WO2019082180A1 - An electrical stimulation device and methods of using the device - Google Patents

An electrical stimulation device and methods of using the device

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Publication number
WO2019082180A1
WO2019082180A1 PCT/IL2018/051131 IL2018051131W WO2019082180A1 WO 2019082180 A1 WO2019082180 A1 WO 2019082180A1 IL 2018051131 W IL2018051131 W IL 2018051131W WO 2019082180 A1 WO2019082180 A1 WO 2019082180A1
Authority
WO
WIPO (PCT)
Prior art keywords
device
disorder
nerve
low frequency
method
Prior art date
Application number
PCT/IL2018/051131
Other languages
French (fr)
Inventor
Khaled Khalil
Oren Fuerst
Nisim COHEN
Original Assignee
Magicalfa Inc.
Reinhold Cohn And Partners
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US201762575525P priority Critical
Priority to US62/575,525 priority
Application filed by Magicalfa Inc., Reinhold Cohn And Partners filed Critical Magicalfa Inc.
Publication of WO2019082180A1 publication Critical patent/WO2019082180A1/en

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    • A61N1/02Details
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    • A61N1/0404Electrodes for external use
    • A61N1/0408Use-related aspects
    • A61N1/0456Specially adapted for transcutaneous electrical nerve stimulation [TENS]
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    • A61B5/024Detecting, measuring or recording pulse rate or heart rate
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    • A61B5/103Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
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Abstract

The present disclosure provides an electronic nerve stimulation device comprising an electrical module operable to generate a low frequency signal and an electrode array for applying said signal to a subpopulation of nerves and modulating nerve impulses in said subpopulation and method of using the device in improving a physiological condition.

Description

AN ELECTRICAL STIMULATION DEVICE AND METHODS OF

USING THE DEVICE

TECHNOLOGICAL FIELD

The present invention relates to electrical stimulation device, specifically to electrotherapy brain stimulating or modulating devices and methods for the treatment of several medical and wellness conditions.

BACKGROUND ART

References considered to be relevant as background to the presently disclosed subject matter are listed below:

- U.S. Patent No. 8,190,248

- U.S. Patent No. 6,178,352

- U.S. Patent No. 7,407,478

- U.S. Patent No. 9,452,287

Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

BACKGROUND

Electrical brain stimulation using electronic devices are known in the art. For example, U.S. Patent No. 7,407,478 describes methods of stimulation of deep-brain regions.

U.S. Patent No. 8,190,248 describes devices and methods for detecting, preventing, and/or treating neurological disorders using unique concentric ring electrode component.

U.S. Patent No. 6,178,352 describes a method of controlling the blood pressure in a patient with high blood pressure or low blood pressure utilizing a noninvasive nerve stimulation device applied to the wrist.

U.S. Patent No. 9,452,287 describes a peripheral nerve stimulator can be used to stimulate a peripheral nerve to treat essential tremor, Parkinson tremor, and other forms of tremor. GENERAL DESCRIPTION

In accordance with some aspects, the present disclosure provides, an electronic nerve stimulation device comprising: (i) an electrical module operable to generate a low frequency signal and (ii) an electrode array for applying the low frequency signal to a subpopulation of nerves and modulating nerve impulses in the subpopulation of nerves. In some embodiments, application of the low frequency signal to the subpopulation of nerves modulates neural activity of the central nervous system (CNS).

In accordance with some other aspects, the present disclosure provides a method of improving a physiological condition associated with nerve function in a subject in need thereof, the method comprising application of a low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.

In accordance with some further aspects, the present disclosure provides a method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof, the method comprises the step of applying low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.

In some embodiment, the method comprising positioning on a skin surface of a target organ, an electronic nerve stimulation device comprising an electrical module operable to generate the low frequency signal and an electrode array for applying the low frequency signal to the target organ.

In accordance with some further aspects, the present disclosure provides a method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof, the method comprises the step of applying an electronic nerve stimulation device on a target organ, wherein the electronic nerve stimulation device comprises (i) an electrical module operable to generate a low frequency signal and (ii) an electrode array for applying the low frequency signal to a subpopulation of nerves and modulating nerve impulses in the subpopulation of nerves. In some embodiments, the method comprises application of the device in a limb, or a limb portion. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic representations of an electronic nerve stimulation device (100) comprising an array of electrodes (120), an electric module (140), a power supply (160), and connectors and optionally wire(s) (180) that communicatively couple the electric module, the array of electrodes and the power supply.

Figs. 2A-2C are representations of an electronic nerve stimulation device, Fig. 2A is a representations of a device ("headband"), Fig. 2B is a back view representation, Fig. 2C is a front view representation.

Figs. 3A-3B are graphs of EEG measurement performed at FC5 electrode before (Fig. 3A) and after treatment with a headband device applying a frequency of 3Hz (TCD3) (Fig. 3B).

Figs. 4A-4B are graphs of EEG measurement performed at FC5 electrode before (Fig. 4A) and after treatment with a headband device applying a frequency of 9Hz (TCD9) (Fig. 4B).

Figs. 5A-5B are graphs of EEG measurement performed at FC5 electrode before (Fig. 5A) and after treatment with a headband device applying a frequency of 13Hz (TCD13) (Fig. 5B).

Figs. 6A-6B are graphs of EEG measurement performed at FC5 electrode before (Fig. 6A) and after treatment with a headband device applying a frequency of 23Hz (TCD23) (Fig. 6B).

Fig. 7 is a representative of an electronic nerve stimulation device placed on a wrist (300), with a back view of a wrist band/smart watch (320) and the charging unit (340).

Figs. 8A-8C are representative graphs of deep meditation effectiveness measurement (as expressed by the Muse Meditation EEG headband, the X-axis being the time lapsed measured over a few minutes) performed without a device (Fig. 8A), with a wrist device (Fig. 8B) or with a headband (Fig. 8C).

Fig. 9 is an exemplary representative of a personalized set-up system (400) comprising a an electronic nerve stimulation device (420) adjustable to be placed on a wrist, a measuring unit (440), a mobile phone and a cloud base service (460). DETAILED DESCRIPTION OF EMBODIMENTS

The present disclosure is based on the development of electronic nerve stimulation device designed to apply electric frequencies, specifically low frequency, for non-invasive brain stimulation.

It was found by the inventors that application of low frequency signals to a subpopulation of nerves successfully modulate nerve impulses in the subpopulation of nerves and subsequently modulate neural activity of the central nervous system (CNS), hence modulating brain activity. As such, it was suggested by the inventers that the device described herein may be used in a method of improving and/or treating conditions affected by changing brain waves, for example conditions associated with nervous system activity.

Thus, in accordance with some aspects, the present disclosure provides an electronic nerve stimulation device comprising an electric module operable to generate a low frequency signal and an electrode array for applying the low frequency signal to a subpopulation of nerves and modulating nerve impulses in the subpopulation of nerves. In some embodiments, application of the low frequency signal to the subpopulation of nerves modulates neural activity of the central nervous system (CNS).

The device described herein is a safe device, adaptable for domestic use and as such accessible to a to a wider range of subjects, such as children, adolescent or adults.

The device described herein is adjustable for being placed (applied, associated) on the external skin surface at various target organs of the subject's body. The target organ may be selected to be in close proximity to nerves from the central nerve system (e.g. the forehead, skull or spinal cord) or to nerves from the peripheral nervous system (e.g. a limb, a limb portion, for example on a wrist).

In some embodiments, the electronic nerve stimulation device is configured to be positioned on at least one limb, or limb portion and for stimulation of peripheral nerves. In some embodiments, the electronic nerve stimulation device is configured for wearing on a subject's wrist. In some other embodiments, the electronic nerve stimulation device has a form (shape) of a watch wrist or bracelet.

As shown in the Examples below, it was surprisingly found by the inventors that similar physiological effects in brain activity were observed when the device was positioned (placed) on a subject's skull and on a subject's wrist. Thus, it was suggested that the mechanism underlying the modulation of the neural activity in the brain is the same when the device is placed directly on the brain or when placed on the wrist, all benefiting from the nerve system as the carrier of the nerve signals.

As such it was proposed by the inventors that for the purpose of improving wellbeing associated with nerve activity or treating a physiological condition associated with nerve activity, it is possible to safely apply a low frequency signal to a subpopulation of peripheral nerves in a subject by placing (applying, positioning) the device or any part thereof in a brain remote position (organ) such as a wrist instead of directly on the brain. As detailed herein, a device placed on a subject's wrist has an equal physiological effect as a device placed on a subject's skull, under conditions that the same frequency is applied.

