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WO2025040638A1 - Nouveaux applicateurs radiofréquence de tissu cellulaire, dispositif de tête et utilisations associées - Google Patents

Nouveaux applicateurs radiofréquence de tissu cellulaire, dispositif de tête et utilisations associées Download PDF

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Publication number
WO2025040638A1
WO2025040638A1 PCT/EP2024/073241 EP2024073241W WO2025040638A1 WO 2025040638 A1 WO2025040638 A1 WO 2025040638A1 EP 2024073241 W EP2024073241 W EP 2024073241W WO 2025040638 A1 WO2025040638 A1 WO 2025040638A1
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Prior art keywords
body tissue
btrfa
head device
head
subject
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English (en)
Inventor
Sinisa Jovanovic
Patricia LECCA
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Neurocia Sas
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Neurocia Sas
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Priority to US19/055,896 priority Critical patent/US20250262446A1/en
Publication of WO2025040638A1 publication Critical patent/WO2025040638A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/06—Electrodes for high-frequency therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/40—Applying electric fields by inductive or capacitive coupling ; Applying radio-frequency signals

Definitions

  • the present invention relates to novel body-tissue radiofrequency applicators and non- invasive medical head device useful for treating, preventing, stabilizing and/or reversing the symptoms of dementia and/or neurodegenerative diseases such as Alzheimer’s disease, mild cognitive impairment, cerebral amyloid angiopathy Parkinson’s disease, Lewy body dementia, and frontotemporal dementia, in a subject in the need thereof.
  • the present invention also relates to a novel body-tissue radiofrequency applicators and non-invasive head device useful for treating, preventing and/or alleviating traumatic brain injury (TBI), concussions, and other types of neurological conditions, in a subject in the need thereof.
  • TBI traumatic brain injury
  • the medical head device according to the present invention is further useful for treating, preventing and/or mitigating depression, migraine headaches, myodesopsia, and/or tinnitus, in a subject in the need thereof.
  • the present invention further relates to a wellness head device useful for general wellness purposes, particularly for relieving headaches and signs of fatigues, and/or enhancing general mental and cognitive abilities.
  • Alzheimer’s disease and Parkinson’s disease are among the most common neurodegenerative proteinopathies. While these conditions share some underlying pathological mechanisms, the specific psychological and physiological symptoms vary depending on the affected brain regions.
  • NIBS non-invasive brain stimulation
  • DBS deep brain stimulation
  • NIR near- infrared
  • NIBS includes methods such as 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).
  • ECT electroconvulsive therapy
  • TMS transcranial magnetic stimulation
  • rTMS repetitive transcranial magnetic stimulation
  • tACS transcranial alternating current stimulation
  • CES cranial electrotherapy stimulation
  • tDCS transcranial direct current stimulation
  • TTT transcranial electromagnetic treatment
  • REMFS repeated electromagnetic field shock
  • PBM photobiomodulation
  • NIBS-based medical devices have their components — such as coils, antennas, lasers, or LEDs, which generate electrical, magnetic, electromagnetic, or red/NIR stimulation signals — are often not designed for efficient transcranial administration in humans. These components tend to be too large and bulky for the average human head, failing to provide precise cortical targeting or sufficient signal penetration within the cortex.
  • the size and shape of the antennas and coils in current NIBS head devices are not conducive to regular, convenient use, particularly in home settings.
  • many existing NIBS devices are large, cumbersome apparatuses that require patients to visit hospitals regularly for transcranial brain stimulation treatments. This is not only inconvenient but often impractical for patients suffering from neurodegenerative diseases, who may find it difficult or even impossible to access such treatments on a regular basis.
  • NIBS-based medical devices must efficiently deliver energy into human tissue — such as the head — in a manner that ensures homogeneous distribution and sufficient depth of penetration into cerebral structures. Additionally, these components must be adaptable to the curvature of body tissues, whether it is the human head or other parts of the body, without compromising power efficiency, minimizing energy emission into free space. This is particularly important when the brain of a human subject is targeted.
  • the present invention represents a significant advancement in the field, offering components such as body tissue applicators and non-invasive medical head devices that effectively and reliably deliver electromagnetic signals or a combination of neuro stimulatory signals with high efficiency in terms of absorption and penetration within human tissue, particularly the head. These devices ensure a reliable, homogeneous, and efficient specific absorption rate (SAR), crucial for therapeutic efficacy.
  • the non-invasive medical or wellness head device of the present invention is available in the form of a head device, headset, or compact headcap. Not only is it lightweight and suitable for regular home use, but it also generates a consistent and homogeneous transcranial signal, ensuring effective coverage and penetration within the patient’s cortex.
  • the non-invasive medical head device is designed to stabilize and/or reverse the symptoms of neurodegenerative diseases and proteinopathies, particularly in conditions such as Alzheimer’s disease and Parkinson’s disease.
  • the present invention thus provides novel body tissue radiofrequency applicators (BTRFA) and non-invasive medical device comprising said one or more of said body tissue radiofrequency applicators which are specifically designed for directly administering a homogeneous pulsed electromagnetic signal to a specific body tissue, such as the head or the abdomen, of a human subject.
  • BTRFA body tissue radiofrequency applicators
  • TRFA body tissue radiofrequency applicators
  • the present invention also provides a novel non-invasive 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.
  • the non-invasive medical device according to the present invention is preferably 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.
  • Novel body tissue radiofrequency applicators and non-invasive medical head device are particularly useful for treating and/or preventing neurodegenerative diseases as well as for stabilizing and/or reversing the symptoms of neurodegenerative diseases such as Alzheimer’s disease, mild cognitive Impairment (MCI), Parkinson’s disease, cerebral amyloid angiopathy, dementia with Lewy bodies (DLB), and frontotemporal dementia in a subject in the need thereof.
  • the present invention also relates to novel body tissue radiofrequency applicators and/or non-invasive medical head device for treating and/or preventing and/or alleviating symptoms of traumatic brain injury (TBI), concussions (mild TBI) and other types of neurological conditions in a subject in the need thereof.
  • the present invention further relates to novel body tissue radiofrequency applicators and/or non-invasive medical head device for preventing and/or reducing or eliminating depression or the symptoms of depression, delaying, reducing and/or eliminating depression and its symptoms, reducing and/or relieving migraines, reducing and/or mitigating myodesopsia and vitreous opacities, and/or tinnitus (hardness of hearing) in a subject in the need thereof.
  • the novel body tissue radiofrequency applicators and/or non-invasive head device according to the present invention may be used by healthy patients for general wellness purposes, particularly for relieving headaches and signs of fatigues, and/or enhancing general mental and cognitive abilities.
  • FIG. 1A-B shows a complete schematic view of the X-BTRFA with a coaxial connector structure according to Figure 2 and with meandered antenna wire.
  • FIG. 2 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.
  • Figures 2A-B 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.
  • FIG. 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.
  • Figure 4 shows antenna gain of X-BTRFA surrounded by free space at 0.915 GHz.
  • 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.
  • 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.
  • Figure 7 is a simulation of the SAR(lg) for X-BTRFA placed close to body tissue at 0.915 GHz.
  • FIG. 8A-B 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.
  • FIG. 9 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.
  • Figures 9A-B 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 9 A in a connection to PCB.
  • FIGS 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).
  • Figure 11 is a simulation showing the antenna gain of Y-BTRFA surrounded by free space at 0.915 GHz.
  • 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.
  • 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.
  • Figure 14 is a simulation of the SAR(lg) for Y-BTRFA placed close to body tissue at 0.915 GHz.
  • FIG. 15A-B 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.
  • Figures 16A-B (A) represents the simulation SI 1 parameter results of printed X-BTRFA close to the body tissue. (B) represents simulation SI 1 parameter results of printed Y-BTRFA close to the body tissue.
  • 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.
  • FIGS. 18A-B show 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.
  • 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.
  • FIG. 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.
  • FIG. 21A-B shows a complete view of the Z-BTRFA of Figure 21B with a coaxial connector structure according to Figure 22 and with simple looped antenna wire.
  • FIG. 21B 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 .
  • Figures 22A-B 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.
  • 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.
  • Figure 24 is a simulation showing the antenna gain of Z-BTRFA surrounded by free space or air at 0.915 GHz.
  • 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.
  • 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.
  • Figure 27 is a simulation of the SAR(lg) for Z-BTRFA placed close to body tissue at 0.915 GHz.
  • 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).
  • BTRFA X-BTRFA
  • Y-BTRFA 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).
  • 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 SI 1 -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.
  • 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.
  • Figures 31 A-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Figures 40A-B are schematics 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.
  • Figures 41A-B are schematics of an exemplary arrangement of the arrays of combined units of BTRFAs and LEDs as shown in Figure 20.
  • 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.
  • FIG 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.
