Pulsed current stimulator and method

Abstract

A pulsed current stimulator 100 is provided herein to alleviate or improve at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition. In an embodiment, the pulsed current stimulator comprises a first set of surface electrodes 120 attachable to a user's scalp and configured to stimulate the user's brain; and a stimulus generator 102 configured to generate transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes 120, the tPCS having a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50ps to about 800ps, a duty cycle in a range of about 1 % to about 8% and a peak current value in a range of about 8mA to about 60mA. A pulsed current stimulating method for alleviating or improving a neurological, psychiatric, neuropsychiatric, and / or medical condition using the pulsed current stimulator 100 is also provided.

Description

[0001] PULSED CURRENT STIMULATOR AND METHOD

[0002] The present application generally relates to a pulsed current stimulator and method, in particular, but not exclusively, for stimulating a user’s brain and / or body.

[0003] BACKGROUND

[0004] Conventional transcranial electrical stimulation (tES) protocols typically use currents of no more than 2 milliamperes (mA) for safety purpose. While some studies have safely tested higher intensities up to 4mA, the most commonly applied current intensity in tES research and clinical trials is 2mA, to avoid serious adverse effects or irreversible injury. However, the extent to which current delivered via non-invasive tES penetrates to the targeted neurons and other brain cells in cerebral cortex and connected brain regions is highly dependent on stimulation amplitude. Thus, conventional tES techniques may not be able to penetrate the biological layers, including the scalp, skull, meninges and cerebrospinal fluid (CSF), before reaching the cerebral cortex effectively.

[0005] Conventional tES, which includes conventional transcranial direct current stimulation (tDCS) and low-frequency conventional transcranial alternating current stimulation (tACS), is poorly suited for cell-specific targeting. To elaborate, tDCS delivers a continuous, non -fluctuating direct current that predominantly induces a non-specific, global modulation of cortical excitability, whereas tACS applies a sinusoidal current waveform for producing network-level entrainment through rhythmic subthreshold depolarization. However, such effects remain indirect and brain state-dependent.

[0006] It is an object of the present invention to address problems of the prior art and / or to provide the public with a useful choice.SUMMARY

[0007] According to a first aspect of the present invention, a pulsed current stimulator is provided to alleviate or improve at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition. The pulsed current stimulator comprises a first set of surface electrodes attachable to a user’s scalp and configured to stimulate the user’s brain; and a stimulus generator configured to generate a transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes, the tPCS having a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle of about 1 to about 8% and a peak current value in a range of about 8mA to about 60mA.

[0008] In an embodiment, by configuring the stimulus generator to generate tPCS with a combination of high frequency (about 100Hz to about 500Hz), a narrow pulse width (about 50μs to about 800μs, and a short duty cycle of about 1 to about 8% as described above, the pulsed current stimulator may enhance electric current penetration through biological layers, including the scalp, skull, meninges and cerebrospinal fluid (CSF), compared to continuous current stimulation without a duty cycle and improve modulation of cortical and subcortical targets; enhance user safety compared with low-frequency stimulation techniques with an equivalent duty cycle; and maintain user comfort and safety within accepted limits while achieving therapeutic effects.

[0009] Preferably, the peak current value of the tPCS may be in a range of about 10mA to about 60mA. More preferably, the peak current value of the tPCS may be in a range of about 12mA to about 60mA.

[0010] Advantageously, the pulsed current stimulator may further comprise a second set of surface electrodes attachable to the user’s postcranial body for peripheral stimulation, wherein the stimulus generator may be further configured to generatetranscutaneous pulsed current stimulation (tcPCS) to the second set of surface electrodes, the frequency of the tcPCS may have a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle in a range of about 1 % to about 8% and a peak current value in a range of about 10mA to about 200mA.

[0011] By introducing peripheral stimulation using tcPCS to be performed concurrently or simultaneously to brain stimulation using tPCS, the pulsed current stimulator may be used to treat or improve neurological, psychiatric, neuropsychiatric, and / or medical conditions effectively, especially for disease or disorders that involve alterations of inflammatory cascades.

[0012] Preferably, the frequency of the tPCS may be more than about 120Hz but no more than about 500Hz. More preferably, the frequency of the tPCS may be more than about 200Hz but no more than about 500Hz.

[0013] It is envisaged that for certain applications, the peak current value of the tPCS may be in the range of about 10mA to about 40 mA.

[0014] Further, the pulse width of the tPCS may be in the range about 50ps to about 500µs.

[0015] In an embodiment, the tPCS may have a waveform selected from a group comprising a rectangular pulse waveform, cosine-squared pulse waveform, Dirac pulse waveform, sinc pulse waveform, Gaussian pulse waveform, sawtooth waveform and a triangular waveform.

[0016] Considering the usefulness of the described embodiments, the neurological, psychiatric, neuropsychiatric, and / or medical condition may include diseases or disorders that involve alterations of inflammatory cascades.Specifically, the neurological, psychiatric, neuropsychiatric, and / or medical condition may include one of multiple sclerosis; autoimmune encephalitis; neuromyelitis optica; post-infectious syndromes including long-COVID, Paediatric Acute-onset Neuropsychiatric Syndrome (PANS); neoplastic and paraneoplastic syndromes; central nervous system (CNS) vasculitis; cerebral small vessel disease; Parkinson’s disease; Multiple System Atrophy (MSA), mild cognitive impairment (MCI); dementia; Alzheimer’s disease; autism spectrum disorder (ASD); cerebral palsy (CP); attention deficit hyperactive disorder (ADHD); depression; psychosis; mania; sleep disorders; cerebellar ataxia; perioperative delirium and post-surgery cognitive loss; traumatic brain injury; stroke; spasticity; dystonia; and lupus.

[0017] According to a second aspect of the present invention, a pulsed current stimulating method may be provided for alleviating or improving at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition. The method may comprise attaching a first set of surface electrodes to a user’s scalp; and generating pulsed current stimulation (tPCS) to the first set of surface electrodes to stimulate the user’s brain, wherein the tPCS may have a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle in a range of about 1 % to about 8% and a peak current value in the range of about 8mA to about 60mA.

[0018] Using the tPCS specifically configured with a combination of high frequency, short duty cycle, and narrow pulse width to stimulate a user’s cerebral cortex and connected brain regions, it is surprisingly helpful in alleviating or improving a neurological, psychiatric, neuropsychiatric, and / or medical condition, achieving both safety and efficacy.

[0019] According to a third aspect of the present invention, a pulsed current stimulator may be provided to alleviate or improve at least one symptom in relation to a neurological, psychiatric, neuropsychiatric, and / or medical condition. The pulsedcurrent stimulator may comprise a first set of surface electrodes attachable to a user’s scalp and configured to stimulate the user’s brain, and second or more sets of surface electrodes attachable to the user’s postcranial body for peripheral stimulation; and a stimulus generator may be configured to generate transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes and transcutaneous pulsed current stimulation (tcPCS) to the second set of surface electrodes, wherein the tPCS and tcPCS each may have a frequency in a range of about 100Hz to about 500Hz, and a pulse width in a range of about 50μs to about 800μs and a duty cycle in a range of about 1% to about 8%; wherein the tPCS may have a peak tPCS current value in a range of about 8mA to about 60mA, and the tcPCS may have a peak tcPCS current value in a range of about 10mA to about 200mA.

[0020] By introducing peripheral stimulation using tcPCS to be performed concurrently or simultaneously to brain stimulation using tPCS, the pulsed current stimulator may be used to treat or improve users suffering from neurological, psychiatric, neuropsychiatric, and / or medical conditions effectively, especially for disease or disorders that involve alterations of inflammatory cascades

[0021] Preferably, the peak tPCS current value may be in a range of about 10mA to about 60mA. More preferably, the peak tPCS current value may be in a range of about 12mA to about 60mA.

[0022] In an embodiment, the frequency, pulse width and duty cycle of the tPCS for the first set of surface electrodes may be the same as the frequency, pulse width and duty cycle of the tcPCS for the second set of surface electrodes.

[0023] By delivering tPCS and tcPCS at the same frequency, pulse width and duty cycle, the pulsed current stimulator may produce maximal system-level integration and accelerates therapeutic response, in particular to neurological, psychiatric,neuropsychiatric, and neuroimmune conditions characterized by inflammation, demyelination, and neuronal network dysfunction.

[0024] In an embodiment, the peak tPCS current value for the first set of surface electrodes may be different from the peak tcPCS current value for the second set of surface electrodes.

[0025] By setting the tPCS and tcPCS with different peak current value, the stimulator is able to balance among the requirements of sufficient penetration of the cranial coverings and post cranial skin-electrode interface, effective treatment and safety (or well tolerance).

[0026] Optionally and depending on the application, the peripheral stimulation may include stimulation of the spinal cord, nerve roots, peripheral nerves or extracranial portions of the Vagus nerve or any cranial nerve. Further, stimulating the user’s brain may include the user’s cortex and connected brain regions.

[0027] Considering the usefulness of the described embodiments in relation to the third aspect, the neurological, psychiatric, neuropsychiatric, and / or medical condition may include diseases or disorders that involve alterations of inflammatory cascades.

[0028] Specifically, the neurological, psychiatric, neuropsychiatric, and / or medical condition may include one of multiple sclerosis; autoimmune encephalitis; neuromyelitis optica; post-infectious syndromes including long-COVID, Paediatric Acute-onset Neuropsychiatric Syndrome (PANS); neoplastic and paraneoplastic syndromes; CNS vasculitis; cerebral small vessel disease; Parkinson’s disease; Multiple System Atrophy (MSA); mild cognitive impairment (MCI); dementia; Alzheimer’s disease; ASD; cerebral palsy; ADHD; depression; psychosis; mania; sleep disorders; cerebellar ataxia; peri-operative delirium andpost-surgery cognitive loss; traumatic brain injury; stroke; spasticity; dystonia; and lupus.

[0029] According to a fourth aspect of the present invention, a pulsed current stimulating method may be provided for alleviating or improving at least one symptom in relation to a neurological, psychiatric, neuropsychiatric, and / or medical condition. The method may comprise attaching a first set of surface electrodes to a user’s scalp and second or more sets of surface electrodes to the user’s postcranial body; and generating transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes to stimulate the user’s brain and generating transcutaneous pulsed current stimulation (tcPCS) to the second or more sets of surface electrodes for peripheral stimulation, the tPCS and tcPCS each may have a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs and a duty cycle in a range of about 1% to about 8%; wherein the tPCS may have a peak tPCS current value in the range of about 8mA to about 60mA, and the tcPCS may have a peak tcPCS current value in a range of about 10mA to about 200mA.

[0030] Using the specifically configured tPCS and tcPCS with the specific combination of parameters relating to frequency, duty cycle, and pulse width, the method is surprisingly helpful in alleviating or improving a neurological, psychiatric, neuropsychiatric, and / or medical condition, achieving both safety and efficacy, especially for the diseases that are due to neurological, psychiatric, neuropsychiatric, and neuroimmune conditions characterized by inflammation, demyelination, and neuronal network dysfunction.

