]

the conductivity of brain tissue is:

σ＝0.3300S/m [18]

for 915MHz and μ=4π10 ^-7 MKS, yield:

δ＝2.9cm [19]

thus, the top layer of the cerebral cortex is affected by the TEMT field.

The wavelength of the 915Hz field is:

λ＝3x10 ¹⁰ /915x10 ⁶ ＝32.8cm [20]

thus, the field from the coil located in the cortex is an inductive (near) field, since the wavelength is much greater than the depth into the brain.

This induced electric field from the coil can be derived from the azimuthal vector potential a:

E＝-iωA [21]

the integral expression of a from a coil carrying a current I with radius a is as follows:

wherein the integral is from 0 to pi, and r and z are the radius and axial distance in a cylindrical coordinate system.

When the loop is small compared to the distance to the field point, the expression reduces to:

A[r，z]＝(μlra ² /(r ² +z ² ) ^3/2 [23]

It can be readily seen from equation [23], that the induced E field from the coil will penetrate a distance along the axis approximately equal to the radius of the coil and will extend in the radial direction a distance commensurate with the radius of the coil. Thus, it can be seen that the induced electric field as well as the electromagnetic waves enter the brain.

The E field can be estimated and the mechanical effect of E can also be calculated. In a medium with conductivity σ, SAR is given by the following expression:

SARρ＝σE ² [24]

where ρ is the density. For ρ=1000 kg/m ³ The electric field is given as:

E＝55V/m [25]

the stress energy tensor corresponding to the electric field is:

T＝(E ² /2)[ε+σ/iω]Newtons/m ² [26]

for 915MHz, σ=0.33S/m, and ε=80/(36 pi 10) ⁹ )，

T≈10 ^-6 N/m ² [27]

Notably, this is much less than any molecular force.

The maximum induced charge density and the effect of the E-field on the film can be calculated or estimated according to the following equation.

The current density j from the induced electric field E is:

J＝σE [28]

thus, the maximum possible surface charge density it can deliver to the surface is:

∑＝(iω) ^-1 σE [29]

with 915MHz, and σ=0.33S/m and e=55v/m, we find:

∑＝3.16x10 ^-9 Coulombs/m ² [30]

the nominal surface density of charge in the solid was 16 coulombs/meter ² The induced charge density is thus much less than that which occurs naturally.

The capacitance of the cell membrane is of the order:

C＝10mF/m ² [31]

from the following equation, we can estimate the voltage v across the membrane due to the current density of equation [28 ]:

iωCv＝σE [32]

For 915MHz, C=10mF/m ² sigma=0.22S/m, and e=55v/m. We find that:

v＝1.3x10 ^-6 volts [33]

notably, this is well below the nominal naturally occurring (tens to one hundred) millivolts of membrane potential.

Despite the lower frequency and power levels, as shown in fig. 40 and 41, the transmitter 124 collectively provides global and penetrating TEMT to the human forebrain (including the cortex and underlying structures of the brain). In this embodiment, the success of the treatment is not due to thermal effects. The successful treatment does not appear to be due to large induced electric fields, induced charges or current densities, mechanical stress, or significant changes in membrane potential. Instead, it appears that radio frequency or other pulsed energy acts directly on biomolecules in cells. From the amplitude of the field inducing charge and current density, it appears that this effect will most likely involve resonant interactions of the collective modes. Calculations indicate that very low intensity electric fields with suitable frequencies can be significantly amplified by pi electrons in the biomolecular complex. The TEMT can be used to prevent or even reverse the oligomerization and insoluble amyloid beta (beta) aggregation inside and outside neurons. The TEMT breaks down not only amyloid beta (beta) oligomers, but also billows (tau) and alpha-synuclein oligomers. This is thought to be due to excitation of resonance co-oscillation within brain cells.

In order to interact with the induced electric field of the TEMT, the resonant co-oscillation will have to include an electric charge. Research and calculations have shown that this charge is an electron in a biomolecule, not an ion. The radio frequency falls within 20KHz to 300GHz and the microwave frequency falls within 300MHz to 300GHz. The radio frequency and microwave are described generally as having a center frequency of 5MHz to 300GHz. Resonance in beta amyloid is in the frequency range of 1GHz to 30GHz, with a lower limit approaching 850MHz-950MHz as contemplated herein. Resonance has been observed in these radio frequency/microwave frequency ranges.