The electric module used herein refers to an electronic circuit that is operable to produce (generate) a periodic, oscillating electronic signal. The signal may be a sine wave, a triangle wave or a square wave. In some embodiments, the electric module is configured to generate frequency in the range of about 0.1 Hz to about 50Hz. In some embodiments, the electric module is a low-frequency oscillator (LFO) configured to generate a frequency below approximately 20 Hz. In some further embodiments, the electric module is an audio oscillator configured to generate a frequency in the audio range. In some embodiments, the audio oscillator is configured to generate a frequency in the range of 16Hz to 30Hz.

The electric module according with the present disclosure may be of any form known in the field. For example, the electric module may be a linear or harmonic oscillator, which generate a sinusoidal output. Alternatively, the electric module may be a nonlinear or relaxation oscillator, which generate a non-sinusoidal output, such as a square, sawtooth or triangle wave.

In some embodiments, the electric module may be a feedback oscillator or a negative- resistance oscillator. In some embodiments, the electric module may be a relaxation oscillator. In some embodiments, the electric module may be Voltage-controlled oscillator (VCO). VCO refers to an electronic oscillator whose oscillation frequency is controlled by a voltage input. The applied input voltage determines the instantaneous oscillation frequency. In some embodiments, the electric module is a VCO operable to generate frequency within the range of 0.1 Hz - 50Hz, at times in the range of 0.5Hz to 50Hz, at times in the range of lHz to 30Hz, at times in the range of 2Hz to 25Hz, at times in the range of 2Hz to 15Hz, at times in the range of 2Hz to 13Hz, at times in the range of 2Hz to 9Hz, at times in the range of 3Hz to 30Hz, at times in the range of 3Hz to 25Hz, at times in the range of 3Hz to 15Hz, at times in the range of 3Hz to 13Hz, at times in the range of 3Hz to 9Hz. In some embodiments, the VCO is operable by adjusting the steps of 0.1Hz, at times steps of 0.2Hz, steps of 0.5Hz, steps of lHz, steps of 2Hz. The frequency in the VCO may be generated using 2 pins from a nickel coated programmer, one of which is positive and the other negative such that when the pins are associate with a subject's skin, the circuit is closed and the low frequency is transferred to the target organ.

The electric module described herein may generate at least one low frequency signal. In some embodiments, the electric module may generate a single frequency.

In some embodiments, the electric module may generate at least two low different frequencies at same time, at least three different low frequencies at same time or even more. In some embodiments, the electric module may generate a frequency pattern of one or more low frequencies being altered over time. Generation of more than a single low frequency is referred herein as mixed frequencies.

The low frequency signal as used herein refers to a frequency defined as Extremely low frequency ("ELF") in the ITU designation for electromagnetic radiation.

In some embodiments, the low frequency signal encompasses multiple frequencies ("mixed frequencies").

In some embodiments, the low frequency signal encompasses a single frequency.

In some embodiments, the low frequency signal is between about 0.1 Hz to about 50 Hz. In some embodiments, the low frequency signal is between about 0.5 Hz to about 50 Hz. In some embodiments, the low frequency signal is between about 1 Hz to about 30 Hz. In some embodiments, the low frequency signal is between about 2 Hz to about 25 Hz. In some embodiments, the low frequency signal is between about 2 Hz to about 15 Hz. In some embodiments, the low frequency signal is between about 2 Hz to about 13 Hz. In some embodiments, the low frequency signal is between about 2 Hz to about 9 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 30 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 25 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 15 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 13 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 9 Hz. In some embodiments, the low frequency signal is about 1 Hz, at times about 2 Hz, at times about 3Hz, at times about 4 Hz, at times about 5Hz, at times about 9 Hz, at times about 10 Hz, at times about 11 Hz, at times about 12 Hz, at times about 13Hz, at times about 14 Hz, at times about 15 Hz, at times about 17 Hz, at times about 19 Hz, at times about 20 Hz, at times about 21 Hz, at times about 22 Hz, at times about 23Hz, at times about 24 Hz, at times about 25 Hz or any combination thereof. In some embodiments, the low frequency signal is about 2Hz. In some embodiments, the low frequency signal is about 3Hz. In some embodiments, the low frequency signal is about 9Hz. In some embodiments, the low frequency signal is about 13Hz. In some embodiments, the low frequency signal is about 15Hz. In some embodiments, the low frequency signal is about 23Hz. In some embodiments, the low frequency signal is about 2Hz, about 3Hz, about 9Hz, about 13Hz, about 15Hz, about 23Hz or any combination thereof.

It should be noted that when referring to a low frequency signal being, for example, about or at least about 2Hz, the exemplary value of 2 Hz is in the range of 2Hz encompassing variations of at least ±0.1, at least ±0.2, at least ±0.3, at least ±0.5, at least ±1, at least ±2. For example any value given here with respect to the frequency may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% or 30% higher or lower than the value referred to, the deviation range including integer values or non-integer values.

The electric module can be linked (connected) to an electrode array by a wire or by a wireless link. Such a connection is configured to allow the low frequency signal to be transmitted from the electric module to the electrode array.

The term array of electrodes (also denoted as electrode array or multielectrode arrays (MEAs)) as used herein refers to an electric conductor having multiple plates or shanks through which an electric current enters or leaves an electrolytic cell or other medium or neural signals are obtained or delivered. The type, shape, composition (material), number and any additional parameter characterizing the array of electrodes may vary depending for example on the subject's need. In some embodiments, all the electrodes within the array of electrodes are the same. In some embodiments, at least part of the electrodes within the array of electrodes are the same.

In some embodiments, the array of electrode comprises surface electrodes. In some embodiments, the array of electrodes or at least part thereof, may be soft, pliable, and flexible to be able conform to the target organ it associates. In some embodiments, the array of electrodes or at least part thereof may be stiff. In some embodiments, at least part thereof may be soft, stiff or any combination thereof.

In some embodiments, at least part of the array of electrodes have a ring shape surrounding an internal conducing disc. In some embodiments, at least part of the array of electrodes may be a square, rectangle, ellipse, or polygon.

In some embodiments, at least part of the array of electrodes comprises a metal such as aluminum, gold, platinum, iridium or steel. In some embodiments, at least part of the array of electrodes comprises a non-metal such as conductive polymer. In some at least part of the array of electrodes comprises a metal, non-metal or any combination thereof. In some other embodiments, at least part of the array of electrodes with circular edges which have diameters between 5mm and 20mm.

The frequency applied by the array of electrodes to the subpopulation of nerves can have a sinusoidal waveform or a non- sinusoidal waveform. In some embodiments the level of electric charge used is minuscule, at times between 1 and 2 milliampere at times lower than one-one-hundredth of a single electrical watt.

In some embodiments, the array of electrodes comprises at least two electrodes, at least three electrodes, at least four electrodes, at least five electrodes. In some embodiments, the array of electrodes comprises two electrodes, which may be the same or different. Application of such a frequency to a target organ comprising a subpopulation of nerves does not cause a painful reaction at the organ but merely a tingling or slight itching, if felt at all.

The term "subpopulation of nerves" as used herein refers to a group of nerve cells (also known as neurons) from the central nervous system (CNS) and/or from the peripheral nervous system (PNS). The nervous system is the part in the human body that coordinates actions by transmitting signals to and from different parts of the human body. The nervous system includes two main parts, the CNS and the PNS). The special neurons grouped together in nerves take information (messages) to and from the human body to the central nervous system. The CNS is the brain and spinal cord. The PNS comprises mainly nerves, sensory neurons, ganglia (clusters of neurons) and nerves, which are enclosed bundles of the long fibers, that connect to one another and to the CNS and the CNS to every other part of the body. It should be noted that the PNS can include non-nerve tissue such as connective tissue.

In some embodiments, the subpopulation of nerves are from the CNS. In some embodiments, the array of electrodes provides the low frequency signal to the subpopulation of nerves from the CNS. In some embodiments, the subpopulation of nerves are from the PNS. In some embodiments, the array of electrodes provides the low frequency to the subpopulation of nerves from the PNS.

As detailed herein, the electronic nerve stimulation device is capable of modulating the nerve impulses and/or the neural activity. The term "modulating" encompasses any change or modification in at least one nerve impulse or neural activity in relation to a control or a normal or a baseline level of at least one nerve impulse or neural activity as determined under certain condition.

The term "nerve impulse" as used herein refers to electrical signal transmitted along branches of neurons (named as dendrites) caused by movement of the charged ions. The term "neural activity" as used herein encompasses an neural oscillation, signal or brainwaves being rhythmic or repetitive patterns of neural activity in the central nervous system. Neural signal may be observed throughout the central nervous system at all levels, and include spike trains, local field potentials and large-scale oscillations which can be measured by electroencephalography (EEG). The neural signal can be characterized by at least one of frequency, amplitude or phase.