  • RF generator VCO - Voltage Controlled Oscillator
  • (2) corresponds to amplifiers
  • (3) corresponds to the Resistive RF power divider
  • Figures 44A-B are schematic views of large highly meandered X-BTRFA (50) working at 50-100MHz made of wire or flexy PCB (60), having two halves (70) and X-type central connection (90).
  • A shows the X-BTRFA with X- type central connection realized on a separate piece of rigid PCB (which is a part of a larger PCB containing output RF amplifier), while
  • B shows the X-BTRFA placed close to a rectangular sample of body tissue, for example positioned at 3 mm distance above the body tissue sample.
  • FIG. 45A shows a schematic view of the structure of a highly meandered BTRFA operating in the 50-100 MHz frequency range.
  • This BTRFA is made on a flexible PCB with a thin dielectric layer (60) containing a long elastic central strip (61) with 92 elastic branches (62) orthogonally attached to the central strip.
  • the dielectric layer serves as a base for two identical halves of conductive meandered transmission lines (70) that form the BTRFA structure.
  • the conductive lines (72) that form the BTRFA consist of a thin layer of copper with a width of 0.7 mm and a thickness of 0.035 mm.
  • the central elastic strip (61) allows the BTRFA structure to bend along its longer axis, as shown in Figure 45B, while the elastic orthogonal branches enable bending in the plane orthogonal to the longer axis of the BTRFA. Combining these two types of bending allows the BTRFA to conform to the curvature of the human head and to be positioned at an approximately constant distance (around 3 to 5 mm) from the curved surface of the head.
  • FIG. 46A-B shows a bottom detailed view of the central coaxial connector structure of a large PCB BTRFA (50) working at 50-100MHz.
  • the central PCB connection showed in (A) is X-type and in (B) is Y-type.
  • Both PCB connections comprise a printed circuit board comprising an RF input microstrip line (180), a first electrically conductive layer (190), a second electrically conductive layer (210) and a dielectric layer (220) separating the first and second electrically conductive layer (190, 210).
  • End points Al, A2, Bl and B2 of the two PCBs or 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).
  • (B) shows a zoomed out bottom view of the large meandered BTRFA made of PCB with the central coaxial connector switch.
  • FIGS 47A-C shows one quarter of the BTRFA operating in the 50-100 MHz frequency range. The figure illustrates how the conductive lines (72) meander along the edges of the dielectric elastic branches (62).
  • the dielectric substrate (60) has mechanical vias (64) that serve to attach the BTRFA to the housing in which it is placed. This housing can be made of either fabric or lightweight plastic.
  • (B) shows the central part of the BTRFA with four connection points (Al , A2, B 1 , and B2) to which the RF excitation signal is applied. There are metallized vias (74) on the conductive lines (72).
  • vias allow the total length of the BTRFA transmission line to be shortened and its operating frequency to be changed by appropriately connecting the corresponding pairs of vias (which are symmetrical with respect to the center of the BTRFA) using pairs of conductive shorting connectors (76), as shown in (C).
  • Figure 48 shows the frequency characteristic of the reflection coefficient obtained from the electromagnetic simulation of the BTRFA structure shown in Figure 44B, indicating good matching at 48.94 MHz and 95 MHz.
  • Figures 49A and 49B show the power distribution of the same BTRFA at the resonant frequencies of 48.94 MHz and 95 MHz.
  • Figure 49A indicates that at 48.94 MHz (marked with a vertical line in Fig. 49A), the BTRFA placed close to body tissue accepts 88.8% (0.444/0.5) of the total available power (0.5 W), while about 11.11% (0.0555/0.5) is reflected back to the RF generator. Approximately 69.99% (0.349/0.5) of the power accepted by the BTRFA is delivered to the body tissue. The metal loss is about 18.92% (0.0496/0.5), which is higher than for the BTRFA at 915 MHz due to the very long and thin conductive line.
  • Figure 49B shows that at 95 MHz (marked with a vertical line in Fig. 49B), the BTRFA placed close to body tissue accepts 80.2% (0.401/0.5) of the total available power (0.5 W), while about 19.8% (0.09899/0.5) is reflected back to the RF generator. Approximately 58.5% (0.2925/0.5) of the power accepted by the BTRFA is delivered to the body tissue [61]
  • Figure 50 shows the power distribution for the BTRFA surrounded by free space. It can be seen that at both frequencies (around 50 MHz and around 100 MHz, marked by vertical lines) where resonance occurred when the BTRFA was near a sample of body tissue the entire RF signal power was reflected back to the generator, as was the case with the BTRFA designed for 915 MHz. This demonstrates that all presented BTRFAs achieve efficient RF energy transfer only to the body tissue in their immediate vicinity.
  • Figures 51 A-B are schematics of an exemplary arrangement of two large meandered BTRFAs working at 50-100 MHz, each BTRFA unit being positioned on each side of the head, thereby covering the brain, namely frontal, parietal, occipital lobes.
  • A is a side view of the head.
  • B is a front view of the head.
  • 52A is a top view of the head, 51B is a right view of the head.
  • Figures 52A-B are schematics of an exemplary arrangement of two large meandered BTRFAs working at 50-100 MHz, each BTRFA unit being positioned on each side of the head, thereby covering the brain, namely frontal, parietal, occipital lobes.
  • A is a top view of the head.
  • B is a side view of the head.
  • Figure 53 shows the SAR distribution of the signal at 50 MHz achieved using two BTRFAs arranged as shown in Figures 51 and 52, around a simplified model of the human head.
  • the generator power is set so that the maximum SAR value is limited to 2 W/kg (1g).
  • (A) shows the shaded area where the SAR value exceeds 0.5 W/kg (1g)
  • (B) shows the shaded area where the SAR value exceeds 0.2 W/kg (1g). It can be seen that the presented BTRFAs achieve a very deep penetration of the RF signal at 50 MHz.
  • Figure 54 shows the SAR distribution of the signal at 100 MHz on the same model.
  • the generator power is set so that the maximum SAR value is limited to 2 W/kg (1g).
  • (A) shows the shaded area where the SAR value exceeds 0.2 W/kg (1g) using the X type BTRFA.
  • (B) shows the shaded area where the SAR value exceeds 0.2 W/kg (1g) using the Y type BTRFA.
  • a solid penetration depth is achieved, but it is somewhat lower than in the case of stimulation with the same BTRFA at 50 MHz.
  • Figures 55A-B are schematics of the external global design the non-invasive head device of the present invention which is present in the form of a compact hat (or “augmented hat”).
  • A) is a side view and
  • B) is a top view.
  • 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.
  • body tissue radiofrequency applicators 50 are referred hereinafter as BTRFA or BTRFAs when plural.
  • Body tissue radio frequency applicators (50) are configured for emitting a pulsed RF electromagnetic signal to an adjacent human tissue at a frequency in a range of 20 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 20 and 3000 MHz.
  • the body tissue radiofrequency applicator 50 comprises a wire or PCB structure 60 for being positioned adjacent to or in proximity to said human tissue.
  • the wire or PCB structure 60 has an overall bow tie shape, or a butterfly shape, or highly meandered compact shape (as shown in Figures 1 A, 50 and 51) 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 or a PCB 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.
  • said at least two sections or two halves 70 of said applicator 50 are symmetrical.
  • the wire or PCB 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 or PCB 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 or PCBs 80 being connected to said inner coaxial or first conductor structure 100 and a second end of each of these wires or PCBs 80 being connected to said outer coaxial or second conductor structure 110.
  • 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 or PCBs 80 being connected to said inner coaxial or first conductor structure 100 and a second end of each of these wires or PCB
  • the ends of the wires or PCBs 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 or PCBs 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.
  • the ends of the wires or PCBs 80 may be 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, 9, and 47.
  • the ends of the wire or PCB 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 or PCBs 80 being connected to the outer coaxial or second conductor structure 110 thereby form a V-shaped line and the ends of the wires or PCBs 80 being connected to the inner coaxial or first conductor structure 100 thereby form a V-shaped line.
  • both ends of the wire or PCB 80 in one half of the wire or PCB 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.
  • Figure 21B 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 or PCB structure 60 with the applicator wires/PCBs 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 21A with the ends Al, A2, Bl 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.
  • 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 21B in a connection to PCB.
  • the end points Al, A2, Bl and B2 of the two wires or PCBs 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.
  • a bottom GND layer 210 and a dielectric substrate 220 is also shown.
  • Figure 21A shows a complete view of the Z-BTRFA 140 of Figure 21B with a coaxial connector structure 90 according to Figure 22A or according to Figure 22B and with simple looped antenna wire.
  • the BTRFA (50) when the BTRFA (50) according to the present invention may comprise a central coaxial connector structure having a central PCB connection showed either X-type and or Y-type.
  • the BTRFA made of PCB may comprise a central coaxial connector switch allowing to switch from one X-type connection to the Y-type connection and the other way around without the need of replacing the entire BTRFA within the head device.