However, from the above it has been found that the induced electric field seems to be small compared to the naturally occurring cell field. The associated current density appears to be much smaller than that which occurs naturally. The induced mechanical stress appears to be much smaller than the stress associated with molecular forces. The induced interfacial charge appears to be small compared to the naturally occurring charge. However, as described above, and as shown more fully below, the resonant frequency of the relevant biomolecules depends on: electron density, whether electrons are conductive or insulating, the shape of the region containing the electrons, and the surrounding dielectric of the relevant biomolecules present in the brain of a person suffering from or at risk of suffering from alzheimer's disease.

The coarse Drude (Drude) model (as described in detail below) concludes the following: the charges involved are electrons in biomolecules in and around the brain, not ions in electrolytes inside or outside the brain cells. The delude (Drude) model (shown below) shows that: resonance exists at frequencies where significant amplification of the applied field can occur. This large amplification can only occur for electrons, since the ions have too much viscous drag. Electrons are believed to be pi electrons associated with a conjugate bond (such as those found in beta amyloid of alzheimer's disease) because the valence electrons appear to have a resonance frequency much higher than the GHz frequency used by TEMT. Under these parameters, the resonance interactions have destructive effects on the molecular complex, rather than thermal activation of heat shock proteins.

The interaction of GHz electric fields with biomolecules in the brain will be described by a simple delude (Drude) model and parameter distribution applied to finite conductors to obtain Cole-Cole curve characteristics of the tissue.

The delude (Drude) model of the interaction charge is obtained by applying newton's second law f=ma for particles with mass m and charge E affected by a perturbed electric field E. The velocity of the particle is denoted by v and the form of frictional resistance on the particle is assumed to be-mνv, where ν is

mdv(t)/dt＝-mνv(t)+eE(t) [34]

In the TEMT treatment, an oscillating electric field is applied. Accordingly, it is assumed that the electric field has a time dependence

E(t)＝E exp[iωt] [35]

In this case the number of the elements to be formed is,

v(t)＝v exp[iωt] [36]

and v is simply of the formula

v＝{e/m(iω+ν)}E [37]

If the number density of these charges present is N, the current density j is given by

j＝Nev [38]

That is to say

j＝{Ne ² /m(iω+ν)}E [39]

In terms of angular plasma frequency

ω _p ² ＝4πNe ² /m [40]

This can be written as

j＝(1/4π){ω _p ² /(iω+ν)}E [41]

From the above we can see that the current in the conductor caused by the electric field is greater than the number of conductive charges present (e.g. square ω of the plasma frequency _p ² Shown), and the greater the collision frequency v, the smaller the current.

To determine the net field and the conductor, assume that the conductor described by equation [41] is subjected to an externally applied electrical displacement field in the z-direction:

D _app ＝D _app i _z ＝ε _ext E _app i _z [42]

and the conductor has a range w of about z=0 in the z direction and a large area a in the xy plane. Here E _app Is an electric field applied in a large area A and epsilon _ext Is the dielectric constant outside the conductor.

The current density will lead to a surface charge density

∑＝j/iω [43]

Deposited on the surface at z=w/2, and an equal surface charge density of opposite sign is deposited on the surface at z= -w/2, wherein the magnitude of the electric field in formula [41] is given by

E＝D _app -4π∑ [44]

As it is the "net" field resulting from the applied field minus the "back" field due to the induced surface charge density. (here we assume that no external current contributes to the surface charge density other than the current described by displacement Dapp.)

E＝[(-ω ² +iων)/{-ω ² +ω _p ² +iων}]D _app [45]

With respect to [45 ]]Is that it has a resonance denominator { - ω ² +ω _p ² +iων}。

It is noted that this result can also use the expression of the impinging plasma as the internal dielectric epsilon=1-omega _p ² /(ω ² -iων) by requiring a displacement vector D perpendicular to the area a _app Obtained by continuous processing.