Neural signal can be characterized by various frequency band (range): alpha activity are at a frequency of 7.5-12.5 Hz, delta activity are at a frequency of 1-4 Hz, theta activity are at a frequency of 4-8 Hz, beta activity is at a frequency of 12-30 Hz.

Alpha waves (alpha frequency) are electromagnetic oscillations in the frequency range of 7.5-12.5 Hz arising from synchronous and coherent (in phase/constructive) electrical activity of thalamic pacemaker cells in humans. They place the brain in states of relaxation times, non-arousal, meditation, hypnosis Beta waves or beta rhythm (beta frequency), is the term used to designate the frequency range of human brain activity between 12 and 30 Hz (12 to 30 transitions or cycles per second). They awaking awareness, extroversion, concentration, logical thinking, active conversation.

Theta waves is an oscillatory pattern in EEG signals recorded either from inside the brain or from electrodes glued to the scalp. They are found in day dreaming, dreaming, creativity, meditation, paranormal phenomena, out of body experiences, ESP, shamanic journeys.

Delta waves are high amplitude brain waves with a frequency of oscillation between 1 to 4 hertz. Delta waves, like other brain waves, are recorded with an electroencephalogram (EEG) and are usually associated with the deepest stages of sleep (3 and 4 NREM), also known as slow-wave sleep (SWS), and aid in characterizing the depth of sleep.

Without being bound by theory, it was suggested by the inventors that application of at least one frequency signal (the low frequency signal described herein) which is within (or close to) the frequency range of the neural activity modulate the nerve impulse. Such a modulation may mimic the CNS's frequencies, causing the brain to respond to the emitted signals from the device thereby creating brain waves of different wavelengths and types.

For example, it was suggested that application of a frequency of 2Hz or 3Hz by the device described herein may modulate the brain to mimic and create mainly delta and theta waves, the frequency of 9 or 13 Hz by the device described herein may modulate the brain to mimic and create mainly alpha waves, whereas the frequency of 23 Hz by the device described herein may modulate the brain to mimic and create mainly beta waves. As detailed herein, such low frequencies are utilized for arousal of the brain activity.

The device described herein or any part thereof may be applied (positioned, placed, associated) with the skin's surface at any target organ. In some embodiments, the electrode array is configured for association with the skin's surface. It should be noted that the term "association" (or placement or application or positioning) in this context, encompasses bringing the device or any part thereof to a close contact (proximity) with the external surface of the skin. The association results in contacting the device or any part thereof with the skin surface to allow physical contact of at least part of the device with the external skin surface. It should be further noted that the device or any component/part thereof is not implanted under the subject's skin. In some embodiments, the electronic nerve stimulation device is a portable device. The device has dimensions enabling it to be portable as well as being light-weight for mobile and immediate use.

In connection with some embodiments in which the subpopulation of nerves are CNS nerves, the device or at least the electrode array is applied in close proximity with nerves from the CNS.

In some embodiments, the device or any part thereof is configured for association with the skin's surface at a target organ, for example the forehead of a subject. In some embodiments, the electrode array is configured for association with the skin's surface at a target organ, for example the forehead of a subject. In some embodiments, the electrode array is configured for association with the skin's surface at a target organ, for example the spinal cord of a subject.

In connection with some embodiments in which the subpopulation of nerves are PNS nerves, the device or at least the electrode array is applied in close proximity with nerves from the PNS. In some embodiments, the device or any part thereof is configured for association with the skin's surface at a target organ, for example a limb portion. In some embodiments, the electrode array is configured for association with the skin's surface at a target organ, for example a limb portion. In some embodiments, the electrode array is configured for association with the skin's surface at a target organ, for example a wrist of a subject.

As detailed herein, it was surprisingly found that the low frequency signal can be equally applied to a subpopulation of nerves from the CNS or from the PNS in order to affect the subject condition. In other words, modulation of the neural activity in the subject's brain is equally achieved by modulation of central nerve impulse or peripheral nerve impulse.

The array of electrodes may cause a selective modulating nerve impulses in the subpopulation of nerves using specific stimulation parameters. For example, application of specific frequency can affect, for example small nerve and not large nerves and visa- versa. Thus, it was suggested by the inventors that selection of specific frequency to be applied may determine the subpopulation of nerves to be modulated and hence as detailed herein, the physiological condition to be treated/improved. For example, application of a specific frequency can cause a nerve related to sensation to be modulated, but not a peripheral nerve related to motor control or application of a specific frequency can cause a nerve related to pain to be activated, but not a peripheral nerve related to a psychiatric condition.

The electronic nerve stimulation device in accordance with some embodiments, comprises a power supply. The power supply may be include any known techniques in the field. In some embodiments, the power supply may comprises a battery, a wall-plug adapter or a combination thereof. In some embodiments, the power supply is a battery. In some embodiments, the power supply is a battery of about 2 Volt to about 9 Volt or about 3 Volt to about 9 Volt.

The array of electrodes, the electric module and the power source may be linked (connected) such that the power source provide power to the electric module, and the electric module generate the low-frequency for transmission to the array of electrodes. Such linking (connection) may be by a wire or wireless link or any combination thereof.

Once the device or the array of electrodes are placed on a subject's skin at a target organ, (for example scalp or wrist) a device operated by a battery such as 9 volt battery applies a low frequency (corresponding to a small current) modulating the activity in targeted regions of the brain.

Fig. 1 illustrates an exemplary electronic nerve stimulation device lOO.The electronic nerve stimulation device 100 can include an array of electrodes 120, placed in proximity to a target organ (not shown) in the body to apply low frequency to modulate transmission of neural signals to subpopulations nerves, an electric module 140, a power supply 160, and optionally wire(s) 180 that communicatively couple the electric module 140 with the array of electrodes 120 and the electric module 140 with the power supply 160. The dashed line represented by 180 may refer to wire or to wireless connection. As detailed herein, the power supply 160 may provide current to the electric module 140, which can use this current to generate the low frequency and to apply the frequency to the array of electrodes 120. The array of array of electrodes 120 can provide the low frequency received from the electric module 140 to the subpopulation of nerves thereby modulating the transmission of neural signals along the nerve subpopulations.

Fig. 2 illustrates an exemplary electronic nerve stimulation device having a shape of an subject's head or a portion of the subject's head and adoptable for being placed on a subject's skull 200. The electronic nerve stimulation device 200 has a shape of an arch (headband) for being placed on an individual's back-head, the device having with two protruding electrodes on each side (220, 240), such the left electrode 220 is touching the left (skull location AF3) and the left electrode 240 is touching the right (skull location AF4) forehead. The device also includes an on/off button 260. This button 260 also serves as a user interface for adjusting the low frequency (value e.g. 2Hz, range e.g. from 2Hz to 3Hz and duration of operation e.g. 3 minutes). The selection of frequency may be done using a color-coding convention for assisting a subject to use the required frequency. Positioning of the device on the head may be done using the frontal ends (280).

The electronic nerve stimulation device can be associated to the skin surface by a variety of means. For example, association (contact) can be made through attachment to forehead, for example using a suction cap or vacuum cap. In some embodiments, operation of the device may be by contacting the device with the forehead. In some embodiments, the electric module may be attached to the forehead, followed by application of low frequency signal from the array of electrodes.

In some other embodiments, the electronic nerve stimulation device may form part of a cap worn by subject. The cap may be made of any fabric, such as a cloth fabric or synthetic polymer mesh. In accordance with such embodiments, the electric module are affixed (attached) to the cap to make an array of electric modules across the whole head of the subject, producing required frequencies.

Fig. 7 illustrates an exemplary electronic nerve stimulation device adoptable for being placed on a wrist of a subject (300). The electronic nerve stimulation device has a shape of a watch with two electrodes on the device part in connection with the skin surface (back side) (320) for applying the low frequency signal. The device may in the form of watch, bracelet or any device having a shape adoptable for being placed on the wrist. The device may include a charging unit (340).

The electronic nerve stimulation may be connected by a wire or wirelessly to a mobile phone and/or to a cloud based services to transfer information.

In accordance with some embodiments, the device described herein may comprise a measuring unit. The measuring unit may comprises at least one sensor and/or an accelerometer. In some embodiment, the at least one sensor is a Photoplethysmography (PPG) sensor. PPG sensors use a light-based technology to sense physiological parameters such rate of blood flow as controlled by the heart's pumping action. In some embodiments, the at least one sensor may be placed on a part of the device that is in contact with the skin surface. For example, the at least one sensor may be placed on the "back" of a wrist-watch to contact the skin.

In accordance with some embodiments, the at least one sensor is configured to measure physiological parameter of a subject. In some embodiments, the at least one sensor may be configured to measure at least one of heart rate, heart rate variability (HRV), breathing pattern derived stress, blood pressure, blood flow, temperature, oxygen level, level of tremor or physical activity.