[0031] It would be apparent that features relating to one aspect may be applicable and used interchangeable with features relating to the other aspects.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Fig. 1 illustrates a block diagram of a pulsed current stimulator according to a first embodiment of the present invention;

[0033] Fig. 2 illustrates an example of a high-frequency monophasic tPCS signal generated by the pulsed current stimulator of Fig. 1;

[0034] Fig. 3 illustrates a flowchart of a pulsed current stimulating method based on the pulsed current stimulator of Fig. 1;

[0035] Fig. 4(a) and Fig. 4(b) illustrate electrode montage adopted in a trial of the pulsed current stimulator of Fig. 1 in children with ASD;

[0036] Fig. 5 illustrates electrode montage adopted in a trial of the pulsed current stimulator of Fig. 1 in adults with sleep disorder (chronic insomnia);

[0037] Fig. 6 illustrates an electric field modelling simulating an electric field induced by a tPCS signal provided by the electrode montage of Fig. 5;

[0038] Fig. 7 illustrates electrode montage adopted in a trial of the pulsed current stimulator of Fig. 1 in adults with mild cognitive impairment (MCI) and mild dementia;

[0039] Fig. 8(a) and Fig. 8(b) illustrate two electrode montages adopted in a trial of the pulsed current stimulator of Fig. 1 in adults with Parkinson’s disease;

[0040] Fig. 9 illustrates an example of conventional transcranial direct current stimulation (tDCS);Fig. 10 illustrates an example of a conventional transcranial alternating current stimulation (tACS);

[0041] Fig. 11(a) illustrates an electric field induced in the cerebellar region by tPCS signal generated by the pulsed current stimulator of Fig. 1;

[0042] Fig. 11 (b). illustrates a simulation of how Purkinje cells in the cerebellum respond to tPCS signal generated in Fig. 11(a);

[0043] Fig. 12 illustrates a block diagram of a pulsed current stimulator according to a second embodiment of the present invention;

[0044] Fig. 13 illustrates some locations for attaching second set of surface electrodes of the pulsed current stimulator of Fig. 12;

[0045] Fig. 14 illustrates a flowchart of a pulsed current stimulating method based on the pulsed current stimulator of Fig. 12;

[0046] Fig. 15(a) and Fig. 15(b) illustrate two electrode montages adopted in a trial of the pulsed current stimulator of Fig. 12 in adults with Multiple Systems Atrophy (MSA);

[0047] Figs. 16(a), 16(b) and 16(c) illustrate electrode montages adopted in a trial of the pulsed current stimulator of Fig. 12 in adults with stroke.

[0048] DETAILED DESCRIPTION

[0049] Fig. 1 illustrates a block diagram of a pulsed current stimulator 100, according to a first embodiment of the present invention. The pulsed current stimulator 100 comprises a stimulus generator 102 and a head harness 104. The head harness 104 is configured to detachably connect to the stimulus generator102 and operable to receive current signals from the stimulus generator 102. The stimulus generator 102 comprises a host unit 106, and a power adapter 108 configured to provide power to the host unit 106. The host unit 106 comprises a casing (not shown) made of ABS plastic, a touch-screen display (not shown) mounted on the top of the casing, adjustable channel knobs (not shown) for controlling intensity of output current, and a circuit board 110 located inside the casing. The circuit board 110 comprises a main control module 112, a pulse module 114, a digital display circuit 116 and a communication module 118. The head harness 104 comprises a first set of surface electrodes 120.

[0050] The main control module 112 is a main processing unit for the circuit board 110. The main control module 112 comprises a microcontroller unit (MCU) configured to generate pulse waveform including the pulse shape, pulse width, pulse frequency, duty cycle etc., and to control the touch screen that interacts with users, a crystal oscillator clock control circuit, a communication microprocessor configured to communicate with other modules or chips (e.g. the pulse module 114, display etc.), a three-terminal voltage stabilizing circuit (which further comprises step-down switch voltage regulator, voltage stabilizing circuit and bipolar junction NPN transistors) that controls input power, and a reset circuit etc. A pulse is generally understood to mean a rapid, transient change in the amplitude of a signal from a baseline value to a higher or lower value, followed by a rapid return to the baseline value i.e. a pulse having a discrete value. The pulse may have various shapes, such as rectangular pulse, cosine-squared (raised cosine) pulse, Dirac pulse, sinc pulse, Gaussian pulse, sawtooth, triangular etc.

[0051] The pulse module 114 is configured to primarily determine the intensity of current that flows out from the stimulus generator 102 to the first set of surface electrodes 120 of the head harness 104. The pulse module 114 comprises a microcontroller which is configured to determine pulse amplitude, such as the output voltage value and / or output current value. The adjustable channel knobson the host unit 106 are operable by a user to adjust intensity of output current. The output current is sent to the main control module 112 via a digital encoder, which then gives direct instructions to the pulse module 114. The pulse module 114 generates stimulus and specifically, transcranial pulsed current stimulation pulses to the head harness 104.

[0052] The stimulus generator 102 including the pulse module 114 is configured to generate a transcranial pulsed current stimulation (tPCS) for supplying to the first set of surface electrodes 120 of the head harness 104. The tPCS has a frequency in a range of 100Hz to 500Hz, a pulse width in a range of 50µs to 800µs and a peak current value in the range of 8mA to 60mA. A duty cycle of tPCS is in a range of 1% to 8%. Due to the ‘high frequency’ being used in the context of this invention, the pulsed current stimulator may be referred to as a high frequency transcranial pulsed current stimulation (hf-tPCS).

[0053] The digital display circuit 116 is controlled by the main control module 112 and connected to the touch-screen display. The communication module 118 comprises wireless communication functions such as Bluetooth® and is operable to enable connection between the main control module 112 and some other parts (e.g. pulse module 114, external smart devices (not shown)).

[0054] Fig. 2 illustrates an example of a high-frequency tPCS signal generated by the pulsed current stimulator 100. The tPCS signal has a rectangular pulse waveform. The tPCS signal has an average current of 1mA per second, a frequency of 100Hz and a duty cycle of 5.0%. Each cycle of the tPCS signal comprises a pulse width of 500µs and an idle period of 9500µs. During the pulse width, stimulation is “on” with a current value reaching 20mA; and during the idle period, stimulation is “off” as the current value is 0mA. That said, throughout each whole cycle, the peak current amplitude applied to the area where the first set of surface electrodes is applied is 20mA. Therefore, the average total current applied to the user in one cycle of the tPCS signal illustrated in Fig. 2 is average 1mA persecond, calculated by [(500 / 10000)*20mA)*100 cycles + (9500 / 10000)*0mA*100 cycles] / 100 cycles.

[0055] The tPCS signal may be used to stimulate a user’s cerebral cortex and connected brain regions to alleviate or improve at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition, including diseases or disorders that involve alterations of inflammatory cascades. Some examples of the conditions are: ASD, mild cognitive impairment (MCI), dementia, sleep disorder, stroke, cerebellar ataxia, Parkinson’s disease, Multiple System Atrophy(MSA), ADHD, multiple sclerosis; autoimmune encephalitis; neuromyelitis optica; post-infectious syndromes including long-COVID, Paediatric Acute-onset Neuropsychiatric Syndrome (PANS), etc.; neoplastic and paraneoplastic syndromes; CNS vasculitis; cerebral small vessel disease; Alzheimer’s disease; cerebral palsy; depression; psychosis; mania; perioperative delirium and post-surgery cognitive loss; traumatic brain injury; spasticity; dystonia; and lupus.

[0056] The at least one symptom may comprise any of social functioning disorder, communication disorder, repetitive behaviours, sensory processing disorders, cognitive and emotional dysfunction in relation to ASD; hyperactivity, inattentiveness, impulsivity in relation to ADHD; cognitive dysfunction, memory loss, loss of functionality, behavioural and emotional disorders, movement disorders in relation to mild cognitive impairment; cognitive dysfunction, memory loss, loss of functionality, behavioural and emotional disorders, movement disorders in relation to dementia; motor dysfunction (including tremors, bradykinesia, postural instability, rigidity, swallowing difficulties, axial and gait disturbances, speech and facial expression, fine motor skills, dyskinesia, akinesia, spasticity, fatigue related to motor effort) and non-motor dysfunctions (including autonomic dysfunction, sleep dysfunction, cognitive dysfunction, psychiatric / neuropsychiatric symptoms, sensory symptoms, gastrointestinal symptoms) in relation to Parkinson’s disease; motor dysfunction (includingtremors, gait and balance disturbance, limb coordination deficits, speech and bulbar symptoms swallowing difficulties, fatigue related to motor effort) and nonmotor dysfunctions (including autonomic dysfunction, sleep dysfunction, cognitive dysfunction, psychiatric / neuropsychiatric symptoms, sensory symptoms, gastrointestinal symptoms) in relation to Multiple System Atrophy (MSA) and cerebellar ataxia; motor dysfunction (including tremors, gait and balance disturbance, limb coordination deficits, spasticity, dystonia; aphasia, swallowing difficulties, fatigue related to motor effort) and non-motor dysfunctions (including autonomic dysfunction, sleep dysfunction, cognitive dysfunction, psychiatric / neuropsychiatric symptoms, sensory symptoms, gastrointestinal symptoms), in relation to stroke; and insomnia, parasomnia, hypersomnia, excessive daytime sleepiness, circadian rhythm sleep disorders, sleep-related movement disorders, restless leg syndrome, periodic limb movement disorder in relation to sleep disorder.

[0057] Fig. 3 illustrates a flowchart of a pulsed current stimulating method based on the pulsed current stimulator 100, for alleviating or improving a neurological, psychiatric, neuropsychiatric, and / or medical condition. The method comprises a step 302 of attaching the first set of surface electrodes 120 of the head harness 104 to a user’s scalp; and a step 304 of generating a tPCS signal using the stimulus generator 102 and providing the tPCS signal to the first set of surface electrodes 120.