Thus, for a conductor, if ω _p ² > iων and ω ² ≈ω _p ² The amplitude of the resonance denominator may be very small and the amplitude of the net electric field E acting on the conductive charge may be very large.

At resonance, formula [45 ]]The molecules in (a) are about omega _p ² And the denominator has about omega _p v.

Thus, for a conductor, if ω _p ² > iων and ω ² ≈ω _p ² At this resonance, then, the net electric field E acting on the conductive charge is greater than the applied electric field E _app Large epsilon _ext ω _p ² /ω _p ν＝ε _ext ω _p V times, i.e. magnification of

Magnification = epsilon _ext ω _p /ν [46]

When this ratio is large, the resulting field can be very destructive.

To modify the delux (Drude) model to describe an insulator rather than a conductor, only a single term needs to be added in the delux (Drude) process of equation [34 ]. Thus, equation [34] describes that the charge is free to move around under the influence of an electric field, encountering only the drag caused by the collision. In an insulator, the charge is not free to move around, but is constrained. Thus, if we denote the charge displacement at position r by ζ (r), then equation [1] will describe the insulator if we add a term-kζ (r) to the right hand side of equation [1 ]:

mdv(t)/dt＝-mνv(t)+eE(t)-Kξ(r) [47]

For a disturbance having the form E (t) =eexp [ iωt ], the formula [8] for the current density will become

j＝(1/4π){iωω _p ² /(-ω ² +ω _o ² +iων)}E [48]

Wherein omega _o ² =k/m because ζ= (1/iω) _V 。

And the equation [12] that relates the net field to the applied field becomes

E＝[(-ω ² +ω _o ² +iων)/{-ω ² +ω _o ² +ω _p ² +iων}]ε _ext E _app [49]

Thus, for an insulator, if ω _p ² +ω _o ² > iων and ω ² ≈ω _p ² +ω _o ² The amplitude of the resonance denominator may be very small and the amplitude of the net electric field E acting on the confined charge may be very large. The applied field at resonance has an amplification of about

Magnification = epsilon _ext [ω _p ² +ω _o ² ] ^1/2 /ν [50]

When an electric charge moves in a viscous medium, the collision frequency is sometimes expressed by the viscosity η of the medium.

This can be done by stokes law which gives the viscous force F acting on a spherical object with radius a moving through the medium at a velocity v _visc ：

F _visc ＝6πηav [51]

Comparing this with the resistance mv in equation [34], we see that in viscous media,

ν＝6πηa/m [52]

thus, in viscous media, the collision frequency is proportional to the viscosity, and since the mass of the charge is proportional to the cube of the radius, the collision frequency is inversely proportional to the square of the radius.

The complex dielectric "constant" of biological tissue approximately satisfies the Cole-Cole distribution in the radio frequency range:

ε(ω)＝ε _∞ +{ε _o -ε _∞ }/{1+(iωτ) ^(1-α) } [53]

this formula can be divided into a real part ε 'and an imaginary part ε' as follows:

ε’＝ε _∞ +(1/2){ε _o -ε _∞ }[1-sinh((1-α)×)/{cosh((1-α)x)+cos{απ/2)}] [54]

ε”＝(1/2){ε _o -ε _∞ }[cos{απ/2)/{cosh((1-α)x)+sin{απ/2)}] [55]

x＝In(ωτ) [56]

furthermore, the conductivity can be written as the imaginary part of the dielectric constant:

σ＝iωε” [57]

this type of distribution can be obtained from the Deruud (Drude) expression above by allowing the distribution of parameters in the expression. Thus, the parameter distribution in the delude (Drude) expression means that in biological tissue it is possible to observe the desired resonance at several frequencies instead of at only one frequency.

The electric field applied by the TEMT coil has been demonstrated above to be very small, on the order of 55V/m, compared to the naturally occurring cell field. From this it follows that: in order to produce a significant effect, certain resonance phenomena must have been included in brain cells, wherein the applied field is amplified at resonance.