In some embodiments, the physiological data may be obtained from a commercial device comprising at least one sensor, such as a commercial watch, for example an Apple Watch being used in combination with the device described herein.

In some embodiments, the measuring unit may comprise means to transfer the physiological parameter generated by the measuring unit to an external database for storage and/or for analysis. For example, the physiological data can be transferred to health care authority managing the subject health condition. This information could be used in order to further optimize the treatment (i.e. low frequency) and all of which could be used to determine the regimen for the subject.

Alternatively, the device described herein may be adjustable to a cell-phone using an application for transmitting the collected physiological information to an external database.

A combination of the device described herein with a measuring unit, optionally a mobile- phone and an external databased (such as a cloud base server) are all collectively denoted as personalized set-up. The measuring unit may be an internal part of the device, an external part of the device (optionally commercial) or any combination thereof. The personalized set-up may be used for determining personalized treatmentlwellbeing of a subject in need thereof.

Fig. 9 is an exemplary representative of a personalized set-up (400) comprising a an electronic nerve stimulation device (420) adjustable to be placed on a wrist, at least one measuring unit (440), and a cloud base service (460). The set up (400) may also include a mobile phone for (460) collecting the information and transferring the information to the cloud base device. In the exemplary representative of Fig. 9, the measuring unit is external to the device, however, as noted above, the measuring unit may be an integral part of the device (the dashed line in Fig. 9 represents an option). In addition, the personalized set-up may comprise all the components within the device such that the analysis and feedback to the subject are all performed internally within the device.

The present disclosure also provides a system comprising multiple electronic nerve stimulation devices, at least two, at least three, at least four, at least ten. The multiple devices may be the same or may be different. The similarity may be for example by applying the same frequency and being associated with the same target organ. By the use of multiple devices, at least some of the multiple devices are capable of applying different frequencies and/or being associated at different organ targets.

The system comprising at least two device may generate, according with some embodiments, at least two different low frequency. As detailed above, generation of at least two different low frequency may be obtained also from a single device. Thus, the device described herein or a system comprising at least two device are capable to generate multiple different frequencies, at least two different low frequency. The at least two different low frequency may be generated in parallel or sequentially. As detailed herein, generation of at least two different frequencies refers to "mixed frequencies". Thus, mixed frequencies may be generated from a device or from a system comprising at least two devices.

For example, while a first device may apply a frequency modulating nerves related to balance brain waves (neuronal activity) alleviating sleep disorder, a second device, characterized by a different frequency or a different frequency applied by the first device may apply a different second low frequency modulating nerves related to balance brain waves which increase the level of focus and a third device or preset could be used to treat ADHD. Thus, the device described herein either alone or in combination with at least one additional device, has the capability to generate and apply more than one low frequency signal, thereby affecting various conditions.

In some embodiments, the electronic nerve stimulation device can be used to modulate a variety regions of the brain; the motor cortex and frontal cortex regions of the brain; or the lateral sides of the frontal lobe region of the brain. Preferable configuration is synchronized to promote coherence and synchronous behavior between multiple locations in the brain.

Specific types of neural oscillations may also appear in pathological conditions which often are characterized by an aberrant version of a normal oscillation.

Thus, the electronic nerve stimulation device as described herein can be used for treating a variety of conditions associated with nerve activity.

Thus, in accordance with some embodiments, the electronic nerve stimulation device as can be for use in improving a physiological condition in a subject in need thereof by applying a low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.

It is understood that the interchangeably used terms "associated", linked" and "related", when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder condition or pathology causes the second disease, disorder, condition or pathology.

In some embodiments, the physiological condition encompasses any condition which affects wave brains and/or nerves. In some embodiments, the physiological condition is associated with nerve function In some embodiments, the physiological condition associated with nerve function is a neurological disorder.

In accordance with some other aspects, the electronic nerve stimulation device as can be for use in treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof. In some embodiments, the nerve disorder is associated with a brain (cerebral) function. In some embodiments, the nerve disorder is associated with a spinal cord function.

The methods of the invention provide modulation of transmission of neural signals in a subpopulation of nerve, comprising applying low frequency signal to the subpopulation of nerve to modulate the nerve impulses in said subpopulation. In accordance with some aspects, the method comprises placing an array of electrodes on a target organ being in close proximity to nerves from the PNS or from the CNS.

In accordance with some aspects, the present disclosure provides a method of improving a physiological condition associated with nerve function in a subject in need thereof, the method comprises the step of applying low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.

The term physiological condition associated with nerve function as used herein encompasses a variety of conditions associated with changes in brain waves, changes in nerves, function of the nerve system (e.g. the central nervous system). The conditions may be, for example, due to a reduction (inhibition) in the nerve function or a damage (degeneration) in the nerve function.

Diagnosis of a physiological condition associated with nerve function can be diagnosed by a variety of experimental methods, for example X-ray, magnetic resonance imaging (MRI), computerized tomography (CT), Positron emission tomography (PET) and an electroencephalogram (EEG).

In some embodiments, the physiological condition associated with nerve function is associated with changes in the brain wave. The change may be for example in the brain wave being alpha activity, delta activity, theta activity or beta activity. Such brain wave may change, for example, during meditation or yoga.

In some embodiments, the physiological condition associated with nerve function relates to the wellbeing of a subject. In some embodiments, the method is for increasing the mental capability of the brain. In some embodiments, increasing the mental capability comprises at least one of alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity. The following measures alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity, or at least part thereof are collectively denoted as "meditation state" . In some embodiments, the method is for improving the meditation state in a subject.

In some embodiments, the method is for improving blood pressure.

It was suggested that the device described herein balance the brain waves frequencies, which relieve the pressure and tension, and enables the patient to feel relaxed and need to sleep.

In some embodiments, physiological condition associated with nerve function is a nerve disorder. A nerve disorder as used herein refers to a neurological disorder and includes any disorder of the nervous system, including for example paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness.

In accordance with some aspects, the present disclosure provides a method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one nerve disorder in a subject in need thereof, the method comprises the step of applying low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses. In some embodiments, the at least one nerve disorder comprises a vascular disorder, an infection, a structural disorder, a functional disorder, a degenerative disorder or a mental disorder.

A vascular disease is a class of diseases of the blood vessels, the arteries and veins of the circulatory system of the body. Non-limiting examples of vascular disease include Erythromelalgia, Peripheral artery disease, Renal artery stenosis, Buerger's disease, Raynaud's disease, Disseminated intravascular coagulation, Cerebrovascular disease.

A functional disorder is a medical condition that impairs normal functioning of bodily processes that remains largely undetected under examination, dissection or even under a microscope. Non-limiting examples of a functional disorder include Irritable bowel syndrome, Fibromyalgia, Chronic fatigue syndrome, Chronic pelvic pain, Interstitial cystitis or Temporomandibular joint pain, functional neurological symptom disorder.

A structural disorder, in which some part of the body can be seen to be abnormal.

Neurodegeneration (degenerative disorder) is the umbrella term for the progressive loss of structure or function of neurons, including synaptic dysfunction and death of neurons. Many neurodegenerative diseases including Parkinson's and Alzheimer's are associated with neurodegenerative processes. Other examples of neurodegeneration that may be also applicable herein may include Friedreich's ataxia, Lewy body disease, spinal muscular atrophy, multiple sclerosis, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy, hereditary spastic paraparesis, amyloidosis, Amyotrophic lateral sclerosis (ALS), and Charcot Marie Tooth. In some embodiments, the methods of the invention may be applicable for treating a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder may be Alzheimer's disease or Parkinson's disease. A mental disorder is a psychological syndrome or pattern which is associated with distress, disability , increased risk of death, or causes a significant loss of autonomy.

In some further embodiment's, the nerve disorder comprises at least one of epilepsy, insomnia, attention deficit hyperactivity disorder (ADHD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson disease, Alzheimer's disease, depression, anxiety, migraine, stroke, transient ischemic attack (TIA), Pick's disease, Parkinsonism, rigidity, hemiballism, choreoathetosis, dystonia, akinesia, bradykinesia, hyperkinesia, depression, bipolar disorder, anxiety, phobia, schizophrenia, multiple personality disorder, substance abuse, attention deficit hyperactivity disorder, eating disorder, impaired control of aggression, impaired control of sexual behavior, headache, migraine, concussion, post-concussive syndrome, stress- related disorder, hypertension or an infection. In some further embodiment's, the nerve disorder is associated with a seizure. In an embodiment, the method is adjustable for use any individual, irrespective of age, who can, upon need, self-determine the frequency according to predetermined purpose.