[0058] In some examples, frequency of the tPCS signal may be in the range of 100Hz to 500Hz. For example, it may be in the ranges of 110Hz-490Hz, 120Hz-480Hz, 130Hz-470Hz, 140Hz-460Hz, 150Hz-450Hz, 160Hz-440Hz, 170Hz-430Hz, 180Hz-420Hz, 190Hz-410Hz, 200Hz-400Hz, 210Hz-390Hz, 220Hz-380Hz, 230Hz-370Hz, 240Hz-360Hz, 250Hz-350Hz, 260Hz-340Hz, 270Hz-330Hz, 280Hz-320Hz, 290Hz-310Hz, 100Hz-490Hz, 100Hz-480Hz, 100Hz-470Hz, 100Hz-460Hz, 100Hz-450Hz, 100Hz-440Hz, 100Hz-430Hz, 100Hz-420Hz, 100Hz-410Hz, 100Hz-400Hz, 100Hz-390Hz, 100Hz-380Hz, 100Hz-370Hz,100Hz-360Hz, 100Hz-350Hz, 100Hz-340Hz, 100Hz-330Hz, 100Hz-320Hz, 100Hz-310Hz, 100Hz-300Hz, 100Hz-290Hz, 100Hz-280Hz, 100Hz-270Hz, 100Hz-260Hz, 100Hz-250Hz, 100Hz-240Hz, 100Hz-230Hz, 100Hz-220Hz, 100Hz-210Hz, 100Hz-200Hz, 100Hz-190Hz, 100Hz-180Hz, 100Hz-170Hz, 100Hz-160Hz, 100Hz-150Hz, 100Hz-140Hz, 100Hz-130Hz, 100Hz-120Hz, 100Hz-110Hz, 110Hz-500Hz, 120Hz-500Hz, 130Hz-500Hz, 140Hz-500Hz, 150Hz-500Hz, 160Hz-500Hz, 170Hz-500Hz, 180Hz-500Hz, 190Hz-500Hz, 200Hz-500Hz, 210Hz-500Hz, 220Hz-500Hz, 230Hz-500Hz, 240Hz-500Hz, 250Hz-500Hz, 260Hz-500Hz, 270Hz-500Hz, 280Hz-500Hz, 290Hz-500Hz, 300Hz-500Hz, 310Hz-500Hz, 320Hz-500Hz, 330Hz-500Hz, 340Hz-500Hz, 350Hz-500Hz, 360Hz-500Hz, 370Hz-500Hz, 380Hz-500Hz, 390Hz-500Hz, 400Hz-500Hz, 410Hz-500Hz, 420Hz-500Hz, 430Hz-500Hz, 440Hz-500Hz, 450Hz-500Hz, 460Hz-500Hz, 470Hz-500Hz, 480Hz-500Hz, or 490Hz-500Hz, or any other range within the range of 100Hz-500Hz, or any specific and discrete frequency value within any of the above ranges such as 139 Hz, 141 Hz, 201 Hz, 220 Hz, 499 Hz etc.

[0059] In some examples, the tPCS pulse width may be in the range of 50µs to 800µs. For example, it may be in the ranges of 60µs to 790µs, 70µs to 780µs, 80µs to 770µs, 90µs to 760µs, 100µs to 750µs, 110µs to 740µs, 120µs to 730µs, 130µs to 720µs, 140µs to 710µs, 150µs to 700µs, 160µs to 690µs, 170µs to 680µs, 180µs to 670µs, 190µs to 660µs, 200µs to 650µs, 210µs to 640µs, 220µs to 630µs, 230µs to 620µs, 240µs to 610µs, 250µs to 600µs, 260µs to 590µs, 270µs to 580µs, 280µs to 570µs, 290µs to 560µs, 300µs to 550µs, 310µs to 540µs, 320µs to 530µs, 330µs to 520µs, 340µs to 510µs, 350µs to 500µs, 360µs to 490µs, 370µs to 480µs, 380µs to 470µs, 390µs to 460µs, 400µs to 450µs, 410µs to 440µs, 420µs to 430µs, 100µs to 500µs, 100µs to 490µs, 100µs to 480µs, 100µs to 470µs, 100µs to 460µs, 100µs to 450µs, 100µs to 440µs, 100µs to 430µs, 100µs to 420µs, 100µs to 410µs, 100µs to 400µs, 100µs to 390µs, 100µs to 380µs, 100µs to 370µs, 100µs to 360µs, 100µs to 350µs, 100µs to 340µs, 100µs to 330µs, 100µs to 320µs, 100µs to 310µs, 100µs to 300µs, 100µs to290µs, 100µs to 280µs, 100µs to 270µs, 100µs to 260µs, 100µs to 250µs, 100µs to 240µs, 100µs to 230µs, 100µs to 220µs, 100µs to 210µs, 100µs to 200µs, 100µs to 190µs, 100µs to 180µs, 100µs to 170µs, 100µs to 160µs, 100µs to 150µs, 100µs to 140µs, 100µs to 130µs, 100µs to 120µs, 100µs to 110µs, 110µs to 500µs, 120µs to 500µs, 130µs to 500µs, 140µs to 500µs, 150µs to 500µs, 160µs to 500µs, 170µs to 500µs, 180µs to 500µs, 190µs to 500µs, 200µs to 500µs, 210µs to 500µs, 220µs to 500µs, 230µs to 500µs, 240µs to 500µs, 250µs to 500µs, 260µs to 500µs, 270µs to 500µs, 280µs to 500µs, 290µs to 500µs, 300µs to 500µs, 310µs to 500µs, 320µs to 500µs, 330µs to 500µs, 340µs to 500µs, 350µs to 500µs, 360µs to 500µs, 370µs to 500µs, 380µs to 500µs, 390µs to 500µs, 400µs to 500µs, 410µs to 500µs, 420µs to 500µs, 430µs to 500µs, 440µs to 500µs, 450µs to 500µs, 460µs to 500µs, 470µs to 500µs, 480µs to 500µs, 490µs to 500µs, 110µs to 490µs, 120µs to 480µs, 130µs to 470µs, 140µs to 460µs, 150µs to 450µs, 160µs to 440µs, 170µs to 430µs, 180µs to 420µs, 190µs to 410µs, 200µs to 400µs, 210µs to 390µs, 220µs to 380µs, 230µs to 370µs, 240µs to 360µs, 250µs to 350µs, 260µs to 340µs, 270µs to 330µs, 280µs to 320µs, 290µs to 310µs, or any other range within the range of 50µs to 800µs, or any specific and discrete pulse width within any of the above ranges such as 61µs, 67 µs, 241µs, 741µs etc.

[0060] In some examples, peak current value of the tPCS signal may be in the range of 8mA to 60mA. For example, it may be in the ranges of 8mA to 59mA, 8mA to 59mA, 8mA to 58mA, 8mA to 57mA, 8mA to 56mA, 8mA to 55mA, 8mA to 54mA, 8mA to 53mA, 8mA to 52mA, 8mA to 51 mA, 8mA to 50mA, 8mA to 49mA, 8mA to 48mA, 8mA to 47mA, 8mA to 46mA, 8mA to 45mA, 8mA to 44mA, 8mA to 43mA, 8mA to 42mA, 8mA to 41 mA, 8mA to 40mA, 8mA to 39mA, 8mA to 38mA, 8mA to 37mA, 8mA to 36mA, 8mA to 35mA, 8mA to 34mA, 8mA to 33mA, 8mA to 32mA, 8mA to 31mA, 8mA to 30mA, 8mA to 29mA, 8mA to 28mA, 8mA to 27mA, 8mA to 26mA, 8mA to 25mA, 8mA to 24mA, 8mA to 23mA, 8mA to 22mA, 8mA to 21mA, 8mA to 20mA, 8mA to 19mA, 8mA to 18mA, 8mA to 17mA, 8mA to 16mA, 8mA to 15mA, 8mA to 14mA, 8mA to 13mA, 8mA to 12mA, 8mA to11 mA, 8mA to 10mA, 8mA to 9mA, 9mA to 59mA, 9mA to 59mA, 9mA to 59mA, 9mA to 57mA, 9mA to 56mA, 9mA to 55mA, 9mA to 54mA, 9mA to 53mA, 9mA to 52mA, 9mA to 51mA, 9mA to 50mA, 9mA to 49mA, 9mA to 49mA, 9mA to 47mA, 9mA to 46mA, 9mA to 45mA, 9mA to 44mA, 9mA to 43mA, 9mA to 42mA, 9mA to 41 mA, 9mA to 40mA, 9mA to 39mA, 9mA to 39mA, 9mA to 37mA, 9mA to 36mA, 9mA to 35mA, 9mA to 34mA, 9mA to 33mA, 9mA to 32mA, 9mA to 31 mA, 9mA to 30mA, 9mA to 29mA, 9mA to 29mA, 9mA to 27mA, 9mA to 26mA, 9mA to 25mA, 9mA to 24mA, 9mA to 23mA, 9mA to 22mA, 9mA to 21 mA, 9mA to 20mA, 9mA to 19mA, 9mA to 19mA, 9mA to 17mA, 9mA to 16mA, 9mA to 15mA, 9mA to 14mA, 9mA to 13mA, 9mA to 12mA, 9mA to 11 mA, 9mA to 10mA, 10mA to 59mA, 10mA to 58mA, 10mA to 57mA, 10mA to 56mA, 10mA to 55mA, 10mA to 54mA, 10mA to 53mA, 10mA to 52mA, 10mA to 51mA, 10mA to 50mA, 10mA to 49mA, 10mA to 48mA, 10mA to 47mA, 10mA to 46mA, 10mA to 45mA, 10mA to 44mA, 10mA to 43mA, 10mA to 42mA, 10mA to 41mA, 10mA to 40mA, 10mA to 39mA, 10mA to 38mA, 10mA to 37mA, 10mA to 36mA, 10mA to 35mA, 10mA to 34mA, 10mA to 33mA, 10mA to 32mA, 10mA to 31mA, 10mA to 30mA, 10mA to 29mA, 10mA to 28mA, 10mA to 27mA, 10mA to 26mA, 10mA to 25mA, 10mA to 24mA, 10mA to 23mA, 10mA to 22mA, 10mA to 21mA, 10mA to 20mA, 10mA to 19mA, 10mA to 18mA, 10mA to 17mA, 10mA to 16mA, 10mA to 15mA, 10mA to 14mA, 10mA to 13mA, 10mA to 12mA, 10mA to 11 mA, 11 mA to 59mA, 11 mA to 58mA, 11mA to 57mA, 11 mA to 56mA, 11 mA to 55mA, 11 mA to 54mA, 11 mA to 53mA, 11 mA to 52mA, 11mA to 51mA, 11 mA to 50mA, 11 mA to 49mA, 11 mA to 48mA, 11mA to 47mA, 11mA to 46mA, 11 mA to 45mA, 11 mA to 44mA, 11 mA to 43mA, 11 mA to 42mA, 11mA to 41mA, 11mA to 40mA, 11 mA to 39mA, 11 mA to 38mA, 11mA to 37mA, 11mA to 36mA, 11 mA to 35mA, 11 mA to 34mA, 11 mA to 33mA, 11 mA to 32mA, 11mA to 31mA, 11mA to 30mA, 11 mA to 29mA, 11 mA to 28mA, 11mA to 27mA, 11mA to 26mA, 11 mA to 25mA, 11 mA to 24mA, 11 mA to 23mA, 11 mA to 22mA, 11mA to 21mA, 11mA to 20mA, 11mA to 19mA, 11 mA to 18mA, 11mA to 17mA, 11 mA to 16mA, 11 mA to 15mA, 11mA to 14mA, 11 mA to 13mA, 11mA to 12mA, 12mA to 59mA, 12mA to 58mA, 12mA to 57mA, 12mA to 56mA, 12mA to 55mA, 12mA to 54mA, 12mA to 53mA, 12mA to 52mA,12mA to 51mA. 12mA to 50mA. 12mA to 49mA. 12mA to 48mA. 12mA to 47mA 12mA to 46mA, 12mA to 45mA, 12mA to 44mA, 12mA to 43mA, 12mA to 42mA, 12mA to 41 mA, 12mA to 40mA, 12mA to 39mA, 12mA to 38mA, 12mA to 37 mA, 12mA to 36mA, 12mA to 35mA, 12mA to 34mA, 12mA to 33mA, 12mA to 32mA, 12mA to 31 mA, 12mA to 30mA, 12mA to 29mA, 12mA to 28mA, 12mA to 27 mA, 12mA to 26mA, 12mA to 25mA, 12mA to 24mA, 12mA to 23mA, 12mA to 22mA, 12mA to 21 mA, 12mA to 20mA, 12mA to 19mA, 12mA to 18mA, 12mA to 17mA, 12mA to 16mA, 12mA to 15mA, 12mA to 14mA, 12mA to 13mA, 13mA to 60mA, 14mA to 60mA, 15mA to 60mA, 16mA to 60mA, 17mA to 60mA, 18mA to 60mA, 19mA to 60mA, 20mA to 60mA, 21 mA to 60mA, 22mA to 60mA, 23mA to 60mA, 24mA to 60mA, 25mA to 60mA, 26mA to 60mA, 27mA to 60mA, 28mA to 60mA, 29mA to 60mA, 30mA to 60mA, 31 mA to 60mA, 32mA to 60mA, 33mA to 60mA, 34mA to 60mA, 35mA to 60mA, 36mA to 60mA, 37mA to 60mA, 38mA to 60mA, 39mA to 60mA, 40mA to 60mA, 41 mA to 60mA, 42mA to 60mA, 43mA to 60mA, 44mA to 60mA, 45mA to 60mA, 46mA to 60mA, 47mA to 60mA, 48mA to 60mA, 49mA to 60mA, 50mA to 60mA, 51 mA to 60mA, 52mA to 60mA, 53mA to 60mA, 54mA to 60mA, 55mA to 60mA, 56mA to 60mA, 57mA to 60mA, 58mA to 60mA, 59mA to 60mA, 13mA to 59mA, 14mA to 58mA, 15mA to 57mA, 16mA to 56mA, 17mA to 55mA, 18mA to 54mA, 19mA to 53mA, 20mA to 52mA, 21mA to 51 mA, 22mA to 50mA, 23mA to 49mA, 24mA to 48mA, 25mA to 47mA, 26mA to 46mA, 27mA to 45mA, 28mA to 44mA, 29mA to 43mA, 30mA to 42mA, 31mA to 41mA, 32mA to 40mA, 33mA to 39mA, 34mA to 38mA, 35mA to 37mA, 20mA to 39mA, 20mA to 38mA, 20mA to 37mA, 20mA to 36mA, 20mA to 35mA, 20mA to 34mA, 20mA to 33mA, 20mA to 32mA, 20mA to 31mA, 20mA to 30mA, 20mA to 29mA, 20mA to 28mA, 20mA to 27mA, 20mA to 26mA, 20mA to 25mA, 20mA to 24mA, 20mA to 23mA, 20mA to 22mA, 20mA to 21mA, 21mA to 39mA, 22mA to 38mA, 23mA to 37mA, 24mA to 36mA, 25mA to 35mA, 26mA to 34mA, 27mA to 33mA, 28mA to 32mA, 29mA to 31 mA, 21 mA to 40mA, 22mA to 40mA, 23mA to 40mA, 24mA to 40mA, 25mA to 40mA, 26mA to 40mA, 27mA to 40mA, 28mA to 40mA, 29mA to 40mA, 30mA to 40mA, 31 mA to 40mA, 32mA to 40mA, 33mA to 40mA, 34mA to 40mA, 35mA to 40mA, 36mA to 40mA, 37mA to 40mA, 38mA to 40mA,39mA to 40mA, 41mA to 50mA, or any other range within the range of 8mA to 60mA, or any specific and discrete current value within any of these ranges, such as 9mA, 11 mA, 25 mA, 30mA, 31 mA, 43mA, 56mA etc.

