MEDICAL HEAD DEVICE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

FIELD OF THE INVENTION

[1] The present invention relates to a novel non-invasive medical head device useful for stabilizing and/or reversing the symptoms of neurodegenerative diseases and/or proteinopathies. The novel medical head device is particularly useful for stabilizing and/or reversing the symptoms of Alzheimer’s disease and/or Parkinson disease in a subject in need thereof.

BACKGROUND OF THE INVENTION

[2] The brain is the most complex organ. The central nervous system is made of two basic types of cells: neurons and glial cells which include astrocytes, oligodendrocytes, ependymal cells, and microglia, and cells related to blood vessels. The human brain contains over 80 billion neurons responsible for the encephalic electrochemical information processing. Each neuron is connected to even thousands of other nerve cells via synapses forming a complex network. This network is active all the time through electrical impulses, such as action potentials, synaptic activity, and is constantly stimulated, for example, by senses, i.e., the cerebral cortex gets information from the sensory systems, which modifies the electrical activity of the brain, thereby allowing a multitude of vital body functions such as sensory, motor and cognitive functions.

[3] Neurodegeneration may occur over time with loss of neurons and excitatory synapses which are associated with sensory, motor, and cognitive impairments. Despite the overwhelming evidence for synapse loss in contributing to disease etiology, very little is known about the mechanisms involved.

[4] The accumulation of proteins or protein fragments in the brain is a significant feature of age-dependent neurodegenerative diseases. These neurodegenerative proteinopathies which are also known as protein conformational diseases result of the change of conformations of some proteins generating small oligomeric, protofibrils, and then large fibrillary aggregates which lead to neurotoxicity and neurodegeneration. These changes, in terms of size and three-dimensional shape, lead to their selfassociation, elongation and precipitation in specific brain regions, therefore producing the acquisition of pathological protein features. The molecular mechanisms resulting in misfolded protein conformational changes tend to be the same in all the proteinopathies and may include different mechanisms, such as post- translational modifications, the loss of protein clearance or the enhancement of protein production.

[5] Clearance of these proteins has a critical role in the preservation of neuronal cell integrity, and it has been described that, in most neurodegenerative conditions, compromised protein clearance might be able to modulate brain functions and structure, leading to clinical manifestations. In the brain, the deregulation of protein clearance mechanisms, both at the intra-neuronal (autophagy and unfolded protein stress response) and at the extra-neuronal level (interaction among neurons, astrocytes and microglia, phagocytic clearance, autoimmunity, cerebrospinal fluid transport, and transport across the blood-brain barrier), also lead to intra- and extra-neuronal misfolded protein precipitation, respectively.

[6] Several types of dementia which are connected to neurodegenerative proteinopathies and changes in certain brain regions that cause nerve cells (also known as neurons) and their connections to stop working properly. Neurodegenerative proteinopathies may include Alzheimer’s disease (AD), Frontotemporal dementia (FTD), Semantic Dementia (SD), Mild Cognitive Impairment (MCI), Parkinson’s disease (PD), Creutzfeldt-Jacob disease (CJD), Dementia with Lewy bodies (DLB), Huntington disease (HD), and Amyloid Lateral Sclerosis (ALS). The cause of neurodegeneration is atrophy of certain regions of the brain, significantly in the cortex and in the hippocampus.

[7] Together, these diseases affect millions of lives around the world and have devastating economic implications. AD, the most frequently diagnosed among these listed diseases, affects almost one-tenth of the population above 65 years of age, and the number of people suffering from these diseases is increasing rapidly with an increase in life expectancy. It is predicted that by 2050, around 135 million people will be living with various types of neurodegenerative dementia. To this date, there is no cure and thus patients are only treated to alleviate the symptoms. We will be living in a “dementia or Alzheimer pandemic”.

[8] Although proteinopathies present similarities in their pathological mechanisms, the psychological and physiological symptoms of all these disorders vary and depend on the region of the brain affected.

[9] In Alzheimer’s disease pathogenesis, the neuropathological hallmarks are the buildup of extracellular amyloid plaques (amyloidosis) and neurofibrillary tangles (tauopathies) the amyloid plaques and neurofibrillary tangles (tauopathy) The major components of amyloid plaques are Ap i^o and A 1-42 peptides, which aggregate and form -sheets. The Ap peptides are produced by the proteolytic cleavage of the amyloid precursor protein by the beta-amyloid cleavage enzyme 1, and beta and gamma secretases. The AP40 is the predominant isoform of amyloid fragments detected in plasma and cerebrospinal fluid samples, while the AP42 isoform was mainly associated with nucleation, due to its aggregation tendency. In parallel to the extracellular amyloid plaque deposition in AD brains, the Ap intracellular deposition triggers the pathological cascade involving a second neurotoxic molecule: the Tau protein. Therefore, AD is also characterized by the deposition of the intra-neuronal neurofibrillary tangle of hyper-phosphorylated aggregated tau protein. Tau protein is involved in the formation and stabilization of microtubules. Besides the hyper-phosphorylated Tau-induced neurotoxicity, in which the process of tau phosphorylation is believed to be of critical relevance for tangle formation. These aggregates are deposited primarily in the hippocampus and entorhinal cortex. Over time, the damage is widespread affecting areas in the cerebral cortex. The signal is disrupted among the neurons which completely stop working and lose connection with other neurons, thereby leading to atrophy (loss of neurons), memory loss, confusion, mood swings, personality changes, and difficulty in performing even basic routine tasks or daily functions. [10] The progression of Alzheimer's disease can be broadly divided into 7 stages. In the first two stages, it is difficult to tell whether a person is suffering from the disease. Alzheimer’s function as a silent killer that does not show any symptoms in the initial stage unless the patient is clinically diagnosed. As the disease progresses, the patient starts showing mild changes in their behavior. From the third and fourth stages, the disease starts to escalate, and the patient starts showing more prominent signs of the disease. The episodes of memory loss become more frequent and often people suffering from Alzheimer’s disease experience escalated episodes of memory loss that gets worse with time. The disease makes them forget about their daily activities and even hampers their language. From the fifth stage onwards, the patients even start to forget things about themselves and experience other neurological conditions like difficulty in speech and movement. Mood swings, distrust in others, irritability, agitation, and delusion become common traits that hamper the overall well-being of the patient.

[11] Some research demonstrated the link of the disease with cardiovascular ailments and even chronic inflammation. Due to this fatal condition, there is a release of harmful chemicals inside the body that triggers chronic inflammation, causing further damage to the neurons. Apart from that, patients may also suffer from poorly controlled type-2 diabetes, hypertension, high cholesterol, and obesity due to the change in lifestyle. Various research have also shown the impact of this dangerous disease on the sleep cycle.

[12] Aducanumab, the first disease-modifying therapy to be approved for AD, became available on the market for those with MCI due to AD and mild AD dementia in 2021. Aducanumab and Lecanemab are anti-amyloid monoclonal antibodies approved by the US Food and Drug Administration (USFDA) but not approved in Europe. A third anti -amyloid monoclonal antibody, Donanemab is currently under review by the US Food and Drug Administration (USFDA).

[13] The a-synuclein is the major component of the intracytoplasmic fibrillar Eewy Bodies deposits and represents the hallmark of the synucleinopathy lesions which are observed in Parkinson disease, Eewy Body Dementia (LBD) and Multiple System Atrophy. Such synucleinopathy lesions have been also recently reported in Alzheimer’s disease patients. However, the deposition of a-synuclein aggregates in the brainstem is really the neuropathological hallmark of Parkinson disease. The substantia nigra (midbrain) is the primary region affected by the presence of the Lewy bodies which contain aggregation of alpha- synuclein in a clumped form that cells cannot break down. Lewy Body Dementia is characterized by Lewy body accumulation in the cortico-limbic system, while Multiple System Atrophy is characterized by a- synuclein accumulation in basal ganglia, as well as in brainstem and cerebellum. It has been demonstrated that a mutation of the gene encoding for a-synuclein (SNCA) is linked to familial Parkinson’s disease and the change of soluble a-synuclein peptides into amyloid fibrils and intermediate oligomers is a crucial mechanism in the synucleinopathy pathogenesis.

[14] In the case of Parkinson’s disease, many of the neurons which produce the neurotransmitter dopamine in the brain break down or die, leading to a decrease of the dopamine levels and to the symptoms of tremor, slowed movements (bradykinesia), muscle stiffness, a stooped posture and an impaired balance, loss of the ability to perform unconscious movements, including blinking, smiling, swinging the arms when walking. Parkinson’s disease cannot be cured, but medications can help control your symptoms. Such prescriptions include for example Carbidopa-levodopa. Levodopa, the most effective Parkinson's disease medication, is a natural chemical that passes into your brain and is converted to dopamine. Levodopa is combined with carbidopa (Lodosyn), which protects levodopa from early conversion to dopamine outside your brain. Deep brain stimulation (DBS) offered to people with advanced Parkinson's disease who have unstable medication (levodopa) responses. In DBS, surgeons implant electrodes into a specific part of your brain. The electrodes are connected to a generator implanted in the chest near the collarbone of the patient that sends electrical pulses to the brain and may reduce Parkinson's disease symptoms. Surgery involves risks, including infections, strokes, or brain hemorrhage. However, while DBS may provide sustained benefit for Parkinson's symptoms, it doesn't keep Parkinson's disease from progressing.

[15] In the case of Lewy Body Dementia (LBD) or Dementia with Lewy bodies (DLB), subjects may have visual hallucinations, cognitive problems, sleep difficulties, changes in alertness and attention, depression, and apathy. Hallucinations are generally one of the first symptoms. People with Lewy body dementia may include shapes, animals or people, sounds (auditory), smell (olfactory) or touch (tactile) hallucinations. LBD patients may also present poor regulation of body functions, including blood pressure, pulse, sweating and the digestive process. This can result in sudden drops in blood pressure upon standing (orthostatic hypotension), dizziness, falls, loss of bladder control (urinary incontinence) and bowel issues such as constipation. Some of the cognitive problems include confusion, poor attention, visual-spatial problems and memory loss. Other effects include Parkinson's disease signs and symptoms such as movement disorders, such as rigid muscles, slow movement, walking difficulty and tremors. There are no cures for Lewy body dementia. Current treatments are used to improve the symptoms. These medications inter alia include Alzheimer's disease medications, such as rivastigmine (Exelon), donepezil (Aricept) and galantamine (Razadyne), which work by increasing the levels of chemical messengers in the brain (neurotransmitters) believed to be important for memory, thought and judgment. This can help improve alertness and cognition and might reduce hallucinations and other behavioral problems. In some people with moderate or severe dementia, an N-methyl-d-aspartate (NMDA) receptor antagonist called memantine (Namenda) might be added to the cholinesterase inhibitor. Alternatively, medications may include PD medications, such as carbidopa-levodopa (Sinemet, Rytary, Duopa) can help reduce parkinsonian signs and symptoms, such as rigid muscles and slow movement. However, these medications can also increase confusion, hallucinations and delusions. Antipsychotic drugs may be administered, but it can cause severe confusion, severe parkinsonism, sedation and sometimes death.

[16] Frontotemporal dementia (FTD or FTLD) Frontotemporal dementia is an umbrella term for a group of brain disorders that primarily affect the frontal and temporal lobes of the brain. These areas of the brain are generally associated with personality, behavior, and language. It belongs to the category of tauopathies and comprises a heterogeneous spectrum of clinical and neuropathological subtypes that are associated with cognitive and motor disorders. The neuropathology of the FTLD is characterized by abnormal intracellular accumulation of some disease-specific proteins that allow classifying FTLD into different categories. Indeed, the three major recognized pathological FTLD subtypes are the FTLD-tau, FTLD-TDP, and FTLD- FUS. The FTLD-tau is characterized by the aggregation of hyperphosphorylated tau protein in neurons and glia. The FTLD-U has been initially recognized with ubiquitin immunohistochemistry, but it has been subsequently renamed FTLD-TDP considering that the ubiquitinated pathological protein in the majority of FTLD-U cases, was identified in the transactive response DNA binding protein with a molecular weight of 43 kDa. Finally, the FTLD-FUS is characterized by inclusions of fused in sarcoma gene (FUS). There's no single test for frontotemporal dementia. Doctors look for signs and symptoms of the disease and try to exclude other possible causes. The disorder can be especially challenging to diagnose early because symptoms of frontotemporal dementia often overlap with those of other conditions. It has been recently, confirmed that there are shared genetics and molecular pathways between frontotemporal dementia and amyotrophic lateral sclerosis (ALS).

[17] Amyloid Lateral Sclerosis (ALS) is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. ALS is often called Lou Gehrig's disease, after the baseball player who was diagnosed with it. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat, and breathe. There is no cure that can reverse the damage of amyotrophic lateral sclerosis, but some treatments such as Rituzole, Edavarone, etc. . . can slow the progression of symptoms, prevent complications, and make you more comfortable and independent.

[18] Creutzfeldt-Jacob disease (CJD) is a degenerative brain disorder that leads to dementia and, ultimately, death. It belongs to a broad group of human and animal diseases known as transmissible spongiform encephalopathies (TSEs). The name derives from the spongy holes, visible under a microscope, that develop in affected brain tissue. The cause of Creutzfeldt-Jakob disease and other TSEs appears to be abnormal versions of a kind of protein called a prion. Normally these proteins are produced in our bodies and are harmless. But when they're misshapen, they become infectious and can harm normal biological processes. Creutzfeldt-Jakob disease symptoms can be similar to those of other dementia-like brain disorders, such as Alzheimer's disease, but Creutzfeldt-Jakob disease usually progresses much more rapidly. In particular, Creutzfeldt-Jakob disease is marked by rapid mental deterioration, usually within a few months. Early signs and symptoms typically include personality changes, memory loss, impaired thinking, blurred vision, incoordination, difficulty speaking, difficulty swallowing, etc...

[19] Huntington disease (HD) is a rare, inherited disease that causes the progressive degeneration of nerve cells in the brain. Huntington's disease has a wide impact on a person's functional abilities and usually results in movement, cognitive and psychiatric disorders. Medications are available to help manage the symptoms of Huntington's disease. A preliminary diagnosis of Huntington's disease is based primarily on your answers to questions, a general physical exam, a review of your family medical history, and neurological and psychiatric examinations. No treatments can prevent the physical, mental and behavioral decline, and thus no treatments can alter the course of Huntington's disease. Medications can lessen some symptoms of movement and psychiatric disorders. And multiple interventions can help a person adapt to changes in abilities for a certain amount of time.

[20] Accordingly, there is an unmet need for new safe and effective therapies. Countries are more and more setting up proactive planning to address neurodegenerative diseases, and in particular Alzheimer’s disease and related dementias to address emerging needs to aging population, and are promoting Alzheimer’s as a national priority, thereby creating awareness of the disease’s impact on individuals, families, and communities.

[21] So far there are no cures against these neurodegenerative diseases, most of the current drugs have failed, none of these drugs improved or prevented any of the symptoms of the neurodegenerative diseases, or the drugs do not pass the brain blood barrier, and some drugs have been shown to be toxic. The few antiamyloid monoclonal antibodies that have been approved in the US only have low efficacy on mild Alzheimer’s patients.

[22] Several non-drug approaches for treating neurodegenerative diseases have been explored including deep brain stimulation (DBS) and non-invasive brain stimulation (NIBS). NIBS refers to a set of technologies and techniques in which various patterns of electrical, magnetic, electromagnetic, sound, red and/or near-infrared (NIR) stimulations are used transcranially, noninvasively, to alter brain activity from the surface of the scalp (without breaking the skin) and the large-scale networks in which they participate.

[23] NIBS approaches include several approaches, such as for example electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), repetitive transcranial magnetic stimulation (rTMS), transcranial alternating current stimulation (tACS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS), transcranial electromagnetic treatment (TEMT), repeated electromagnetic field shock (REMFS), and photobiomodulation (PBM).

[24] ECT is performed by placing electrodes on the patient’s scalp and a finely controlled electric current is applied while the patient is under general anesthesia. The current causes a brief seizure in the brain. TMS involves passing an electric current through conductive wires of an insulated coil to induce a local magnetic field. The coil or electromagnet is placed on the scalp and generates magnetic field pulses which are supposed to activate axons and cause them to fire action potentials. rTMS is based on repeated application of TMS pulses. tDCS is performed by placing two small electrodes placed on the head to deliver a constant small Direct Current (DC) across the scalp to modulate brain function, altering neuronal excitability. Transcranial alternating current stimulation (tACS) is based on the external application of oscillating electrical currents that are believed to influence cortical excitability and activity.

[25] One of the difficulties of these NIBS-based approaches is that there is little mechanistic understanding of how these stimulations can influence the brain function and can reverse the pathologies underneath these neurodegenerative diseases and thus there are little scientific progress toward rationale design treatments. In addition, there are numerous variable parameters for these NIBS stimulation signals, including inter alia frequency, magnitude, waveshape, polarization, duration, shape of the signal, continuous or pulsated signal, rate of repetition in case of pulsed signal, duty cycle, power, irradiance, energy, fluence, penetration of the signal within the brain, specific absorption rate (SAR), regions and sizes of the cortical brain exposed to the stimulation signal.

[26] Another difficulty is that medical devices which are based on NIBS technologies must include elements, such as for example coils, antennas, laser, or LEDs, for generating electric, magnetic, electromagnetic, or red/NIR stimulation signal, which are generally not adapted for transcranial administration to humans, they are generally too big and bulky for human head sizes, they do not provide a precise exposure of the cortical brain and/or sufficient penetration of the signal within the cortex. Also, sizes and shapes of antennas and coils of the current NIBS head devices are not appropriate for regular and convenient use by the patients, for example in their homes. Most of the existing NIBS medical devices are in fact big apparatus and require the patients to regularly go to the hospital to receive brain transcranial stimulation treatment. This is, however, difficult and even materially not possible for most patients affected with neurodegenerative diseases.