In accordance with some aspects, the method comprises positioning a device or any part thereof onto a skin surface of a target organ, wherein the target organ is in close proximity with PNS nerves or CNS nerves. In some embodiments, the method comprising positioning the array of electrodes with a skin surface of a target organ. In some embodiments, the target organ may be a skull. For example, for the primary motor cortex and primary visual cortex (small sections of the total brain surface), proper positioning is established by the elicited response: muscle contractions when stimulating the primary motor cortex; illusory lights (phosphenes) when stimulating the primary visual cortex. In both of these areas, the effects are very sensitive to emitter position and orientation.

The step of positioning the device on a subject's brain, may comprise positioning a plurality device on the subject's head directed to the target brain region so that the principal direction of current in at least one of the device (specifically the array of electrodes) is transverse to the anterior-posterior axis of the subject's head.

In some embodiments, the target organ may be a limb or a limb portion. In some embodiments, the target organ may be a wrist.

The method described herein comprises application of a low frequency signal to a subpopulation of nerves. The applied frequency, multiple frequencies or the range of frequencies and the duration of application of the low frequency depends on various consideration. Application of a frequency, multiple frequencies or the range of frequencies by the array of electrodes may follow a pre-determined protocol ("predetermined protocol") or may be adjusted during application ("adjustable protocol").

As appreciated, both the pre- determined protocol or the adjustable protocol may include several different frequencies obtained by altering the frequency ("mixed frequencies"). The mixed frequencies comprise different dominant waves. This could be useful, for example, in order to "prime" or enhance activities such as meditation, which is characterized by multiple dominant waves.

In some embodiments, the method comprises application of a low frequency signal using a pre-determined protocol, an adjustable protocol or any combination thereof.

In some embodiments, the method comprises application of low frequency for at least about 30 seconds, at least about 1 minute, at least about 3 minutes, at least about 5 minutes, at least about 10 minutes, at least about 30 minutes, at least about 1 hour. In some embodiments, the method comprises application of low frequency for a time period between about 30 seconds to about 30 minutes, at times between about 1 minute to about 20 minutes, at times between about 1 minute to about 10 minutes.

In some embodiments, the method comprises application of low frequency at least once an hour, at least twice an hour, at least three times an hour, at least four times an hour. In some embodiments, the method comprises application of low frequency at least once daily, at least twice daily, at least three times daily, at least four times daily. In some embodiments, the method comprises application of low frequency at least once a week, at least twice a week, at least three times a week, at least four times a week.

As detailed herein, the low frequency signal is applied in order to improve emotional, psychiatric and mental state of an subject as well as lack of focus, anxiety, depression, nervousness, restlessness or agitation.

In some embodiments, the method comprises application of a low frequency signal between about 0.5 Hz to about 50 Hz, at times between about 1 Hz to about 30 Hz, at times between about 2 Hz to about 25 Hz, at times between about 2 Hz to about 15 Hz, at times between about 2 Hz to about 13 Hz, at times between about 2 Hz to about 9 Hz. In some embodiments, the low frequency signal is between about 3 Hz to about 30 Hz, at times between about 3 Hz to about 25 Hz, at times between about 3 Hz to about 15 Hz, at times between about 3 Hz to about 13 Hz, at times between about 3 Hz to about 9 Hz. In some embodiments, the low frequency signal is about 1 Hz, at times about 2 Hz, at times about 3Hz, at times about 4 Hz, at times about 5Hz, at times about 9 Hz, at times about 10 Hz, at times about 11 Hz, at times about 12 Hz, at times about 13Hz, at times about 14 Hz, at times about 15 Hz, at times about 17 Hz, at times about 19 Hz, at times about 20 Hz, at times about 21 Hz, at times about 22 Hz, at times about 23Hz, at times about 24 Hz, at times about 25 Hz or any combination thereof.

In some embodiments, the low frequency signal is about 2Hz.

In some embodiments, the low frequency signal is about 3Hz.

In some embodiments, the low frequency signal is about 9Hz.

In some embodiments, the low frequency signal is about 13Hz.

In some embodiments, the low frequency signal is about 15Hz.

In some embodiments, the low frequency signal is about 23Hz.

In some embodiments, the low frequency signal is about 2Hz, about 3Hz, about 9Hz, about 13Hz, about 15Hz, about 23Hz or any combination thereof.

As noted herein, the low frequency signal value encompasses variations of at least ±0.1, at least ±0.2, ±0.3, ±0.5, ±1. For example any value given here with respect to the frequency may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values or non-integer values.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a migraine.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of hypertension.

In some embodiments, the method comprises application of a frequency of about 2Hz using a headband or a wrist device for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one of migraine or hypertension. In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of insomnia.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of Parkinson disease.

In some embodiments, the method comprises application of a frequency of about 3Hz using a headband or a wrist device for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one of insomnia or Parkinson.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of ADHD.

In some embodiments, the method comprises improving at least one of calmness, relaxation, focusing (collectively dented herein as meditation state).

In some embodiments, the method comprises application of a frequency of about 9Hz using a headband or a wrist device for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of ADHD.

In some embodiments, the method comprises application of a frequency of about 9Hz using a headband or a wrist device for improving at least one of calmness, relaxation, focusing.

In some embodiments, the method comprises application of a frequency of about 9Hz using a headband or a wrist device for improving at least one of alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity.

In some embodiments, the method comprises application of a frequency of about 9Hz using a headband or a wrist device for improving a meditation state.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of depression.

In some embodiments, the method comprises application of a frequency of about 13Hz using a headband or a wrist device for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of depression.

In some embodiments, the method comprises treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of epilepsy.

In some embodiments, the method comprises application of a frequency of about 15Hz using a headband or a wrist device for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of epilepsy.

The method described herein may comprise a step of collecting data from a subject using the measuring unit, prior to or during treatment. In other words, prior to application of a low frequency signal or during sequential applications of a low frequency signal, the data obtained from the measuring unit may determine/affect the applied low frequency signal, and the duration of application. Thus, the present disclosure also provides personalization of treatment programs (protocols).

In some embodiments, the method comprises a step of monitoring at least one physiological parameter from a subject. For example, by using a device having a shape of a wrist- watch or a commercial watch for measuring heart rate, HRV, breathing patterns derived stress, blood pressure, during, and after treatment, it would be feasible to provide information useful in determining the subject' condition and accordingly the required treatment (e.g. the low frequency signal to be applied). Thus, the method described herein may adjust treatment personalization.

In some embodiments, the method comprise adjusting treatment protocols. The adjustment can be done real-time or near real time in order to enhance the efficacy of the programs. As detailed herein, any physiological data in need of adjusting treatment personalize the and its effectiveness may be collected via sensors on the device or via other sources.

In some embodiments, the method comprise monitoring the treatment effectiveness. In some embodiments, the method comprises measuring (collecting) at least one physiological parameter as described herein prior to and/or during application and/or after termination of application of the low frequency signal.

In some embodiments, the at least one parameter is selected from heart rate, heart rate variability (HRV), breathing pattern derived stress, blood pressure, blood flow, temperature, oxygen level, level of tremor and physical activity.

In some embodiments, the method comprises comparing the at least one physiological parameter obtained prior to and/or during application and/or after termination of application of the low frequency signal in order to determine the differences between the measurements of the at least one parameter, prior to and after application the low frequency signal, thereby adjusting the treatment effectiveness. As appreciate, determining/monitoring treatment effectiveness may be part of the personalized treatment, allowing adjusting subject's own protocol of treatment.

Thus, the method using the device described herein may detect improvements or deterioration of the patient and alter the treatment in terms of number of treatments per unit of time (days/week), length of the treatment, timing during the day, and frequency of treatment (as detailed herein, the device can apply frequencies that are in the range of 0.5Hz to 50Hz and it is expected that different frequencies will be applicable to different patients at different conditions and even at different times. The optimization of the programs could be done remotely through an dedicated application on a mobile phone connected via Bluetooth to the device including the wristwatch or the headband. The data analysis could be based on data obtained from the subject, such as certain frequencies that are effective for the treatments, certain point during the day that are effective, and certain length of treatment that are more effective in different scenarios. Data analysis may be further improved by analysis conducted on the database (for example cloud) to which the phone can be connected, using data and historical data from the subject, as well as insights obtained from usage patterns of other, similar subjects. The connectivity to the cloud could potentially be from the wrist watch itself, provided that some communication means is provided on it, such as a SIM card. The data analysis on the cloud and on the device could be based on insights obtained by Machine Learning and/or Deep Learning algorithms, or by using rule based system, set by humans, machines or a combination thereof. For example, a student going to school and suffering from ADHD may benefit from certain pattern before going to school and another one upon returning from school during school hours, a different boosting pattern might be useful as well.