  • By adding an RF switch to the output circuit of the transmitting RF amplifier it is possible to establish a connection with the feed points Al, A2, Bl, and B2, which can alternately exhibit the characteristics of the X and Y feeding modes of the BTRFA.
  • Both PCB connections may comprise a printed circuit board comprising an RF input microstrip line (180), a first electrically conductive layer (190), a second electrically conductive layer (210) and a dielectric layer (220) separating the first and second electrically conductive layer (190, 210).
  • End points Al, A2, Bl and B2 of the two PCBs or 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).
  • the BTRFA operating at the 50-100 MHz frequency range may have a fully and compactly meandered structure BTRFA.
  • such large BTRFA may be made on a flexible PCB with a thin dielectric layer (63) comprising a long elastic central strip (61) with several elastic branches (62) orthogonally attached to the central strip (61).
  • the dielectric layer (63) may serve as a base for two identical halves of conductive meandered transmission lines (70) that form the BTRFA structure.
  • the conductive lines (72) that form the BTRFA consist of a thin layer of copper which may have for example a width of less than 1mm, for example around 0.7 mm and a thickness of less than 0.05 mm, for example around 0.035 mm.
  • the central elastic strip (61) allows the BTRFA structure to bend along its longer axis, as shown in Figure 45B, while the elastic orthogonal branches enable bending in the plane orthogonal to the longer axis of the BTRFA. Combining these two types of bending allows the BTRFA to conform to the curvature of the human head and to be positioned at an approximately constant distance (around 3 to 5 mm) from the curved surface of the head.
  • such large BTRFA when operating in the 50-100 MHz frequency range, such large BTRFA may be made on a flexible PCB with a thin dielectric layer (63) comprising a long elastic central strip (61) with several elastic branches (62) orthogonally attached to the central strip (61) and may comprise conductive lines (72) meander along the edges of the dielectric elastic branches (62).
  • the dielectric substrate (63) may comprise mechanical vias (64) positioned at the extremities of the elastic branches (62) away from the central strip (61) and outside of the conductive lines (72).
  • Such mechanical vias (64) may serve to attach the BTRFA to the housing in which it is placed.
  • This housing may be made of either fabric or lightweight plastic.
  • the central part of the BTRFA may have four connection points (Al, A2, Bl, and B2) to which the RF stimulatory signal is applied.
  • the BTRFA may also comprise metallized vias (74) placed on the conductive lines (72) at the other the extremities of the elastic branches (62) close to the central strip (61).
  • the BTRFA may further comprise conductive shorting connectors (76) allowing to connect corresponding pairs of metallized vias (74) facing to each other’s (which are symmetrical with respect to the center of the BTRFA), thereby allowing the total length of the BTRFA transmission line to be shortened and its operating frequency to be changed by appropriately connecting the corresponding pairs of vias (which are symmetrical with respect to the center of the BTRFA) as shown in Figure 47C.
  • Body tissue radio frequency applicators or antennas 50 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 20 to 200 MHz, or 50 to 150MHz, or 100-150MHz, or 500 to 1500 MHz, or 800 to 1500 MHz, or 900 to 1000 MHz and most preferably around 900 MHz, or around 915 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 around 50-100 MHz or around 900-915 MHz and is pulsed with a cycle of repetition around 100-200 Hz.
  • 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.
  • EMC electromagnetic compatibility
  • Fig. IB and Fig. 8B show two versions of BTRFA.
  • Each version consists of two conductive wire or PCB loops.
  • the length of each of the conductive wire of PCB loops is preferably approximately (at f c ), which is the free space wavelength of the RF signal delivered to body tissue, at its operating central frequency (f c ).
  • f c 915 MHz
  • the length of each conductive wire or PCB loop would be around 328 mm.
  • f c 50 MHz, the length of each conductive wire or PCB loop would be around 6000 mm.
  • 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).
  • 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 x 0.8 mm), or square (0.5 mm x 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.
  • 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.
  • the BTRFA can be realized on flexy PCBs and integrated with rigid PCBs containing active electronic components of the device.
  • BTRFA of the present invention are preferably made of flexy PCBs.
  • 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.
  • 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 Figures 2B, 9B, 46A, and 47A.
  • connective points Al, A2, Bl, B2 can be connected to the RF feeding transmission line 150 in two different ways as illustrated in Figures IB, 8B, 2, 9, 46A, and 47A.
  • the first connecting way, shown in Fig. IB, 2A, 2B, and 46A assumes connection between points A2 and Bl 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, 2A, and 46A resembles the shape of letter X and therefore this type of BTRFA is named X-type BTRFA 130.
  • the second connecting way shown in Fig. 8B, 9A, 9B, and 47A 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.
  • 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.
  • 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.
  • 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).
  • W/kg watts per kilogram
  • 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.
  • 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.
  • BTRFA working at 915 MHz sizes may range from (20 mm to 300 mm) x (20 mm to 300 mm).
  • Small size BTRFA may be positioned for example on the top of the head from ear to ear, thereby covering for example the temporal and parietal lobes of a brain subject.
  • BTRFA working at 50-100 MHz may have sizes 10 times larger so that a single BTRFA may be designed so as to cover the entire head of the patient.
  • 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.
  • the BTRFA according to the present invention operating at frequency band ranging from 50MHz to 100 MHz and thus has a total wire or PCB length in a range of 2000 to 8000mm, or 3000 to 7000 mm, or around 3000 mm for BTRFA 100 MHz and 6000mm for BTRFA 50Mhz.
  • BTRFAs according to the above preferred embodiments, e.g., X-BTRFAs 130, Y-BTRFAs 120 or Z-BTRFAs 140 may have different efficiency and Specific Absorption Rate (SAR) within the human body tissue.
  • SAR Specific Absorption Rate
  • the BTRFA according to the present invention may have central connections having a “X” connection shape between the conductors and the central antenna wires.
  • 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 or PCB structure 60 with the applicator wires or PCBs 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 or PCBs 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 Figures 2B and 46A with the ends Al, A2, Bl and B2 of the applicator wires/PCBs and the central coaxial connector structure 90.
  • Figures 2B and 46A show 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.
  • the end points Al, A2, Bl and B2 of the two wires or PCBs 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.
  • a bottom GND layer 210 and a dielectric substrate 220 is also shown.
  • Figure 1 A 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 Figures 2B, 44 and 47 and with meandered wire or PCB applicator.
  • 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.
  • the X-BTRFA 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).
  • 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.
  • X-BTRFA exhibited a specific shape of the body tissue that accepted the SAR larger than 2 W/kg (Figure 7).
  • 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.
  • the BTRFA according to the present invention may have central connections having a “Y” connection shape between the conductors and the central applicator 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.
  • the body tissue radio frequency applicator or antenna 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.
  • Figures 9 and 47A show 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.
  • Figures 9B and 47A show 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.
  • 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.
  • a bottom GND layer 210 and a dielectric substrate 220 are also shown.
  • Figures 8A and 47A show a complete view of the Y-BTRFA 120 of Figure 8B with a coaxial connector structure 90 according to Figure 9A or according to Figures 9B and 47A with meandered applicator wire or PCB .
  • Y-BTRFA 120 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).
  • 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).
  • X-BTRFA 130 and Y-BTRFA 120 have high performance or efficiency when placed adjacent to human body tissue, which are dielectric objects having large dielectric constant with specific conductivity.
  • 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.
  • 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.
  • X-BTRFA 130 has central symmetry while Y-BTRFA 120 has axial symmetry.
  • 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.
  • Y-BTRFA 120 also delivered radio frequency 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.
  • 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.
  • 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.
  • 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.
  • BTRFA may be made as printed antenna consisting of thin metal strips printed on a thin dielectric substrate.
  • 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 ( Figures 15A and 45).
  • 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 Figure 46A) and the Y connection ( Figure 15B, right side and Figure 47 A).
  • 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%.
  • 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).
  • BTRFA 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 (Xo/2@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.
  • FIG. 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 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 wire 80 forming the wire structure 60 that are connected to the coaxial connector structure 90.
  • Figure 22 A 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.
  • 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 21 A in a PCB connection.
  • 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.
  • a bottom GND layer 210 and a dielectric substrate 220 is also shown.
  • Figure 21A shows a complete view of the Z-BTRFA 140 of Figure 21B with a coaxial connector structure 90 according to Figure 22, with antenna wire in a shape of a simple (non-meandered) loop.
  • Z-BTRFA 140 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 23A).
  • Z-BTRFA 140 surrounded by free space acted as an omni-directional antenna with a doughnut shaped radiation pattern.
  • 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).
  • Z-BTRFA 140 has axial symmetry.
  • Z-BTRFA 140 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%).
  • 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.
  • 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).
  • Figure 28A shows a curved BTRFA model above a curved multi-layer tissue sample such a human head.
  • 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.