[27] One of the challenges is thus to create applicators for direct stimulation of human body tissues, and particularly that would efficiently deliver the energy into a human body tissue . “Efficiently deliver” includes several tasks besides power efficiency. It is desirable to have energy spread evenly over sufficiently large area to cover, for example, entire surface of a human body tissue, such as the head or the abdomen, with reasonable small number of the applicators. Applicators should also be able to adjust its shape to accommodate the curvature of a body tissue, either the human head of a subject, or any other parts of the human body, without compromising its power efficiency. Furthermore, applicators must be able to direct energy towards a part of a body tissue of a subject, with a minimum energy leakage away from the body tissue, and thus it is desirable to minimize the energy emission into a free space, and rather to maximize the penetration thereof within the human body tissue which is targeted. This is particularly important when the brain of a human subject is targeted.

[28] The quality and therapeutic efficiency of the NIBS-based medical device largely depends on the performance of the components. The challenge is even higher in the case of radio frequency (RF) signal applicators, from which the signal is emitted toward the head. Indeed, unlike standard electromagnetic signal (or radio frequency) antennas which are emitting an electromagnetic signal (or radio frequency) outwardly and are designed to operate surrounded only by free space (or air), the electromagnetic signal or radiofrequency signal applicators for use in NIBS medical devices must be designed for inward exposition to human body, while considering the influence of the electric characteristics of the adjacent human body tissue. Due to the above hurdles, none of the currently existing NIBS medical devices have demonstrated statistically significant results on reversing neurodegenerative symptoms, such as for example on more than one cognitive test.

[29] The present invention constitutes a major advance as it provides with radiofrequency applicators and NIBS medical devices comprising RF applicators that effectively and reliably deliver electromagnetic signal either alone or in combination with red/NIR light in a way that balances comfort, while allowing 80- 90% absorption of the emitted power within the human body tissue with a reliable, reproducible, and efficient specific absorption rate (SAR). Accordingly, RF applicators of the present invention may effectively deliver a therapeutically efficient dosage to the brain cells regardless of the individual subject’s anatomical makeup. The NIBS medical device of the present invention is present in the form of a medical head device, or headset or headcap and not only it has a weight acceptable for regular home-based use, but also can generate a reliable therapeutic transcranial signal in terms of coverage and penetration within the cortex of patients. Furthermore, the medical head device of the present invention is useful for stabilizing and/or reversing the symptoms of neurodegenerative diseases and/or proteinopathies in a subject in need thereof, particularly for stabilizing and/or reversing the symptoms inter alia of Alzheimer’s disease and Parkinson disease.

SUMMARY OF THE INVENTION

[30] The present invention further provides a novel medical device comprising an array of body tissue radiofrequency applicators which are specifically designed for directly administering an homogeneous pulsed electromagnetic signal to a specific body tissue, such as the head or the abdomen, of a subject in need thereof. The present invention also provides a novel medical device comprising a synergistic combination of the body tissue radio frequency applicators with LEDs for simultaneous emissions of signals of pulsed electromagnetic waves in combination with red and near-infrared lights or signals.

[31] The medical device according to the present invention is in the form of a head-mounted wearable non-invasive device which may be placed on the head, in direct contact with the scalp and/or skull of a subject, thereby allowing homogeneous and reliable exposure of the cortex of the subject to said electromagnetic waves in combination with red and near-infrared signals or lights. Such medical head device is particularly useful for treating and/or preventing the symptoms of neurodegenerative proteinopathies, and for stabilizing and/or reversing the symptoms for example of Alzheimer’s disease and/or Parkinson’s disease in a subject in need thereof.

[32] The present invention finally provides a method of treating and/or preventing and/or stabilizing or reversing the symptoms of neurodegenerative proteinopathies and/or diseases, as well as a novel medical device for use in a method of treating and/or preventing and/or stabilizing or reversing neurodegenerative proteinopathies and/or diseases in a subject in need thereof, comprising positioning said medical device at close proximity to the human tissue, for example directly on the head of the subject, and administering a therapeutically efficient dose of pulsed electromagnetic waves either alone or in combination with simultaneous exposure of red and near-infrared light to the head and cortex of a subject in need thereof.

BRIEF DESCRIPTION OF THE FIGURES

[33] Figures 1A-B: (A) shows a complete schematic view of the X-BTRFA with a coaxial connector structure according to Figure 2 and with meandered antenna wire. (B) shows a further schematic view of the body tissue radio frequency applicator or antenna (BTRFA) according to the present invention with an X-type of crisscrossed connection between the coaxial conductors and the central antenna wires. The antenna wires are shown only schematic and simplified as two loops.

[34] Figures 2A-B: (A) shows a detailed view of the X-BTRFA with ends of the antenna wires and the central coaxial connector structure. (B) shows a detailed view (top view on the left and bottom view on the right) of the X-BTRFA in an alternative embodiment to Figure 2A in a connection to a PCB.

[35] Figures 3A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of X-BTRFA surrounded by free space or air and operating at 915 MHz. (B) is a graph showing the power distribution of X-BTRFA surrounded by free space.

[36] Figure 4: shows antenna gain of X-BTRFA surrounded by free space at 0.915 GHz.

[37] Figure 5: is a schematic of the X-BTRFA placed close to body tissue. Dimensions of the body tissue 132x105x40 mm are indicated by way of examples and 3 mm is the distance between the surface of the body tissue and the X-BTRFA.

[38] Figures 6A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of X-BTRFA placed close to body tissue. (B) is a graph showing the power distribution of X-BTRFA placed close to body tissue.

[39] Figure 7: is a simulation of the SAR(lg) for X-BTRFA placed close to body tissue at 0.915 GHz.

[40] Figures 8A-B: (A) shows a complete view of the Y-BTRFA of Figure 8B with a coaxial connector structure according to Figure 9 and with meandered antenna wire. (B) shows a further schematic view of the body tissue radio frequency applicator or antenna (BTRFA) according to the present invention with a Y-type of crisscrossed connection between the coaxial conductors and the central antenna wires. The antenna wires are shown only schematic and simplified as two non-meandered loops.

[41] Figures 9A-B: (A) shows a detailed view of the Y-BTRFA with ends of the antenna wires and the central coaxial connector structure. (B) shows a detailed view (top view on the left and bottom view on the right) of the Y-BTRFA in an alternative embodiment to Figure 9A in a connection to PCB. [42] Figures 10A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of Y-BTRFA surrounded by free space or air and operating at 915 MHz. (B) is a graph showing the power distribution of Y-BTRFAsurrounded with free space (air).

[43] Figure 11 : is a simulation showing the antenna gain of Y -BTRFA surrounded by free space at 0.915 GHz.

[44] Figure 12: is a schematic of the Y-BTRFA placed close to body tissue. Examples of dimensions of the body tissue 132 x 105 x 40 mm are provided and 3 mm may be an exemplary distance between the surface of the body tissue and the Y-BTRFA.

[45] Figures 13A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of Y-BTRFA placed close to body tissue. (B) is a graph showing the power distribution of Y-BTRFA placed close to body tissue.

[46] Figure 14: is a simulation of the SAR(lg) for Y-BTRFA placed close to body tissue at 0.915 GHz.

[47] Figures 15A-B: (A) is a schematic of BTRFA (either X-BTRFA or Y-BTRFA) printed on a thin flexible PCB (“printed circuit board”). The size of the body tissue sample is 132 mm x 105 mm x 40 mm, while the PCB size is 92 mm x 81 mm with thickness of 0. 1 mm. BTRFA is realized with printed conductive line with thickness of 0.0175 mm (17.5 pm) and width of 1 mm. Thin flexible PCB with printed BTRFA is placed at the 3 mm distance above the body tissue sample. (B) is a schematic of the connections between the coaxial cable and printed PCB metal trace for the X connection on the left and the Y connection on the right.

[48] Figures 16A-B: (A) represents the simulation Si l parameter results of printed X-BTRFA close to the body tissue. (B) represents simulation Si l parameter results of printed Y-BTRFA close to the body tissue.

[49] Figures 17A-B: (A) represents the power distribution results of printed model of X-BTRFA close to body tissue. (B) represents the power distribution results of printed model of Y-BTRFA close to body tissue.

[50] Figures 18A-B: (A) shows a Specific Absorption Rate (SAR) simulation for printed X-BTRFA above body tissue. The simulation shows body tissue volume with SAR value of at least 2 W/kg. The SAR value of 2 W/kg or greater covers a wider area within the body tissue, but with a lesser penetration depth at the center of the X-BTRFA, when compared to the Y-BTRFA SAR simulation in 18B. The maximum SAR value is 9.51 W/kg at four places indicated by black dots. (B) shows a Specific Absorption Rate (SAR) simulation for printed Y-BTRFA above body tissue. The simulation shows body tissue volume with SAR value of at least 2 W/kg or greater also covers a wide area within the body tissue, but narrower than the area covered when using X-BTRFA and with a higher penetration depth within the body tissue at the center of the Y-BTRFA, when compared to penetration depth when using X-BTRFA in 18A. The maximum SAR value of 11.9 W/kg is at the center of Y-BTRFA. [51] Figures 19A-C: are schematics of the slight possible variations of the BTRFA extremities which may be further rounded up to accommodate the LEDs as shown in Figure 20. Another advantage of using differently meandered BTRFAs is to optimize the SAR coverage of a human head function of shapes and sizes thereof, especially considering that the overall device is intended to be suitable for various human head sizes.

[52] Figure 20: is a schematic of one BTRFA unit carrying 6 LEDs by way of example. The combination of the BRTFA unit and LEDs is viewed from below; the LEDs being directed towards and placed at proximity to the head. The meandered shape of the BTRFA unit is thus convenient to accommodate several LEDs or any other elements of the device. Particularly, it is useful if the shape of BTRFAs is accommodated in accordance with the LEDs positions to avoid the areas with the maximum red and NIR light intensity. For the best red/NIR light coverage, LEDs may be arranged around a head at as equal distance as possible. Examples of distances in between the various LEDs are provided in the figures in mm.

[53] Figures 21A-B: (A) shows a complete view ofthe Z-BTRFA ofFigure 21B with acoaxial connector structure according to Figure 22 and with simple looped antenna wire. (B) shows a further schematic view of the body tissue radio frequency applicator or antenna (BTRFA) according to the present invention with a Z-type of connection between the coaxial conductors and the central antenna wires. The antenna wires are shown only schematic and simplified as two loops, each loop having the length of about W2@f _c (half of the wavelength at the intended working frequency) unlike X-BTRFA and Y-BTRFA that have two times larger loop lengths of Xo@f _c .

[54] Figures 22A-B: (A) shows a detailed view of the Z-BTRFA with ends of the antenna wires and the central coaxial connector structure. (B) shows a detailed view (top view on the left side and bottom view on the right side) of the Z-BTRFA in a connection to PCB as an alternative embodiment to Figure 22A.

[55] Figures 23A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of Z-BTRFA surrounded by free space or air and operating at 915 MHz. (B) is a graph showing the power distribution of Z-BTRFA surrounded with free space or air.

[56] Figure 24: is a simulation showing the antenna gain of Z-BTRFA surrounded by free space or air at 0.915 GHz.

[57] Figure 25: is a schematic of the Z-BTRFA placed close to body tissue, for example positioned at 3 mm distance above the body tissue sample. Dimensions of the body tissue 132 x 105 x 40 mm are provided by way of example.

[58] Figures 26A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of Z-BTRFA placed close to body tissue. (B) is a graph showing the power distribution of Z-BTRFA placed close to body tissue.

[59] Figure 27: is a simulation of the SAR(lg) for Z-BTRFA placed close to body tissue at 0.915 GHz. [60] Figure 28: a schematic of a curved or bent BTRFA (either X-BTRFA or Y-BTRFA) above curved multi-layer tissue sample, such as a human head, showing from top to bottom with respective thickness: skin (5 mm); skull (6 mm); CSF (cerebrospinal fluid) (3 mm), and the brain grey matter (40 to 47 mm).

[61] Figures 29A-B: (A) is a graph of the Sn-parameter (scattering parameter or reflection: return loss - RL) of curved or bent X-BTRFA above a curved multi-layer tissue sample, such a human head. (B) is a graph of the Sl l-parameter (scattering parameter or reflection: return loss - RL) of curved or bent Y- BTRFA above a curved multi-layer tissue sample, such a human head.

[62] Figures 30A-B: (A) is a graph of the power distribution of curved X-BTRFA placed close to body tissue. (B) is a graph of the power distribution of curved X-BTRFA placed close to multi-layer body tissue.

[63] Figures 31A-B: (A) is a graph of the power distribution of curved Y-BTRFA placed close to body tissue. (B) is a graph of the power distribution of curved Y-BTRFA placed close to multi-layer body tissue.

[64] Figures 32A-B: (A) is a simulation of the SAR(lg) for curved or bent X-BTRFA placed close to body tissue at 0.915 GHz. (B) is a simulation of the SAR(lg) for curved or bent Y-BTRFA placed close to body tissue at 0.915 GHz.

[65] Figures 33A-B: are schematics of an exemplary arrangement of array of eight BTRFAs, two of each BTRFA unit being positioned on each lobe of the brain, namely frontal, parietal, occipital lobes and one BTRFA on each side covering each temporal lobe. (A) is a top view of the head. (B) is a top view of the head.

[66] Figures 34A-B: are simulations of the SAR (1g) obtained when using the arrangement of array of eight BTRFAs as shown in Figure 33. (A) is a semi-front view of the SAR simulation. (B) is a side view of the SAR simulation.

[67] Figures 35A-B: show (A) a schematic of a 3-in-l LED, and (B) the graph of the Relative Luminous Intensity vs angle of such 3-in-l LED.

[68] Figure 36: is a schematic showing an example of the synchronization of the electromagnetic signals 915 MHz with a repetition rate of 200 Hz and a duty cycle of 100% as delivered by BTRFA with RED/NIR signals (at the three wavelengths 660nm, 810nm and 1064nm) as delivered by LEDs with a repetition rate of 40Hz and a duty cycle of 12.5%. The frequency of the electromagnetic signals at 915 MHz has sinusoidal signal with 574875 periods within every 0.625 ms wide pulse.

[69] Figure 37: is a schematic showing an example of the synchronization of the electromagnetic signals 915 MHz with a repetition rate of 200 Hz and a duty cycle of 100% as delivered by BTRFA with RED/NIR signals (at the three wavelengths 660nm, 810nm and 1064nm) as delivered by LEDs with a repetition rate of 40Hz and a duty cycle of 12.5%. The frequency of the electromagnetic signals at 915 MHz has sinusoidal signal with 574875 periods within every 0.625 ms wide pulse.

[70] Figure 38: is a schematic showing an example of the synchronization of the electromagnetic signals 915 MHz with a repetition rate of 200 Hz and a duty cycle of 100% as delivered by BTRFA with RED/NIR signals (at the three wavelengths 660nm, 810nm and 1064nm) as delivered by LEDs with a repetition rate of 40Hz and a duty cycle of 12.5%. The frequency of the electromagnetic signals at 915 MHz has sinusoidal signal with 574875 periods within every 0.625 ms wide pulse.

[71] Figures 39A-C: is a similar schematic of the example of the combination of one BTRFA (60) unit carrying six LEDs (200) as shown in Figure 20, but also showing (5) the output amplifier; (11) the PCB for output amplifier and BTRFA; (12) the PCB for LED; (14) the Power supply and control lines; (15) the LED power lines; and (16) the RF signal coaxial cable. (A) is a view from below (the LEDs shining towards the body tissue), and (B) is a side view of the same combination. (C) is a closer look the (11) PCB output amplifier and BTRFA showing in more details (5) the output amplifier; (14) the Power supply and control lines; and (16) the RF signal coaxial cable

[72] Figures 40A-B: is a schematic of the medical head device as shown in Figure 33, but also showing the combinations of the array of BTRFA with the array of LEDs, each BTRFA carrying for example six LEDs, as well as (9) the central unit PCB; (10) the Power supply PCB; (11) the PCB for output amplifier and BTRFA; and (12) the PCB for LED. (A) is a side view of the medical device positioned on the head and (B) is a top view of the medical device positioned on the head.

[73] Figures 41A-B: are schematics of an exemplary arrangement of the arrays of combined units of BTRFAs and LEDs as shown in Figure 20. The simulation of RED/NIR light exposure on the head as shown (A) in a front view and (B) in a back view, clearly shows a homogeneous coverage of the RED/NIR light on the whole head.

[74] Figures 42A-C: correspond to different views of the schematics and RED/NIR simulations shown in Figure 41. (A) is a side view of the head; (B) is a top view of the head; (C) is a semi-side view of the head.

[75] Figure 43: is a block diagram of the entire electronic circuit of the medical head device according to the present invention with eight BTRFA, each of the BTRFA carrying six LEDs. (1) corresponds to RF generator (VCO - Voltage Controlled Oscillator); (2) corresponds to amplifiers; (3) corresponds to the Resistive RF power divider (1 to 2); (4) corresponds to the Resistive RF power divider (1 to 4); (5) corresponds to the Output amplifiers; 60 corresponds to BTRFA; (200) corresponds to LEDs (either single LEDs or 3-in-l CHIP LEDs); (8) corresponds to Controller; (9) corresponds to the Central unit PCB; (10) corresponds to the Power supply PCB; (11) corresponds to PCB for output amplifier and BTRFA; (12) corresponds to the PCB for LED; and (13) corresponds to the External Battery.

DETAILED DESCRIPTION OF PRFERRED EMBODIMENTS

[76] According to a first aspect, the present invention provides body tissue applicators (or antennas) 50 which are radiofrequency applicators specifically designed for application of an electromagnetic field or waves inwardly directly to human body tissue. These body tissue radiofrequency applicators 50 are referred hereinafter as BTRFA or BTRFAs when plural. [77] Body tissue radiofrequency applicators 50 according to the present invention are configured for emitting a pulsed RF electromagnetic signal to an adjacent human tissue at a frequency in a range of 500 MHz to 3000 MHz and at a repetition rate in a range of from 10 to 400 Hz. BTRFA 50 are thus configured for emitting a pulsed RF electromagnetic signal to an adjacent human tissue at a single or narrowband working frequency ranging between 500 MHz and 3000 MHz.