[0061] In some examples, duty cycle of the tPCS signal may be in the range of 1% to 8%. For example, it may be in the ranges of 1 % to 7%, 1 % to 6%, 1 % to 5%, 1 % to 4%, 1% to 3%, 1% to 2%, 2% to 8%, 2% to 7%, 2% to 6%, 2% to 5%, 2% to 4%, 2% to 3%, 3% to 8%, 3% to 7%, 3% to 6%, 3% to 5%, 3% to 4%, 4% to 8%, 4% to 7%, 4% to 6%, 4% to 5%, 5% to 8%, 5% to 7%, 5% to 6%, 6% to 8%, 6% to 7%, or 7% to 8%, or any specific and discrete duty cycle within any of the above ranges such as 3%, 5%, 6%, 7% etc.

[0062] In a preferred example, the tPCS may have a frequency of more than 120Hz but no more than 500Hz, a duty cycle in the range of 1% to 8%, and a peak current value in the range of 8mA-60mA.

[0063] In another preferred example, the tPCS may have a frequency of more than 200Hz but no more than 500Hz, a duty cycle in the range of 1% to 8%, and a peak current value in the range of 8mA-60mA.

[0064] In another preferred example, the tPCS may have a frequency of 100Hz to 500Hz, a duty cycle in the range of 1% to 8%, and a peak current value in the range of 10mA to 60mA.

[0065] In another preferred example, the tPCS may have a frequency of 100Hz to 500Hz, a duty cycle in the range of 1% to 8%, and a peak current value in the range of 12mA to 60mA.

[0066] In another preferred example, the tPCS may have a frequency of 100Hz to 500Hz, a duty cycle in the range of 1% to 8%, and a peak current value in the range of 10mA to 40mA.In another preferred example, the tPCS may have a frequency of 100Hz to 500Hz, a duty cycle in the range of 1 % to 8%, and an average current intensity in a range of 0.6mA to 0.7mA per second.

[0067] As a specific example for children with ASD, it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with a frequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 0.7mA per second, and a peak current amplitude of about 12.5 mA, having a monophasic rectangular pulse waveform.

[0068] As another specific example for adults with sleep disorder (chronic insomnia), it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with a frequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 0.6mA per second, and a peak current of about 10.7 mA, having a monophasic rectangular pulse waveform.

[0069] As another specific example for adults with mild cognitive impairment, it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with a frequency of about 100Hz, a pulse width of about 500 µs, a duty cycle of 5.0%, an average current intensity of about 0.6mA per second, and a peak current of about 12 mA, having a monophasic rectangular pulse waveform.

[0070] As another specific example for paediatric patients with ADHD, it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with a frequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 0.7 mA per second, and a peak current of about 12.5 mA, having a monophasic rectangular pulse waveform.

[0071] As another specific example far patients with Parkinson’s Disease, it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with afrequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 1.0 mA per second, and a peak current of about 17.9 mA, having a monophasic rectangular pulse waveform.

[0072] Various trials have been conducted to verify the safety and efficacy of the present invention in alleviating or improving symptoms in relation to neurological, psychiatric, neuropsychiatric, and / or medical conditions. Generally, it has been found that using the above described (high frequency) tPCS is particular useful for improving / treating / alleviating at least one symptom as described above. Results of a few of these trials will be discussed in detail as below.

[0073] Trial of the Pulsed Current Stimulator in Children with ASP

[0074] A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to paediatric ASD. The trial was a multi-centre, double-blinded, sham-controlled, randomized clinical trial. Non-verbal subtests were used for non-verbal participants to ensure accurate evaluation of intellectual potential. Exclusion criteria includes epilepsy, craniotomy, implanted devices, severe psychiatric conditions (e.g., psychosis, schizophrenia), active scalp infection, obstructive sleep apnoea, active benzodiazepine, risperidone or haloperidol use, or prior non-invasive brain stimulation.

[0075] A total of 312 children with ASD aged 3 to 14 years old completed this trial. Each child with ASD underwent 20 sessions of prefrontal-cerebellar tPCS treatment, with each session lasts for 20 minutes. The 20 sessions were conducted on consecutive weekdays, Monday to Friday, over 4 weeks. Generally, a child (or children) is understood to mean someone of less than 18 years old.

[0076] As a double-blinded study, all the children were randomized into two groups, a sham-tPCS group and an active-tPCS group. In the active-tPCS group, thechildren were treated with tPCS signals applied to their scalp through the first set of surface electrodes 120. In the active group, there was a 10-second ramp-up to 0.7 mA at the beginning of each session, followed by treatment with tPCS signal throughout the session, which is in turn followed by a 10-second ramp down before the session ends. In the sham group, for each session, there was a 10-second ramp-up to 0.7 mA followed by a 10-second ramp down to 0 mA, and 0 mA was maintained for the remainder of the session.

[0077] Immediately after each session, participants in both groups were given a one-hour behavioural therapy administered by blinded occupational therapists. This included applied behaviour analysis (ABA) therapy, structured education, playbased therapy and speech therapy, rotated for each participant, such that each therapy was administered five times during the 20-session treatment course. These therapies constitute routine clinical care for ASD in the country where the trials were undertaken with modest efficacy evidenced in prior studies. They were included to provide a consistent foundation for all study participants.

[0078] The safety of both the active-tPCS and sham-tPCS interventions were monitored throughout the 20 sessions by experienced clinical staff in all centres. Urine test was performed before and after the 20 sessions to assess for unintended metabolic changes. Participants were instructed to report other adverse events experienced during or after treatment that were not included in the list of serious adverse events (SAEs).

[0079] Figs. 4 (a) and (b) illustrate electrode montage adopted in this trial. The first set of surface electrodes 120 comprises an anode electrode 402 and a cathode electrode 404. During the sessions for each child with ASD, the anode electrode 402 was attached to the child’s scalp over the right cerebellar hemisphere (the location for EEG (64-channel): CB2), and the cathode electrode 404 was attached to the child’s scalp over the left dorsolateral prefrontal cortex (the location for EEG (64-channel): F3).The pulse module 114 is configured to generate tPCS signal with a frequency of about 400Hz, a pulse width of about 140μs (a duty cycle of 5.6%). In this experiment, the tPCS has a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 0.7mA per second while the peak current of each pulse is about 12.5 mA. The stimulus generator 102 is configured to supply the generated tPCS to the first set of surface electrodes 120 during the period described above for each session.