  • X-BTRFA 130 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 31B 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.
  • FIGS 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.
  • 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.
  • 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.
  • the operating frequency of such applicator depends on the applicator size which is related to the total wire length in each of two antenna branches.
  • 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, about 3000 mm at around 100 MHz, and about 6000 mm at around 50 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.
  • 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.
  • 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.
  • [146] is directed to body tissue radiofrequency applicators (50) as described above for use in a method of for treating, preventing, stabilizing and/or reversing the symptoms of neurologic disorders, such as neurodegenerative diseases such as Alzheimer’s disease, Frontotemporal dementia and variants thereof, cerebral amyloid angiopathy, Parkinson’s disease, Lewy body dementia, in a subject in need thereof, 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.
  • neurologic disorders such as neurodegenerative diseases such as Alzheimer’s disease, Frontotemporal dementia and variants thereof, cerebral amyloid angiopathy, Parkinson’s disease, Lewy body dementia
  • the body tissue radiofrequency applicators (50) as described above may be used for preventing and/or alleviating brain injuries, such as concussions, traumatic brain injuries, and/or post stroke disorders, as well as for treating, preventing and/or mitigating depression, migraine headaches, myodesopsia, and/or tinnitus in a subject in the need therefor, 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.
  • brain injuries such as concussions, traumatic brain injuries, and/or post stroke disorders
  • mitigating depression migraine headaches, myodesopsia, and/or tinnitus
  • the body tissue radiofrequency applicators (50) as described above may further be used by healthy patients for general wellness purposes, particularly for relieving headaches and signs of fatigues, and/or enhancing general mental and cognitive abilities.
  • 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 50 to 200MHz, or from 100-150 MHz, or from 800 to 1500 MHz, or from 900 to 1000 MHz.
  • Preferred frequencies of the signal are from 50-100MHz or from 850 to 950MHz. Most preferred frequencies are around 100MHz or 900 MHz or 915 MHz.
  • the electromagnetic signal used for transcranial administration may be continuous or pulsed.
  • electromagnetic signal When electromagnetic signal is pulsed, it is following 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.
  • 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 around 80-100MHz, around 900-915 MHz and is pulsed with a cycle of repetition around 100-200 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.
  • 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.
  • SAR specific absorption rate
  • body tissue radiofrequency applicators (50) 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.
  • 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.
  • 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.
  • 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.
  • the present invention thus also provides a novel wellness head device (“augmented hat”) or a medical head device comprising one or more body tissue radiofrequency applicators (50) as described above.
  • Said body tissue radiofrequency applicators are configured for emitting an electromagnetic signal at a frequency ranging from 20 to 3000 MHz, or from 50 to 1000 MHz, preferably from 50-100 MHz or from 850-950MHz, 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 wellness head device or 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.
  • 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.
  • 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.
  • the wellness head device or medical head device 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.
  • 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.
  • 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.
  • the wellness head device or medical head device may comprise one or more body tissue radiofrequency applicators (50).
  • Said one or more BTRFA may emit an electromagnetic field or signal at a frequency ranging from 20 to 3000 MHz, or from 50-200MHz, or from 50-100MHz, 800 to 1500 MHz, or from 850 to 1000 MHz, or 900 to 950 MHz. Most preferred frequencies are around 50-100MHz, or around 80- 100MHz, or around 900-915 MHz.
  • the electromagnetic signal which is radiated from the BTRFA for transcranial administration may be preferably in a pulsed electromagnetic waveform.
  • the non-invasive head device comprises 1 or 2 BTRFA as showed in Figure 52.
  • the non-invasive head device preferably comprises a single large BTRFA covering the whole skull or head of the subject as showed specifically in Figure 52.
  • the non-invasive head device comprises between 1 and 16 BTRFA, or between 6 and 10, or around 8-10 body tissue radiofrequency applicators (50), preferably 8 body tissue radiofrequency applicators as showed in Figure 33.
  • 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.
  • SAR energy specific absorption rate
  • the wellness head device or medical device 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.
  • the BTRFA may be radiating on and off in sequential order.
  • 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.
  • 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 abovedescribed pulsed RF electromagnetic energy does not raise the temperature of the targeted body tissue.
  • the wellness head device or 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.
  • 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.
  • a standing wave pattern is produced, as the two output waves combine to produce both constructive and destructive interference. If the two emitted frequencies are "in-phase", they line up in time and their peaks occur at the same time, which produces a particular standing wave pattern. When the peaks of the signals do not line up, the signals are "out of phase” with each other, and the standing wave pattern 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.
  • this also can move and/or steer the signal to different locations in the brain. This is referred to as beamforming.
  • beamforming The combination of multiple body tissue radiofrequency applicators and the ability to beamform allows for complete coverage of all regions of the brain.
  • the wellness head device or 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 emitters at the same time, or frequencies may be generated and distributed to the body tissue radiofrequency applicators. This may be scaled to more emitters and more frequencies, with a specific example of eight emitters and three frequencies.
  • the wellness head device or medical device 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 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.
  • the wellness head device or medical head device comprises 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 transmitting and being idle, the applicator system utilizes the idle time for one BTRFA to activate the other RF applicator.
  • 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.
  • the wellness head device or medical head device emits electromagnetic waves in a pulse fashion and sequentially through one or two BTRFA at a frequency of around 50-100 MHz and with a cycle of repetition for each antenna at 10-200, 40-200 Hz, 40-100 Hz, or 100-200 Hz.
  • the wellness head device or 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 10-200, 40-200 Hz, 40-100 Hz, or 100-200 Hz.
  • Power levels and specific absorption rate 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.
  • 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.
  • Wellness head device or 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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 .
  • 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 z.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.
  • 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.
  • the LEDs 200 may be spaced by 30 to 60 mm, to by 40 to 50mm between each other’s.
  • 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.
  • RED and NIR LED diodes of the medical head device 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.
  • 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.
  • the wellness head device or medical head device 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%.
  • 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.
  • PC-HD heat dissipation
  • 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.
  • 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%.
  • 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).
  • Preferred medical head device 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%.
  • the present invention thus relates to a wellness head device or medical head device comprising one or two BTRFA as described above delivering pulsed electromagnetic signal at a frequency of 80-100 MHz and a repetition rate of around 200 Hz simultaneously and in combination with an array of 50-100 LEDs, which are delivering pulsed RED and NIR lights at 630 nm and 810 nm, and 1060 nm with a pulsation rate of 40Hz to the brain of a subject.
  • the wellness head device or 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.
  • 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.
  • 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.
  • the electronic control unit/system comprises electronic means to generate the therapeutic pulsed electromagnetic signal and means for signal amplification.
  • 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.
  • 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 50-100 MHz, or around 915 MHz;
  • 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);
  • each of 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).
  • (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
  • (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).
  • the medical head device 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.
  • 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.
  • 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.
  • the wellness head device or 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.
  • the battery may be any suitable battery such as a lithium rechargeable battery.
  • 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.
  • 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.
  • 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 present invention thus 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 (AD), mild cognitive Impairment (MCI) and amnestic mild cognitive impairment (aMCI), Parkinson’s disease, cerebral amyloid angiopathy, dementia with Lewy bodies (DLB) including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), frontotemporal dementia, variants thereof such as semantic dementia, primary progressive aphasia, and Pick’s disease, in a subject in need thereof, comprising positioning the BTRFA or medical head device, at close proximity to the head of the subject, activating 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 (S)
  • 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.
  • SAR specific absorption rate
  • 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.
  • mental alienation also included schizophrenia and mood swings.
  • 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.
  • AD Alzheimer’s-type dementia
  • Dr. Alois Alzheimer in 1906 was first described and diagnosed by Dr. Alois Alzheimer in 1906.
  • AD is characterized as a severe, chronic, and progressive neurodegenerative disorder. 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 55 million people worldwide.
  • amyloidosis amyloidosis
  • tauopathies neurofibrillary tangles
  • amyloid plaques APi ⁇ 4o and A
  • 3 peptides are produced by the proteolytic cleavage of the amyloid precursor protein by the beta-amyloid cleavage enzyme alpha, and beta and gamma secretases.
  • AD 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.
  • 3 intracellular deposition triggers the pathological cascade involving a second neurotoxic molecule: the tau protein which is normally involved in the formation and stabilization of microtubules. Therefore, AD is also characterized by the deposition of the intra-neuronal neurofibrillary tangle (NFT) of hyperphosphorylated aggregated tau protein.
  • NFT intra-neuronal neurofibrillary tangle
  • Beta-amyloid plaques and tau aggregates are initially deposited primarily in the hippocampus, the entorhinal cortex posterior and the cingulate cortex which are critical areas for memory and spatial orientation. Over time, the pathology becomes more widespread, affecting the entire cerebral cortex. The signal is disrupted among the neurons which completely stop working and lose connection with other neurons, thereby leading to brain atrophy (loss of neurons), memory loss, confusion, mood swings, personality changes, and difficulty in performing even basic routine tasks or daily functions.