Developing a simple framework by using the delude (Drude) model helps identify what type of cellular component might be involved and concludes the following:

if a conductive (mobile) charge is involved, the applied field may be amplified

Magnification ratio＝ε _ext ω _p /ν

At resonance omega ² ≈ω _p ² Omega at this time _p ² > iων. Where ω is the (angular) frequency of the TEMT field, ω _p Is composed of [40 ]]Defined plasma frequency, v is the collision frequency of the charge, and ε _ext Is the dielectric constant of the region around the conductor.

Similar amplification can occur for the isolated (constrained) charge and is given in equation [50 ].

In biological tissue, there is a distribution in the delude (Drude) parameters, so resonance can occur over a wider frequency range than just a single frequency.

The collision frequency v may be related to the viscosity η [ reference 52] when the charge passes through a viscous medium (e.g., a cell electrolyte).

The final observations led us to believe that the important charges involved in TEMT are electrons in cellular biomolecules, not ions in intracellular or extracellular electrolytes. Thus, typical ions in the electrolyte are Na ⁺ . Its hydration radius is approximately 1 angstrom. Na has a molecular weight of 23 and the hydrated ion has 6 water molecules in its innermost hydrated shell. Thus, we can assign a molecular weight of about (23+6x18) =131 to the hydrated ion. The corresponding mass is about 1.3x10 ^-22 Gram (g). When the viscosity of water is about 0.01 poise, formula [52 ]]Given the typical ion collision frequency in the electrolyte:

v＝6πηa/m＝6πx10 ^-2 10 ^-8 /1.3x10 ^-22 ≈1.4x10 ¹³ sec ^-1

this typical ion collision frequency is four orders of magnitude greater than the 1GHz (resonance) frequency of TEMT, indicating that ions are unlikely to be the charges involved in any resonance amplification of the applied field. The biomolecular electrons involved are believed to be those that are conductive-most likely pi electrons from conjugated bonds. The reason is that the bound electrons (valence electrons) have a resonance frequency that is much higher than the GHz-type frequency that is effective in TEMT. Therefore, TEMT is effective in treating alzheimer's disease because the GHz field it applies interacts with internal biomolecular electron resonance.

The above calculations assume that the treated biomolecular complex has a simple broad bulk geometry. However, although the resonant frequency may depend on the shape of the composite, the resonant amplification of pulsed energy fields (e.g., radio frequency and microwave fields) is not limited to a bulk geometry. The biomolecular complexes around and in brain tissue have different geometries, and pi electrons are present not only in beta amyloid complexes but also in ubiquitous microtubules. Thus, the different shapes of the conductive pi electron complexes are considered below by using the delude (Drude) model.

Electrons occupying these geometries will be characterized by a simple frequency-dependent dielectric constant epsilon (omega). This dielectric constant is derived by a simple Drude (Drude) model which derives an expression of the frequency dependent dielectric constant as described above:

ε(ω)＝1-ω _p ² {ω ² -ω _o ² -iων} ^-1 [58]

here, ω is the (angular) frequency and v is the electron collision frequency.

Measuring amount

ω _p ² ＝4πNe ² /m [59]

Is the square of the (angular) plasma frequency, where N is the electron number density, e is the electron charge, and m is the electron mass.

Measuring amount

ω _o ² ＝K/m [60]

Is the square of the (angular) recovery frequency, where K is the recovery force constant;

and v is the collision frequency of the electrons. For insulators, ω _o ² Is non-zero. For conductors, ω _o ² ＝0。

When the delude (Drude) computational model is applied to arbitrary geometries, such as long cylinders, discs, ellipsoids, infinitely thin long ellipsoids (thin needles), infinitely thin flat ellipsoids (thin discs), the result is a change in both resonant frequency and field magnification. Composites have been shown to experience an amplified internal electric field at a specific frequency.