[78] The body tissue radiofrequency applicator 50 comprises a wire structure 60 for being positioned adjacent to or in proximity to said human tissue. The wire structure 60 has an overall butterfly or bow tie shape and is divided into an arrangement of at least two sections or two halves 70, each of these sections or halves 70 comprising a wire 80 having a first and a second end. Said arrangement of at least two sections or two halves 70 of said applicator 50 may be symmetrical or asymmetrical. Preferably, said at least two sections or two halves 70 of said applicator 50 are symmetrical. The wire 80 in each of these at least two sections or halves 70 is meandered or forms one or preferably several wire loops, and the wire 80 in each of these at least two sections or halves 70 is connected to a central connector structure 90, which can be a central coaxial connector structure 90, having an first conductor structure 100 or inner coaxial conductor 100 and a second conductor structure 110 or outer coaxial conductor 110, a first end of each of these wires 80 being connected to said inner coaxial or first conductor structure 100 and a second end of each of these wires 80 being connected to said outer coaxial or second conductor structure 110.

[79] In a first preferred embodiment of the present invention, the ends of the wires 80 being connected to the inner coaxial or first conductor structure 100 extend unbroken and preferably along a straight line across the central connector structure 90 from one half 70 to the other half 70. The ends of the wires 80 being connected to the outer coaxial or second conductor structure 110 do not extend unbroken across the central connector structure 90 from one half 70 to the other half 70 but preferably form an interrupted straight line.

[80] According to this preferred embodiment, the ends of the wires 80 connected to the central connector structure 90, when looking in top view onto said central connector structure 90, are fully crisscrossed in the form of a X or forming a X-shaped structure 130 as shown in Figures 1 and 2. Such bow-tie complex butterfly shape BTRFA having X-type central connection are referred hereinafter as X-BTRFA 130.

[81] According to a second preferred embodiment, the ends of the wires 80 are connected to the inner coaxial or first conductor structure 100 extend unbroken along a Y -shaped line from one half 70 to the other half 70. The ends of the wires 80 being connected to the outer coaxial or second conductor structure 110 thereby form a Y-shaped line that is interrupted by the central connector structure 90. The ends of the wires 80 connected to the central connector structure 90, when looking in top view onto said central connector structure 90, are half crisscrossed with each crisscrossed half being Y-shaped. BTRFA according to this embodiment is referred to herein below as “Y-BTRFA” 120. The Y-BTRFA 120 according to the present invention is shown in Figures 8 and 9. [82] According to a third preferred embodiment, the ends of the wire 80 of each of these sections or halves 70 when connecting to the central connector structure 90 forms a structure as shown in Figures 21 and 22, wherein the ends of the wire of one half 70 connect to the inner coaxial or first conductor structure 100 and the ends of the wire of the other half 70 connect to the outer coaxial or second conductor structure 110. BTRFA according to this aspect is referred to herein below as “Z-BTRFA” 140. The ends of the wires 80 being connected to the outer coaxial or second conductor structure 110 thereby form a V-shaped line and the ends of the wires 80 being connected to the inner coaxial or first conductor structure 100 thereby form a V-shaped line. Other than in the Y-BTRFA 120, in the Z-BTRFA 140 both ends of the wire 80 in one half of the wire structure 60 are connected to the inner coaxial or first structure 100 whereas both ends of the wire 80 in the other half of the wire structure are connected to the outer coaxial or second structure 110. BTRFA according to this embodiment is referred to herein below as “Z-BTRFA” 140.

[83] Figure 2 IB shows a further schematic view of the body tissue radio frequency applicator (BTRFA) according to the present invention with a Z-type of connection between the coaxial conductors and the central antenna wires. The wire structure 60 with the applicator wires 80 are shown only schematic and simplified as two loops. Figures 21B also shows in a schematic way a voltage source 150 and the coaxial connector structure 90. It also shows the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 of the wire structure 60 that are connected to the coaxial connector structure 90. Figure 22A shows a detailed view of the Z-BTRFA 140 of Figure 21 A with the ends A 1 , A2, B 1 and B2 of the antenna wires and the central coaxial connector structure 90. One can further see the inner coaxial conductor 100, the outer coaxial conductor 110, an insulator 170 between these, and solder or connection points 160.

[84] Figure 22B shows a detailed view (top view on the left side and bottom view on the right side) of the Z-BTRFA 140 in an alternative embodiment to Figure 2 IB in a connection to PCB. One can see that the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 are connected to either an RF input microstrip line 180 or to a top GND layer 190 at the connection points 160. Also shown is a bottom GND layer 210 and a dielectric substrate 220. Figure 21A shows a complete view of the Z-BTRFA 140 of Figure 2 IB with a coaxial connector structure 90 according to Figure 22A or according to Figure 22B and with simple looped antenna wire.

[85] Body tissue radiofrequency applicators or antennas 50 according to the present invention are preferably configured for emitting a pulsed electromagnetic signal to an adjacent human tissue at a single working frequency or narrow frequency band in a range from 800 to 1500 MHz, or 900 to 1000 MHz and most preferably around 900 MHz, 915 MHz, or 918 MHz. The electromagnetic energy or signal is preferably pulsed with a rate of repetition comprised within the range of from 10 to 300 Hz, or from 20 to 270 Hz, or from 30 to 250 Hz, or from 40 to 240 Hz, or from 100 to 220 Hz, preferably at or around 40 Hz, 100 Hz, or 200 Hz. The electromagnetic signal is thus pulsed every 4 to 5 milliseconds. Most preferred electromagnetic energy signal has a frequency of 915 MHz and is pulsed with a cycle of repetition around 200 Hz.

[86] The major function of the BTRFA, and an important aspect of the invention, is to efficiently deliver RF energy into a body tissue. “Efficiently deliver” includes several tasks besides power efficiency. It is desirable to have RF energy spread evenly over sufficiently large area to cover, for example, entire surface of a human head with reasonable small number of the BTRFAs. BTRFA should also be able to adjust its shape to accommodate the curvature of a human head without compromising its power efficiency. It is also desirable to minimize the RF energy emission into a free space for easier fulfilling all existing electromagnetic compatibility (EMC) requirements and regulations. In addition, since the medical device should be suitable for various human head sizes and to target different types of neurodegenerative diseases, it is advantageous to provide several versions and shapes of BTFRAs to obtain specific coverage area and depth of exposure to the stimulatory signals.

[87] Fig. IB and Fig. 8B show two versions of BTRFA. Each version consists of two conductive loops. The length of each of the conductive loops is preferably approximately A (at f _c ), which is the free space wavelength of the RF signal delivered to body tissue, at its operating central frequency (f _c ). For f _c = 915 MHz, the length of each conductive loop would be around 328 mm.

[88] Conductive loops can be made of a metal wire, preferably consisting of some low loss metal, like copper, usually with round (circular) cross section. The diameter of the wire could preferably be between 0.1 mm and 1 mm. Wire diameters smaller than 0.1 mm could increase RF signal losses and therefore decrease the overall efficiency of the device. Moreover, smaller diameters than 0. 1 mm could be sensitive to mechanical deformations unless otherwise supported. Larger wire diameters than 1 mm could be impractical for fabrication and meandering the loop into optimal form. Also, increasing the wire diameter above 1 mm would not significantly affect (lower) the RF losses nor will be beneficial in some other way (for the projected power levels for current device application). Taking all above into consideration, a preferred wire diameter is between 0.5 mm and 0.9 mm. The wire cross section could be different than round, for example rectangular (0.1 mm * 0.8 mm), or square (0.5 mm * 0.5 mm). At frequencies below 3 GHz, these rectangular cross sections would be equivalent to the circular cross sections of the same area size.

[89] Conductive loops may also be made of printed transmission lines, which are printed tin metal strips with thicknesses from 0.01 mm (and above) and the widths of 0.5 mm (and above), printed on thin dielectric substrate that provides mechanical support. Using such printed transmission lines, the BTRFA can be realized on flexy PCBs and integrated with rigid PCBs containing active electronic components of the device.

[90] Conductive loops have connecting points marked in Fig. IB and 8B as Al and A2, for the first loop, and Bl and B2, for the second loop. [91] RF transmission line 180 connects the conductive loops with a generator of RF signal 150. RF transmission line 180 could be either coaxial cable, as illustrated in Fig. IB and Fig. 8B, or printed transmission line (microstrip or some other type) as illustrated in Fig. 2B and Fig. 9B.

[92] The connective points Al, A2, Bl, B2 can be connected to the RF feeding transmission line 150 in two different ways as illustrated in Fig. IB and Fig. 8B (as well as in Fig. 2 and Fig. 9).

[93] The first connecting way, shown in Fig. IB, 2A, and 2B, assumes connection between points A2 and B 1 that are also connected to the central conductor of the coaxial cable/transmission line 100 and further to the output of the RF generator 150. Also, points Al and B2 are both connected to the outer conductor 110 of the coaxial cable and further connected to the electrical ground, which is also the reference ground for RF generator 150. This crossover connection between points Al to B2 and A2 to Bl in Fig. IB and 2A resembles the shape of letter X and therefore this type of BTRFA is named X-type BTRFA 130.

[94] The second connecting way, shown in Fig. 8B, 9A and 9B, assumes connection between points Al and Bl that are also connected to the central conductor 100 of the coaxial cable/transmission line 90 and further to the output of the RF generator 150. Also, points A2 and B2 are both connected to the outer conductor 110 of the coaxial cable 90 and further connected to the electrical ground, which is also the reference ground for RF generator 150. This connection between points Al to Bl and A2 to B2 in practical realization of BTRFA connection to coaxial cable resembles the shape of letter Y and therefore this type of BTRFA is named Y-type BTRFA 120.

[95] The loop sizes of Xo = 328 mm (at fc=915MHz) of X-BTRFA 130 and Y-BTRFA 120 are relatively large. BTRFA consisting of two simple, elliptical, non-meandered loops would have a relatively large physical size. However, such a large area would be unequally covered with RF signal as illustrated.

[96] Figure 21 shows a third version of BTRFA. It comprises two conductive loops. The length of each of the conductive loops is approximately A/2 (at f _c ), which at f _c = 915 MHz, the length of each conductive loop would be around 160 mm. This version requires connection between points Al and A2 that are also connected to the central conductor 100 of the coaxial cable/transmission line 90 and further to the output of the RF generator 150. Points B2 and B2 are both connected to the outer conductor 110 of the coaxial cable 90 and further connected to the electrical ground, which is also the reference ground for RF generator 150. This configuration is the same as the configuration of bow-tie antennas. However, with only slight modifications of the loop lengths, this antenna design can operate in proximity to body tissue having most of the RF energy delivered to the body tissue and only a small portion radiated in a free space, which is for body tissue applicators undesired feature that should be suppressed.

[97] In addition to being suitable for providing an efficient and reliable zone of electromagnetic exposure, they also provide a reliable, reproducible, and efficient specific absorption rate (SAR) within the treated or targeted human brain tissue. SAR is the measure of the rate of energy which is absorbed per unit of mass of a human body when exposed to a radiofrequency electromagnetic field and is expressed in watts per kilogram (W/kg). Preferred SAR values according to the present invention range from 0.5 to 3 W/kg. Most preferably SAR values are from 1 to 2 W/kg or from 1.5 to 2 W/kg such as 1.5 W/kg or about 1.5 W/kg or such as 2 W/kg or about 2 W/kg.

[98] Body tissue radiofrequency applicators or antennas according to the present invention may have variable shapes and sizes adaptable to any part of human body tissues for which treatment is desired. They may have different sizes, depending on their positioning onto the head and within the medical head device. For example, sizes may range from (20 mm to 300 mm) x (20 mm to 300 mm). Such sizes may be relatively large ranging from (80 mm to 200 mm) x (100 mm to 300 mm) such as 100 x 200 mm or preferably 140 x 160 mm, or may be small ranging from (20 mm to 60 mm) x (70 mm to 120 mm) such as 30 mm x 90 mm or preferably 40 mm x 80 mm. BTRFA of smaller sizes may be positioned for example on the top of the head from ear to ear, thereby covering the temporal and parietal lobes of a brain subject.

[99] The largest dimension or length of the BTRFA is determined by the operating frequency which is approximately half wavelength including the influence of the adjacent body tissue. Therefore, when operating at around 915 MHz, the wire or PCB length of the RF applicator according to the present invention may be between 200 and 800 mm, preferably around 600 mm. Preferably, the BTRFA according to the present invention operating at a 915 MHz frequency band has a total wire or PCB length in a range of 500 to 700 mm or 550 to 650 mm with each halves having a wire or PCB length of half of that, i.e., around 300 mm.

[100] BTRFAs according to the above preferred embodiments, X-BTRFAs 130, Y-BTRFAs 120 or Z-BTRFAs 140 may have different efficiency and Specific Absorption Rate (SAR) within the human body tissue.

[101] According to the first embodiment, the BTRFA according to the present invention may have central connections having a “X” connection shape between the conductors and the central antenna wires.

[102] As shown in Figure IB, the X-BTRFA corresponds to the body tissue radio frequency applicator 50 or antenna (BTRFA) with an X-type of crisscrossed connection between the coaxial conductors and the central antenna wires. The wire structure 60 with the applicator wires 80 are shown only schematic and simplified as two loops. Figure IB also shows in a schematic way a voltage source 150 and the coaxial connector structure 90. It also shows the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 of the wire structure 60 that are connected to the coaxial connector structure 90. Figure 2A shows a detailed view of the X-BTRFA 130 of Figure 2B with the ends Al, A2, B 1 and B2 of the antenna wires and the central coaxial connector structure 90. One can further see the inner coaxial conductor 100, the outer coaxial conductor 110, an insulator 170 between these, and solder or connection points 160.

[103] Figure 2B shows a detailed view (top view on the left side and bottom view on the right side) of the X-BTRFA 130 in a connection to PCB, and thus in an alternative embodiment to Figure 2A. One can see that the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 are connected to either an RF input microstrip line 180 or to a top GND layer 190 at the connection points 160. Also shown is a bottom GND layer 210 and a dielectric substrate 220. Figure 1A shows a complete view of the X- BTRFA 130 of Figure IB with a coaxial connector structure 90 according to Figure 2A or according to Figure 2B and with meandered antenna wire.

[104] For X-BTRFA 130 the total wire length in each branch should be about two times larger than in the case of Z-BTRFA, or approximately one wavelength (at the desired operating frequency) (~ 330 mm at 915 MHz). The resonant frequency of such antenna can be changed if the BTRFA is placed close to a large dielectric object having high relative dielectric constant (relative dielectric permittivity), which is for a body tissue typically between 45 and 55.

[105] When the X-BTRFA surrounded by free space (air) and operating at 915 MHz, Sn-parameter (scattering parameter or reflection: return loss - RL) graph in Figure 3A showed a huge reflection in almost the entire observed frequency range with quite poor matching at 1186 MHz with RL of -2.6865 dB only, while the reflection at 915 MHz was almost total (-0.10368 dB).

[106] Furthermore, the power distribution graph of X-BTRFA surrounded by free space (Figure 3B) showed that at 915 MHz (marked with a vertical line) X-BTRFA accepted only 2.36% (0.011795/0.5) of total available power (0.5 W), while more than 97.5% (0.488204/0.5) is reflected back to a RF generator. The total dielectric loss was negligible (3.3196xl0 ^-5 /0.5). The metal loss was also small (0.0015/0.5= 0.3%) as well as the radiated power of 2% (0.01032/0.5).

[107] When surrounded by free space, the X-BTRFA was a bi-directional antenna with two major beams facing opposite direction parallel to the applicator plane. X-BTRFA provided maximum directivity in both beams of about 6 dBi, while due to huge reflection at 915 MHz, the maximum realized gain is only -10.8 dBi (Figure 4).

[108] Advantageously, when the X-BTRFA was placed in proximity of a large sample of body tissue, as shown in Figure 5 (with exemplary dimensions of body tissue of 132x105x40 mm and for example at a distance of 3 mm between the surface of the body tissue and the X-BTRFA), the resonant frequency shifted down to 915 MHz with a satisfying RL value (-12.424 dB as shown in Figure 6A). The exact resonant frequency can be easily finetuned as it also depends on the distance between the X-BTRFA and the surface of the tissue.

[109] In addition, as shown in Figure 6B, at 915 MHz (marked with a vertical line), X-BTRFA placed close to body tissue accepted 94.27% (0.471394/0.5) of total available power (0.5 W), while only about 5.7% (0.02861/0.5) was reflected back to the RF generator. Almost 92.1% (0.46054/0.5) of the power accepted by X-BTRFA was delivered to the body tissue. The metal loss was about 1.358% (0.00679/0.5), while about 0.8127% (0.004064/.5) was radiated to the free space.

[110] X-BTRFA exhibited a specific shape of the body tissue that accepted the SAR larger than 2 W/kg (Figure 7). In addition, the maximum SAR for X-BTRFA in this setup was 10.8 W/kg, which meant that the RF energy was widely and evenly spread by X-BTRFA within the exposed area of the human body tissue.

[111] According to the second embodiment, the BTRFA according to the present invention may have central connections having a “Y” connection shape between the conductors and the central antenna wires as shown in Figures 8 and 9. Such bow-tie complex meandered butterfly shape BTRFA having Y-type central connection are referred hereinafter as Y-BTRFA 120.

[112] As shown in Figure 8B, the body tissue radio frequency applicator or antenna (BTRFA) according to the present invention with a Y-type of crisscrossed connection between the coaxial conductors and the central antenna wires. The wire structure 60 with the antenna wires 80 are shown only schematic and simplified as two loops. Figures 8B also shows in a schematic way a voltage source 150 and the coaxial connector structure 90. It also shows the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 of the wire structure 60 that are connected to the coaxial connector structure 90. Figure 9 shows a detailed view of the Y-BTRFA 120 of Figure 8 with the ends Al, A2, Bl and B2 of the applicator wires and the central coaxial connector structure 90. One can further see the inner coaxial conductor 100, the outer coaxial conductor 110, an insulator 170 between these, and solder or connection points 160.

[113] Figure 9B shows a detailed view (top view on the left side and bottom view on the right side) of the Y -BTRFA 120 in an alternative embodiment to Figure 9A in a connection to PCB . One can see that the end points Al, A2, Bl and B2 of the two wires 80 in each of the two halves 70 are connected to either an RF input microstrip line 180 or to a top GND layer 190 at the connection points 160. Also shown is a bottom GND layer 210 and a dielectric substrate 220. Figure 8A shows a complete view of the Y-BTRFA 120 of Figure 8B with a coaxial connector structure 90 according to Figure 9A or according to Figure 9B and with meandered antenna wire.