The present method thus also provides collection of data from the subjects, thereby assisting subjects such as school students or college students, as well as individuals who are in need of a calmed alertness level, enabling them to cope and solve complex tasks and problems in their everyday lives. In addition and as noted herein, the device may be used by patients suffering from a wealth of indications for example ADHD, ADD, Parkinson, high blood pressure, depression or anxiety. As noted above, the invention provides methods for treating disorders as specified above. The term "treatment as used herein refers to the application of a low frequency according with the invention to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.

The term "amelioration" as referred to herein, relates to a decrease in the symptoms, and improvement in a subject's condition, wherein the improvement may be manifested in the forms of inhibition of pathologic processes or with a well-being condition of a subject.

The term "inhibit" and all variations of this term is intended to encompass the restriction or prohibition of the progress and exacerbation of pathologic symptoms or a pathologic process progress.

The term "eliminate" relates to the substantial eradication or removal of the pathologic symptoms and possibly pathologic etiology, optionally, according to the methods of the invention described herein.

The terms "delay" or "delaying the onset" and all variations thereof are intended to encompass the slowing of the progress and/or exacerbation of a disorder as described herein.

It should be appreciated that the terms "inhibition", "moderation", "reduction" or "attenuation" as referred to herein, relate to the retardation, restraining or reduction of a process, specifically, any of the a disorder described herein by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%, 100% or more.

The term "improving" as used herein refers to an increase of at least one measured parameter as described herein, by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%, 100% or more.

The present invention relates to the treatment of subjects, or patients, in need thereof. By "patienF or "subject in need' it is meant any organism who may be affected by the above- mentioned conditions, and to whom the preventive and prophylactic compositions and methods herein described is desired.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps disclosed herein as such methods steps may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

It must be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. NON-LIMITING EXAMPLES

Example 1: Evaluation of the Transcranial Doppler (TCD) device

TCD devices

The four devices used in this study were TCDs emitting frequency as follows: (i) emitting at 2Hz ("TCD2"), (ii) emitting at 3Hz ("TCD3"), (iii) emitting at 9Hz or emitting at 13 Hz ("TCD9,13") or (iv) emitting at 23 Hz ("TCD23").

Electroencephalogram (EEG) measurements

Baseline EEG measurements were taken for 2-3 minutes before the TCD treatment for each volunteer, using the EPOC™ neural headset device produced by the EMOTIV company (see also Stage 1 below).

Example 1A: Effect of TCD treatment

General Procedures and Measurements

A group of twenty four volunteers at age 16 to 80 were treated for 10-30 minutes with each one of the three devices detailed above: (i) emitting at 3Hz (TCD3), (ii) emitting at 9Hz or 13 Hz (TCD9,13) or (iii) emitting at 23 Hz (TCD23). The transcranial devices (TCD) were placed on the skull of the volunteers so that they are in contact with skull positions at the anterior fontal left side (known as AF3) (left forehead) and the anterior fontal right side (known as AF4).

Volunteers selected for this study were diagnosed with at least one disorder being insomnia, ADHD, epilepsy, lack of focus, calmness, attentiveness, alertness and lack of concentration .

Step 1— Baseline EEG measurements

Baseline EEG measurements were taken for 2-3 minutes prior to the TCD treatment for each volunteer, using the EPOC™ neural headset device produced by the EMOTIV company.

The EPOC™ device has 14 electrodes which were placed at various skull locations. In the examples below (one Example for each TCD emitting frequency), only the FC5 EPOC™ electrode EEG readings was used for calculations and charting, as this skull location seems to be the most reliable. The results of all other 13 EPOC™ electrode EEG readings are not provided. The figures also indicate the intersection between the FC5 EEG readings trace and the TCD device's emitting wavelength. This intersection indicates the power of the EEG signal at the TCD device wavelength, before and after TCD treatment.

Step 2— TCD device treatment

In this step, the TCD device (TCD3, TCD9,13 or TCD23) (shown in Fig. 2A) was applied on the volunteer's head as depicted in Figs. 2B and 2C so as the device's two electrodes were placed at skull positions AF3 and AF4 and the device was activated by pressing the activation button. The treatment was continued for 10-30 minutes.

Step 3— Post-treatment EEG measurements

Following the volunteer's treatment with the TCD device, post-treatment EEG readings were taken for 2-3 minutes using the EPOC™ neural headset device produced by the EMOTIV company. As with the baseline measurements, the graphs below detail only the EPOC™ FC5 electrode readings. All other 13 EPOC™ electrode EEG readings are not depicted in the charts. The charts also indicate the intersection between the FC5 EEG readings trace and the TCD device's emitting wavelength. This intersection indicates the power of the EEG signal at the TCD device wavelength, after TCD treatment. These readings were compared to the baseline EEG readings. Readings different from baseline EEG readings were interpreted as a positive sign for the effect of the transcranial device.

The EPOC™'s device EEG readings were processed using Fast Fourier Transform (FFT) calculations using the MATLAB computing language.

Results:

Studies using TCD3 device - 3Hz

Comparison of the EEG pattern at the FC5 electrode prior to (Fig. 3 A) and after treatment (Fig. 3B) indicated that application of a 3 Hz frequency influenced the EEG pattern as evident by the strength of the 3Hz frequency signal.

As a result of the TCD3 treatment the volunteers reported the need to sleep.

Studies using TCD9 operated at 9 Hz

Comparison of the EEG pattern at the FC5 electrode prior to (Fig. 4A) and after treatment (Fig. 4B) indicated that application of a 9 Hz frequency influenced the EEG pattern.

As a result of the TCD9 treatment the hyperactive volunteers reported to be more focused and relaxed.

Studies using TCP 13 operated at 13 Hz

Comparison of the EEG pattern at the FC5 electrode prior to (Fig. 5 A) and after treatment (Fig. 5B) indicated that application of a 13 Hz frequency influenced the EEG pattern.

As a result of the TCD13 treatment the volunteers reported being focused and relaxed.

Studies using TCD23 - 23 Hz

Comparison of the EEG pattern at the FC5 electrode prior to (Fig. 6A) and after treatment (Fig. 6B) indicated that application of a 23 Hz frequency influenced the EEG pattern at the beta wave power at the 13 Hz frequency.

As a result of the treatment with TCD23 the volunteers reported being more focused and active.

Example 2 - Clinical studies of Insomnia patients using TCD3- 3 Hz

Selection of volunteers and clinical protocol:

Volunteers (n=21, ages: 28-64, Gender: M/F) were selected on the basis of routine visits to Biomed center clinic in Galilee (Israel). After an explanation of the device and signing of an informed consent form, they were asked to continue their daily activities and to maintain their habits and to use the device for half an hour before sleep time. Half of the patients received a placebo device (Sham device, composed of a similar unit but without any active electronic). All usual medications for other illness were kept unchanged during the study period of three month.

At baseline, the sleep time was documented for every subject. The next visit was scheduled for the coming one month and they were asked to prepare a daily report of time to fall asleep and sleeping length. For the last two visits time to fall asleep, and sleep time were documented and careful investigations of wellbeing and of adverse effect were undertaken.

Results

Eleven subjects (on treatment arm) reported in the second visit (after one month) that they started to feel better and sleep better after the first week, and instead of staying one hour on bed before sleeping, they reported that the stayed on average 15 minutes, after 1 month they reported that instead of three hours sleeping per night in average, they started to sleep between 5 hours, and 5-6 hours at the end of second month and 6- 7+ hours at the last month.

Six subjects reported no effect (4 of them had placebo and 2 had used the device). The other 5 patients that had Sham devices, reported about minor enhancement.

Table 1: the effect of the device on Insomnia

Figure imgf000032_0001

Example 3 - studies of depression patients using TCD13-13 Hz

A 86 year old female diagnosed with a long history of major depression was recruited for this study. The patient has diagnosed with continued restless and emotionless behavior, feeling irritable and has lost interest in her routine activities. The clinical signs included sadness, scarceness, tiredness and easily fatigued as well as sleeplessness. Treatment using a combination of psychotherapy and pharmacotherapy (asenta 1 caps\d, ebixa 30 mg\d, clonex, zyprexa, cipralex)was unsuccessful and after one year of treatment, her condition was worsen without the ability to sustain persistent mood and cognitive function, frustrated with intense anxiety and hopelessness.

The patient was tested using TCD13 Hz.

One week after initiation of treatment the patient reported a significant improvement in the mood and an increase control of the anxiety. Her family reported a positive personality changes, more active and more appropriately engaged with her family. She was more interested in socializing and she stopped crying and was not afraid anymore. The patient continued to use the TCP 13 Hz once to twice daily for 2 months (and still using it) and her family reported that she has significantly improved, she is experiencing happiness and calmness, as well as improved sleep and lack of depressive manifestations.