For convenience, the resonance frequencies for each of the five shapes are summarized in table 4, and the approximate magnification (ratio of the internal field to the applied field) multiples at these resonance frequencies are summarized in table 5. In both tables 4 and 5, it is assumed that:

the composite is a good electronic conductor, i.e. characterizes the recovery frequency ω of the binding force _o Is assumed to be close to zero and ignored (ω) _o -＞0)；

Assuming that the electron impact frequency v is much smaller than the (angular) frequency (v < < ω) of the applied field;

assuming the dielectric constant epsilon of the external medium _ext Larger ((ε) _ext >>1) As in the case of intracellular and extracellular electrolytes, wherein ε _ext ≈80。

Table 4 approximates the above-listed approximate (angular) resonance frequencies of the frequency-dependent dielectric substance of equation [58 ].

Table 5 is directed to equation [58] by the approximation listed above prior to Table 4]The frequency-dependent dielectric substance of (2) has an approximate amplification factor (E _int / _Eapp )。

Tables 4 and 5 show that different shapes of biomolecular complexes can amplify externally applied electric fields at specific resonance frequencies. Both the resonant frequency and the amplification at the resonant frequency depend on the shape of the composite. For the first four of the five biomolecular shapes, the frequency at which resonance (and field amplification) occurs is lower than the expected frequency for the bulk electron conductor. Only in the fifth case of randomly oriented thin flat ellipsoids (discs) will the plasma frequency of the internal conductive electrons resonate. In the other four cases, the dielectric of the external medium willResonance reduction (1/ε) _ext ^1/2 ) Multiple times. Furthermore, for thin conductive cylinders and thin conductive plates, an additional decrease in resonance frequency occurs, which depends on the ratio of the thickness of the conductor to its large dimension.

Tables 4 and 5 also show that when the shape of the composite causes the resonance frequency to decrease from the plasma frequency (the frequency at which bulk dielectric resonates), the magnitude of the field amplification also decreases. For the first four cases, the amplification factor is reduced by 1/ε _ext ^1/2 Proportional to the ratio. Furthermore, for the first two cases of thin cylinders and sheets, a reduction in terms of the ratio of thickness to large dimension is also included. The maximum magnification occurs in the case of randomly oriented thin oblate ellipsoids (disks): here, the magnification is greater than ε _ext Directly proportional. In all cases, the large amplification is also dependent on the small collision frequency v of the conductive electrons.

The foregoing has shown that the low amplitude of the pulsed electromagnetic energy field and the large viscous damping of ions in brain cells are directed towards the interaction of the electromagnetic field with intramolecular electrons. The above also shows that in a simple broad bulk geometry, the conductive electrons can amplify the low intensity field at a specific resonance frequency. The broad distribution of parameters in the tissue is demonstrated by the Cole-Cole distribution of dielectric properties, which allows these resonances to occur over a broad frequency range. The above also shows that these results also apply to clusters of biomolecules with different shapes, and that the resonance amplification of the electromagnetic field is not limited to a bulk geometry, but that resonance frequency tuning can be achieved by changing the shape of the complex. In view of the above, it is believed that the success in treating Alzheimer's disease and other neurodegenerative diseases in accordance with the present invention is due to interactions with pi conjugated systems, such as typical pi conjugated biomolecules expected to be present in the brain.

Recent studies have shown that the vibration modes of proteins are in the THz frequency range, rather than the much lower radio frequency range of interest of 3MHz to 300 GHz. Cytoskeletal wirelike structures may have low vibration frequencies, but the viscous damping of these modes will be very large. To counteract damping, energy may be provided by ATP or GTP hydrolysis.

Recently for conductive polymersThe state was studied and significant progress was made in the organic conductor. It has been found that the conductivity is higher than the conductivity of the secondary insulator (10 ^-16 S/cm) through the conductivity (10) of the semiconductor ^-7 .10 ² S/cm) to good conductor conductivity (10) ⁴ S/cm-10 ⁸ S/cm). Conductivity is strongly dependent on the doping of the polymer: for example, the polymer in NaCl electrolyte may have a very considerable 10S/cm conductivity). Band gap theory is not sufficient to understand the conduction mechanism, as doping plays such important roles: resulting in various charge carriers (e.g., polarons, dual-polarons, and solitons). The mobility of these charge carriers is not determined by the usual viscosity mechanism but can be much smaller, depending on the dopant, temperature, and intrinsic structure.