[0080] T able 1 below presents the number of adverse events reported in the active-tPCS group. Overall, the results show that, the tPCS treatment was well tolerated by all participants throughout the trial. Generally, no serious adverse events were reported, and side effects reported were limited to mild headache (n =13) and temporary scalp redness (n = 27) underneath the electrode sites, which selfresolved within about 30 minutes after stimulation cessation. No participants from either group withdrew from the trial due to adverse reactions. This demonstrates that parameters of the tPCS signal generated by the pulsed current stimulator 100 in this experiment is safe and well-tolerated.Table 1. Number of Adverse Events Reported in the Active-tPCS Group

[0081] Mild Adverse Events Week 1 Week 2 Week 3 Week 4 Active- Sham- Active- Sham- Actsve- Sham- Active- Shem- tPCS tPCS tPCS tPCS tPCS tPCS tPCS tPCS (n=155) (n-15?} (n-155) (n-157) (n-155> {n=157) (n-155) (n-157 > Skin 6 0 4 0 8 0 S X redness / itchiness

[0082] Mild Headache 4 2 3 1 3 1 3 1 trouble Sleeping nil nil nil nil nil nil nil nil Scalp Pain nil nil nil nil nil nil nil nil Neck Patn nil Oil nil nil nil ns! nil nil Moderate Adverse Week 1 Week 2 Week 3 Week 4 Events Active- Sham- Active- Sham- Active- Shem- Active- Shsm- tPCS tPCS tPCS tPCS tPCS tPCS tPCS tPCS Nausea nil nil nil nil nil nil nil ml Scalp burns nil nil nil nil nt! nil nil ml Severe Headache nil nil nil nil nil nil nil nil Dizziness nil nil nil nil nil nil nil nil

[0083]

[0084] Abnormal Urine test nil nil nil nil nil nil nil nil Adverse Events {AE) were eoiiafert across ail the 8 participating hospital sites. Subjects that experienced aCvetse events were only recanted as *1" if they had not bean recarded in the previous weeks, to avoid dupfcatinn. An AE is classified as ''teitd*, if they self- resofved and / or did not require further medical action. An AE is classified as ’moderate* if they require medical intervention. An AE is classified as ’serious* tf it results in death, is life-threatening, requites i patient haspstBtizafion or pralangation of existing hospitalization cr results in persistent or significant disabiliSy / incapasity.

[0085] To measure the outcome, clinical characteristics of the children with ASD were evaluated using three measurements: Autism Treatment Evaluation Checklist (ATEC) (primary outcome) which indicates more severe symptoms by higher scores, Autism Behaviour Checklist (ABC) which indicates more severe symptoms by higher scores, and Childhood Sleep Habits Questionnaire (CSHQ) which is a parent-report tool to assess children’s sleep patterns.

[0086] Table 2 below presents baseline participants’ demographic and clinical characteristics in this trial. As shown in Table 2, before the treatment, there was no statistical significance between the sham group and the active group in all the domains, including ATEC total scores, ABC total scores and CHSQ total scores used in this trial. Therefore, if statistical significance is observed in any of the clinical characteristics between the two groups after the treatment, it would demonstrate that the treatment is effective at least in improving or alleviating that symptom in relation to children with ASD.Table 2. Baseline Participants’ Demographic and Clinical Characteristics

[0087] Group Statistics Demographic Characteristics Sham (n — 157)

[0088]

[0089] Active (n = 155)

[0090]

[0091] χ2valueaAge (years, mean a- S. D.) 5,1 st 1,5 5,1 ± 1.7 0.06 0.80 Age group 0.16 0,69 Pre-school: 3-6 years 140 136

[0092] Schoo! age: 7-14 years 17 19

[0093] Sex 1.13 0.29 Male 121 (77.1%) 127 (81.9%)

[0094] Female 36 (22.9%) 28 ( 18.1 %)

[0095] Clinical Characteristics Mean (S. D.) Mean (S. D j t P-valne** Speech / language / communication 17.20 (6.30) 17.30 (6,15) ”0.14 0.89 Sociability 18.65 (6.93) 17.61 (6.40) 1.37 0.17 Sensory / cognitive awareness 18.45 (6.57) 17.06 (6.22) 1.91 0.06 Physical / health / behaviour 16.84 (8.19) 15.30 (7.79) 1.71 0.09 ATEC Total 71.13 (22.65) 67.27 (20.79) 1.57 0.12 Sensory 10.83 (5.64) 12.28 (5.69) -2.26 0.02 Relating 17,82 (6.38) 17.77 (4.66) 0.07 0.95 Body & object use 11.24 (6.43) 11.54 (6.36) —0.41 0.68 Language 16.31 (5,79) 16.88 (5.17) -0.91 0,36 Social self-help 11.70 (4.36) 11.70 (4.34) -0.01 1.00 ABC Total 67.90 (18.22) 70.2(16.6) -1.15 0.25 Bedtime resistance 10.66(2.94) 9.99 (2,78) 2.07 0,04 Sleep anxietv 4,62 (2.81) 5.16 (2.48) - 1.79 0.08 Sleep duration 5.53 (5.91) 5.47 (2,03) 0.26 0,80 Parasomnia 11.67 (4.77) 11.37 (4.74) 0.56 0.58 Night 'wakening 5.36 (2,31) 5,39 (2.33) -0.09 0.93 Sleep disordered breathing 4.87 (2.44) 4.64 (2.25) 0.88 0.38 Daytime sleepiness 13.57 (4.80) 13.39 (4,34) 0,36 0.72 Sleep onset delay 1.92 (0.73) 1.95 (0.82) −0.35 0.72 CHSQ total 58.20 (16.20) 57.35 (15.07) 0.48 0.63 » P < 0.05 was used to assess statistical signiiicance for baseline demographics of participants tn the sham-tPCS (n “ 157) and active-tPCS (n -• 155) groups as originally assigned.

[0096] bBonferroni correction (ATEC: P< 0.0125; ABC: < 0.01; CSHQ: *< 0.00625) - (S) was used to assess statistical significance for ATEC, ABC and CSHQ total and subdomain scores between groups.

[0097] Table 3 illustrates post-treatment analysis of covariance (ANCOVA) results for ATEC, ABC and CSHQ scores in this trial. In short, the treatment results demonstrate significant improved social functioning and sleep among children in the active group compared to the sham group, which will be discussed in detail below.Table 3. Post-treatment Analysis of Covariance (ANCOVA) - ATEC, ABC, CSHQ Without Baseline Adjustment with Baseline Adjustment

[0098] Sham Group Active Group Sham Active Adjusted Mean Diff P-value* Effect Size Mean (SD) Mean (SD) Group Group (95% CI)

[0099] Outcome Variables Mean Mean [Sham Minus Active]

[0100] Speech / language / communication 16.3 (6.4) 15.7 (6.0) 16.32 15.62 0.70 (−0.18, 1.48) 0.08 (NS) 0.01 Soci&biUty 17.5(6.5) 15.0(5.7) 17.13 15.41 1.72(0.88,257) 801(8) 8.85 Sensory / cognitive awareness 17.3 (6.5) 15.6 (6.0) 16.74 16.12 0.62 (−0.18, 1.42) 0.13 (NS) 0.01 Physical / health / behaviour 16.0 (7.6) 14.0 (7.2) 15.33 14.52 0.81 (0.01, 1.60) 0.05 (NS) 0.01

[0101] ATEC Tefal 67.8(22.3) 69.1 (20.0) 65.35 61.85 3.59(1.43,5.56) <881(8 8.84 Sensory 10.5 (5.6) 10.9 (5.2) 11.12 10.26 0.86 (0.22, 1.50) .009 (S) 0.02

[0102] Relating 17.4 (6.2) 16.5 (4.4) 17.34 16.47 0.87 (0.13, 1.60) 0.02 (NS) 0.02

[0103] Body & object use 10.8(6.4) 10.3(6.1) 10.96 10.14 0.82(0.07.1.56) 0.03 (NS) 0.02 Language 16.3 (5.0) 15.7 (5.1) 16.51 15.47 1.04 (0.23, 1.85) 0.01 (NS) 0.02

[0104] Social self-help 11.2 (4.2) 11.0 (4.2) 11.22 10.94 0.28 (−0.30, 0.86) 0.35 (NS) 0.00

[0105] ABC Total 663(18.1) 64.2(15,7) 67.23 63,23 4. M (2.26, 5.75) <881 (8) 9.06 Bedtime resistance 10.1 (2.9) 9.4 (3.2) 9.77 9.7 0.07 (−0.33, 0.48) 0.73 (NS) 0.00

[0106] Sleep anxiety 4.5 (2.7) 4.6 (2.1) 4.68 4.36 0.32 (0.08, 0.57) 0.01 (NS) 0.02

[0107] Sleep duration 5.5 (1.8) 5.1 (2.1) 5.44 5.11 0.33 (0.04, 0.63) 0.03 (NS) 0.02 Parasomnia 11.4 (5.0) 10.6 (5.2) 11.2 10.74 0.46 (0.11, 0.81) 0.01 (NS) 0.02

[0108] Night wakening 5.2 (2.3) 5.0 (2.3) 5.16 5.03 0.13 (−0.08, 0.34) 0.22 (NS) 0.01

[0109] Sleep disordered breathing 4.8 (2.5) 4.5 (2.3) 4.69 4.65 0.04 (−0.07, 0.16) 0.49 (NS) 0.00 Daydime Sleepiness 13.2(4.7} 12.2(5.0) 13.12 12,27 8.85(9.39,1.39) <.901 (S) 0.04

[0110] Sleep onset delay 1.8 (0.7) 1.8 (0.8) 1.84 1.81 0.03 (−0.08, 0.15) 0.59 (NS) 0.01

[0111] CHSQ Total ' 56.3(16.7) 53,2(17.4) 55.88 53.69 2.19 (1.19.320) <.091 tS) 0.06

[0112] tPCS: transcranial pulsed current stimulation; SD: standard deviation; CI: Confidence Interval; ATEC: Autism treatment evaluation checklist; ABC: Autism behaviour checklist; CSHQ: Childhood sleep habits Questionnaire

[0113] ‘ Bonfetroni correction (ATEC: P 0.0125; ABC: P < 0.01; CSHQ: P < 0.00625 } - (S) was used to assess statistical ignificance for ATEC. ABC and CSHQ total and subdomain scores between groups.

[0114] Social Functioning Improvement:

[0115] ATEC

[0116] • After 20 sessions, the mean ATEC total score was improved by -7.17 points (10.7%) in the active-tPCS group compared to -4.13 points (5.8%) in the sham-tPCS group. ANCOVA revealed a significantly greater improvement in the active-tPCS group (difference, -3.50; 95%CI, -5.56 to -1.43; P <.001, partial eta squared (qp2) effect size: 0.04) than the sham- tPCS group. The ATEC sociability subscale contributed most significantly to the group difference in total scores (difference, -1.72; 95%CI, -2.57 to -0.88; P <.001, partial eta squared (qp2) effect size, 0.05).