  • the progression of Alzheimer's disease can be broadly divided into seven stages. During the first two stages, often referred to as the mild stage, it is challenging to determine whether a person is suffering from the disease. Alzheimer's typically acts as a silent condition, with no obvious symptoms appearing in the early stages unless the patient undergoes clinical diagnosis. As the disease progresses, patients begin to show mild changes in their behavior. The third and fourth stages, known as the moderate stages, are usually the longest and can last for several years. During these stages, the disease starts to escalate. Although the person may still function independently, memory lapses become more frequent and severe, leading to increasing difficulties in daily activities and language use. As Alzheimer's continues to progress, the individual requires more extensive care and support from family members and caregivers.
  • BTRFA, non- invasive medical head devices, and methods according to the present invention are particularly useful for preventing and/or stabilizing and/or reversing the symptoms of Alzheimer’s disease (AD) of a subject at any stage of the AD, e.g., either mild, moderate and/or severe stages according to National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association (NINCDS- ADRDA) criteria. They may be administered or applied to the head of said subject for one treatment each day or for multiple, spaced-apart treatments each day.
  • AD Alzheimer’s disease
  • NINCDS- ADRDA National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association
  • 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.
  • Combination of these signals provide a deeper penetration through the meninges, cranial material, and then through the brain matter.
  • simultaneous stimulations with these signals are expected to provide synergistic molecular and biological effects which are manyfold.
  • 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 antiinflammatory 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.
  • COX-2 enzyme cyclo-oxygenase 2
  • TNFa tumor necrosis factor
  • ROS reactive oxygen species
  • 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.
  • neuropsychological tests there is a battery of neuropsychological tests to identify symptoms and to monitor the efficacy of the treatment on the progression of Alzheimer’s disease.
  • Most widely used neuropsychological tests include ADAS-Cog- Plus or ADAS-Cogl4 (Alzheimer's Disease Assessment Scale-Cognitive Subscale 14) 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.
  • Alzheimer subjects at mild, moderate and even severe stages having used the non-invasive 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.
  • 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).
  • synergistic effects are expected in terms of increased degradation and clearance of beta-amyloid plaques and of amyloid beta oligomers in the plasma and the cerebrospinal fluid of the subject. More precisely, increased destabilization of insoluble amyloid-
  • AD subjects are expected to have a change from baseline of Alzheimer's markers such as beta-amyloid 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.
  • Alzheimer's markers such as beta-amyloid 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.
  • t-tau total tau
  • p-tau phospho-tau
  • 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.
  • t-tau total tau
  • p-tau phospho-tau
  • 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.
  • Mild Cognitive Impairment is a condition characterized by cognitive decline that is greater than expected for a person’s age and education level but does not interfere significantly with daily life activities.
  • Amnestic Mild Cognitive Impairment (aMCI) is a subtype of MCI where memory loss is the predominant cognitive impairment.
  • MCI is characterized by cognitive decline that is greater than expected for a person’s age and education level with diverse causes ranging from vascular issues to early-stage neurodegenerative diseases. Indeed, etiologic causes include vascular factors such small vessel disease, stroke, or other cardiovascular conditions, but neurodegenerative diseases such as early-stage Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions can manifest as MCI.
  • MCI Metabolic and systemic conditions, and even by psychiatric conditions, such as depression and anxiety.
  • the symptoms of MCI include general cognitive decline, including issues with memory, attention, language, and executive function. MCI is typically considered an intermediate stage between normal cognitive aging and dementia. It can progress to more severe cognitive decline or remain stable.
  • tests and biomarkers may be used to detect and monitor the progression of the disease. Tests may include for example Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and Clock Drawing Test. Biomarkers vary depending on the underlying cause but may include neuroimaging (MRI for structural changes, PET scans for metabolic activity), and cerebrospinal fluid (CSF) analysis for protein levels (e.g., amyloid-beta, tau).
  • MCA Montreal Cognitive Assessment
  • MMSE Mini-Mental State Examination
  • CSF cerebrospinal fluid
  • aMCI is primarily associated with early-stage Alzheimer's disease, where the amyloid plaques and neurofibrillary tangles begin to affect the hippocampus and related brain regions responsible for memory. aMCI is often viewed as a precursor to Alzheimer's disease, with a higher likelihood of progressing to dementia. It involves the same pathological processes as Alzheimer's disease, with early amyloid deposition and tau-related neurofibrillary tangles beginning in the hippocampus and entorhinal cortex. Predominant symptoms are memory impairment, especially difficulty recalling recent events, names, or appointments. Other cognitive domains are less affected, and the ability to perform daily tasks is mostly intact.
  • the Petersen criteria are often used, requiring memory complaints (preferably corroborated by an informant), objective memory impairment, largely preserved general cognitive function, and intact daily activities, with no dementia.
  • Several tests and biomarkers may be used to detect and monitor the progression of the disease.
  • Such cognitive tests may be specific tests for memory, such as the Rey Auditory Verbal Learning Test (RAVLT) and the California Verbal Learning Test (CVLT), which assess delayed recall and recognition memory.
  • RAVLT Rey Auditory Verbal Learning Test
  • CVLT California Verbal Learning Test
  • Biomarkers indicative of Alzheimer's disease are also used to monitor aMCI, such as decreased amyloidbeta 42 and increased total tau or phosphorylated tau in CSF, as well as amyloid PET imaging showing amyloid plaques in the brain.
  • Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer's disease. It primarily affects movement control. It is characterized by the loss of dopamine-producing neurons in the substantia nigra, a region of the brain that plays a critical role in regulating movement. PD is the second most common neurodegenerative disorder after Alzheimer's disease. PD is caused by a combination of genetic and environmental factors, with oxidative stress and mitochondrial dysfunction playing a role in its pathogenesis. The core pathophysiological feature of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine depletion in the striatum, a key region involved in motor control.
  • Such neuron loss is caused by intracellular inclusions composed of alpha-synuclein and other proteins are found in the brains of PD patients. These Lewy bodies are also associated with neuronal death.
  • the loss of dopamine disrupts the normal functioning of the basal ganglia, leading to the characteristic motor symptoms of PD, including tremors, rigidity, and bradykinesia. There are characteristic motor and non-motor symptoms.
  • Motor symptoms comprise resting tremor, bradykinesia, e.g., slowness of movement and difficulty initiating movements, rigidity, postural instability, cognitive impairment, mood disorders such as depression, anxiety, and apathy, as well as sleep disturbances.
  • PD progresses from mild, unilateral symptoms to severe disability requiring full-time care.
  • Stage 1 or mild wherein symptoms typically affect only one side of the body (unilateral) and daily activities are generally not impaired.
  • Stage 2 or moderate wherein symptoms become bilateral, but there is no impairment of balance, and daily tasks may take longer but can still be completed.
  • Stage 3 or mid-stage wherein balance becomes impaired, and falls become more common. The individual is still fully independent but experiences significant difficulty with tasks.
  • Stage 4 or advanced wherein severe disability, requiring help with daily activities, and wherein the person can still walk or stand unassisted but with great difficulty.
  • Stage 5 or severe wherein the individual is often bedridden or confined to a wheelchair, and full-time care is required.
  • Parkinson's Disease The diagnosis of Parkinson's Disease is primarily clinical, based on the criteria established by the Movement Disorder Society (MDS) and the UK Parkinson’s Disease Society Brain Bank. Key diagnostic criteria include bradykinesia plus at least one of the following: resting tremor, rigidity, or postural instability, and response to dopaminergic therapy.
  • MDS Movement Disorder Society
  • UK Parkinson’s Disease Society Brain Bank Key diagnostic criteria include bradykinesia plus at least one of the following: resting tremor, rigidity, or postural instability, and response to dopaminergic therapy.
  • the primary method for diagnosing PD is clinical evaluation, including neurological examination and patient history. Imaging examinations include DaTscan (SPECT): Can be used to visualize dopamine transporter levels in the brain and MRI. Cerebrospinal Fluid (CSF) Alpha- Synuclein Biomarkers: Lower levels of alpha-synuclein in the CSF are potential biomarkers for PD.
  • SPECT DaTscan
  • CSF Cerebrospinal Fluid
  • Alpha- Synuclein Biomarkers Lower levels of alpha-synuclein in the CSF are potential biomarkers for PD.
  • One or more BTRFA or the medical head device according to the present invention may be placed on the head, in direct contact with the scalp and particularly at the back of the head of a subject, i.e., over and in close proximity of the occipital lobes, 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.
  • Patients affected by episodes of depression may wear the medical head device daily for several consecutive months with a regimen of 1 to 2 hour per day with intervals of 7-9h between the treatment.