In addition, 48 patients diagnosed with depression were treated with TCD-13 device and more than 80% reported enhancement and positive change in their wellbeing within two weeks of treatment.

Example 4 - studies of Migraines patients using TCD2- 2Hz

This study was performed with 19 patients (13 severe migraine and 6 medium migraine). Most of the patients reported that that they have improved following a month of treatment (30 minutes daily) from having reduced migraine attacks five times a month to once or twice a month.

All volunteers were diagnosed by their own doctors before starting the study. The results of this study are based on individual reports of the patients themselves and measured by scale from 0-10, as 0 demonstrates severe situation while 10 demonstrates the mild. The study included 19 patients from age 21-56 years old, 13 of them were diagnosed as severe with more than five attacks per month and 6 as medium with up to three attacks per month. Following the pilot study additional patients were treated with similar results. The results summary are provided below: Table 2: The effect of the device on migraine

Figure imgf000034_0001

1 -medium 26/f 8 10

2-medium 24/m 7 9 10

3-medium 40/m 6 10

4-medium 27/M 5 7 9 10

5-medium 42/m 9 10

6-medium 47/m 7 7 7 7 Additional results of patient beyond initial study

Figure imgf000035_0001

Example 5 - studies of ADHD patients using TCD9- 9Hz

Twenty-three patients were treated using the 9 Hz device, and after one week of treatment, nineteen of them stopped using their regular medicaments (Ritalin). In addition, they reported that they felt better, and felt calm and concentrated at the end of the first month of treatment.

Example 6 - studies of Epilepsy in rats model using TCD-15 Hz device

This study used a small variant of 15 Hz device (TCD15) device to evaluate the effect in pilocarpine induced rat model of epilepsy.

Male aged 10 or 3 months Sprague Dawley (SD) rats provided by Harlan laboratories, Israel were used in this study. The average body weight was 332.9 g at study initiation in the two study groups (on Day 1). The minimal and maximal weight recorded in each group was within the range of ± 20 % of the group mean.

The pilocarpine model of epilepsy in rats was applied in order to evaluate the Test Device protection potential against temporal lobe pilocarpine-induced seizures.

Stimulation by the tested device decreased the duration of the seizures on all study days mostly for the more sever seizures (Stages 3 and 4 on Racine scale). Since the seizures develop with time after pilocarpine exposure, the most pronounced effect was recorded on Day 2. Conclusion of the rat study: Stimulation by the tested device indicated a possible therapeutic potential of the device for the treatment of epilepsy.

The pilocarpine model of epilepsy in rats was applied in order to evaluate the Test Device protection potential against temporal lobe pilocarpine-induced seizures.

Stimulation by the tested device decreased the duration of the seizures on all study days mostly for the more sever seizures (Stages 3 and 4 on Racine scale). Since the seizures develop with time after pilocarpine exposure, the most pronounced effect was recorded on Day 2. Nevertheless, this therapeutic effect did not reach statistical significance, mostly due to the small number of animals in this study groups.

Conclusion of the rat study: Stimulation by the tested device indicated a possible therapeutic potential of the device for the treatment of epilepsy.

Example 7 - studies of Parkinson patients using TCP- 3 Hz device

The results showed improvement in the task, and motor symptoms improved as well. The 10 patients were tracked for 3 weeks and had multiple stimulations, not only did motor symptoms improve, but their quality of life improved as well. When their symptoms were more controlled, the patients were more relax and active. 8 of them have been totally improved with no motor symptoms.

Example 8 - studies of Hypertension patients using TCP- 2Hz device

37 hypertension patients used the device and 81 % of them reported their blood pressure (BP) was balanced within the first month of usage,

All patients used the device 10-30 minutes twice daily. However 16 patients reported that they have used the device only once a day after two weeks of usage.

30 patients have reached normal level of BP within the first month. 3 patients have no change. 4 patients has a minor change. Table 3: The effect of the device on blood pressure

Patients/G average Before One month after Comments and age using

l- M/51 140-50/85-90 120-30/80-90 Reach Normal BP

2-M/47 150-60/100 125-35/70-75 Reach Normal BP

3-M/63 135-40/85 120-30/80-90 Reach Normal BP

4-F/52 160-70/100 150-60/95-100 Minor change

5-M/55 140-50/80-90 140-50/80-90 No change

6-F/41 140-50/90-5 120-30/80-90 Reach Normal BP

7-F/69 140-50/95-100 130-35/80-90 Reach Normal BP

8-M/49 150-55/90-5 130-35/70-75 Reach Normal BP

9-F/50 140-50/90-5 120-30/80-90 Reach Normal BP

10-M/49 150-60/70-5 120-30/80-90 Reach Normal BP l l-M/61 145-55/95-100 145-55/95-100 No change

12-M/72 140-50/80-5 120-30/80-85 Reach Normal BP

13-F/48 140-50/90-100 120-30/80-90 Reach Normal BP

14- M/62 140-50/75-80 120-30/70-80 Reach Normal BP

15-F/49 140-50/80-5 120-30/80-85 Reach Normal BP

16- M/56 150-55/90-5 120-30/80-90 Reach Normal BP

17-F/44 140-50/75-80 130-35/70-75 Reach Normal BP

18-F/61 140-50/90-100 140-50/85-90 Minor change

19- M/44 140-50/80-5 140-50/80-5 No change

20-F/56 150-55/90-5 140-50/80-5 Minor change

21- M/54 150-60/70-5 130-35/70-75 Reach Normal BP

22-F/33 140-50/80-5 125-35/70-75 Reach Normal BP 23-M/47 140-50/90-100 120-30/80-90 Reach Normal BP

24-M/59 140-50/75-80 120-30/80-90 Reach Normal BP

25-F/67 150-55/90-5 130-35/70-75 Reach Normal BP

26-M/63 150-155/90-5 120-30/80-90 Reach Normal BP

27-M/58 140-50/80-5 130-35/70-75 Reach Normal BP

28-F/53 150-60/70-5 130-35/70-75 Reach Normal BP

29-F/46 135-40/85-90 130-35/70-75 Reach Normal BP

30-M/39 140-50/90-100 120-30/80-90 Reach Normal BP

31-M/49 150-60/80-5 120-30/80-90 Reach Normal BP

32-F/40 150-155/90-5 130-35/80-85 Reach Normal BP

33- M/70 135-40/85-90 130-35/70-75 Reach Normal BP

34-M/55 150-60/80-5 120-30/80-90 Reach Normal BP

35— F/50 135-40/85-90 120-30/80-90 Reach Normal BP

36-F/38 150-60/90-100 140-50/85-90 Minor change

37- M/52 150-60/80-5 120-30/80-90 Reach Normal BP

Example 9 - Equivalence of the effect of A wrist wearable device

A wrist wearable device such as a smart watch or bracelet that could potentially operate in conjunction with a mobile phone compatible with current mobile operating systems such as Android and IOS was used.

The smart watch transmitted electric pulse within a frequency range of IHz to 23 Hz, as may be determined by the user.

Specification of a smart watch

1. Bluetooth: v4.0 BLE

LED: 0.66" OLED

Material: TPU + ABS Battery: Lithium Ion polymer battery

Capacity: 3.5V/80mAH

Standby Time: 7-10days

Color: Black, Blue, Red

Dimension: 250*24* 13mm

2. Heart rate detection

3. Waterproof IP67 depth

4. Green light static heart rate monitoring

5. Sports pedometer

6 The distance calculator

7. Calories burned

8. Sleep quality monitoring

9. Remind intelligent bluetooth synchronization

10. Touch operation

11. Accurate detection

12. charger type:USB connector

Fig. 7 is an exemplary depiction of the wristband/smart watch. Fig. 7 also highlights the charging of the wristband/smart watch via a computer USB port.

The similar effect of a the head band and the smart watch on the state of meditation

The effect of the 9Hz headband was compared with the wrist watch set to emit 9Hz frequency with 3 people (two of the inventors and a third person). The results were compared to the same people at around the same time, without wearing any device. The comparison tool was the Muse EEG headband. Muse is connected by Bluetooth to a phone which documents (after signal processing) the "Calmness effect" which documents the ranges of brainwaves dominant among people in deep relaxation.

Muse is an EEG headband that documents the efficiency of a session of Mindfulness Meditation by a user. The green zone on the graphs document the time frames where the user is Calm. The summary of % describes the percentage of time during a session the user was in Calm area. Calm reflects a combination of multiple brain waves characterized by experience meditators.

As documented, and as expected, the percentage of time the people were in "calmness" mode without wearing a device and without meditating, was fairly low. When wearing an active headband or the wristband operating to emit 9Hz, Muse documented EEG results that are typically documented by people in deep meditation. That is, both the headband and the wristwatch had a similar effect on the brain waves of the users.