[0117] • Table 4 presents data of participants achieving clinically meaningful change in post-hoc ATEC total scores; and Table 5 presents results of Chi-Square test analysis of the difference between the groups shown in Table 4. In this exploratory analysis, a reduction of >10% in ATEC totalscores at post-treatment is used as a reference for clinical significance.

[0118] 54.2% (84 out of 155) of participants in the active-tPCS group achieved a reduction of >10% in ATEC total scores at post-treatment, whereas only 30.6% (48 out of 157) of participants in the sham-tPCS group achieved the same. Table 5 shows that the difference is statistically significant (p<0.001).

[0119] ABC

[0120] • The ATEC results were supported by the results of the ABC, a secondary outcome measurement used for evaluating ASD behaviours in the study. After 20 sessions, the mean ABC total score was improved by -6.0 points (8.5%) in the active-tPCS group compared to -1.6 points (2.4%) in the sham-tPCS group. ANCOVA revealed a significantly greater improvement in the active-tPCS group (difference, -4.00; 95%CI, -5.75 to-2.26; P <.001; partial eta squared (ηp2) effect size: 0.06). The results for the sensory subdomain also show a significant difference (difference: −0.86; 95%CI, −1.50 to −0.22; P =.009; partial eta squared (ηp2) effect size, 0.02).

[0121] • Table 6 presents the results of participants achieving clinically meaningful change in post-hoc ABC total scores; and Table 7 presents results the Chi- Square test analysis of the difference between the groups shown in Table 6. In this exploratory analysis, a reduction of >10% in ABC scores is used as a reference for clinical significance. 40.6% (63 out of 155) of participants in the active-tPCS group achieved a reduction of >10% in ABC scores at post-treatment, compared to 19.7% (31 out of 157) in the sham- tPCS group. Table 7 shows that the difference is statistically significant (p<0.001).Sleep Improvement

[0122] CSHQ

[0123] • Post-treatment, mean CSHQ total score was improved by -4.15 (7.2%) in active-tPCS group vs. -1.9 (3.3%) in sham-tPCS group. ANCOVA revealed a significantly greater improvement in the active-tPCS group (difference, -2.19; 95%CI, -3.20 to— 1.19; P <.001; partial eta squared ( p2) effect size: 0.06). The results for the daytime sleepiness subdomain score also demonstrate a significant difference (difference, -0.85; 95%CI, -1.30 to -0.39; P < 0.001; partial eta squared (qp2) effect size: 0.04). • Table 8 presents the results of participants achieving clinically meaningful change in post-hoc CSHQ total scores; and Table 9 presents results the Chi-Square test analysis of the difference between the groups shown in Table 8. In exploratory analysis, using >10% CSHQ total score improvement as a measure of clinically meaningful benefit, 46.5% (72 out of 155) of participants in the active-tPCS group achieved a reduction of >10% in CSHQ scores at post-treatment, compared to 15.9% (25 out of 157) in the sham-tPCS group. Table 9 shows that the difference is statistically significant (p<0.001).

[0124] Compared to sham-tPCS treatment, active-tPCS treatment led to statistically significant and clinically meaningful improvements in social functioning as measured by the ATEC scores (primary outcome) and the ABC scores (secondary outcome). Sensory processing, as measured by the ABC sensory subdomain, was also shown to be improved significantly in the active-tPCS group compared to the sham-tPCS group. In addition, active-tPCS was also demonstrated to significantly improve sleep dysfunctions compared to sham-tPCS, in particular, daytime sleepiness, as measured by the CSHQ scores.

[0125] These results demonstrate that prefrontal-cerebellar tPCS (with parameters of a frequency of about 400Hz, a pulse width of about 125μs, monophasic rectangularpulse waveform, an average current intensity of about 0.7mA, and a peak current of about 12.5 mA) can significantly improve social functioning and sleep in children with ASD, aged 3-14 years, which is surprisingly advantageous especially when there is currently no known cure for ASD. In other words, tPCS treatment may serve as a viable non-pharmacological alternative for ASD.

[0126] Table 4. Participants Achieving Clinically Meaningful Change in Post-hoc ATEC Total Scores

[0127] ATEC * Change in ATEC Crosstabulation

[0128] Change in ATEC

[0129] Total score Total score Total score reduction reduction without

[0130] >=10% 0 to <10% reduction Total ATEC Sham-tPCS Group Count 48 65 44 157

[0131] Expected Count 66.4 54.3 36.2 157.0 % Within ATEC 30.6% 41.4% 28.0% 100.0% Active-tPCS Group Count 84 43 28 155

[0132] Expected Count 65.6 53.7 35.8 155.0 % within ATEC 54.2% 27,7% 18.1% 100.0% Total Count 132 108 72 312

[0133] Expected Count 132.0 108.0 72.0 312.0 % within ATEC 42.3% 34.6% 23.1% 100.0%

[0134]

[0135] Table 5. Chi-Square tests for Table 4

[0136] Chi-Square Tests

[0137] Asymptotic

[0138] Significance

[0139] Value df (2-sided)

[0140] Pearson Chi-Square 17.843® 2 | <.001

[0141] Likelihood Ratio 18.029 2 <.001

[0142] Linear-by-Linear Association 14.213 1 | <.001

[0143] N of Valid Cases 312

[0144] a. 0 cells (0.0%) have expected count less than 5. The minimum expected

[0145] count is 35.77,

[0146]

[0147] Table 6. Participants Achieving Clinically Meaningful Change in Post-hoc ABC Total Scores

[0148] ABC * Change in ABC Crosstabulation

[0149]

[0150] Change in ABC

[0151] Total score Total score

[0152] reduction reduction

[0153] Total score

[0154] >=10% 0 to <10 % without reduction Total ABC Sham-tPCS Count 31 63 63 157

[0155] Expected Count 47.3 64.4 45.3 157.0 % within ABC 19.7% 40.1% 40.1% 100.0% Active-tPCS Group Count 63 65 27 155 Group

[0156] Expected Count 46.7 63.6 44.7 155.0

[0157] 40.6% 41.9% 17.4% 100.0% Total Count 94 128 90 312

[0158] Expected Count 94.0 128,0 90.0 312.0 % within ABC 30.1% 41.0% 28.8% 100.0%

[0159]

[0160] Table 7. Chi-Square tests for Table 6

[0161] Chi-Square Tests

[0162] Asymptotic

[0163] Significance

[0164] Value df (2-sided)

[0165] Pearson Chi-Sq i;are 25.313s2 <.001

[0166] Likelihood Ratio 25.944 2 <.001

[0167] Ltnear-by-L inear Association 25.077 1 <.001

[0168] N of Valid Cases 312

[0169] a. 0 cells (0.0%) have expected count less than 5. The minimum expected

[0170] count is 44.71.

[0171]

[0172] Table 8. Participants Achieving Clinically Meaningful Change in Post-hoc CSHQ Total Scores

[0173] CSHQ * Change in CSHQ Crosstabulation

[0174] Change in CSHQ

[0175] Total score Total score

[0176] reduction reduction Total score

[0177] >=10% 0 to <10% without reduction Totstl CSHQ Shara-tf’CS Group Count 79 53 137 Expected Count 48.8 64.4 43.8 157.0 % within CSHQ 15.9% 50.3% 33.8% 100.0% Active-tPCS Group Count 72 49 34 155 Expected Count 48.2 63.6 43.2 155.0 % within CSHQ 46.5% 31.6% 21.9% 100.0%! Total Count 97 128 87 312 Expected Count 97.0 128.0 87.0 312.0

[0178]

[0179] % within CSHQ 31.1% 41.0% 27.9% 100.0%Table 9. Chi-Square tests for Table 8

[0180] Chi-Square Tests

[0181] Asymptotic Significance Value (2-sided) Pearson Chi-Square 33.942a2 <.001 Likelihood Ratio 35.028 2 <001

[0182] Linear-by-Linear Association 23.686 1 <.001

[0183] N of Valid Cases 312

[0184] a. 0 cells (0.0%) have expected count less than 5. The minimum expected count is

[0185]

[0186] 43.22.

[0187] Trial of the Pulsed Current Stimulator in Adults with Sleep Disorder (Chronic Insomnia)

[0188] A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to sleep disorder (chronic insomnia). It was conducted as a single-center, doubleblinded, sham-controlled randomized clinical trial. 30 adults with chronic insomnia (with or without depression), aged 18 to 60 years old, joined the trial. Participants had baseline Pittsburgh Sleep Quality Index (PSQI) score 11-21; stable insomnia medication for >30 days and average whole-night actigraphy-derived total sleep time (TST) of <480 minutes (<8 hours). Individuals with mild to moderately severe depressive symptoms were assessed using Diagnostic and Statistical Manual of Mental Disorders (DSM-V). Each adult underwent 12 sessions of bilateral cerebellar tPCS stimulation, at 30 minutes per session, Monday to Saturday, over 2 weeks. In the active group, the adults were treated with tPCS signals applied to their scalp through the first set of surface electrodes 120. There was a 10-second ramp-up to 0.6 mA at the beginning of each session, followed by treatment with tPCS signal throughout the session, which is in turn followed by a 5-second ramp down before the session ends. In the sham group, there was a10-second ramp-up to 0.6 mA followed by a 5-second ramp down to 0mA, and 0mA was maintained for the remainder of the session.

[0189] Fig. 5 illustrates electrode montage adopted in this trial. During the sessions for each adult with sleep disorder, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the right cerebellar hemisphere (the location for EEG (64-channel): CB2), and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the left cerebellar hemisphere (the location for EEG (64-channel): CB1).

[0190] The tPCS signal generated and supplied to the first set of surface electrodes 120 has a frequency of about 400Hz, a pulse width of about 140μs (a duty cycle of 5.6%). The tPCS has a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 0.6mA per second while the peak current of each pulse is about 10.7 mA.

[0191] The results were evaluated using four measurements: Wrist Actigraphy Sleep measures (Primary outcome: Actigraphy Total Sleep Time); Pittsburg Sleep Quality Index (PSQI); Depressive Symptoms using Zung Self-rated Depression Score (SDS); Anxiety Symptoms using Zung Self-rated Anxiety Score (SAS).