  • the electromagnetic waves either alone or in combination with red and near-infrared lights is sufficient to cause a diminishment or elimination of tremors, resting tremor, bradykinesia, cognitive impairment, and mood disorders. It is believed that the radiation causes an upregulation of endogenous compounds in the brain, including neurotrophic factors, that serve to enhance neural growth, neurogenesis, and/or plasticity of neural function that cause the beneficial effects in the brain, and/or that the radiation results in a more normal balance of neurotransmitters in the brain.
  • the medical head device may be used alone or in combination with Parkinson’s disease medications such as carbidopa- levodopa.
  • Lewy Body Dementia is a type of progressive dementia associated with the presence of Lewy bodies, e.g., accumulation of alpha-synuclein protein within neurons. It is one of the most common causes of dementia, following Alzheimer's disease and vascular dementia. These inclusions which are found in various brain regions, including the cerebral cortex, limbic system, and brainstem, disrupt the normal functioning of brain cells, particularly in areas responsible for cognition, movement, and behavior. LBD is associated with dysfunction in several neurotransmitter systems, particularly dopamine and acetylcholine. The loss of dopamine-producing neurons leads to parkinsonian symptoms, while cholinergic deficits contribute to cognitive and attentional impairments.
  • LBD often coexists with other neuropathological features, such as amyloid plaques and neurofibrillary tangles seen in Alzheimer’s disease, which complicates diagnosis and contributes to the clinical variability.
  • LBD encompasses two related conditions: Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD).
  • DLB Dementia with Lewy Bodies
  • PDD Parkinson’s Disease Dementia
  • DLB is diagnosed when cognitive and motor symptoms develop within one year of each other, or when cognitive symptoms appear first.
  • PDD is diagnosed when motor symptoms precede cognitive decline by more than a year.
  • Symptoms include fluctuations in attention and alertness, visual hallucinations, memory loss typically less prominent early on compared to Alzheimer's disease, as well as bradykinesia, rigidity, and resting tremor resembling Parkinson’s disease.
  • CSF Cerebrospinal Fluid
  • Frontotemporal dementia is a group of neurodegenerative disorders primarily affecting the frontal and temporal lobes of the brain. It is characterized by progressive changes in behavior, personality, language, and motor function. FTD is one of the most common forms of dementia in people under 65 years old, although it can also occur in older individuals. Semantic Dementia (SD) and Primary Progressive Aphasia (PPA) are subtypes or language variants of FTD, with distinct patterns of language decline.
  • Pick’ s disease is another subtype of FTD characterized by the presence of Pick bodies, which are abnormal tau protein inclusions in neurons of the frontal and temporal lobes. These tau aggregates form the characteristic Pick bodies, which are spherical tau inclusions found in affected brain cells.
  • Alzheimer’s disease are typically found in the swollen, ballooned neurons known as Pick cells in the cortex.
  • the disease involves the loss of neurons and gliosis (an increase in the number of glial cells due to damage) in the affected areas of the brain, leading to the progressive atrophy of these areas and to the symptoms of the disease. Symptoms overlap with those of FTD including behavioral changes, language difficulties, and cognitive decline.
  • SD is characterized by the progressive degeneration of the anterior temporal lobes (particularly on the left side), a critical area for semantic memory, often with an accumulation of TDP-43 protein. Degeneration in these areas leads to a progressive loss of the ability to understand or produce meaningful language, a hallmark of semantic dementia.
  • the diagnosis of Semantic Dementia is based on the consensus criteria for Frontotemporal Lobar Degeneration (FTLD), focusing on progressive loss of semantic memory and left temporal lobe atrophy on neuroimaging.
  • FTLD Frontotemporal Lobar Degeneration
  • PPA specifically affects language capabilities due to degeneration in the frontal and temporal lobes.
  • the underlying pathologies include tauopathies, and TDP-43 proteinopathies, and, in some cases, Alzheimer's disease pathology.
  • PPA Planar Dementia
  • Symptoms of FTD may include cognitive decline with difficulty with planning, judgment, and problemsolving, often with relatively preserved memory early in the disease, as well as behavioral changes: disinhibition, apathy, lack of empathy, compulsive behaviors, and changes in eating habits.
  • Symptoms of SD and PPA include a gradual decline in language abilities, individuals lose knowledge of word meanings, leading to difficulty naming objects (anomia) and understanding words. These dementia progress in three stages early, with mild cognitive and behavioral changes and language difficulties. The moderate or middle stage wherein symptoms become more pronounced, with increasing behavioral abnormalities, significant impact on daily functioning, and profound loss of vocabulary and understanding of words.
  • CSF biomarkers such as levels of tau protein, TDP-43 and AP1.42 peptide, and thus helping to distinguish between FTD and Alzheimer’s disease.
  • Imaging biomarkers include MRI and CT showing atrophy in the frontal and temporal lobes, FDG-PET allowing to detect hypometabolism in the affected regions, and amyloid PET for detecting amyloid plaques, particularly in the case of PPA.
  • Neuropsychological Testing for FTD allow assessing executive function, social cognition, and behavior. Speech and language tests include the Western Aphasia Battery (WAB) and Boston Naming Test, as well as and Pyramids and Palm Trees Test assess semantic memory and naming abilities.
  • Cerebral amyloid angiopathy is characterized by amyloid plaques deposit in the walls of the cerebral blood vessels, increasing the risk of vessel rupture and microbleeds. This can lead to cognitive decline and, in some cases, vascular dementia. Symptoms can include recurrent hemorrhagic strokes, cognitive impairment, and, in severe cases, dementia.
  • BTRFA and non-invasive medical head device as described above may be used in a method of treating and/or preventing and/or alleviating traumatic brain injury (TBI), concussions (mild TBI) and other types of neurological conditions such as brain tissue ischemia from stroke, post-stroke disorders, head injury, cerebral injury, neurological injury in a subject in need thereof, comprising administering the combination of said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators with said red and/or near-infrared signals generated by the one or more LEDs.
  • TBI traumatic brain injury
  • demild TBI concussions
  • other types of neurological conditions such as brain tissue ischemia from stroke, post-stroke disorders, head injury, cerebral injury, neurological injury in a subject in need thereof, comprising administering the combination of said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators with said red and/or near-infrared signals generated by the one or more LEDs.
  • the present invention thus provides a method of treating and/or preventing and/or alleviating brain injuries, such as concussions, traumatic brain injuries, post stroke disorders, in a subject in need thereof, comprising positioning the BTRFA or medical head device, at close proximity to the head of the subject, activating 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 or LEDs at specific wavelengths as described above.
  • SAR specific absorption rate
  • Traumatic brain injury (hereinafter known as TBI) remains as one of the leading causes of morbidity and mortality for civilians and for soldiers on the battlefield and is a major health and socio-economic problem throughout the world.
  • the World Health Organization projected that by 2020, road traffic accidents, a major cause of traumatic brain injury, will rank third as a cause of the global burden of disease and disablement, behind only ischemic heart disease and unipolar depression. Recently, the demographics of traumatic brain injury have shifted to include more cases due to falls in middle-aged and older subjects.
  • Tissue damage from head injuries such as traumatic brain injury’ generally arises from the mechanical damage of the trauma event and subsequent secondary’ physiological responses to the trauma event.
  • moderate to severe traumatic brain injury' can produce mechanical damage by direct trauma to brain tissue that can cause the disruption of cell membranes and blood vessels, resulting in direct and ischemic neuronal death.
  • secondary' physiological responses such as inflammation and swelling can result in further damage and even death of healthy brain tissue.
  • astrocytes and microglia often react to head injury conditions and by secreting destructive cytokines (e.g.
  • IL-6 TNF-ot, IFN-v, and IL-6
  • other inflammatory’ molecules such as glutamate, reactive oxygen and nitrogen species, which, alone, or in combination, can be neurotoxic. While the primary' and immediate consequences of mechanical trauma to neurons cannot be undone, secondary pathological sequelae, specifically brain swelling and inflammation, are situational candidates for intervention.
  • Concussions are typically mild TBI and are caused by a blow or jolt to the head or body that causes the brain to rapidly move back and forth within the skull. It may cause temporary loss of consciousness, confusion, headaches, and dizziness.
  • Flead injuries encompass any trauma to the scalp, skull, or brain.
  • Cerebral injury refers to any damage to the brain tissue itself from lack of oxygen, trauma, stroke. This can include injuries from stroke, trauma, or lack of oxygen (hypoxia). These neurological disorders or conditions result in significant brain damage and substantial local cerebral inflammation.
  • One or more BTRFA or the non-invasive medical device according to the present invention may be placed in proximity and in direct contact with the injured area on the head, or in direct contact with the scalp and/or skull respectively, thereby allowing homogeneous and reliable exposure of the injured area or the entire cortex of the subject to said electromagnetic waves either alone or in combination with red and near-infrared lights.