[114] When surrounded by free space (air), Y-BTRFA 120 operating at 915 MHz provided a very large reflection at 915 MHz (-1.3756 dB) and moderate matching at 1103 MHz with RL of -8.0303 dB (Figure 10A).

[115] Also, as shown in Figure 10B, at 915 MHz (marked with a vertical line) Y-BTRFA 120 accepted only 27. 15% (0. 1357405/0.5) of total available power (0.5 W), while more than 72% (0.364/0.5) is reflected back to an RF generator. The total dielectric loss was negligible (3.1141xl0 ^-5 /0.5). The metal loss was also small (0.001313/0.5= 0.26%) while the radiated power is about 27% (0.13559/0.5).

[116] Y-BTRFA 120 surrounded by free space acted as a bi-directional antenna with two major beams facing opposite direction normal to the antenna plane. With a perfect match such antenna achieved maximum gain in both beams of about 2.48 dBi, while due to huge reflection at 915 MHz, the maximum realized gain was only -3.32 dBi (Figure 11).

[117] When Y-BTRFA 120 was placed in proximity of a large sample of body tissue (Figure 12), the resonant frequency shifted down to 898 MHz with much better RL value (-18 dB as shown in Figure 13 A) than in the case of Y-BTRFA 120 surrounded by free space as shown in Figure 10A. The exact resonant frequency also depends on the distance between the X-BTRFA 130 and the surface of the tissue and may be easily adapted.

[118] The graph of power distribution at 915 MHz (marked with a vertical line) at Figure 13B, showed that Y-BTRFA 120 placed close to body tissue accepted 93% of total available power (0.5 W), while only about 7% (0.03494/0.5) was reflected back to a RF generator. Almost 86.3% (0.4316/0.5) of the power accepted by Y-BTRFA 120 is delivered to the body tissue. The metal loss is about 0.6% (0.003266/0.5), while about 6. 12% (0.0306/.5) is radiated to the free space. Figure 14B showed the shape of the body tissue that accepted the SAR larger than 2 W/kg. The maximum SAR for Y-BTRFA 120 in this setup was 18.9 W/kg.

[119] X-BTRFA 130 and Y-BTRFA 120 according to the above embodiments of the present invention have high performance or efficiency when placed adjacent to human body tissue, which are dielectric objects having large dielectric constant with specific conductivity. In particular, BTRFAs having either X or Y types of connections have been shown to deliver between 85% and 92% of radiofrequency energy available from the generator to the adjacent body tissue. In addition, BTRFA can deliver a large amount of radiofrequency energy to a large area and volume of the body tissue directly exposed to the BTRFAs, with a high SAR value up to around 10 W/kg or up to 18 W/kg.

[120] Topologically, X-BTRFA 130 has central symmetry while Y-BTRFA 120 has axial symmetry.

[121] X-BTRFA 130 delivered radiofrequency energy within a large volume of a body tissue with maximum SAR value at four spots symmetrically placed around the connector. The tissue closest to connector received relatively low SAR value. X-BTRFA 130 achieved a SAR value up to 10.8 W/kg. X- BTRFA 130 radiated only about 0.8% of radiofrequency energy into a free space. This is a significant characteristic that could eliminate additional shielding for achieving the required EMC standards.

[122] Y-BTRFA 120 also delivered radiofrequency energy within a large volume of a body tissue similar to the X-BTRFA 130, but with maximum SAR value close to connector. Y-BTRFA 120 achieved a SAR value up to 18.9 W/kg. Y-BTRFA 120 radiated about 6.2% of radiofrequency energy into a free space which is also very satisfying.

[123] Both types of applicators according to the present invention, X-BTRFA 130 or Y-BTRFA 120 may be wired or printed on a PCB. BTRFA may be realized as flexible PCB integrated with PCB (optionally also carrying LEDs 200 and active RF components) or like old fashion wired antenna, sufficiently flexible and attached to a PCB. The PCB may be made on anything which can be easily curved or bent, such as any casting foil. Preferred BTRFA according to the present invention are printed on flexible curved PCB.

[124] When X-BTRFA 130 or Y-BTRFA 120 are wired antennas or applicators, they may be made for example of metal such as copper wire or any other suitable antenna wire. The metal must be sufficiently flexible for generating applicators having complex bowtie butterfly shapes according to the present invention.

[125] Optimal thickness of wires may easily be determined by a skilled person in the art. For practical mechanical realizations the thinner is better, but it increases metal losses and therefore decreases the overall efficiency. Wired BTRFA preferably have a wire diameter in a range from 0.1 mm and 1 mm, or between 0.2 mm and 1 mm, or between 0.3 mm to 1 mm, preferably at or around 0.5 mm or at or 0.6 mm. BTRFAs with a very thin wires with dimensions 0.1 mm x 0.2 mm were also made and tested. Besides a slight increase of losses in metal, the reduction of the wire thickness provided similar characteristics of the BTRFA, thereby showing that BTRFA provided the desired characteristics even with a very thin wire or printed transmission line as long as necessary mechanical rigidity was maintained.

[126] Alternatively, BTRFA may be made as printed antenna consisting of thin metal strips printed on a thin dielectric substrate. In particular, both Y and X versions of BTRFA according to the present invention may be realized as a printed structure on very thin and flexible dielectric substrate. Optimal thickness or widths of the printed lines can be easily determined by a skilled person in the art. The metal thickness is reduced to 0.035 mm (or even to 0.0175 or even lower if the appropriate flexy PCB technology is used, while the dielectric thickness is 0.1 mm or even thinner (Figure 15A). Printed BTRFA have identical dimensions and shapes as that of wire BTRFA and described above. Also, printed BTRFA were placed at the same distance from body tissue sample with side with printed metal facing toward the tissue. The connections between the coaxial cable and printed PCB metal trace for the X connection (Figure 15B, left side) and the Y connection (Figure 15B, right side).

[127] A comparison of printed BTRFA has been conducted and simulation Sn results obtained with printed X-BTRFA and printed Y-BTRFA (Figures 16A-B). Furthermore, a power distribution comparison was conducted between printed X-BTRFA 130 and printed Y-BTRFA 120 (Figures 17A-B) and showed similar results as obtained for corresponding wire models.

[128] Printed X-BTRFA 130 accepted 92.4% (0.46199/0.5) of total available power (0.5 W), while 7.6% (0.038/0.5) was reflected back to the RF generator. About 90.132% of the power accepted by X-BTRFA 130 is delivered to the body tissue (Figures 17A). The metal loss increased to 1.575% from the corresponding wire model 1.358%, which was expected due to significantly thinner printed metal conductors. The radiated power was slightly reduced to 0.694% from the previous 0.8127%.

[129] Printed Y-BTRFA 120 accepted 90.36% (0.4518/0.5) of total available power (0.5 W), while 9.6% (0.048/0.5) was reflected back to the RF generator. About 84.439% of the power accepted by Y-BTRFA 120 is delivered to the body tissue (Figures 17B). The metal loss increased to 1.15% from the previous 0.64%, which was expected due to significantly thinner printed metal elements. The radiated power was slightly reduced to 4.8% from the previous 5.4% (0.027/.5). [130] As described above, BTRFA according to the present invention may have central connections having between the conductors and the central antenna wires as shown in Figures 21 and 22. Such bow-tie butterfly shape BTRFA having two time smaller loop lengths (W2@f _c - half of the wavelength at the intended working frequency), unlike X-BTRFA and Y-BTRFA that have two times larger loop lengths of Xo@f _c and central connection to the input transmission line or coaxial cable are referred hereinafter as Z- BTRFA.

[131] As shown in Figure 21B, the body tissue radio frequency applicator (BTRFA) with a Z-type of connection between the coaxial conductors and the central antenna wires. The wire structure 60 with the applicator wires 80 are shown only schematic and simplified as two loops. Figures 2 IB also shows in a schematic way a voltage source 150 and the coaxial connector structure 90. It also shows the end points Al, A2, Bl and B2 of the wire 80 forming the wire structure 60 that are connected to the coaxial connector structure 90. Figure 22A shows a detailed view of the Z-BTRFA 140 of Figure 21A with the ends Al, A2, Bl and B2 of the applicator wires 80 and the central coaxial connector structure 90. One can further see the inner coaxial conductor 100, the outer coaxial conductor 110, an insulator 170 between these, and solder or connection points 160.

[132] Figure 22B shows a detailed view (top view on the left side and bottom view on the right side) of the Z-BTRFA 140 in an alternative embodiment to Figure 21A in a PCB connection. One can see that the end points Al, A2 are connected to an RF input microstrip line 180, while the end points Bl and B2 are connected to a top GND layer 190 at the connection points 160. Also shown is a bottom GND layer 210 and a dielectric substrate 220. Figure 21A shows a complete view of the Z-BTRFA 140 of Figure 2 IB with a coaxial connector structure 90 according to Figure 22, with antenna wire in a shape of a simple (nonmeandered) loop.

[133] When surrounded by free space (air), Z-BTRFA 140 operating at 915 MHz provided moderate reflection at 915 MHz (-2.89 dB) and a very good matching (low reflection) at 1083.8 MHz with RL of - 16.888 dB (Figure 23 A).

[134] Also, as shown in Figure 23B, at 915 MHz (marked with a vertical line) Z-BTRFA 140 surrounded by free space (air) accepted about 48.7% (0.2434/0.5) of total available power (0.5 W), while about 51.2% (0.2435/0.5) is reflected back to an RF generator. The total dielectric loss was negligible since the only dielectric within the analyzed model was isolator within the coaxial cable that was made of Teflon (PTFE - Polytetrafluoroethylene). The metal loss was also small (0.002117/0.5= 0.42%) while the radiated power is about 48.7% (0.2435/0.5).

[135] Z-BTRFA 140 surrounded by free space acted as an omni-directional antenna with a doughnut shaped radiation pattern. With a perfect match such antenna could achieve maximum omnidirectional gain of about 2 dBi, while due to -3dB reflection at 915 MHz, the maximum realized gain was reduced to -1 dBi (Figure 24). [136] When Z-BTRFA 140 was placed in proximity of a large sample of body tissue (Figure 25), the resonant frequency shifted down to 915 MHz with much better RL value (-14.929 dB as shown in Figure 26A) than in the case of Z-BTRFA 140 surrounded by free space as shown in Figure 21 A. The exact resonant frequency also depends on the distance between the Z-BTRFA 140 and the surface of the tissue and may be easily adapted.

[137] The graph of power distribution at 915 MHz (marked with a vertical line) at Figure 26B, showed that Z-BTRFA 140 placed close to body tissue accepted 96.78% (0.48392/0.5) of total available power (0.5 W), while only about 3.2% (0.016/0.5) was reflected back to a RF generator. Almost 90.49% (0.452/0.5) of the power accepted by Z-BTRFA 140 is delivered to the body tissue. The metal loss is about 0.6% (0.003018/0.5), while about 5.75% (0.02876/.5) is radiated to the free space. Figure 27 showed the shape of the body tissue that accepted the SAR larger than 2 W/kg. The maximum SAR for Z-BTRFA 140 in this setup was 23.7 W/kg.

[138] Topologically, Z-BTRFA 140 has axial symmetry.

[139] When compared to the X-BTRFA 130 and Y-BTRFA 120, Z-BTRFA 140 delivered radiofrequency energy within a smaller volume of a body tissue but with the highest maximum SAR value up to 23.7 W/kg, close to connector. Z-BTRFA 140 radiated about 5.75% of radiofrequency energy into a free space which is comparable to the amount radiated by Y-BTRFA 120 (6.12%), but much larger than in case of X-BTRFA 130 (0.8%).

[140] Considering all the presented characteristics of the X-BTRFA 130, Y-BTRFA 120, and Z-BTRFA 140, each of the showcased types can find its application in devices used for efficient and controlled delivery of electromagnetic wave energy to various bodily tissues. X-BTRFA 130 provides a uniform distribution over a broader tissue volume with very low radiation losses, meaning the smallest portion of electromagnetic energy that is radiated into the surrounding space. Y-BTRFA 120 provides a greater depth of penetration of electromagnetic waves into living tissue, while maintaining an unchanged coverage width and slightly higher levels of SAR. Z-BTRFA 140 may achieve a maximum depth of penetration with the highest SAR value in significantly smaller volume and surface area of tissue.

[141] Applicators, namely Y-BTRFA 120, X-BTRFA 130 or Z-BTRFA 140 according to the present invention, being either wired or PCB, may be flat or curved to adapt to the form of the targeted body tissue, such as for example the head or skull of the patient. The total length of the wire is extended due to replacing the homogeneous tissue model with multi-layer model (with various dielectric constant and conductivity for each layer). By way of example, Figure 28A shows a curved BTRFA model above a curved multi-layer tissue sample such a human head.

[142] Power distribution comparisons between X-BTRFA 130 (Figure 30A) and Y-BTRFA 120 (Figure 3 IB) placed close to multi-layer body tissue showed that at 915 MHz (marked with a vertical line) X- BTRFA 130 placed close to body tissue accepts 99.4% (0.497/0.5) of total available power (0.5 W), while about 0.6% (0.00299/0.5) was reflected back to an RF generator. Almost 96.2% (0.481/0.5) of the power accepted by X-BTRFA 130 was delivered to the body tissue. The metal loss is about 1.14% (0.005726/0.5), while about 2% (0.01/.5) was radiated to the free space. At 915 MHz (marked with a vertical line in Figure 31A) Y-BTRFA 120 placed close to body tissue accepts 96.4% (0.482/0.5) of total available power (0.5 W), while about 3.4% (0.017/0.5) was reflected back to an RF generator. Almost 89.1% (0.445/0.5) of the power accepted by Y-BTRFA 120 was delivered to the body tissue. The metal loss was about 0.726% (0.00363/0.5), while about 6.56% (0.0328/.5) was radiated to the free space. Both BTRFA according to the present invention thus provided excellent efficiency with 96.2% and 89.1% of RF energy were delivered to body tissue respectively for the X-BTRFA 130 and the Y-BTRFA 120.

[143] Power distribution across the various tissue layers comprising the head was also tested using X- BTRFA 130 and Y-BTRFA 120. Figure 30B showed that of total available power (0.5 W) at 915 MHz (marked with a vertical line) X-BTRFA 130 delivers about: 60% (0.300/0.5) to Brain, 25% (0.125/0.5) to Skin, 7.3% (0.03655/0.5) to CSF, and 3.6% (0.0186/0.5) to Bone/Skull. Figure 3 IB showed that of total available power (0.5 W) at 915 MHz (marked with a vertical line) Y-BTRFA 120 delivers about: 60% (0.29/0.5) to Brain, 18.778% (0.0938/0.5) to Skin, 9.46% (0.0473/0.5) to CSF, and 2.5% (0.0125/0.5) to Bone/Skull.

[144] Figures 30B and 3 IB demonstrated an additional interesting fact about the power distribution at BTRFA second resonance (1.8 GHz). It can be seen almost equal efficiency in power delivering to dielectric materials (body tissue) at 915 MHz and at 1.8 GHz. However, at 1.8 GHz RF power delivered to the skin increases, while brain layer accepted about 39% to 42% which is 10% to 15% drop related to percentage at 915 MHz. This result is in accordance with general characteristics of RF waves and inverse proportionality of penetration depth relative to frequency. This clearly showed that BTRFA according to the present invention provided superior characteristics at working frequencies around 915 MHz.

[145] SAR distributions have been analyzed for X-BTRFA 130 and Y-BTRFA 120 operating at 915 MHz with limited SAR values of 1 W/kg, 2 W/kg, 2.5W/kg, 5 W/kg, with a generator having a power of 1 W and placed at 3 mm of the head surface.

[146] Results for SAR values of 1 W/kg and 2 W/kg showed that X-BTRFA 130 provided more spread and scattered SAR distribution, while Y-BTRFA 120 gives more centered SAR distribution. For SAR values greater than 5 W/kg, X-BTRFA 130 provided a few small hotspots that are spread away from the center, while Y-BTRFA 120 provided significantly larger volume beneath the center of the applicator. The maximum SAR (1g) value for X-BTRFA 130 is 5.89 W/kg and for Y-BTRFA 120 is 8.6 W/kg (data not shown), which means that X-BTRFA 130 distributed RF energy more evenly with smaller and less intense. SAR values were obtained only during pulse duration; the total energy delivered would be reduced depending on the repetition rate of the signal. [147] Such distinctive characteristics provided more flexibility since both applicators could be used separately and in combination, thereby allowing to obtain specific and desired SAR distributions to a specific area of the treated human tissue. In particular, both X-BTRFA 130 and Y-BTRFA 120 may be used in combination within the same medical device, such as a transcranial medical device in order to adapt the radiofrequency exposure and SAR to specific parts of the brain.

[148] The operating frequency of such antenna depends on the antenna size which is related to the total wire length in each of two antenna branches. For Y-BTRFA 120 the total wire length as well as the overall wire shape is identical as for X-BTRFA 130, which gives wire length in each branch of approximately one wavelength (at the desired operating frequency) which is about 320 mm at 915 MHz. The resonant frequency of such antenna can be changed if antenna is placed close to a large dielectric object having high relative dielectric constant (relative dielectric permittivity), which is a body tissue typically between 45 and 55.

[149] According to a second aspect, the present invention relates to the use of body tissue radiofrequency applicators (50) described above for direct administration of an electromagnetic field to a targeted human tissue, as well as a medical comprising above described BTRFA, and a method of directly administering an electromagnetic field to a targeted human tissue, comprising positioning BTRFA adjacent or in direct contact to the human tissue, thereby allowing direct administration of said electromagnetic waves. The present invention also relates to a method of directly administering an electromagnetic field or signal to human body tissue comprising BTRFA as described above adjacent or in direct contact to the human tissue and allowing direct administration of said electromagnetic waves.

[150] Targeted human tissues which may be treated by or exposed to such electromagnetic signal may include any parts of the human body, such as for example and without any limitations, the human head or skull, the frontal part and/or the temporal parts, and/or the occipital part of the head, the neck, the abdomen of a human body. Preferred human body tissues comprise the human head, optionally the neck and possibly abdomen. Most preferred human body tissues comprise the human head.