[0192] Table 10 presents baseline demographic and clinical characteristics of the adults recruited for this trial. Table 11 presents post-treatment outcomes analysed using rank ANCOVA. Table 12. presents association of age with outcome variables across all participants. Table 13. presents association between change in Actigraphy TST and change in SAS and SDS in the active-tPCS Group after treatment.Table 10. Baseline Demographic and Clinical Characteristics Characteristic Group

[0193] Overall Sham Active- Statist! P- N = 30 N = 15 tPCS c value N = 15

[0194] Sex, n (%) 0.427aMale 9 (30.00%) 3 (20.00%) 6 (40.00%)

[0195] Educational level, n 2.40020.121b(%)

[0196] Junior high school 10 (33.33%) 3 (20.00%) 7 (46.67%)

[0197] or below

[0198] Senior high school 20 (66.67%) 12 (80.00%) 8 (53.33%)

[0199] or above

[0200] Age, mean ± SD 43 ± 12 38 ± 12 49 ± 11 -2.686c0.012cHeight (cm), median 160 (158, 159 (156, 160 (158, 88.500d0.328d(Q1, Q3) 166) 166) 167)

[0201] Weight (kg), mean ± 56 ± 8 55 ± 7 57 ± 9 -0.530c0.600cSD BMI, mean ± SD 20.93 ± 21.02 ± 20.84 ± 0.213C0.833c2.36 2.53 2.26

[0202] Depression, n (%) 17 (56.67%) 9 (60.00%) 8 (53.33%) 0.713bAnxiety, n (%) 14 (46.67%) 9 (60.00%) 5 (33.33%) 2.143b0.143bBenzodiazepine use, 14 (46.67%) 7 (46.67%) 7 (46.67%) 0.000b>0.999 n (%) b Anti-depression 9 (30.00%) 6 (40.00%) 3 (20.00%) 0.427amedication, n (%)

[0203] Anti-psychotic 9 (30.00%) 2 (13.33%) 7 (46.67%) 0.109bmedication, n (%)

[0204] Actigraphy outcomes

[0205] Actigraphy TST, mean 328 ± 71 366 ± 62 291 ± 61 184.00e0.002e± SD

[0206] Actigraphy SL, 5.5 (3.3, 4.2 (2.7, 6.0 (4.0, 93.00d0.430dmedian (Q1, Q3) 7.3) 7.7) 7.3)

[0207] Actigraphy SE, mean 86.3 ± 6.4 84.3 ± 7.6 88.4 ± 4.2 77.00e0.148e± SD

[0208] Actigraphy TIB, mean 383 ± 93 437 ± 81 330 ± 71 186.00d0.002d± SD

[0209] Actigraphy WASO, 34 (27, 70) 65 (30, 89) 27 (23, 36) 173.50d0.012d

[0210]

[0211] median (Q1, Q3)Actigraphy No. of 16 (11, 21) 19 (15, 28) 11 (10, 18) 179.00d0.006dawakening, median

[0212] (Q1, Q3)

[0213] Actigraphy Avg. 2.60 (2.11, 2.64 (2.15, 2.53 (2.10, 128.00 0.534dawakening (minutes), 3.25) 3.84) 3.24) 0d

[0214] median (Q1, Q3)

[0215] PSQI outcomes

[0216] PSQI global, median 17.00 16.00 17.00 71.50d0.088d(Q1, Q3) (15.00, (14.00, (16.00,

[0217] 18.00) 18.00) 18.00)

[0218] Subjective sleep 0.080cquality, n (%)

[0219] 2 points (fairly bad) 7 (23.3%) 6 (40.0%) 1 (6.7%)

[0220] 3 points (very bad) 23 (76.7%) 9 (60.0%) 14 (93.3%)

[0221] Sleep latency, n (%) 0.215c2 points (moderate 8 (26.7%) 6 (40.0%) 2 (13.3%)

[0222] difficulty)

[0223] 3 points (severe 22 (73.3%) 9 (60.0%) 13 (86.7%)

[0224] difficulty falling

[0225] asleep)

[0226] Sleep duration, n (%) 0.477a1 point (6-7 hours) 2 (6.7%) 0 (0.0%) 2 (13.3%)

[0227] 2 points (5-6 12 (40.0%) 7 (46.7%) 5 (33.3%)

[0228] hours)

[0229] 3 points (< 5 16 (53.3%) 8 (53.3%) 8 (53.3%)

[0230] hours)

[0231] Habitual sleep 0.701aefficiency, n (%)

[0232] 0 points (> 85% 7 (23.3%) 7 (46.7%) 0 (0.0%)

[0233] sleep efficiency)

[0234] 1 point (75-84%) 3 (10.0%) 1 (6.7%) 2 (13.3%)

[0235] 2 points (65-74%) 7 (23.3%) 5 (33.3%) 2 (13.3%)

[0236] 3 points (< 65%) 13 (43.3%) 2 (13.3%) 11 (73.3%)

[0237] Sleep disturbances, n 0.481a(%)

[0238] 1 point (mild sleep 10 (33.3%) 4 (26.7%) 6 (40.0%)

[0239]

[0240] disturbances)2 points (moderate 15 (50.0%) 7 (46.7%) 8 (53.3%) sleep

[0241] disturbances)

[0242] 3 points (severe 5 (16.7%) 4 (26.7%) 1 (6.7%)

[0243] sleep

[0244] disturbances)

[0245] Use of sleep 0.598amedication, n (%)

[0246] 2 points (once or 4 (13.3%) 3 (20.0%) 1 (6.7%)

[0247] twice a week)

[0248] 3 points (three or 26 (86.7%) 12 (80.0%) 14 (93.3%)

[0249] more times a

[0250] week)

[0251] Daytime dysfunction, 0.090an (%)

[0252] 0 points (no 1 (3.3%) 1 (6.7%) 0 (0.0%)

[0253] daytime

[0254] dysfunction)

[0255] 1 point (mild 2 (6.7%) 0 (0.0%) 2 (13.3%)

[0256] daytime

[0257] dysfunction)

[0258] 2 points (moderate 19 (63.3%) 8 (53.3%) 11 (73.3%)

[0259] daytime

[0260] dysfunction)

[0261] 3 points (severe 8 (26.7%) 6 (40.0%) 2 (13.3%)

[0262] daytime

[0263] dysfunction)

[0264] SAS, median (Q1, 54 (48, 63) 60 (55, 71) 48 (40, 54) 199.50d<0.001 Q3) d SDS, median (Q1, 56 (47, 67) 67 (58, 83) 47 (41, 55) 208.00d<0.001 Q3) d Abbreviations: BMI = body mass index; SD = standard deviation; TST = total sleep time; SL= sleep latency; SE = sleep efficiency; TIB = time in bed; WASO = wake after sleep onset; SAS- Zung Self-Rating Anxiety Scale; SDS = Zung Self-Rating Depression Scale; PSQI-Pittsburg Sleep Quality Index.

[0265] P-values were obtained using:aFisher's exact test,bPearson's Chi-squared,cWelch

[0266]

[0267] Two Sample t-test,dWilcoxon rank sum test,eWilcoxon rank sum exact testHolm-Bonferroni correction was performed for the seven actigraphy subcategories, after correction, significant group differences remained for total sleep time (TST), time

[0268]

[0269] in bed (TIB), wake after sleep onset (WASO), and number of awakenings.

[0270] Table 11 Post-treatment Outcomes Analysed Using Rank ANCOVA Outcome Median (Q1, Mean ± SD Adjusted Adjuste P Effe variable Q3) mean rankad mean valu ct (post(Meant SD) rank ebsizectreatment Diff Btw

[0271] ) Grp

[0272] (95% Cl)

[0273] Sha Active Sha Active Sha Active

[0274] m -tPCS m -tPCS m -tPCS

[0275] (n=1 (n=15 (n=1 (n=15 (n=1 (n=15

[0276] 5) ) 5) ) 5) )

[0277] Actigrap 367 364 372.2 372.6 355.3 389.5 34.25 0.02 0.18 hy TST (325, (340, 5 ± 3 ± 2 7 (1.60, 2 0

[0278] 404) 403) 48.60 42.51 ±10.4 ±10.4 66.89)

[0279] 2 2

[0280] Actigraph 5.33 5.00 4.79 4.98 4.78 4.99 0.21 0.99 0.00 y SL (1.86 (3.67, + + + + (-1.81, 5 0

[0281] 6.00) 3.48 1.61 0.70 0.70 2.24)

[0282] 6.67)

[0283] Actigraph 80.5 89.1 82.95 88.29 84.08 87.16 3.08 0.03 0.16 y SE (79.3 (86.2, + + + + (0.00, 0 3

[0284] 90.0) 6.43 3.25 1.03 1.03 6.16)

[0285] 87.8)

[0286] Actigraph 456 401 449.3 422.7 424.8 447.2 22.42 0.43 0.02 yTIB (406, (386, 7 ± 3 ± 5 ± 6 ± (-11.22, 2 3

[0287] 499) 453) 49.25 50.82 10.55 10.55 56.06)

[0288] Actigraph 80 43 72.34 45.12 63.54 53.92 -9.62 0.08 0.10 y WASP (50, (34, + ±16.7 + + (-24.97, 3 7

[0289] 88) 53) 29.31 7 4.96 4.96 5.72)

[0290] Actigraph 23.5 17.7 22.25 18.42 20.37 20.29 -0.08 0.52 0.01 y No. of (19.0 (14.3, + + + + (-4.86, 0 6 awaken in 22.0) 6.46 6.03 1.53 1.53 4.70)

[0291]

[0292] g 26.0)Actigraph 3.16 2.68 3.26 2.54 3.13 2.67 -0.46 0.01 0.19 y Avg. (2.14 (1.97, ±1.16 + + + (-0.91, 7 4 awaken in 3.03) 0.63 0.15 0.15 -0.02)

[0293] g 4.05)

[0294] (minutes)

[0295] PSQI outcomes

[0296] PSQI 16 12 15.80 12.53 16.36 11.97 -4.39 <0.0 0.45 global (15, (10, + + + + (-6.47, 01 1

[0297] 17) 16) 2.62 3.31 0.70 0.70 -2.30) Subjectiv 3 (2, 1 (1, 2.60 1.27 2.71 1.16 -1.54 <0.0 0.51 e sleep 3) 2) + + + + (-2.22, 01 0 quality 0.83 0.88 0.23 0.23 -0.87)

[0298] Sleep 3 (2, 2 (2, 2.60 2.07 2.69 1.97 -0.72 0.01 0.19 latency 3) 3) + + + + (-1.24, 6 5 0.51 0.88 0.18 0.18 -0.20)

[0299] Sleep 3 (2, 1 (1, 2.73 1.20 2.71 1.22 -1.49 <0.0 0.58 duration 3) 1) + + + + (-1.99, 01 9

[0300] 0.46 0.86 0.17 0.17 -0.99)

[0301] Habitual 1 (0, 2 (1, 1.20 1.53 1.65 1.08 -0.57 0.21 0.05 sleep 2) 2) + + + + (-1.49, 6 6 efficiency 1.21 1.06 0.29 0.29 0.36)

[0302] Sleep 2 (1, 1 (1, 2.00 1.13 1.90 1.23 -0.68 0.00 0.24 disturban 3) 1) + + + + (-1.13, 7 4 ces 0.85 0.52 0.15 0.15 -0.22)

[0303] Use of 3 (2, 3 (3, 2.53 2.67 2.58 2.62 0.04 0.42 0.02 sleep 3) 3) + + + + (-0.61, 2 4 medicatio 0.83 0.90 0.22 0.22 0.69)

[0304] n

[0305] Daytime 2 (2, 1 (1, 2.13 1.33 2.10 1.37 -0.73 0.02 0.18 dysfunctio 3) 2) + + + + (-1.32, 1 3 n 0.92 0.62 0.20 0.20 -0.14) Psychiatric scales

[0306] SAS 60 40 62.33 40.58 57.38 45.54 -11.85 <0.0 0.40

[0307] (55, (35, + ±7.66 + + (-17.58, 01 9 69) 46) 8.97 1.76 1.76 -6.12) SDS, 68 41 69.08 40.83 61.02 48.89 -12.13 <0.0 0.40 Median (58, (39, ±11.8 ±6.38 + + (-17.24, 01 8

[0308]

[0309] 81) 44) 9 1.52 1.52 -7.03)aAdjusted mean rank represents the baseline-adjusted average rank of the outcome derived from the Rank ANCOVA model.