  • the electromagnetic waves either alone or in combination with red and near-infrared lights may promote neuroregeneration, reduce inflammation, improve blood flow, modulating neural activity, stimulating cellular repair, reducing oxidative stress, and enhancing synaptic plasticity.
  • ATP adenosine triphosphate
  • NVF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • the non-invasive medical head device and/or BTRFA alone placed at proximity of a targeted area may have anti-inflammatory effects, which are critical in neurological conditions by modulating the activity of inflammatory cytokines and reducing the infiltration of inflammatory cells into the affected areas. This helps limit the extent of brain damage following a TBI, a stroke, a concussion, etc.., leading to improved outcomes and faster recovery.
  • Such treatment enhance microcirculation and increase blood flow in the brain, by promoting the dilation of blood vessels and reducing blood viscosity, thereby improving oxygen delivery to brain tissues.
  • Restoring the blood flow to the brain is compromised, PEMF therapy can help restore circulation and oxygenation, reducing the risk of further ischemic damage and supporting the recovery of brain function.
  • Patients may be treated non-invasive treatment daily for several consecutive months with a regimen of 5 to 30 min or 10 to 20 min per day for one or more months.
  • BTRFA and medical head device as described above may be used in a method of treating and/or preventing and/or reducing or eliminating depression or the symptoms of depression, delaying, reducing and/or eliminating depression and its symptoms, reducing and/or relieving migraines, reducing and/or mitigating myodesopsia and vitreous opacities, and/or tinnitus (hardness of hearing) in a subject in need thereof, comprising administering the combination of said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators with said red and/or near-infrared signals generated by the one or more LEDs.
  • the present invention thus provides a method of treating and/or preventing and/or mitigating the symptoms and/or relieving depression, migraines, myodesopsia, and/or tinnitus in a subject in need thereof, comprising positioning the BTRFA or medical head device, at close proximity to the head of the subject, activating 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 or LEDs at specific wavelengths as described above.
  • SAR specific absorption rate
  • One or more BTRFA or the medical head device according to the present invention 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.
  • Patients affected by episodes of depression may wear the medical head device daily for several consecutive months with a regimen of 5 to 30 min or 10 to 20 min per day.
  • the electromagnetic waves either alone or in combination with red and near-infrared lights is sufficient to cause a diminishment or elimination of depression and its symptoms, and/or delays, reduces, or eliminates the onset of depression or depressive symptoms.
  • the medical head device may be used alone or in combination with antidepressant medications presently available, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SSNRIs).
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • SSNRIs selective norepinephrine reuptake inhibitors
  • Migraines and migraine episodes can be debilitating and can affect patient quality of life and productivity.
  • the migraine episode may last for up to 2 to 3 days and may require medical attention in at least some instances.
  • a migraine episode can include four phases: a premonitory phase also referred to as “pre-headache”; an aura phase which may include visual symptoms such as flashes of lights or formations of dazzling lines, blurred or shimmering or cloudy vision, and tunnel vision or nonvisual symptoms such as auditory and/or olfactory hallucinations, vertigo, tingling, and hypersensitivity to touch; a headache phase; and a postdrome phase with symptoms of fatigue, poor concentration, poor comprehension, and/or lowered intellect level.
  • the disorder can manifest on a daily basis, and when occurring on fifteen days or more a month can be called chronic migraine.
  • Patients affected by migraines, headaches or migraine episodes may wear the medical head device at the apparition of the first symptoms (for example during the pre-headache phase) or during a migraine attack during 5, 10, 15, 20, 25 or 30 min depending on the intensity of the pain and may repeat the same administration 7-8 hours thereafter.
  • the medical head device may be used alone or in combination with pharmaceutical treatments.
  • Tinnitus is a symptom that is perceived as a continuous or intermittent noise in the ear even when there is no external sound source, and the patient is suffering from headache, sleep disorders, nervous breakdowns, depression, etc. Tinnitus has a large individual difference and various causes. Most common cause is a decrease in function due to aging of the sensory nerve system; a kind of neuro-electrical spurious generated by the cochlea hair cell damage or degeneration caused by disease, aging, fatigue, mental anxiety and stress, as well as certain brain neurological diseases.
  • BTRFA or the medical head device according to the present invention are particularly active for tinnitus caused by fatigue and it may be placed at proximity or as to cover the auditory organs tissues during 5 to 30 min once or twice per day with at least 7 hours interval for synergistically stabilizing and/or relieving the symptoms of tinnitus and/or of the hearing loss.
  • myodesopsia which is caused by the formation of other collagen-based structures in the form of light scattering opacities responsible for the phenomenon of floaters, eye floaters, or vitreous floaters. These collagenous aggregates scatter light and cast shadows on the retina, which are perceived by the patient as grey objects of different sizes and shapes.
  • myodesopsia was previously not considered a serious problem in ophthalmology, many patients with symptomatic vitreous floaters experience a significantly negative impact on their quality of life. In terms of vision, studies have shown that while there can be slight loss of visual acuity, there is significant degradation in contrast sensitivity function, which likely accounts for profound unhappiness in some cases.
  • BTRFA or the medical head device according to the present invention are particularly active for myodesopsia caused by eye fatigue and it may be placed at proximity to the frontal lobes or the fronto-temporal lobes or the whole head during 5 to 30 min once or twice per day with at least 7 hours interval for synergistically stabilizing and/or relieving the symptoms of myodesopsia and eye fatigue.
  • BTRFA and non-invasive head device as described above may be used by healthy patients for general wellness purposes, particularly for relieving headaches and signs of fatigues, and/or enhancing brain activity and cognitive abilities, comprising administering the combination of said pulsed electromagnetic signal generated by the one or more body tissue radiofrequency applicators with said red and/or near-infrared signals generated by the one or more LEDs.
  • the present invention thus provides a method of improving general wellness purposes, particularly for relieving headaches and signs of fatigues, and/or enhancing general mental and cognitive abilities in a healthy subject, comprising positioning the BTRFA or medical head device, at close proximity to the head of the subject, activating 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 an efficient dose of pulsed electromagnetic waves or field at a specific frequency and a specific absorption rate (SAR) and to red and NIR lights or LEDs at specific wavelengths as described above.
  • SAR specific absorption rate
  • the ability of the brain to be stimulated and enhanced is well recognized as brain plasticity and is a fundamental property of the brain nervous system.
  • the non-invasive head device according to the present invention is a valuable tool for maintaining overall health and well-being, as it may be beneficial to improve blood flow, reduce inflammation, and support cellular energy production.
  • the non-invasive medical device according to the present invention is present in the form of a hat or augmented hat ( Figure 53) which the patient may wear few times per week or on a daily basis for 10 to 20 min depending on the sought effect, without any constrains, feeling of pain or heat, while continuing his daily routine. Regular use thereof can contribute to a more energized, focused, and balanced state of mind and body, making it an appealing option for those seeking to enhance their quality of life.
  • 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
  • BBM blood brain biomarkers
  • Ap42 blood brain biomarkers
  • Ap40 blood brain biomarkers
  • tau blood brain biomarkers
  • LC-MS/MS mass spectrometry-based plasma assay
  • 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 (z.e.. ApoE2, ApoE3, ApoE4 isoforms) to determine APOE 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).
  • the Amyloid Probability Score (APS) based on the plasma AP42/40 ratio, APOE genotype (detennined 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 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.
  • Example 1.2 Indications for use
  • the non-invasive medical device 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. It 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 1.3 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.
  • MMSE Mini-Mental State Examination
  • 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.
  • ADAS-Cog-Plus or ADAS-Cogl4 Alzheimer's Disease Assessment Scale-cognitive Subscale 14
  • 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.
  • 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-cogl4 is expected to improve by over 4 points following 2-month treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. Impact on sleep time/sleep efficiency
  • 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.
  • Alzheimer’s disease subjects treated with the non- invasive medical device according to the present invention for at least a 2-month are expected to present improvements in one or more of the above tests and scores compared to baseline.
  • CBI Caregiver Burden Inventory
  • CTT2/CTT1 in the performance on Color Trails Test
  • GDS Geriatric Depression Scale for caregivers
  • change in Positive Aspects of Caregiving scale in ADL SAD or ADSC-ADL-sev: Alzheimer's Disease Cooperative Study - Activities of Daily Living for Severe Alzheimer's Disease score, in the Digit Span forward and Digit Span backward score.
  • 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 healthrelevant activity and behavior using the Collaborative Aging Research Using technology (CART) platform developed by the Oregon Center for Aging & Technology (ORCATECH).
  • CART Collaborative Aging Research Using technology
  • ORCATECH Oregon Center for Aging & Technology
  • 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, z.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.
  • the PrecivityAD2TM blood test from the company C2N (www.PrecivityAD.com) is used to measure plasma A
  • the ratio plasma AP42/AP40 has been shown to reflect amyloid removal.
  • plasma p-tau217 reduction was evidenced to correlate with changes in amyloid and tau load (references 22-23).