[151] According to a preferred aspect, the present invention is directed to body tissue radiofrequency applicators (50) as described above for use in a method of stabilizing and/or reversing the symptoms of a neurodegenerative disease comprising placing the body tissue radiofrequency applicators (50) at proximity to the human head of a subject in need thereof and allowing direct transcranial administration of said electromagnetic waves or field to the head of said subject. The present invention is also directed to a transcranial medical device comprising the body tissue radiofrequency applicators (50) as described above.

[152] According to this preferred aspect, the whole head and brain, or specific parts of the head, such as the frontal lobe, and/or the parietal lobe, and/or the occipital lobe, and/or the temporal lobe may be thus transcranially exposed to the electromagnetic field or signal at frequency ranging from 500 to 3000 MHz, or preferably from 800 to 1500 MHz, more preferably from 900 to 1000 MHz. The preferred frequency of the signal is around 900 MHz or 915 MHz. Most preferably, the electromagnetic signal used fortranscranial administration is pulsed with a cycle of repetition of the electromagnetic energy or field is within the range of 10 to 300 Hz, or 20 to 270 Hz, or 30 to 250 Hz, or 40 to 240 Hz, or 100 to 220 Hz, preferably around 40 Hz, 100 Hz, or 200Hz. When the rate of repetition of the electromagnetic signal is 200Hz, this means that the signal is pulsed every 5 milliseconds (See Figures 36-38). Most preferred electromagnetic energy signal has a frequency of 915 MHz and is pulsed with a cycle of repetition around 200 Hz. The specific absorption rate (SAR) within the treated or targeted human brain tissue ranges between 0.5-3 W/kg. Most preferably SAR values are between 1-2 W/kg, or around 1.5 or 2 W/kg.

[153] As described herein above, body tissue radiofrequency applicators (50) according to the present invention generate electromagnetic waves or fields which efficiently penetrate within the human skull and human cortex. In effect, 80-90% of the emitted power is absorbed by the head of the subject. BTRFA thus provides a reliable, reproducible, and efficient specific absorption rate (SAR) within human brain tissue. BTRFAs according to the present invention are thus particularly useful for transcranial administration of said electromagnetic waves toward the skull and brain of a subject, and thus may be advantageously embedded into a medical head device.

[154] Indeed, body tissue radiofrequency applicators (50) according to the present invention may have variable shapes and sizes to fit and adapt to various subject skull shapes and sizes, thereby enhancing coverage of whole brain or of specific lobes of the brain of the subject. In addition, they may advantageously be designed with inwardly curved/bent shapes in both length and width dimensions, and thus be positioned at proximity of rounded portions of the skull, such as for examples the frontal, parietal, temporal, occipital parts, to further optimize enhanced coverage to whole brain regions and/or specific cortical brain regions. Furthermore, as described above, X-BTRFA 130 and/or Y-BTRFA 120, and optionally Z-BTRFA 140 may be selected according to the desired zone and shape of electromagnetic signal and desired power and SAR distribution within the desired area of the treated human tissue.

[155] Another important advantage of the body tissue radiofrequency applicators (50) of the present invention is that the resonance frequency is significantly widened, thereby allowing a good matching when exposed at different distances to a head.

[156] Therefore, according to a third aspect, the present invention thus further provides a novel medical head device comprising an array of one or more body tissue radiofrequency applicators (50) configured for emitting an electromagnetic signal at a frequency ranging from 500 to 3000 MHz, said array of one or more body tissue radiofrequency applicators (50) being combined with an array of one or more LEDs (200) configured for emitting red and/or near-infrared signals, wherein said combined arrays of one or more body tissue radiofrequency applicators (50) and of one or more LEDs (200) are embedded within or attached to said head device, wherein said medical head device is configured to fit on head of a subject, and wherein said combined arrays of one or more body tissue radiofrequency applicators (50) and of one or more LEDs (200) are positioned such that they are adjacent to said head when the medical head device is worn by the subject. The medical head device may thus comprise body tissue radiofrequency applicator (50) as described herein above and which may be chosen among X-BTRFA, Y-BTRFA, and/or Z-BTRFA.

[157] The medical head device according to the present invention may be positioned over the head of a subject, thereby allowing said one or more body tissue radiofrequency applicators (50) as to deliver to the whole head and brain, or specific parts of the head and brain, such as the frontal lobe, and/or the parietal lobe, and/or the occipital lobe, and/or the temporal lobe, a therapeutically effective amount of the electromagnetic field or signal.

[158] Said one or more body tissue radiofrequency applicators (50) may thus be embedded within the medical head device proximal to the head of a subject when the device is worn by the subject, so that the electromagnetic signal is inwardly directed towards the head of the subject. In addition, the body tissue radiofrequency applicators are spaced apart so as to apply a homogenous pulsed electromagnetic energy or field directed toward the head of the subject without no or minimal overlap of the pulsed electromagnetic energy or field. The head and cortex of the subject thus may receive a directional and homogeneous exposure of electromagnetic field. This allows for a more focused treatment, without as much power loss from radiation going into the air away from the head.

[159] The medical device according to the present invention may thus also comprise a head unit, such as for example a head cap, a helmet, or a headset which holds the array of said one or more body tissue radiofrequency applicators at proximity and in predetermined positions relative to the head of a subject. Preferably, the array of said one or more BTRFA units are held by and within the head unit and connected by flexible means to each other’s, to adapt to different head sizes of subjects. Each of them may be enclosed in separate cases which are connected to each other by flexible connecting means, thereby allowing the BTRFA units to be pressed against the subject head, hair, and skull.

[160] As described above, the medical head device according to the present invention may comprise X- BTRFA 130 and/or Y-BTRFA 120 and optionally Z-BTRFA 140 depending on the targeted body tissue area and desired depth of penetration, and in order to take profit of their specific distinct characteristics. Indeed, as described herein above, Y-BTRFA 120 being capable of delivering a deeper penetration of the electromagnetic signal with a maximum in the center, while the X-BTRFA 130 have a wider area of exposure of the electromagnetic signal but lesser deep penetration thereof.

[161] According to the present invention, the medical head device may comprise between 1 and 16 BTRFA, or between 6 and 10 body tissue radiofrequency applicators (50). It is preferably a multi -emitter head device comprising around 8-10 body tissue radiofrequency applicators (50), preferably 8 body tissue radiofrequency applicators.

[162] Said array of one or more BTRFA may emit an electromagnetic field or signal at a frequency ranging from 500 to 3000 MHz, or from 800 to 1500 MHz, or from 850 to 1000 MHz, or 900 to 950 MHz. Most preferred frequencies are around 900 MHz or 915 MHz. Furthermore, the electromagnetic signal which is radiated from the BTRFA for transcranial administration may be preferably in a pulsed electromagnetic waveform. The rate of repetition of the electromagnetic energy or field may be within the range of 10 to 400 Hz, or 20 to 300 Hz, or 30 to 300 Hz, or 20 to 270 Hz, or 30 to 250Hz, or 40 to 250Hz, or 40 to 240 Hz, or 100 to 220 Hz, and preferably around 40 Hz, 100 Hz, or 200 Hz. Preferred rate of repetition of the pulsed electromagnetic signal is pulsed around 200Hz, thereby allowing a duration of each pulsed signal of around 5 milliseconds. Most preferred electromagnetic energy signal has a frequency of 915MHz and is pulsed with a cycle of repetition around 200Hz.

[163] In addition, said one or more BTRFAs of the medical head device are configured such that the energy specific absorption rate (SAR) within a treated or targeted human tissue, such as human cortex, is in a range of from 0.5 to 10 W/kg or from 0.5 to 3 W/kg, or 1 to 2.5 W/kg, or 1.5 to 2 W/kg, and preferably around 2 W/kg.

[164] The medical device according to the present invention may thus comprise an array of said one or more BTRFAs which may be activated sequentially or in combination to produce a radiation pattern that is used for the treatment of the brain. Preferably, the BTRFA may be radiating on and off in sequential order. Therefore, the medical device may be a multi-emitter head device, wherein when one BTRFA is off, another BTRFA may be on, so that each BTRFA emits in a sequential fashion, one after the other. This also allows for a single therapy waveform generator to be shared by multiple applicators.

[165] The subject wearing the medical head device may receive a homogeneous exposure of a pulsed electromagnetic signal and does not experience any uncomfortable sensation of heat or pain. Indeed, said above-described pulsed RF electromagnetic energy does not raise the temperature of the targeted body tissue.

[166] The medical head device may have a single BTRFA which is active at a time, or one or more BTRFA which may be activated in sequence or simultaneously. Preferably, said one or more body tissue radiofrequency applicators of the medical head device are delivering pulsed electromagnetic waves in a sequential manner such that no two applicators are simultaneously delivering or discharging.

[167] Operating the applicator system in this fashion maximizes brain coverage, however, there may be a need for a more focused deeper treatment in certain areas of the brain. This deeper penetration can be accomplished by simply simultaneously activating the array of one or more body tissue radiofrequency applicators transmitting the same waveform. Indeed, when multiple body tissue radiofrequency applicators are actively transmitting the same waveform, propagation waves are summed in the radiation field, producing peaks in specific areas in the field, thus allowing treatment energy to be focused in specific areas of the brain. Therefore, when body tissue radiofrequency applicators are activated at the same time, they may provide treatment to different brain regions/areas at the same time, and in particular target areas in the brain. For example, if two body tissue radiofrequency applicators are emitting the same frequency, a standing wave patern is produced, as the two output waves combine to produce both constructive and destructive interference. If the two emited frequencies are "in-phase", they line up in time and their peaks occur at the same time, which produces a particular standing wave patern. When the peaks of the signals do not line up, the signals are "out of phase" with each other, and the standing wave patern changes. With several body tissue radiofrequency applicators active, if the phase of the signal between the body tissue radiofrequency applicators is varied, the peaks can be moved, and/or steered, to different locations in the brain. In another example, if the power levels of the different signals are changed, this also can move and/or steer the signal to different locations in the brain. This is referred to as beamforming. The combination of multiple body tissue radiofrequency applicators and the ability to beamform allows for complete coverage of all regions of the brain.

[168] Alternatively, the medical head device may have an array of one or more body tissue radiofrequency applicators, wherein each BTRFA emits a different frequency. A first BTRFA may be radiating at a high frequency while a second BTRFA radiates at a lower frequency, and the radiating characteristics may switch such that the first BTRFA is radiating at a low frequency while the second BTRFA radiates at the high frequency. A specific frequency could be distributed to multiple emiters at the same time or frequencies may be generated and distributed to the body tissue radiofrequency applicators. This may be scaled to more emiters and more frequencies, with a specific example of eight emiters and three frequencies. For example, it is possible to have a medical head device with one or more body tissue radiofrequency applicators (50) and three different RF frequencies to ensure total penetration and coverage into each of the predetermined locations.

[169] The medical device according to the present invention may thus comprise an array of one or more BTRFA chosen among X-BTRFA 130 and/or Y-BTRFA 120, and optionally Z-BTRFA 140, depending on the desired depth and area of coverage of the electromagnetic signal to the targeted body tissue. X-BTRFA 130 provides a uniform distribution over a broader tissue volume with very low radiation losses, meaning the smallest portion of electromagnetic energy that is radiated into the surrounding space. Y-BTRFA 120 provides a greater depth of penetration of electromagnetic waves into living tissue, while maintaining an unchanged coverage width and slightly higher levels of S AR. Z-BTRFA 140 may achieve a maximum depth of penetration with the highest SAR value in significantly smaller volume and surface area of tissue.

[170] According to a preferred embodiment, the medical head device comprises an array of one or more body tissue radiofrequency applicators (50) which are activated in sequence thereby allowing delivery of full brain exposure to the electromagnetic signal. This sequential activation of the multiple body tissue radiofrequency applicators (50) positioned on the head unit allows for only one BTRFA to be active at any given time, and thus since a pulsed treatment includes periods of actively transmiting and being idle, the applicator system utilizes the idle time for one BTRFA to activate the other RF applicator. For example, for an antenna system with “N” BTRFAs, if each BTRFA applicator is active time is 1/N, the idle time outside this active time can be used to activate other RF applicators, and the areas of the brain that can be treated in the same treatment session is multiplied by N.

[171] Most preferably, the medical head device emits electromagnetic waves in a pulse fashion and sequentially through an array of eight BTRFA at a frequency of around 915 MHz and with a cycle of repetition for each antenna at 200 Hz. Each BTRFA of the preferred head device is thus activated every 5 milliseconds (ms). The duration for switching from one BTRFA to another one is 5 ps.

[172] Power levels and specific absorption rate (SAR) may range between 0.5-10 W/kg. Most preferably SAR values are between 1-8 W/kg, and more precisely around 1.5 or 2, or 3 W/kg. As described above, the brain temperature of said subject remains stable or is not significantly raised during and/or after exposure of said subject to said electromagnetic treatment.

[173] The array of said one or more body tissue radiofrequency applicators (50) is combined, within the medical head device according to the present invention, with an array of one or more light emitting diodes (LED) 200 configured for emitting red and/or near-infrared signals, thereby allowing administering a synergistic combination of pulsed electromagnetic signal with RED and near-infrared (NIR) light to the body tissue of a subject in need thereof. LEDs of the medical head device are described herein above. Sources of lights may be light emitting diodes (LED) 200 or a low-level laser source in the red and near infrared (NIR) part of the spectrum.

[174] Medical head devices comprising LEDs are preferred. Said one or more LEDs of medical head device are configured for emitting red and/or near-infrared signals, wherein said red signals have a wavelength in a range of from 620 to 680 nm and said near-infrared signals have a wavelength in a range of from 800 to 1100 nm. Red signal or lights may be delivered at one wavelength of 620 nm to 670 nm, preferably at a peak wavelength at or around 630 nm, 660 nm, or 670 nm. NIR signal or lights may be emitted at wavelengths ranging from 808 to 880 nm, preferably at a peak wavelength of around 810 nm, 830 nm, or 880 nm, and optionally additional NIR lights emitted at wavelengths ranging from 1060 to 1070 nm. Preferably, RED and NIR wavelengths lights are combined, for example first lights in the red spectra within wavelengths ranging from 620 to 670 nm are shined at directly to the head and thus the brain of a subject in combination with second NIR lights at wavelengths ranging from 808 to 880 nm, and with third NIR lights with wavelengths at or around 1060 to 1070 nm.

[175] LEDs 200 used in the medical head device preferably have a power ranging from 25 mW to 1 W, more preferably, around 50 m to 500 mW, and may be adapted depending on the selected repetition frequency and duty cycle of the LEDs 200. Preferably, red signals and near-infrared signals are pulsed with the same or a different repetition rate ranging from 10 Hz to 100 Hz, or 10-60 Hz, or around 20 Hz, or around 40 Hz.

[176] LEDs 200 have beam spot sizes ranging from 0.1 to 1 cm ² . The power density or irradiance for each LED 200 is preferably between 10 and 100 mW/cm ² , more preferably around 50 mW/cm ² . The energy delivered per LED 200 ranges preferably from 1 to 50 Joules, more preferably, around 25 or 30 Joules per LED. The fluence, which is the energy density (dose) for each LED 200 multiplied by the duration of the treatment in seconds preferably ranges from 5 to 200 J/cm ² , more preferably around 100 J/cm ² . Finally, the dose per session which is calculated by multiplying the energy density per LED 200 or fluence by the number of LEDs, preferably ranges between 2000 and 7000 J/cm ² , more preferably from 3000 and 6000 J/cm ² , and even more preferably around 5000 J/cm ² .

[177] BTRFA emitting pulsed electromagnetic signal or waves and LEDs 200 emitting red and/or NIR lights are combined within the medical head device according to the present invention. LEDs 200 may be fixed to each BTRFA unit, each of the BTRFA units preferably comprising between 2 and 10 LEDs, or between 4 and 8 LEDs and preferably around 6 LEDs per BTRFA unit. Therefore, a preferred medical head device as described comprises between 8-10 BTRFA and may further comprise a total number of LEDs 200 ranging from 30 and 80 LEDs 200, or between 40 and 60 LEDs 200, or around 50 LEDs 200 and preferably a total of 48 LEDs 200 i.e., 6 LEDs 200 per BTRFA unit. Figure 39 illustrates a preferred embodiment wherein a single BTRFA unit carrying 6 LEDs 200. The whole unit of BTRFA combined with the six LEDs 200 may be enclosed in a thin hollow case connected with each other’s by some elastic or flexible connection means. The side of the hollow case which is in direct contact with the head of the patient, and thus placed in between the BTRFA and LEDs 200 and the skull is made of or is covered with some biocompatible thin and transparent membrane. Figure 40 illustrates a preferred embodiment showing the medical head device comprising eight BTRFA units carrying six LEDs 200 per each BTRFA. BTRFAs may be positioned at around 1-4 mm, or preferably around 2-3 mm and the LEDs 200 are positioned at around 8-14 mm, or 10-14 mm, or preferably around 12 mm from the skull of the subject wearing the medical head device.

[178] Within the medical head device according to the present invention, the one or more body tissue radiofrequency applicators (50) of the array of the one or more body tissue radiofrequency applicators (50) and the one or more LEDs of the array of the one or more LEDs (200) are spaced apart and located such so as to apply a preferably relatively homogenous pulsed electromagnetic energy and a preferably relatively homogeneous red and/or near-infrared signal directly to the head of the subject without no or minimal overlap of the signals. Depending on the number of LEDs fixed to each BTRFA, the LEDs 200 may be spaced by 30 to 60 mm, to by 40 to 50mm between each other’s. Advantageously, the shapes of each BTRFA unit may be slightly modified to hold the LEDs 200 without blocking any RED and NIR emissions. By way of example, possible slight modifications of the extremities of the BTRFA which may be rounded as shown in Figures 19A-C.

[179] RED and NIR LED diodes of the medical head device according to the present invention, may be activated together at the same time either in a continuous manner or in a series of alternating pulses. Red & NIR LED diodes are preferably activated in a series of alternating pulses overlapping one or more complete sequence of the emission of the pulsed electromagnetic waves by the BTRFA. The cycle of repetition of the LED pulses may be 40 Hz with a 50% duty cycle. In that case, the duration of each pulse is 12.5 mS, followed by 12.5 mS pause. The total LED power consumption and heat dissipation (PC-HD) is 50% of the maximum. Alternatively, the cycle of repetition of the LED pulses may be 20 Hz with a 50% duty cycle. In that case, the duration of each pulse is 25 mS, followed by 25 mS pause. The total LED power consumption and heat dissipation (PC-HD) is 50% of the maximum.