Amyloid fibril formation is a common feature of many unrelated diseases including alzheimer's disease, diabetes, prion disease, and familial amyloidosis. Pi accumulation is thought to play an important role in amyloid fibril formation. Attractive non-bonded conjugated pi electronic systems tend to fix fibrils together in different (typically four) configurations. Three aromatic residues are most common, namely tryptophan, tyrosine, and phenylalanine.

The presence of conjugated pi electron systems in amyloid fibrils and the demonstrated amplified radio frequency interactions of similar systems doped by immersion in electrolytes suggest that successful treatment of alzheimer's disease with radio frequency electromagnetic radiation may involve interactions of radio frequency or other pulsed electromagnetic fields with these pi electron systems. Disruption of the system may lead to disruption of amyloid fibrils. Binding of the conductive chains has been demonstrated to be significantly different in size from the two chains that prevent conduction. Moreover, the interaction between conducting systems whose conductivity is anisotropic (as in pi-electron systems) has proven to be strongly dependent on the density of the participating electrons.

It is therefore believed that successful treatment of alzheimer's disease and other neurodegenerative diseases with low power electromagnetic fields (e.g., in the radio frequency range) involves resonant interactions with conjugated pi electron systems in biomolecules around or within brain tissue (e.g., in beta amyloid present in the brain of alzheimer's patients). Other targets include the Tao (tau) protein, particularly the tangle Tao (tau) protein, which is present in brain cells of Alzheimer's disease patients. Other areas that may be targeted include leaky blood brain barriers, inflamed parts of the brain, and trash proteins of the brain.

It is believed that especially the leaky blood brain barrier (which is found to be damaged in Alzheimer's patients, allowing neurotoxic plasma derived components to enter the brain) can be treated with non-resonant heat activated heat shock proteins. It has also been found that there is a correlation between brain inflammation in Alzheimer's disease and other forms of dementia and the presence of trash proteins in the inflamed areas. According to the present invention, since activated heat shock proteins repair or destroy malformed proteins, the inflamed part of the brain is a natural target for heat shock protein therapy, which is thermally activated by an electromagnetic field. Low power resonance treatment of alzheimer's disease and other neurodegenerative diseases may be directed to molecular and tissue targets in which the applied electromagnetic field interacts with pi electron stacking resonances in these target biomolecular complexes and tissues, including beta amyloid, which is a feature of the brain of alzheimer's disease. This interaction disrupts the structural integrity of beta amyloid or other molecular complexes. The resonant frequency of this interaction has been shown to depend on several factors including the number density of electrons, whether the electrons are conductive or insulating, the shape of the region containing the electrons, and the surrounding dielectric. The width of the resonance frequency has proved to be strongly dependent on the collision frequency of the electrons. It has been found that the usable electromagnetic fields are in the frequency range of radio frequencies and microwaves as described above.

Although several embodiments have been described in detail for purposes of illustration, various modifications may be made without departing from the scope and spirit of the invention. The invention, therefore, is not to be restricted except in the spirit of the appended claims.

Claims

1. A method for preventing or treating a neurodegenerative disease including alzheimer's disease, comprising the steps of:

determining that the individual has or is at risk of having a neurodegenerative disease;

providing pulsed electromagnetic energy, including radio frequency or microwaves, having selected energy parameters including wavelength or frequency, duty cycle, and pulse train duration, wherein the pulse energy parameters are selected to sufficiently raise the temperature of the tissue being treated to stimulate heat shock protein activation in the tissue or fluid being treated; and

the pulse energy is applied to the brain of the individual to prevent or treat the neurodegenerative disease.

2. The method of claim 1, wherein the pulsed electromagnetic energy is directed to one or more of a leaky blood brain barrier, an inflamed portion of the brain, a trash protein of the brain, beta amyloid of the brain, or tangle (tau) protein of the brain.

3. The method of claim 1 or 2, wherein the pulse energy comprises a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5.0%, and a pulse train duration between 0.2 and 0.4 seconds.

4. A method as claimed in claim 3, wherein the radio frequency is generated using a coil having a radius of between 2 mm and 6 mm and a turns of between 13 and 57 amperes.