  • 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.
  • the change score may thus be determined by calculating the ratio of plasma AP1-42 peptide after treatment over baseline. Also, increased levels 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. Therefore, monitoring the change in the ratio of APi-42 / AP1.40 may be indicative of the efficiency of the treatment.
  • Tau protein forms insoluble filaments that accumulate as neurofibrillary tangles (NFT) in AD.
  • At least 2 months of treatment with the non-invasive medical device of the present invention is expected to result in some increase in plasma t-tau (total tau protein) levels, since it induces the dissociation of the tau tangles and thus an increase in monomeric tau within plasma of the treated Alzheimer disease subjects.
  • the change score is determined by calculating the ratio of plasma and CSF tau after treatment over the baseline plasma tau levels.
  • NF-L neurofilament light
  • Example 2 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on mild cognitive impairment (MCI) and amnestic mild cognitive impairment (aMCI)
  • the objectives are to evaluate cognitive the use of the non-invasive medical device may have neural impacts on MCI and aMCI during a pilot feasibility study.
  • Participants having more than 50 years old and meeting the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for MCI or aMCI due to Alzheimer's disease may be enrolled.
  • the patients undergo a 2-month trial of the daily treatment at home each for 20 minutes per session. All patients undergo clinical and cognitive assessment, blood sample collection, and structural and resting state functional MRI scans pre and post treatment.
  • NIA-AA National Institute on Aging and Alzheimer's Association
  • MCI or aMCI Several outcome measures may be used for monitoring the efficiency of the treatment of patients affected by MCI or aMCI, such as changes from pre- to post- treatment on mental status and cognitive function assessed by Mini-Mental State Examination (MMSE), changes from pre- to post-treatment on verbal learning and memory assessed by California Verbal Learning Test II (CVLTII), changes from pre- to post-treatment on visuospatial memory assessed by Brief Visuospatial Memory Test Revised (BVMT-R), changes from pre- to post-treatment on processing speed assessed by Trail Making Test (TMT)-part A, and/or changes from pre- to post-treatment on Quality of life using QOL-AD.
  • MMSE Mini-Mental State Examination
  • CVLTII California Verbal Learning Test II
  • BVMT-R Brief Visuospatial Memory Test Revised
  • TMT Trail Making Test
  • Example 3 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on Parkinson’s disease
  • Patients having more than 18 years old, with Idiopathic Parkinson's disease H & Y 1-3 (Hoehn&Yahr), and MMSE score above 22 may be enrolled.
  • Parkinson subjects treated with the non-invasive medical device according to the present invention for at least a 2- month are expected to present improvements in one or more of the following outcome measures compared to baseline: Change from baseline in motor clinical signs progression evaluation (Scores on the Movement Disorder Society- Sponsored Revision of the Unified Parkinson's Disease Rating Scale), non-motor behavioral signs progression evaluation (Scores on the non-motor scales Behavioral Evaluation in Parkinson's disease), non-motor clinical signs progression evaluation (Scores on the non-motor scales Lille Apathy Rating Scale), evolution of the quality of life (Parkinson Disease Quotation (PDQ-39) quiz score), assessment of tremor, akinesia and stiffness, speech, walking and balance disorders, walking speed evaluation and of walking parameters (score in the "freezing of gait" questionnaire), as well as ARENA, learning and memory change from baseline to post-testing, learning and memory change from baseline to post-testing.
  • Scores on the Movement Disorder Society- Sponsored Revision of the Unified Parkinson's Disease Rating Scale non
  • Example 4 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on traumatic brain injury
  • the purpose of this study is to examine effectiveness of an at-home use of the non-invasive medical head device according to the present invention on mild-moderate traumatic brain injury cases. Participants are expected to complete two months of treatment at home 3 times to 6 times a week. Each home treatment is 30 minutes. Participants are randomized. Group 1 receives both a series of sham and a series of real treatments and Group 2 receives two series of real treatments. Sham and Real devices are identical in look and feel, except no or very little electromagnetic signals and photons are emitted from the sham head devices.
  • Each participant is assigned his/her own medical head device for hygiene reasons.
  • the assigned device will be provided to each participant at a 1-hour in-office training session, after the first Neuropsychological (NP) Testing. Training that includes both verbal and written instructions will be provided, along with demonstration of use of the device. A treatment log, storage box and alcohol wipes for cleaning are provided. The first treatment is completed at the training session.
  • NP Neuropsychological
  • a staff person will telephone each participant weekly, to fill out a questionnaire about the intervention including inquiring if the treatments are being performed, if the treatment log sheets are being filled out, and note if there are any questions, concerns or problems.
  • MRI scans are administered to examine behavioral and brain changes before and after the treatment.
  • MRI scans examine some mechanism of treatment including changes in blood flow, functional connectivity and neurochemicals.
  • Outcome measures include functional MRI: resting-state functional-connectivity Magnetic Resonance Imaging (rs-fc MRI), California Verbal Learning Test (CVLT), Long-Delay Free Recall (LDFR) is the Primary Outcome Measure which examines verbal learning, organization and memory.
  • the subtest LDFR, CVLT-II specifically assesses long- delay (20 min), verbal memory, which can be affected after brain injury.
  • Example 5 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on migraine headaches
  • This pilot study aims to validate the efficiency of the non-invasive medical head device for treatment in patients with migraine and tension-type headache symptoms.
  • Various physiological measurements are taken before, during, and after the treatments, including skin type, weight, height, blood pressure, and heart rate. Additionally, data from questionnaires on pain and headache symptoms will be analyzed. This addresses the need for effective pain management strategies in cases where medication-based treatments may have unwanted side effects.
  • Outcome measures include headache pain as assessed using the Visual Analog Scale from zero to 10.
  • Example 6 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on tinnitus The aim is to determine the effectiveness of the non-invasive medical head device for mitigating and/or alleviating tinnitus. Patients having unilateral tinnitus for at least 3 months may be enrolled. They follow at home treatment with the medical head device for 1 to 2 months, for 20-30 min daily. Efficiency of the treatment is assessed by numerical estimates of tinnitus severity before and after treatment.
  • Example 7 Pilot clinical phase for testing safety and efficacy of the non-invasive medical head device on depression
  • the objective is to validate the efficiency of the non-invasive medical head device on a cohort study of patients having depression, refractory to antidepressant drugs and/or with a score on Hamilton Depression Scale (HAM-D17) above 17.
  • Patients may use the medical head device daily for 1 to 2 months, 20-30 min per session.
  • the outcome measures include the change in the Hamilton Depression Scale (HAM-D 17), life quality (WHO-5 scale), response and remission.

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Abstract

La présente invention concerne un nouvel applicateur radiofréquence de tissu cellulaire (50), dénommé BTRFA, ainsi qu'un dispositif de tête médicale non invasive utile pour stabiliser et/ou inverser les symptômes de maladies neurodégénératives et/ou de protéinopathies. Les nouveaux BTRFA et le dispositif de tête médicale sont particulièrement utiles pour stabiliser et/ou inverser les symptômes de la maladie d'Alzheimer et/ou de la maladie de Parkinson chez un patient en ayant besoin. L'applicateur radiofréquence de tissu cellulaire est configuré pour émettre un signal électromagnétique pulsé à une fréquence dans une plage de 20 à 3000 MHz à une vitesse de répétition dans une plage de 10 à 400 Hz.
PCT/EP2024/073241 2022-08-18 2024-08-19 Nouveaux applicateurs radiofréquence de tissu cellulaire, dispositif de tête et utilisations associées Pending WO2025040638A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303425A1 (en) * 2011-11-04 2014-10-09 Ivivi Health Sciences, Llc Method and apparatus for electromagnetic treatment of cognition and neurological injury
US20200360709A1 (en) * 2012-05-25 2020-11-19 Ojai Retinal Technology, Llc System and method for preventing or treating alzheimer's and other neurodegenerative diseases
WO2024038209A1 (fr) * 2022-08-18 2024-02-22 Neurocia Sas Dispositif de tête médicale pour traitement de maladies neurodégénératives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140303425A1 (en) * 2011-11-04 2014-10-09 Ivivi Health Sciences, Llc Method and apparatus for electromagnetic treatment of cognition and neurological injury
US20200360709A1 (en) * 2012-05-25 2020-11-19 Ojai Retinal Technology, Llc System and method for preventing or treating alzheimer's and other neurodegenerative diseases
WO2024038209A1 (fr) * 2022-08-18 2024-02-22 Neurocia Sas Dispositif de tête médicale pour traitement de maladies neurodégénératives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LOPEZ OL ET AL., CURR OPIN NEUROL., vol. 24, no. 6, December 2011 (2011-12-01), pages 532 - 541
MCKHANN G ET AL., ALZHEIMERS DEMENT., vol. 7, no. 3, May 2011 (2011-05-01), pages 263 - 269

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