[180] The medical head device according to the present invention may comprise “wavelength-sequential” LED sequence. One LED at a specific wavelength is active at a time for 25 ms, followed by 25 ms pause, while all other LEDs emitting at a different wavelength or at different wavelengths are OFF. Repetition frequency for such sequence is 10 Hz, with duty cycle of each LED of 25%. There is a complete pause between each LED emission/activation sequence. The total LED power consumption and heat dissipation (PC-HD) is 18.75% of the maximum. Possible alternative of the “wavelength-sequential” LED sequence may be without a pause in between each LED emission/activation sequence. One wavelength is active at a time for 12.5ms. Repetition frequency for such sequence is 26.666 Hz, with duty cycle of each LED of 33.33%. The total LED power consumption and heat dissipation (PC-HD) is 33.33% of the maximum. In addition, it is possible to have variations of the duration of the single LED pulse, all having the same duty cycle of each LED of 33.33%, PC-HD equal to 33.33% of the maximum, and all BTRFA operating under equal alternating “LED conditions”.

[181] According to a preferred embodiment, the electromagnetic field or signals delivered by the BTRFA is synchronized with the RED and NIR signals or lights delivered by the LEDs by adjusting the duty cycle of electromagnetic and RED/NIR signals within the medical head device.

[182] Different synchronizations may be used. By way of example, BTRFA may deliver an electromagnetic field at 915 MHz with a rate of repetition (or repetition frequency) of 200 Hz and a duty cycle of 100%. Simultaneously, LEDs may deliver RED/NIR signals at the wavelengths described above with a repetition frequency of 40 Hz and a duty cycle of 0.125 or 12.5% (see Figure 36), or with a repetition frequency of 40 Hz and a duty cycle of 0.1 or 10% (see Figure 37), or again with a repetition frequency of 40Hz and a duty cycle of 0.2 or 20% (see Figure 38).

[183] Preferred medical head device according to the present invention thus comprises BTRFA for simultaneous emissions of pulsed electromagnetic waves as described herein above combined with lights delivering RED and NIR signal within preferably three different wavelengths comprising a first peak wavelength of around 660 nm, a second peak wavelength at around 810 nm, and a third peak wavelength at around 1065 nm, the RED and NIR signals being pulsed with a rate of repetition (or frequency repetition) of 40Hz and with a duty cycle of 12.5%.

[184] According to a most preferred embodiment, the present invention thus relates to a medical head device comprising an array of eight BTRFA as described above delivering pulsed electromagnetic signal at a frequency of 915 MHz and a repetition rate of around 200 Hz simultaneously and in combination with an array of 48 LEDs, ?.e., 6 LEDs per each BTRFA unit, or 8 LEDs per each BTRFA, which are delivering pulsed RED and NIR lights at 630 nm and 810 nm, and 1060 nm to the brain of a subject.

[185] Preferably, the medical head device according to the present invention is embedded with BTRFA in combination with 3-in-l LEDs which comprise three CHIPS in one single LED unit emitting at three RED and NIR wavelengths, such as for example 660 nm, 810 nm and 1064 nm.

[186] An example of 3-to-l LEDs which was custom-made (Figure 35) as having the following specifications: a first CHIP emitting at 660-665 nm, 2.0-2.4 V, 20-30 lumens, 350 mA; a second CHIP emitting at 805-810 nm, 2.0-2.4 V, 100-200 mW, 350 mA; and a third CHIP emitting at 1050-1070 nm, 2.0-2. 4V, 100-200 mW, 350 mA.

[187] Modelling of the RED and NIR signal exposure showed that the cosine distribution of the Luminous Intensity can be described as RLI(P)= RLImax ^x cos(P). The that Relative Luminous Intensity (RLI) along any straight line shifted for angle P from the central line can be calculated as a product of maximum value of RLI (RLImax), that occurred along the central line and the cosine function of angle p.

[188] When applying the theoretical cosine distribution to calculate luminous power distribution over a flat plane placed at a distance h below the light source was applied, and based on that, the total light power (relative to total available power from the LED) delivered to the concentric circles placed within the observed flat plane was calculated as a function of the circle radii Rci, Rc2, Res, Rc4 and Res.

[189] By way of example, a 3-in-l LED having an average power of 455 mW, a pulsed signal with duty cycle of 0.125 gives equivalent total power of about 57 mW, and it could be adjusted to some other values by changing duty cycle value, for example it could be tuned to an average total power of 100 mW by adjusting the duty cycle.

[190] Overall power delivered to the central circuit (as well as for the area between circle 1 and 2 and between circle 2 and 3) was by definition equal to 0.25 Ptot = 25 mW, which means that during the 30 min exposure all these three surfaces received equal amount of energy of 0.025 W x 1800 s = 45 J. The remaining two shaded areas (between circle 3 and 4 and between circle 4 and 5) were exposed, also by definition, to overall power of 0.15 P _tot and 0.05 P _to t,and therefore during 30 min exposure they received energy of 0.015 W x 1800 s = 27 J and 0.005 W x 1800 s = 9 J.

[191] During the same time all 32 LEDs could deliver 32 x 171 J = 5472 J. Major part of this energy would be absorbed by upper layers of the head, while only 10% to 20% (547.2 J to 1094.4 J) would be delivered to the brain. This energy quantity could be increased by extending the exposure time or by increasing the duty cycle value or by increasing the number of LEDs. [192] BTRFA and LEDs as described above, preferably enclosed in hollow cases which are connected by flexible or elastic connection means are embedded within the medical head device together with the whole electronic circuit allowing the functioning thereof.

[193] The electronic control unit/system comprises electronic means to generate the therapeutic pulsed electromagnetic signal and means for signal amplification. For example, the electronic control unit/system may comprise (a) a single transmitter to sequentially drive antenna sets, (b) a switching device to select for each activation period in an activation sequence of the array of BTRFA set to be driven, and a controller. The controller, for each activation sequence determines a power output of each BTRFA and generates an adjusted control signal for the single transmitter such that the power output of at least one BTRFA is the same as an average value, regardless of the load of the BTRFA.

[194] An example of the electronic circuit is depicted in Figure 43. Such electronic circuit comprises:

[195] (i) a RF central generator (1) which may be a voltage-controlled oscillator, able to generate the required frequency of the electromagnetic signal as described above, and preferably at 915 MHz or around 915 MHz;

[196] (ii) an appropriate number of amplifiers with sufficient gain and output power capabilities as required by the next amplifying stage and for compensation of the power losses introduced by resistive power dividers (3) and (4) or, in the case of output amplifier (5) to achieve the sufficient output level of RF signal at the BTRFA input in order to achieve the required SAR value within a treated body tissue, such as for example three pre-amplifiers: a first amplifier (2) allowing the achieve the power which is connected via short printed microstrip RF transmission line and a resistive power divider 1 to 2 (3) to two second stage amplifiers (14);

[197] (iii) the second stage amplifiers (14) being connected to the RF central generator (1) via resistive RF power divider 1 to 2 (3), and connected to the PCB for output amplifier (11) via resistive RF power divider 1 to 4 (4);

[198] (iv) eight PCBs (11) each carrying one output amplifier (5) and one BTRFA (6) and connected to the central PCB unit (9) by flexible coaxial cables carrying RF signal from outputs of resistive RF power divider 1 to 4 (4). Each of eight PCB units (11) is also connected by flexible wires to the power supply unit (10) as well as to the control unit (8) that provides pulsed digital signals for switching on and off the output amplifiers (5). Each of the eight PCB units (11) are connected by flexible conductive wires, providing pulsed power supply, with six 3 in 1 LED diodes (7) each placed on small separate PCB (12) that provides cooling and mechanical support for the LEDs (7).

[199] (v) a means for generating synchronizing digital signals at the repetition rate of 200 Hz (or similar) for switching on and off the output amplifiers (5) in accordance to the sequence plan, which may be a microprocessor or with other digital components (flip flop type); and [200] (vi) a means for generating synchronizing digital signals at the repetition rate of 40 Hz (or similar) for switching on and off the 3 ini LEDs (7) in accordance to the sequence plan, which may be a microprocessor (the same used for (v) or different) or with other digital components (flip flop type).

[201] The medical head device according to the present invention may have a control box for ON/OFF switching by the patient or the caregiver, a battery, and optionally a timer, and/or means for shielding out- radiation, and/or feedback means.

[202] For practical and convenient use of the medical head device, means for generating and amplifying the therapeutic pulsed electromagnetic waves as well as RED & NIR lights is as small as possible, allowing a patient to wear the device while being able to move around in his home, either reading, watching TV, sleeping, cooking, etc.

[203] The control box for activating said one or more BTRFA and LED units may be either part of the head device or separated from the head device and connected to it via a cable. Preferably, the medical head device comprises a head unit with BTRFA and LED units connected to the controller or control box which can be worn on the arm or conveniently placed nearby for example on a table, a chair back, etc.

[204] The battery may be any suitable battery such as a lithium rechargeable battery.

[205] The timer may be for example a stop-timer which automatically turn the device off at the end of the use of the subject. The medical device may also include a treatment status indicator which may indicate that treatment is complete, for example via an audio, visual or tactile indicator.

[206] Means for shielding out-radiation allow eliminating EM waves radiating away from the subject head when the head unit is positioned over the head of the subject. Such means may comprise shield.

[207] Feedback means may be used to adjust treatment parameters. For example, if a particular patient is responding better to a particular frequency within the therapy, the treatment may be adjusted to use this favorable frequency more.

The medical head device as described above may be used in a method of treating and/or preventing neurodegenerative diseases, and/or in a method of stabilizing and/or reversing symptoms of neurodegenerative diseases in a subject in need thereof, comprising positioning the medical head device at close proximity to the head of a subject in the need thereof and administering the combination of said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators (50) with said red and/or near-infrared signals generated by the one or more LEDs (200).

[208] By activating the array of said one or more BTRFA in combination and simultaneously with the array of said one or more red and NIR lights, the head and cortex of the subject may transcranially receive a therapeutically efficient dose of pulsed electromagnetic waves or field at a specific frequency and a specific absorption rate (SAR) and to red and NIR lights as described above for a predetermined absorption period. [209] The present invention thus also provides a method of treating and/or preventing neurodegenerative proteinopathies and/or diseases, as well as a method of stabilizing and/or reversing symptoms of neurodegenerative diseases, such as Alzheimer’s disease, in a subject in need thereof, comprising positioning the medical head device as described above, at close proximity to the head of the subject, activating the array of said one or more BTRFA in combination and simultaneously with the array of said one or more red and NIR lights, and transcranially exposing the head and cortex of the subject to a therapeutically efficient dose of pulsed electromagnetic waves or field at a specific frequency and a specific absorption rate (SAR) and to red and NIR lights at specific wavelengths as described above.

[210] Said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators (50) is administered or applied to the head of said subject for one treatment each day or for multiple, spaced-apart treatments each day. Regime of administration may consist for example applying or positioning the medical head device of the invention onto the head of a subject for 15-60 min or for 30-60 min, preferably either once a day or twice a day, so that therapeutically effective doses of pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators (50) and of pulsed red and/or near-infrared signal generated by the one or more LEDs (200) is simultaneously administered or applied to the head of said subject.

[211] Combination of these signals provide a deeper penetration through the meninges, cranial material, and then through the brain matter. In addition, simultaneous stimulations with these signals are expected to provide synergistic molecular and biological effects which are manyfold. These synergistic effects include an increase of mitochondrial activity with an increase of adenosine triphosphate (ATP) production and thus an enhanced metabolic capacity, thereby contributing to overcome the low ATP level associated with many neurological disorders, as well as increased anti-inflammatory effect, possibly via the inhibition of the cyclo-oxygenase 2 (COX-2 enzyme), the inhibition of NF-kB and tumor necrosis factor (TNFa), as well as a decrease of the oxidative stress and the decrease of reactive oxygen species (ROS) production. In addition, we expect a beneficial regulation of other pro- and anti-inflammatory cytokines in brain parenchyma wherein pro-inflammatory macrophages with Ml phenotype present in the brain of subjects are triggered to switch to M2 anti-inflammatory phenotype enabling the phagocytosis and degradation of the amyloid plaques and beta amyloid aggregates by newly active M2 macrophages and microglia. Synergistic effects further include increased hemoglobin oxygenation and increased vasodilation, which leads to improved cerebral blood flow, oxygenation, and nutritional supplementation to the brain parenchyma.

[212] The medical head device and methods according to the present invention are particularly useful for synergistically stabilizing and/or reversing the symptoms of the most common dementia which is Alzheimer’s disease.

[213] The general term for this phenomenon, dementia, was first used in the early 19th century. At that time, dementia was regarded as a form of what was called “mental alienation”, which also included schizophrenia and mood swings. Today, various types of dementia are distinguished, but all have a common definition that, on the basis of World Health Organization diagnostic criteria, may be stated as follows: "a gradual loss of memory and of the ability to form and organize ideas, severe enough to interfere with activities of daily living, and present for at least six months" .

[214] The cognitive and social problems associated with dementia result not from psychiatric disorders, but rather from organic causes that have been well characterized: specifically, an abnormally high number of neurons deteriorating and dying in certain parts of the brain. In this sense, the various forms of dementia are part of the broader category of neurodegenerative diseases.

[215] Cognitively, subjects with Alzheimer’s disease generally experience memory problems. They may often repeat the same question or buy the same thing twice. They may become disoriented, wandering around their own neighborhood for hours, or lose their sense of time. They may become confused if they must attempt tasks that require abstract planning, such as running errands or making transfers when travelling by public transit.

[216] Linguistically, to compensate for having forgotten specific words, people with dementia tend to use catch-all terms like “thingy” or “gizmo”. They may also have problems in remembering important dates such as birthdays, or the names of famous people. Their motor skills may also be impaired when they try to operate familiar household appliances.

[217] Emotionally, people with dementia may become sad, unstable, or even verbally or physically aggressive. They may act socially disinhibited and overfamiliar at sometimes, and fearful or suspicious at others, or they may experience episodes of euphoria, depression, or anxiety.

[218] Behaviorally, people with dementia show less interest in other people, lose contact with their friends, and gradually give up their leisure pastimes. Often their movements become slower, which can, for example, make it hard for them to drive a car, or simply to comb their hair or brush their teeth.

[219] The best-known form of dementia is Alzheimer’ s-type dementia, commonly known as Alzheimer’s disease. It is also the most widespread form, accounting for 60 to 65% of all dementia cases.

[220] Alzheimer’s disease (AD) was first described and diagnosed by Dr. Alois Alzheimer in 1906. AD is characterized as a severe, chronic, and progressive neurodegenerative and incurable disorder, associated with memory loss combined with cognition impairment, abnormal behavior, and personality changes. With life expectancy continually growing increasing, number of AD cases is growing drastically and treating AD patients is becoming urgent. According to WHO, AD is the most common cause of dementia, accounting for as many as 60 to 70% of senile dementia cases and affecting 47.5 million people worldwide in 2015.

[221] Alzheimer’ s-type dementia affects the brain only. And within the brain, it is the thin layer of grey matter, the cortex that is affected. In this type of dementia, the first observable deficits begin in the hippocampus and the entorhinal cortex. [222] The hippocampus is a brain structure embedded deep in the temporal lobe of each cerebral cortex. It is an important part of the limbic system, a cortical region that regulates motivation, emotion, learning, and memory. The entorhinal cortex is an area of the brain located in the medial temporal lobe and functions as a hub in a widespread network for memory, navigation, and the perception of time. The entorhinal cortex is the main interface between the hippocampus and neocortex. These two parts of the brain that are relatively old in evolutionary terms and that are involved in memory, so these deficits take the form of memory disorders. Subsequently, other functions become impaired as well, such as language, orientation in time and space, the ability to plan activities, the ability to recognize faces and objects, and so on.

[223] Earliest signs comprise forgetting most recent events and conversations. There is then a continuous decline in thinking, behavioral and social skills that disrupts a person's autonomy. As the disease progresses, a person with Alzheimer's disease will develop severe memory impairment and lose the ability to talk and carry out everyday tasks.

[224] International standards for the diagnosis of Alzheimer’s disease have been established based on medical history, neuropsychological testing, clinical examination, and laboratory assessments.

[225] Criteria for the clinical diagnosis of Alzheimer’s disease have first been defined and published in 2011 by the NIA-AA working group. These criteria, which are commonly referred to as NIA-AA criteria, have been reliable for the diagnosis of Alzheimer’s disease (Lopez OL et al. Curr Opin Neurol. 2011 December; 24(6): 532-541. doi: 10.1097/WCO.0b013e32834cd45b) as they take into consideration different biomarkers to support the clinical diagnosis of the different stages of the disease.

[226] These criteria, which are commonly referred to as the NINCDS-ADRDA criteria are regularly revised. The most recent revision was published in 2011 (McKhann G et al., Alzheimers Dement. 2011 May; 7(3): 263-269. doi: 10. 1016/j .jalz.2011.03.005). According to the WHO Alzheimer’s disease typically progresses slowly in three general stages: mild, moderate, and severe, (https://www.who.int/news- room/fact-sheets/detail/dementia).

[227] In the mild stage of Alzheimer’s, the person may function independently. He or she may still drive, work and be part of social activities. The person may however feel as if he or she is having memory lapses, such as forgetting familiar words or the location of everyday objects.

[228] Common difficulties include inter alia coming up with the right word or name; remembering names when introduced to new people; having difficulty performing tasks in social or work settings; forgetting material that was just read; losing or misplacing a valuable object; experiencing increased trouble with planning or organizing. Symptoms may not be widely apparent at this stage, but family and close friends may notice these difficulties.

[229] The moderate stage of Alzheimer's is usually the longest stage and can last for many years. As the disease progresses, the person with Alzheimer's will require a greater level of care. [230] During the middle stage of Alzheimer’s, dementia symptoms are more pronounced, the person may confuse words, get frustrated or angry, and act in unexpected ways, such as refusing to bathe. Damage to nerve cells in the brain can also make it difficult for the person to express thoughts and perform routine tasks without assistance.