As shown in Fig. 8A, for person 1, without the watch, the person was determined to be at a deep meditation state 14% during the tested time, whereas with the watch (Fig. 8B), the same person was determined to be at a deep meditation state 60% during the tested time. With the headband, the results were 87% of the time, the subject was in meditation state (Fig. 8C).

For person 2 (data not shown), without the watch, the person was determined to be at a deep meditation state 29% during the tested time, whereas with the watch, the same person was determined to be at a deep meditation state 37% during the tested time.

For person 3 (data not shown), without the watch, the person was determined to be at a deep meditation state 57% during the tested time, whereas with the watch, the same person was determined to be at a deep meditation state 76% during the tested time. With the headband, the results were 93% of the time, the subject was in meditation state.

An additional experiments, conducted for 10 minutes, without the watch, the person was determined to be at a deep meditation state 16% during the tested time, whereas with the watch, the same person was determined to be at a deep meditation state 43% during the tested time.

That is, both means of applying the frequency has a similar effect either applied from the wrist or from the brain. It is known that individuals who have practiced meditation for a much longer time displayed higher theta and alpha power than non-meditators Surprisingly, by using the device on the Alpha and/or Theta even without meditation, let along while meditating, it is expected the effectiveness of meditation to be enhanced. Specifically, it is a common complaint by meditators that they cannot fully benefit from the technique and studies have shown it takes a long time to reach the results of experienced meditators.

Claims

CLAIMS:
1. An electronic nerve stimulation device comprising an electrical module operable to generate a low frequency signal and an electrode array for applying said signal to a subpopulation of nerves and modulating nerve impulses in said subpopulation.
2. The device of claim 1, wherein the application of said signal to said subpopulation modulates neural activity of the central nervous system (CNS).
3. The device of claim 1 or 2, configured for association with a limb portion and stimulation of peripheral nerves.
4. The device of claim 3, wherein the device or the electrode array are configured for wearing on a subject's wrist.
5. The device of any one of claims 1-4, wherein the low frequency is between about 0.5 hertz (Hz) to about 50 Hz.
6. The electronic nerve stimulation device of claim 5, wherein the low frequency is between about 2 Hz to about 25 Hz.
7. The electronic nerve stimulation device of claim 6, wherein the low frequency is between about 2 Hz to about 15 Hz.
8. The device of any one of claims 1 to 7, wherein said electrical module and said array of electrodes are linked by a wire or wireless link.
9. The electronic nerve stimulation device of any one of claims 1 to 8, comprising a user interface for adjusting the frequency of said signal.
10. The device of any one of claims 1 to 9, wherein said module, said array and said user interface are linked by a wire or wireless link.
11. The device of any one of claims 1 to 10, wherein the electrode array is configured for association with the skin's surface.
12. The device of claim 11, configured for association with the skull.
13. The device of claim 11, wherein the electrode array is in association with a forehead of a subject.
14. The device of claim 11 , wherein the electrode array is in association with the wrist of a subject.
15. The device of any one of claims 1 to 14, for use in improving a physiological condition associated with nerve function in a subject in need thereof.
16. The device of claim 15, wherein the physiological condition associated with nerve function is a nerve disorder associated with a brain function.
17. The device of claim 15, wherein the physiological condition associated with nerve function is at least one of alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity.
18. The device of any one of claims 1 to 14, for use in treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof
19. The device of claim 18, wherein the nerve disorder comprises a vascular disorder, an infection, a structural disorder, a functional disorder, a degenerative disorder or a mental disorder.
20. The device of claim 19, wherein the nerve disorder is at least one of epilepsy, insomnia, attention deficit hyperactivity disorder (ADHD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson disease, Alzheimer's disease, depression, anxiety, migraine, stroke, transient ischemic attack (TIA), Pick's disease , Parkinsonism, rigidity, hemiballism, choreoathetosis, dystonia, akinesia, bradykinesia, hyperkinesia, depression, bipolar disorder, anxiety, phobia, schizophrenia, multiple personality disorder, substance abuse, attention deficit hyperactivity disorder, eating disorder, impaired control of aggression, impaired control of sexual behavior, headache, migraine, concussion, post-concussive syndrome, stress- related disorder hypertension or an infection .
21. The device of any one of claims 1 to 14, for use in treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a disorder associated with a spinal cord function in a subject in need thereof.
22. A method of improving a physiological condition associated with nerve function in a subject in need thereof, the method comprising application of a low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.
23. The method of claim 22, wherein the physiological condition associated with nerve function is at least one of alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity.
24. The method of claim 22, wherein the physiological condition associated with nerve function is a nerve disorder.
25. A method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof, the method comprises the step of applying low frequency signal to a subpopulation of nerve, thereby modulating, in the subpopulation of nerve, nerve impulses.
26. The method of any one of claims 22 to 25, comprising positioning on a skin surface of a target organ, an electronic nerve stimulation device comprising an electrical module operable to generate the low frequency signal and an electrode array for applying the low frequency signal to the target organ.
27. The method of any one of claims 22 to 26, comprising application of the low frequency signal to the subject's skull, preferably to the forehead of a subject.
28. The method of any one of claims 22 to 26, comprising application of the low frequency signal to a limb portion of a subject, preferably to a subject's wrist.
29. The method of any one of claims 22 to 28, comprising application of the low frequency for a time period between about 30 seconds to about 30 minutes.
30. The method of any one of claims 22 to 28, comprising application of the low frequency signal for a time period between about 1 minute to about 10 minutes.
31. The method of any one of claims 22 to 30, comprising application of the low frequency in a range between about 0.5 hertz (Hz) to about 50 Hz.
32. The method of claim 31, comprising application of the low frequency in a range between about 2 Hz to about 25 Hz.
33. The method of claim 31 , comprising application of the low frequency of about 2Hz, about 3Hz, about 9Hz, about 13Hz, about 15Hz, about 23Hz or any combination thereof.
34. The method of any one of claims 25 to 33, wherein the nerve disorder comprises a vascular disorder, an infection, a structural disorder, a functional disorder, a degenerative disorder or a mental disorder.
35. The method of claim 34, wherein the nerve disorder is at least one of is at least one of epilepsy, insomnia, attention deficit hyperactivity disorder (ADHD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson disease, Alzheimer's disease, depression, anxiety, migraine, stroke, transient ischemic attack (TIA), Pick's disease, Parkinsonism, rigidity, hemiballism, choreoathetosis, dystonia, akinesia, bradykinesia, hyperkinesia, depression, bipolar disorder, anxiety, phobia, schizophrenia, multiple personality disorder, substance abuse, attention deficit hyperactivity disorder, eating disorder, impaired control of aggression, impaired control of sexual behavior, headache, migraine, concussion, post-concussive syndrome, stress- related disorder, hypertension or an infection.
36. The method of claim 35, wherein the nerve disorder is at least one of migraine, hypertension, insomnia, Parkinson disease, ADHD, depression or epilepsy.
37. The method of any one of claims 22 to 36, comprising application of a frequency of about 2Hz for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one of migraine or hypertension.
38. The method of any one of claims 22 to 36, comprising application of a frequency of about 3Hz for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one of insomnia or Parkinson disease.
39. The method of any one of claims 22 to 36, comprising application of a frequency of about 9Hz for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of ADHD.
40. The method of any one of claims 22 to 36, comprising application of a frequency of about 9Hz for improving at least one of alertness, memory, focus, stress, motor, speech, cognitive function, intelligence, concentration, remembering ability, vigor, creativity calmness, relaxation or focusing.
41. The method of any one of claims 22 to 36, comprising application of a frequency of about 13Hz for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of depression.
42. The method of any one of claims 22 to 36, comprising application of a frequency of about 15Hz for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of epilepsy.
43. The method of any one of claims 22 to 42, wherein the application of low frequency signal to said subpopulation modulates neural activity of the central nervous system (CNS).
44. A method of treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a nerve disorder in a subject in need thereof, the method comprises positioning electronic nerve stimulation device of any one of claims 1 to 21 on an organ of the subject.
45. The method of any one of claims 22 to 44, comprising measuring at least one physiological parameter in a subject in need thereof prior to and/or after application of the low frequency signal, wherein the at least one parameter is selected from heart rate, heart rate variability (HRV), breathing pattern derived stress, blood pressure, blood flow, temperature, oxygen level, level of tremor or physical activity.
46. The method of claim 45, determining the differences between the measurements of the at least one parameter, prior to and after application the low frequency signal, to thereby adjust treatment protocol.
47. The method of claim 45 or 46, comprising self-measuring by the subject the at least one physiological parameter.
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