5. The method of any one of claims 1-4, wherein the pulse energy parameter is selected and applied to the brain to induce resonant interactions within biomolecules within and around brain tissue.

6. The method of claim 5, wherein the pulsed energy forms a resonant interaction with a conjugated pi electron system in the biomolecule.

7. The method of claim 6, wherein the resonance interaction disrupts the structural integrity of beta (beta) amyloid molecules.

8. The method of claim 5, comprising the steps of: a plurality of spaced apart electromagnetic emitters are disposed adjacent the head of the individual.

9. The method of claim 8, wherein the electromagnetic fields of the spaced apart radio frequency transmitters do not overlap.

10. The method of claim 8, comprising the steps of: the power level of each emitter is set so that the specific absorption rate in the brain is between 1.0W/kg and 2.0W/kg.

11. The method of claim 8, wherein each transmitter transmits a radio frequency field at 850 to 950 megahertz every 4 to 5 milliseconds.

12. The method of claim 5, wherein the pulse energy is applied to the brain for multiple daily intervals of treatment.

13. A method for preventing or treating a neurodegenerative disease including alzheimer's disease, comprising the steps of:

providing pulse energy, including radio frequency or microwave, having selected energy parameters including wavelength or frequency, duty cycle, and pulse train duration; and

applying the pulse energy to the brain of the individual to prevent or treat the neurodegenerative disease;

wherein the pulse energy is directed to one or more of a leaky blood brain barrier, an inflamed portion of the brain, a trash protein of the brain, beta (beta) amyloid of the brain, or tangle (tau) proteins of the brain; and

wherein the pulse energy parameter is selected to substantially increase the temperature of the tissue being treated, thereby stimulating heat shock protein activation in the tissue or fluid being treated.

14. The method of claim 13, wherein the pulse energy comprises a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5.0%, and a pulse train duration between 0.2 and 0.4 seconds.

15. The method of claim 14, wherein the radio frequency is generated using a coil having a radius between 2 millimeters and 6 millimeters and a turns between 13 and 57 amperes.

16. A pulse energy system for preventing or treating neurodegenerative diseases including alzheimer's disease, comprising:

a pulsed electromagnetic energy source, including radio frequency or microwave, having selected energy parameters including wavelength or frequency, duty cycle and pulse train duration, is applied to the brain, wherein the pulse energy parameters are selected to substantially raise the temperature of the tissue being treated, thereby stimulating heat shock protein activation in the tissue or fluid being treated.

17. The system of claim 16, wherein the pulsed electromagnetic energy is directed to one or more of a leaky blood brain barrier, an inflamed portion of the brain, a trash protein of the brain, beta amyloid of the brain, or tangle (tau) protein of the brain.

18. The system of claim 1 or 2, wherein the pulse energy comprises a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5.0%, and a pulse train duration between 0.2 and 0.4 seconds.

19. The system of claim 18, wherein the radio frequency is generated using a coil having a radius between 2 millimeters and 6 millimeters and a turns between 13 and 57 amperes.

20. The system of any one of claims 16-19, wherein the pulse energy parameter is selected and applied to the brain to induce resonant interactions within biomolecules within and around brain tissue.

21. The system of claim 20, wherein the pulsed energy forms a resonant interaction with a conjugated pi electron system in the biomolecule.

22. The system of claim 21, wherein the resonance interaction disrupts structural integrity of beta (beta) amyloid molecules.

23. The system of claim 20, wherein a plurality of spaced apart electromagnetic emitters are disposed adjacent the head of the individual.

24. The system of claim 23, wherein the electromagnetic fields of the spaced radio frequency transmitters do not overlap.

25. The system of claim 23, wherein the power level of each emitter is set to provide a specific absorption rate in the brain of between 1.0W/kg and 2.0W/kg.

26. The system of claim 23, wherein each transmitter transmits a radio frequency field at 850 to 950 megahertz every 4 to 5 milliseconds.

27. The system of claim 20, wherein the pulse energy is applied to the brain for multiple daily intervals of treatment.