[231] Symptoms, which vary from person to person, may include being forgetful of events or personal history; feeling moody or withdrawn, especially in socially or mentally challenging situations; being unable to recall information about themselves like their address or telephone number, and the high school or college they attended; experiencing confusion about where they are or what day it is; requiring help choosing proper clothing for the season or the occasion; having trouble controlling their bladder and bowels; experiencing changes in sleep patterns, such as sleeping during the day and becoming restless at night; showing an increased tendency to wander and become lost; demonstrating personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like handwringing or tissue shredding. In the middle stage, the person living with Alzheimer’s can still participate in daily activities with assistance but need more intensive care from family and caregivers.

[232] There is a battery of neuropsychological tests to identify symptoms and the progression of Alzheimer’s disease. Most widely used neuropsychological tests include ADAS-Cog-Plus or ADAS-Cogl3 (Alzheimer's Disease Assessment Scale-Cognitive Subscale 13) and MMSE (Mini Mental State Examination), logical Memory Tests I and II by around 3.0 points, Trail Making Tests A and B, Boston Naming Test, Auditory Verbal Learning Tests before and after at least 2-month treatment.

[233] The MMSE test is a 30-point questionnaire used to measure the severity and the progression of cognitive impairment. The administration of the test takes between 5 and 10 minutes and examines functions including registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands and orientation. Any score of superior to 24 out 30 indicates a normal cognition, a score between 19-23 points indicates mild cognitive impairment, a score between 10-18 points indicates severe cognitive impairment, and scores inferior to 9 points indicate severe cognitive impairment.

[234] ADAS-Cog-Plus or ADAS-Cogl4 test is one of the most widely used cognitive metric for Alzheimer disease treatment. The maximum score of 85 points shows poor cognitive performance. The ADAS-Cogl4 assesses multiple cognitive domains including memory, language, praxis and orientation.

[235] Since a typical decline in ADAS-cogl4 is expected for Alzheimer’s disease subjects is around 4 points over a 12- to 15- month period, use of medical head device according to the present invention is expected to reverse cognitive decline (as measured by ADAS-cogl4) back to the cognitive levels of the subjects 12- to 15- months earlier.

[236] Typical neuropathological hallmarks of AD are deposition of (1) extracellular beta-amyloid plaques (or senile plaques) composed of toxic amyloid-[3 aggregates (mainly beta-amyloid 42 or A[342 peptide) which accumulate into insoluble plaques and aggregate into neurotoxic oligomeric amyloid-[3 species between the neurons, and (2) intracellular neurofibrillary tangles (NFT) originated from hyperphosphorylation of the microtubule-associated protein tau. These plaques and NFT appear initially in the hippocampus then extending to the cortical grey matter. Several lines of evidence suggest that the small oligomeric forms of amyloid-P and tau act synergistically to promote synaptic dysfunction in Alzheimer’s disease (AD). These aggregates and plaques are very toxic for the neurons and the pathology gradually result in the loss of neuronal connections, death of the neurons (mostly pyramidal neurons of the temporal cortex) and the destruction of the nervous system.

[237] On the molecular level, the amyloid-P aggregates or plaques are produced through sequential cleavage of transmembrane amyloid precursor protein (APP) by P- and y -secretases. The process of amyloid-P proteolytic cleavage generates the release of several amyloid-P isoforms, among which amyloid- P peptide of 42-amino acids (AP1-42 peptide) is the most insoluble and thus has the highest propensity to aggregate into extracellular amyloid-P plaques. Therefore, concentrations of AP1-42 in cerebrospinal fluid of AD patients are decreased.

[238] Tau proteins are abundantly present in the cytosol of neurons, where they function to stabilize microtubules. In AD, an imbalance between kinases and phosphatases results in a hyperphosphorylation of tau, which leads to detachment of tau from microtubules and to its accumulation into NFT.

[239] During the neurodegenerative process, tau (T-tau or total tau) and phosphorylated tau (P-taui8i) proteins are also released into the extracellular space. Concentrations of tau in cerebrospinal fluids of AD patients are thus increased.

[240] The formation of plaques and NFT promotes neuronal injury and, consequently, neuronal and synaptic degeneration in AD.

[241] CSF Ap 1-42 (biomarker for Ap deposition), total tau protein (T-tau; biomarker for neuronal injury), and phosphorylated tau at threonine 181 (P-taui8i; biomarker for NFT) are thus validated CSF biomarkers of AD. As indicated above, concentration of AP1-42 decreases over time in AD subjects, while P-taui8i and T-tau concentrations increase in AD patients compared to healthy subjects.

[242] The medical head device according to the present invention may be beneficial to subjects of 65 years and older, who have been diagnosed with mild-to-moderate stage of Alzheimer's Disease, according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, and who are scoring between 16-26 at the Mini -Mental State Examination (MMSE).

[243] Mild-to-moderate Alzheimer subjects after having used the medical head device according to the present invention for 1 hour twice daily for at least two consecutive months with at least 7-hour interval between those daily uses, are expected to experience positive cognitive and executive changes, improvements of the quality of life with improved sleep, less anxiety and agitation, less apathy and/or improved mood and energy as well as decreased burden of the caregivers. [244] The subject may see improved cognitive performance of Alzheimer’s disease patients and reverse cognitive decline as measured by neuropsychological tests, or in any tests described in the Examples below, such as for example ADAS-cogl4, MMSE, or Rey AVLT (Rey Auditory Verbal Learning Test).

[245] In addition, synergistic effects are expected in terms of increased degradation and clearance of betaamyloid plaques and of amyloid beta oligomers in the plasma and the cerebrospinal fluid of the subject. More precisely, increased destabilization of insoluble amyloid-[3 plaques and/or neurofibrillary tangles within the brains of AD patients; and/or dissociation of insoluble amyloid-[3 deposits in senile plaques into soluble A[3 oligomers/monomers and/or of the neurofibrillary tangles; and/or elimination of the soluble A oligomers/monomers and tau monomers in the cerebrospinal fluid and plasma of AD patients.

[246] AD subjects are expected to have a change from baseline of Alzheimer's markers such as betaamyloid peptides 1-40 and 1-42, total tau (t-tau), and phospho-tau (p-tau) in blood and CSF prior and upon completing 2-month treatment with device described above. In particular, increased levels of AP1-40 and AP1-42 soluble monomeric peptides and of oligomeric Ap aggregates in the plasma and in cerebrospinal fluid (CSF) are expected following to a 2-month treatment with medical head device according to the present invention. Plasma and CSF levels of beta-amyloid peptides 1-40 and 1-42, total tau (t-tau), and phospho- tau (p-tau) may be easily analyzed using ELISA tests.

[247] Finally, said synergistic effects include increased synaptogenesis and neurogenesis through activation of brain derived neurotrophic factor (BDNF), as well as neuroprotection thru the reversal of apoptotic signaling processes by inhibiting glycogen synthase kinase 3 beta (GSK3beta).

[248] In addition, subjects early, mild or moderate Alzheimer or their caregivers may notice significant improvements in their sleep, less anxiety and agitation, less apathy and/or improved mood and energy.

[249] The medical device according to the present invention is in the form of a head-mounted wearable non-invasive device which may be placed on the head, in direct contact with the scalp and/or skull of a subject, thereby allowing homogeneous and reliable exposure of the cortex of the subject to said electromagnetic waves either alone or in combination with red and near-infrared lights. Such medical head device is useful for treating and/or preventing neurodegenerative proteinopathies and/or diseases and particularly useful for slowing and/or even reversing the symptoms of AD and PD. It may be used in combination with pharmaceutical treatments.

[250] According to the present invention, the frequency of the pulsed electromagnetic waves or field may range between 800 to 1500 MHz, or around 900 MHz, or 915 MHz. Cycle of repetition of the pulsed electromagnetic waves or field is within the range of 10 to 300 Hz, or 20 to 270 Hz, or 30 to 250 Hz, or 40 to 240 Hz, or 100 to 220 Hz, preferably around 40 Hz, 100 Hz, or 200 Hz. Preferably, the EM signal is pulsed every 4 to 5 milliseconds. Most preferably, the pulsed electromagnetic waves or field has a frequency of 915 MHz and is pulsed with a cycle of repetition around 200 Hz. [251] The specific absorption rate (SAR) may range between 0.5-10 W/kg. Most preferably, SAR values are between 1-8 W/kg, and more precisely around 1.5 or 2, or 3 W/kg. As described above, the brain temperature of said subject remains stable or is not significantly raised during and/or after exposure of said subject to said electromagnetic treatment.

[252] The duration of the exposure is continued according to a predetermined schedule which may be once a week, twice a week, or more for alternating days, daily or twice a day. The emitters or antennas may be active and the duration of the treatment per session may be between 5 minutes and 120 minutes, or around 15 minutes, around 30 minutes up to 1 hour per session. The treatment is a long-term treatment of at least 1 or 2 months or several months or longer for therapeutic efficacy. Preferred treatment protocol comprises a daily treatment of 1 hour per day for at least 2 months. Most preferred treatment includes 2 hours per day, 1 hour in the morning and 1 hour in the evening with a 7-hour interval in between for at least 2 months.

[253] The medical head device according to the present invention allows forthe patients to have complete mobility for moving throughout their home. Treatment may be administered in-home by patient’s caregiver (spouse, family member, nurse, etc..), rather than through an out-patient facility. It is a safe and easy-to-use device with a single switch on/off command and a pre-set 1-hour timing The subjects feel nothing, neither heat nor pain, during treatment. Patients may be seated and undergo another activity such as for example sleeping, reading, or watching television during the one-hour treatment.

[254] BTRFA, medical head devices, and methods according to the present invention are useful for treating and/or preventing, or for stabilizing and/or reversing the symptoms of neurodegenerative diseases chosen among Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), Frontotemporal dementia (FTD), Parkinson’s disease (PD), Creutzfeldt-Jacob disease (CJD), Dementia with Lewy bodies (DLB), Huntington’s disease (HD), and Amyloid Lateral Sclerosis (ALS). Treatment and/or prevention of these neurodegenerative diseases comprise alleviation of both brain pathologies and behavioral symptoms.

[255] BTRFA, medical head devices, and methods according to the present invention are particularly useful for stabilizing and/or reversing the symptoms of Alzheimer’s disease (AD), such as cognitive impairment due to AD.

[256] Reversing and/or stabilizing AD cognitive impairment may comprise a decrease of the rate of [3- amyloid and tau oligomer deposition, enhancing the mitochondrial functions within neurons of the subject, enhancing cognitive performance and/or function, enhancing the working or short-term memory performance of the subject, i.e., the ability of a subject to temporarily store and manipulate information or hold a small amount of information in mind in an active, readily available state for a short period of time, enhancing the neuronal oscillatory activity as measured by EEG: decreasing of Theta and Delta brain waves and increasing the Alpha and Beta brain waves of the subject, and thus the capacity of attention or focus of the subject. [257] Stabilization or even reversal of the symptoms of AD may be assessed by the level of Alzheimer’s markers such as Amyloid-P or tan oligomers in the blood, cerebrospinal fluid or brain of the subject. Neurochemical analysis may be conducted on plasma samples to assess the level of Amyloid-P 1-40 and Amyloid-P 1-42 using, for example Amyloid-P ELISA analysis.

EXAMPLES

Example 1: Pilot clinical phase for testing safety and efficacy of the medical head device on Alzheimer's disease

Example 1.1: Enrollment of patients

Device is intended for adults of 65 years and older, who have been diagnosed with mild or moderate stage of Alzheimer's Disease, according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, and who are scoring between 16-26 at the Mini -Mental State Examination (MMSE).

In addition, blood brain biomarkers (BBM), such as Ap42, Ap40, and tau are used as pre-screening tool to increase the prevalence of brain Ap and tau pathology before confirming the AD diagnostic. These BBM will be also used as main inclusion criterion to select patients for which BBM can achieve sufficiently high diagnostic performance. The BBM will be assessed by using a mass spectrometry-based plasma assay (LC- MS/MS), namely the PrecivityAD™ blood test which is marketed by company C2N (www.PrecivityAD.com). This test simultaneously quantifies plasma amyloid beta (AP) 42 and 40 (Ap42 and Ap40) concentrations and identifies the presence of plasma Apolipoprotein E (ApoE) isoform-specific peptides isoforms ApoE2, ApoE3, ApoE4 isoforms) to determine A OE genotype. The test’s statistical algorithm combines the AP42/40 ratio, established APOE genotype to determine status of patients’ brain amyloidosis. Studies have demonstrated that lower plasma Ap42/Ap40 ratio, in combination of the well- established risk factors of APOE4 status and age, correlate with brain amyloidosis as measured using amyloid PET imaging (references 16 and 17). Therefore, the Amyloid Probability Score (APS) based on the plasma AP42/40 ratio, APOE genotype (determined by the ApoE peptide isoforms) and patient age will be assessed to select patients having higher probability of brain amyloid burden. Subjects having a AP42/40 Ratio >0.089, the presence of apoE4 allele, and an APS ranging from 58-100 will be selected (see Table 1 below). The amyloid Probability Score (APS) represents the estimated likelihood from 0 (low likelihood) to 100 (high likelihood) that the patient is currently positive to amyloid PET imaging (presence of amyloid plaques) based on their AP42/40 ratio, age, and established APOE genotype.

Table 1: Example 1.2: Exclusion criteria

Subjects who are excluded include:

Patients with history of epileptic seizures or epilepsy;

Patients with metal implants in the head, (i.e. cochlear implants, implanted brain stimulators, aneurysm clips) with the exception of metal implants in mouth;

Patients with stroke, brain lesions, cerebrovascular condition, significant head trauma (loss of consciousness greater than half an hour, or related anterograde amnesia), multiple sclerosis; or personal history of previous neurosurgery or brain radiation;

Patients with any signs or symptoms of increased intracranial pressure, as determined in a neurological examination;

Patients with demonstrated brain micro-hemorrhages;

Patients with cardiac pacemakers;

Patients with implanted medication pumps;

Patients with significant heart disease.

Example 1.3: Indications for use

The medical head device according to the present invention is self-contained and has been designed for in- home daily treatment, allowing for complete mobility and comfort in performing daily activities during treatment. The device has a custom control panel that is powered by a rechargeable battery. This control panel/battery box may be worn on the upper arm and wired to specialized antennas in the headset worn by the subject. For each day of in-home treatment, the subject wears the headset for two one-hour treatment: 1-hour in the morning and 1-hour in the afternoon or evening with at least a 7-hour rest in between the treatment.

Example 2: Exploratory clinical phase and Intended outcomes and clinical benefits for Alzheimer’s disease patients

It is expected that Alzheimer's patients, most likely at the mild-to-moderate stage may see some improvements in one or more the following outcomes compared to baseline, after at least 2-month treatment with the medical device according to the present invention. This is expected to be reflected in a lesser burden for the caregiver and improved quality of life of the patients and family. In particular, changes from baseline at 2 months into treatment, in one of the following symptoms, mood and behavioral symptoms, depression, anxiety, irritability, inappropriate behavior, sleep disturbance, psychosis, and/or agitation are particularly expected.

Example 2,1: Mini -Mental State Examination (MMSE) The Mini -Mental State Exam (MMSE) is a brief, structured test of mental status that takes about 10 minutes to complete. It involves 11 questions that check for thinking, communication, understanding, and memory impairments. Specifically, the MMSE assesses six areas of mental abilities:

Orientation of time and place: Orientation to time and space is tested by asking the person if they know the time and date, where they are, the day of the week, the month, the year, and the season. Attention and concentration: The person's ability to concentrate throughout the exam is evaluated, as well as with tasks like spelling a word backward or counting backward from 100.

Short-term memory recall: Short-term memory is tested with such tasks as asking the person to memorize a series of items and then repeat them back.

Language skills: Word recall is tested, for example, by showing the person an object and asking them to name it.

Visuospatial abilities: Visuospatial abilities (a person's perception of 3D objects and their relationship to each other) are tested by asking the person to describe the spatial relationship, or distance, between two objects.

Ability to understand and follow instructions: The person may be given a series of tasks while their ability to follow instructions is evaluated.

Scores on the MMSE range from 0 to 30, with scores of 25 or higher being traditionally considered normal. Scores less than 10 generally indicate severe impairment, while scores between 10 and 20 indicate moderate dementia. People with early-stage Alzheimer's disease tend to score in the 20 to 25 range. The level of impairment and the impact of the executive functions are listed in the Table 2 below:

Table 2:

Mild-to-moderate Alzheimer’s subjects having above 65 years old and scoring between 16-26 at the MMSE are expected to show some improvements to their cognitive impairment.

Example 2,2: Alzheimer's Disease Assessment Scale-cognitive Subscale 14 (ADAS-Cog-Plus or ADAS- Cogl4) Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cogl4) is one of the most widely used cognitive scales in clinical trials and is the "gold standard" for assessing antidementia treatments. ADAS-Cogl4 consists of 14 competencies: word recall, commands, constructional praxis, object and finger naming, ideational praxis, orientation, word recognition, remembering word recognition instructions, comprehension of spoken language, word finding difficulty, spoken language ability, delayed word recall, number cancellation, and maze task. The ADAS-Cogl4 scale ranges from 0 to 90. Higher scores indicate greater cognitive impairment._ADAS-cog-14 tests include the series of subtests as listed in Table 3 below: Table 3:

Alzheimer’s disease subjects treated with the medical device according to the present invention are for at least a 2-month are expected to present enhanced cognitive performance. Indeed, compared to baseline, the average performance in the ADAS-cogl3 is expected to improve by over 4 points following 2-month treatment.

Example 2,3: CDR-SB score

The clinical dementia rating Sum of Boxes (CDR-SB) test may be used to follow the slowing effect of the medical device according to the present invention on the progression of the Alzheimer’s disease compared to baseline. This test may be applied to interventional trials for tracing the progression of cognitive impairment (CI) in the early or mild stage of Alzheimer’s disease. The CDR-SB is the sum score of six cognitive or functional domains, including memory, orientation, judgment and problem solving, community affairs, home hobbies, and personal care. Thus, function- and performance-based information is acquired simultaneously. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR-SOB score is obtained by summing each of the domain box scores, with scores ranging from 0 to 18 (higher score indicates greater cognitive impairment).

CDR-SB test after treatment of at least 2 months is expected to reflect a slowing and stabilization of the disease progression or even a reversion to normal cognition in treated Alzheimer’s disease subjects compared to baseline.

Example 2,4: Impact on the Quality-of-Life Scale in Alzheimer's disease (QOL-AD)

The QOL-AD is a standard quality of life measure that asks parallel questions of Alzheimer’s disease patients and their caregivers. The QOL-AD is a series of questions designed to be administered to individuals with dementia, to obtain a rating of a patient's quality of life from both the patient and the caregiver. It includes assessments of the individual's relationship with friends and family, concerns about finances, physical condition, mood, and an overall assessment of life quality.

Current quality of life is rated as poor (1 point), fair (2 points), good (3 points) or excellent (4 points) in 13 areas: physical health, energy, mood, living situation, memory, family, marriage, friends, self, ability to do chores around the house, ability to do things for fun, money, and life as a whole. Score ranges from 0 (worse quality of life) to 52 (best quality of life).

This outcome is a change of the score after treatment compared to baseline, derived by subtracting Baseline from scores after treatment. A higher change score = decline in perceived quality of life. A lower or negative change score = improved perceived quality of life.

Example 2,5: Impact on the Neuropsychiatric Inventory (NPI) score

NPI is a well-validated, reliable, multi-item instrument to assess psychopathology (e.g., behavioral symptoms) in AD based on a questionnaire completed by the participants' study partners/based on a standardized caregiver interview.

NPI assesses the frequency, severity and level of distress caused by 12 common dementia-related behaviors: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep, and appetite/eating.

Symptoms are rated in terms of frequency (l=rarely, <lx/week; 2=sometimes, ~lx/week; 3=often, several times/week; and 4=very often, >lx/day) and severity (l=mild; 2=moderate; 3=severe).

The composite symptom domain score (frequency x severity) ranges from 0 (no behavioral symptoms) to 144 points. The total NPI score ranges from 0 to 144. Caregiver distress is rated for each positive neuropsychiatric symptom domain (0=no distress; l=minimal distress; 2=mild distress; 3=moderate distress; 4=severe distress; and 5=very severe distress). Higher total NPI scores indicate more symptoms and/or more severe symptoms with more numerous, frequent, and/or more severe dementia-related behaviors.

Example 2,6: Change in the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS CGIC) score.

The ADCS CGIC gives the Clinician's assessment of the patient's response to the treatment. It is intended to be used as a measure of clinically meaningful change. The ADCS-CGIC focuses on clinicians' observations of change in the patient's cognitive, functional, and behavioral performance since the beginning of a trial. It relies on both direct examination of the patient and interview of the caregiver. Scored as marked/moderate/minimal improvement or worsening or no change.

Example 2,7: Change in the Electroencephalogram's (EEG)

The EEG recordings will give insight into the effect on the neural activity of the brain. It is recognized that Alzheimer's patients generally experience a slowing of their EEG activity with EEG waves as slow as theta or delta neuronal waves. It is expected that Alzheimer's patients undergoing treatment with the medical device according to the present invention increase their neuronal activity to alpha waves as well as their attention to their direct environment and discussions with their caregivers and family.

Example 2,8: Change in total sleep time/sleep efficiency

This can be easily assessed by analyzing the sleep data reported by an Actigraph activity monitor. The activity monitor may be attached to a wristband and worn by the subject through the study completion. Treated Alzheimer's disease patients are expected to show less agitation and anxiety in the late afternoon and to experience a better quality of their sleep.

Example 2,9: Change in Caregiver Burden Inventory (CBI)

The CBI is a standard measure that includes 24 items and 5 domains. Caregivers are asked to rate how often each statement describes their feelings (never, rarely, sometimes, quite frequently, nearly always). The total score may range from 0 to 96 with higher scores reflecting greater feelings of burden.

Example 2, 10: Change in Positive Aspects of Caregiving Scale

The Positive Aspects of Caregiving Scale is a standard measure that asks caregivers to rate their agreement/disagreement with 11 statements about positive aspects of caregiving on a 5-point scale (disagree a lot ... agree a lot). Scores can range from 11 (few positive aspects of providing care for someone with dementia) to 55 (many positive aspects of providing care for someone with dementia). This outcome is a change of the score after treatment from baseline.

Example 2, 11: Change in the clock-drawing test

The clock-drawing test is used for screening for cognitive impairment and dementia and as a measure of spatial dysfunction and neglect. The score ranges from 0 (none correct) to 5 (all correct). A score greater than or equal to 4 is considered "normal". The outcome is a change score from baseline after treatment.

Example 2, 12: Change in the CTT2/CTT1: Performance on Color Trails Test CTT is a non-verbal test of visual attention, graphomotor sequencing, and effortful executive processing abilities (i.e., sustained attention and set shifting).

Measure Description: The Color Trails Test (CTT) is a neuropsychological test that assesses frontal and executive functioning, while minimizing the cultural and language barriers inherent in similar measures such as the traditional Trail Making Test.

For test 1, the participant uses a pencil to rapidly connect circles numbered 1 through 25 in sequence.

For test 2, the participant rapidly connects numbered circles in sequence, alternating between two different colors.

The index is a ratio of the time it takes to complete the Color Trails Test (CTT) 2 over the time it takes to complete the CTT 1. The index provides a method for partialling out the effects of undivided attention and simple perceptual tracking on the alternating demands of CTT-2.

Higher index scores indicate greater interference, less cognitive flexibility.

A higher index score indicates less cognitive flexibility, a lower ability to shift attention.

Example 2, 13: Change in ADSL-ADL: Alzheimer's Disease Cooperative Study Activities of Daily Living ADCS-ADL assesses the competence of patients with AD in basic and instrumental activities of daily living (ADLs). It can be completed by a caregiver in questionnaire format or administered by a clinician/researcher as a structured interview with a caregiver. ADCS-ADL scores range from 0-53, with higher scores indicating greater independence.

Example 2, 14: Change in EQ-5D: European Quality of Life Scale

The EQ-5D is a standardized instrument for use as a measure of health outcomes. It includes measures of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems.

The EQ visual analogue scale (VAS) records the respondent's self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'. This information can be used as a quantitative measure of health as judged by the individual respondents.

Example 2, 15: Change in GPS: Geriatric Depression Scale FOR CAREGIVERS

This test consists in a short form for the caregivers comprising a 15 -item yes/no scale that measures depressive symptoms in older individuals. Scores range from 0-15. Higher scores reflect the presence of more depressive symptoms. A score of 0-5 is normal; a score > 5 suggests depression; a score > 10 is strong indicator of depression.

This outcome is a change score: Baseline GDS score - GDS score after treatment.

Example 2,16: Change in Positive Aspects of Caregiving scale The Positive Aspects of Caregiving Scale is a standard measure that asks caregivers to rate their agreement/disagreement with 11 statements about positive aspects of caregiving on a 5 -point like scale (disagree a lot ... agree a lot). Scores can range from 11 (few positive aspects of providing care for someone with dementia) to 55 (many positive aspects of providing care for someone with dementia).

This outcome is a change score: score after treatment - baseline score. A larger (or positive) change score = increase in positive aspects of caregiving. A negative (or smaller) change score = decrease in positive aspects of caregiving.

Example 2,17: Change in ADL SAD or ADSC-ADL-sev: Alzheimer's Disease Cooperative Study - Activities of Daily Living for Severe Alzheimer's Disease score

ADL SAD assesses the performance of activities of daily living by patients with Alzheimer's disease. The assessment includes 19 questions. Subscales will be summed to compute the total score. The total score ranges from 0 - 54 with higher scores indicating less functional impairment and greater competence. Example 2, 18: Changes in the Digit Span forward and Digit Span backward score.

The digit span test is a very short test that evaluates the Alzheimer’s patient’s cognitive status consisting in saying a series of numbers and asking the patients to repeat them back to you in the same order you say them. The first series is three numbers, such as "3, 9, 2." Each number is said in a monotone voice, one second apart. The person repeats those numbers back to you. The next step is to speak a series of four numbers, such as, "4, 7, 3, 1." Again, the individual repeats those back to you. The test is continued in the same manner by increasing the series of numbers to five and the patients are asked to repeat the numbers back to you. Some test versions stop after a series of five numbers, while other versions continue increasing the series of numbers by one each time until the answers are incorrect. Administering this test forward and backward allows to assess the short-term memory and the working memory.

It is expected that Alzheimer’s patients having received treatment with the medical device according to the present invention will improve their attention span and their short-term memory compared to baseline.

Example 2,19: Digital biomarkers

Assessment of the impact of the treatment with the medical device according to the present invention may be made by using digital biomarkers. These include real-time, continuous, and non-invasive home-based assessment of health-relevant activity and behavior using the Collaborative Aging Research Using technology (CART) platform developed by the Oregon Center for Aging & Technology (ORCATECH).

The CART platform is a multi-functional digital technology platform allowing to assess in real-time and in a non-obtrusive manner the health and wellness of Alzheimer’s patients. The platform comprises ambient technology, wearables, and other sensors installed in the homes of Alzheimer’s patients. The sensors include for example passive infrared sensors (motion activity detectors) which monitor the walking speed as well as the amount of time participants spend in each room of their home and how often they move around in their home; actigraphy watches are provided to measure the total activity; electronic pillboxes recording when and which pillbox doors are opened/closed; contact door sensors monitoring the amount of time spent outside of their homes, etc. . .

Such variety of home-based sensors are thus used to monitor the impact of the treatment with the medical device according to the present invention inter alia on the walking speed, the sleep activity, activity and social engagement, ?.e., time out of the home, mobility patterns of the patients within their homes (e.g., reflecting agitation, apathy, depression), computer use, medication-taking adherence, driving patterns, metadata from online behavior. Alzheimer's patients and their caregivers are expected to notice a decrease in agitation and anxiety, and improvement of sleep, a higher attention span which may improve computer use, social engagement, medication-taking adherence.

Example 3: Changes in plasma levels of a combination of fluid biomarkers prior and upon completing the 2-month treatment

Following plasma levels of a combination of biomarkers allows precise monitoring of the disease progression and treatment response.

Several tests either based on the Elisa technique or mass spectrometry may be used.

By way of example, the PrecivityAD2™ blood test from the company C2N (www . Preci vity AD . com) is used to measure plasma Ap42 and Ap40, as well as plasma total tau (T-tau), and plasma phosphorylated tau 217 (pTau217) and calculate the plasma Ab42/40, plasma pTau217/non-phospho-tau217 ratio, and Amyloid Probability Score-2. Indeed, the ratio plasma Ap42/Ap40 has been shown to reflect amyloid removal. Also, plasma p-tau217 reduction was evidenced to correlate with changes in amyloid and tau load (references 22- 23). In addition, plasma biomarkers Ap42, Ap40, Glial Fibrillary Acidic Protein (GFAP) and Neurofilament light chain (Nf-L) are measured using the Simoa multiplex Bead-Based Advantage Assays of Quanterix (Neurology 4-Plex E; catalog numberl03670) to monitor the effects of the disease modifying treatment at 2 months after treatment.

Amyloid Ap40 is a 40 amino acid proteolytic product from the amyloid precursor protein (APP) that has gained attention as a biomarker correlating with Alzheimer disease (AD) onset, mild cognitive impairment, vascular dementia, and other cognitive disorders. Beta-secretase cleavage of APP initially results in the production of an APP fragment that is further cleaved by gamma-secretase at residues 40-42 to generate two main forms of amyloid beta, Ap40 and Ap42. Amyloid beta (AP) peptides (including a shorter Ap38 isoform) are produced by different cell types in the body, but the expression is particularly high in the brain. Accumulation of Ap in the form of extracellular plaques is a neuropathological hallmark of AD and believed to play a central role in the neurodegenerative process. Ap40 is the major amyloid component in these plaques and is thought to be an initiating factor of AD plaques. In healthy and disease states Ap40 is the most abundant form of the amyloid peptides in both cerebrospinal fluid (CSF) and plasma (10-20X higher than Ap42). Recent studies suggest that a decrease in the ratio of Ap42/Ap40 may indicate AD progression. Ap42 is a 42 amino acid proteolytic product from the amyloid precursor protein that has gained considerable attention as a biomarker correlating with Alzheimer disease (AD) onset, mild cognitive impairment, vascular dementia, and other cognitive disorders. Amyloid beta (Ap) peptides (including the shorter Ap38 and Ap40 isoforms) are produced by many cell types in the body but the expression is particularly high in the brain. Accumulation of Ap in the form of extracellular plaques is a neuropathological hallmark of AD and thought to play a central role in the neurodegenerative process. Substantial clinical validation has now been developed around disease relevance of cerebrospinal fluid (CSF) levels of Ap42, and there follows a significant interest in measuring blood levels of this marker. Concentrations of Ap42 in blood are over 100- fold lower than in cerebrospinal fluid, (typically single pg/mL range), requiring very high analytical sensitivity for its reliable measurement.

Glial Fibrillary Acidic Protein (GFAP) is a class-III intermediate filament majorly expressed in astrocytic glial cells in the central nervous system. Astrocytes play a variety of key roles in supporting, guiding, nurturing, and signaling neuronal architecture and activity. Monomeric GFAP is about 55kD. It can form both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with neurofilament protein (such as NF-L). GFAP is involved in many important CNS processes, including cell communication and the functioning of the blood brain barrier. As a potential biomarker, GFAP has been shown to associate with multiple diseases such as traumatic brain injury, stroke, brain tumors, etc. . .

Neurofilament light (NF-L) is a 68 kDa cytoskeletal intermediate filament protein that is expressed in neurons. It is associated with the 125 kDa Neurofilament medium (NF-M) and the 200 kDa Neurofilament heavy (NF-H) to form neurofilaments. They are major components of the neuronal cytoskeleton and are believed to function primarily to provide structural support for the axon and to regulate axon diameter. Neurofilaments can be released in significant quantity following axonal damage or neuronal degeneration. Example 3, 1: Level of AB1-40 and AP1-42 soluble monomeric peptides and of oligomeric AB aggregates in the blood and CSF

Level increase of AP1-40 and AP1-42 soluble monomeric peptides and of oligomeric Ap aggregates are expected to peak in the blood and cerebrospinal fluid (CSF) of subjects after completion of the 2-month treatment with a medical head device according to the present invention. This is consistent with an induced dissociation of both soluble oligomeric and insoluble Ap aggregates in the brain. Such dissociation includes not only dissociation of oligomeric Ap inside of the neurons but also dissociation of insoluble Ap deposits in senile plaques into soluble Ap oligomers/monomers with the resulting increase in CSF as they are making their way to the CSF.

Plasma levels of AP42

Although Ap42 is present in plasma, it is unclear whether it originates from peripheral sources or from the brain. Because Ap can be transported bidirectionally across the blood-brain barrier, it has been hypothesized that there may be an equilibrium between CSF and plasma pools of Ap. Decreased levels of Ap42 in CSF occur in conjunction with cognitive decline. However, patients with mutations in chromosome 21 that cause early-onset familial AD and patients with trisomy 21 have increased levels of plasma Ap42 before the onset of the symptoms of dementia. Therefore, it is possible that plasma Ap42 levels increase with cognitive decline.

The change score is determined by calculating the ratio of plasma Ap42 after treatment over baseline.

CSF levels of AP42

Ap42 is a biomarker of AD pathology. CSF levels of Ap42 decrease in conjunction with the cognitive decline. The change score is determined by calculating the ratio of CSF Ap42 after treatment compared to baseline. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF levels of Ap42 compared to baseline.

Example 3,2: Level of total tau protein (t-tau)

In addition, 2 months of TEMT resulted in some increase in plasma t-tau (total tau protein) levels. Since soluble t-tau is almost totally monomeric tau, this increase reflected that the TEMT also induced a dissociation of the tau tangles and thus an increase in monomeric tau within plasma of the treated Alzheimer disease subjects who received TEMT.

Plasma level of Tau

Tau, the microtubule-associated protein, forms insoluble filaments that accumulate as neurofibrillary tangles in Alzheimer's disease (AD). Research suggests that plasma tau levels increased with AD severity. The change score is determined by calculating the ratio of plasma tau after treatment over the baseline plasma tau levels. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in plasma tau compared to baseline.

CSF level of Tau

Tau forms insoluble filaments that accumulate as neurofibrillary tangles in AD. Increased levels of tau in CSF are a key characteristic of AD and is considered to result from neurodegeneration. The change score is determined by calculating the ratio of week 16 CSF tau over baseline CSF tau. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF tau compared to baseline.

Example 3,3: Levels of Neurofilament Light Chain (NfL)

Plasma Levels of NfL

NfL is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. The change score is determined by calculating the ratio of plasma levels of NfL after treatment over the baseline levels of plasma NfL. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in plasma levels of NfL compared to baseline.

CSF Levels of NfL There is a strong relationship with cerebrospinal fluid (CSF) NfL, suggesting that these biomarker modalities reflect the same pathological process. The change score IS determined by calculating the ratio of week CSF NfL over baseline CSF NfL. Thus, a change score of 1 signifies no change compared to baseline and change scores < 1 or > 1 reflect a decrease or an increase in CSF NfL compared to baseline.

Example 4: Potential disease modifying treatment in subjects at risk

The objective is determine whether the treatment with the medical device according to the present invention may prevent or slow the rate of amyloid beta (Ap) pathological disease accumulation demonstrated by A positron emission tomography (PET) imaging and by assessing fluid biomarkers of Alzheimer’s disease such as the ratio AP42/ AP40, total tau, p-tau, NfL in blood (plasma) and/or in the cerebrospinal fluid (CSF) compared to a control group.

During enrollment, participants undergo longitudinal assessments that include clinical assessment, cognitive testing, magnetic resonance imaging (MRI) and amyloid imaging, and analysis of cerebrospinal fluid (CSF).

This study will enroll individuals who are either known to have a known disease-causing mutation, or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. This study will enroll participants who are asymptomatic and are within a specific window of time of expected age at onset for their family and/or mutation.

The ability to identify individuals destined to develop Alzheimer's disease with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Participants of the study have not yet developed any symptoms of Alzheimer's disease. They are "asymptomatic" carriers of mutations and are expected to perform normally on standard cognitive and functional testing. Further, most mutation carriers have levels of Alzheimer's disease associated amyloid beta (AP) and non-A biomarkers that are the same as non-carriers. Imaging and/or fluid biomarkers are used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes may be also collected.