[0310] bP-values were obtained using Rank ANCOVA model. After correction, some variables that are <0.05 is no longer be significant, the significant ones are bolded.cEffect sizes represent partial η2. Partial η2effect size: Small effect = ~0.01; Medium effect = -0.06; Large effect = > 0.14.

[0311] Multiplicity adjustment:

[0312] • For six secondary actigraphy outcomes, Holm-Bonferroni correction (a = 0.05) indicated no outcomes remained significant after correction; total sleep time (TST) was prespecified as the primary outcome and exempt.

[0313] • For PSQI global score and seven subcomponents, Holm-Bonferroni correction (a = 0.05) identified PSQI global score, subjective sleep quality, sleep duration and sleep disturbances as statistically significant after adjustment; remaining subcomponents were not significant.

[0314]

[0315] Table 12. Associations of Age with Outcome Variables across all Participants (n = 30)

[0316] Outcome variable Spearman’s Raw FDR- Significant P p-valueaadjusted q- after FDR valueb

[0317] Actigraphy TST - Baseline -0.330 0.075 0.208 No Actigraphy TST - Post -0.201 0.286 0.397 No Actigraphy SL - Baseline 0.308 0.098 0.233 No Actigraphy SL - Post 0.034 0.860 0.905 No Actigraphy SE - Baseline 0.086 0.653 0.825 No Actigraphy SE - Post 0.134 0.481 0.687 No Actigraphy TIB - Baseline -0.340 0.066 0.200 No Actigraphy TIB - Post -0.291 0.119 0.264 No Actigraphy WASO - -0.270 0.149 0.298 No Baseline

[0318] Actigraphy WASO - Post -0.250 0.182 0.331 No Actigraphy No. of -0.359 0.051 0.170 No Awakenings - Baseline

[0319] Actigraphy No. of -0.213 0.259 0.373 No Awakenings - Post

[0320] Actigraphy Avg. awakening -0.075 0.694 0.851 No

[0321]

[0322] - BaselineActigraphy Avg. awakening -0.155 0.413 0.629 No

[0323] - Post

[0324] SAS - Baseline -0.408 0.025 0.125 No SAS - Post -0.418 0.022 0.110 No SDS - Baseline -0.273 0.144 0.288 No SDS - Post -0.333 0.072 0.205 No PSQI global - Baseline 0.112 0.556 0.758 No PSQI global - Post -0.326 0.078 0.217 Noa* p<0.05 ** p<0.01

[0325] bTo account for multiple testing, raw p-values are reported alongside Benjamini- Hochberg false discovery rate (FDR)-adjusted q-values (q = 0.05). No correlations

[0326]

[0327] remained statistically significant after correction for multiple comparisons.

[0328] Table 13. Association between Change in TST and Changes in SAS, SDS in the Active-tPCS Group at Post-treatment

[0329] Change Change in Change in in TST SDS SAS Kendall's Change in Correlation 1.000 -0.390* 0.048 tau_b TST coefficient

[0330] Sig. (2-tailed) 0.042 0.804 N 15 15 15 Change in Correlation -0.390* 1.000 -0.029 SDS coefficient

[0331] Sig. (2-tailed) 0.042 .882 N 15 15 15 Change in Correlation 0.048 -0.029 1.000 SAS coefficient

[0332] Sig. (2-tailed) 0.804 0.882

[0333] N 15 15 15 Spearman's Change in Correlation 1.000 -0.554* 0.070 rho TST coefficient

[0334] Sig. (2-tailed) 0.032 0.805 N 15 15 15 Change in Correlation -0.554* 1.000 -0.014 SDS coefficient

[0335] Sig. (2-tailed) 0.032 0.960

[0336]

[0337] N 15 15 15Change in Correlation 0.070 -0.014 1.000 SAS coefficient

[0338] Sig. (2-tailed) 0.805 0.960

[0339] N 15 15 15 Abbreviation:

[0340] Change in TST: % change in baseline to post-treatment actigraphy TST

[0341] Change in SDS: % change in baseline to post-treatment SDS

[0342] Change in SAS: % change in baseline to post-treatment SAS

[0343] * Correlation is significant at the 0.05 level (2-tailed).

[0344]

[0345] From tables 10 to 13, the skilled person would appreciate that the treatment results demonstrate significantly improved total sleep time measured objectively by wrist actigraphy and significant improvement in subjective sleep quality in the active tPCS group, as measured by the Pittsburg Sleep Quality Index compared to the sham group, for example:

[0346] Objective Sleep Outcomes - Following the tPCS treatment, results were processed by conducting between-group comparison using rank ANCOVA and were adjusted in view of the baseline values. The processed results reveal a significantly greater increase in actigraphy Total Sleep Time (TST) in the active-tPCS group compared with the sham group (adjusted mean rank difference = 34.25 minutes; 95% Cl: 1.60 to 66.89; P = 0.022), with a large effect size (partial η2= 0.180). Although post-treatment TST was similar between the sham group [372.25 minutes (SD = 48.6)] and the active tPCS group [372.63 minutes (SD = 42.51)], the extent of change differed substantially due to baseline disparities. Specifically, the sham group showed only a minimal increase of 6.25 minutes (1.7%), whereas the active tPCS group demonstrated a marked improvement of 81.63 minutes (28.1%). Details are presented in Table 11.

[0347] Subjective Sleep Outcomes - Secondary subjective sleep outcomes were assessed using the Pittsburgh Sleep Quality Index (PSQI). Similarly, the results were processed by conducting between-group comparison using rank ANCOVA.The processed results revealed a significantly greater improvement in PSQI global score in the active-tPCS group compared with the sham group (adjusted mean rank difference = -4.39; 95% Cl: -6.47 to -2.30; P < 0.001), with a large effect size (partial η2= 0.451). In the sham group, post-treatment PSQI global scores were 15.80 (SD = 2.62), reflecting a minimal improvement of 0.13 points (0.8%). In contrast, the active tPCS group showed a post-treatment score of 12.53 (SD = 3.31), representing a substantial reduction of 4.87 points (28.0%). After Holm-Bonferroni correction, significant between-group differences were also observed for the PSQI subcomponents of Subjective Sleep Quality (adjusted mean rank difference = -1.54; 95% Cl: -2.22 to -0.87; P < 0.001; partial η2= 0.510), Sleep Duration (adjusted mean rank difference = -1.49; 95% Cl: -1.99 to -0.99; P < 0.001; partial η2= 0.589), and Sleep Disturbances (adjusted mean rank difference = -0.68; 95% Cl: -1.13 to -0.22; P = 0.007; partial η2= 0.244), favoring the active-tPCS group. No other PSQI subcomponent scores remained statistically significant after correction. Details are presented in Table 11.

[0348] • Psychological Outcomes - Secondary psychological outcomes were evaluated using the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). The mean post-treatment SAS score was 62.33 (SD = 9.0) in the sham group and 40.58 (SD = 7.7) in the active-tPCS group, corresponding to mean reductions from baseline of 0.67 points (1.1%) and 7.42 points (15.5%), respectively. The results of between- group rank ANCOVA demonstrate a significant reduction in anxiety symptoms in the active-tPCS group compared with the sham group (adjusted mean rank difference = -11.85; 95% Cl: -17.58 to -6.12; P < 0.001 ), with a large effect size (partial η2= 0.409). Similarly, post-treatment SDS scores were 69.1 (SD = 11.9) in the sham group and 40.8 (SD = 6.4) in the active-tPCS group, reflecting mean reductions of 2.1 points (3.1%) and 7.2 points (15.0%) from baseline, respectively. Results of rank ANCOVA reveals a significant between-group difference favouring active- tPCS for depression symptom reduction (adjusted mean rank difference =-12.13; 95% Cl: -17.24 to -7.03; P < 0.001), with a large effect size (partial η2= 0.408). Details are presented in Table 11.

[0349] • Effect of Age did not confound the results - At baseline, participants assigned to the active tPCS group were significantly older than those in the sham group (49 ± 11 vs. 38 ± 12 years, P= 0.012) and could potentially confound post-treatment outcomes. Exploratory analyses using Spearman’s rank correlation were conducted to examine the relationship between age and key sleep and affective outcome variables across all participants (n = 30). As shown in Table 12, age was not significantly associated with any objective sleep parameters measured by actigraphy or with subjective sleep quality as assessed by the PSQI global score at either baseline or post-intervention (all p > 0.05). This indicates that the significant improvement in sleep outcomes in the active-tPCS group compared to the sham group was not due to baseline age differences between the groups but related to the intervention itself.

[0350] • Significant association between improvement in Actigraphy TST and reduction in depressive symptoms in the active-tPCS Group at post- treatment- Exploratory post-hoc analyses were performed in the active- tPCS group using Kendall rank correlation coefficient test and Spearman’s rank correlation coefficient test and to examine associations between changes in actigraphy total sleep time (ATST) and changes in depression (ASDS) and anxiety (ASAS) scores within the active-tPCS group. A significant negative correlation was observed between ATST and ASDS (Kendall's τb= -0.390, P = 0.042; Spearman’s p = -0.554, P = 0.032), indicating that the increase in TST after tPCS was associated with greater reduction in self-rated depression scores. No other correlations reached statistical significance. The correlation results are presented in Table 13.Fig. 6 illustrates an electric field modelling simulating an electric field induced by a tPCS signal provided by the electrode montage of Fig. 5. The simulation was performed based on an adult head model built from T1 -weighted MRI to estimate how the cerebellum and nearby brain regions are exposed, using Sim4Life™ software V8.2 (ZMT, Zurich, Switzerland). Using the high-resolution MIDA™ head model, 4-cm cylindrical electrodes were placed at the same positions as in the trial (i.e. the electrode montage of Fig. 5) and tissue conductivities from the IT’IS Tissue Properties Database v4.2 were assigned. In Fig. 6, the left colour bar shows the delivered current density, measured in amperes per square meter (A / m2), wherein lighter colour means stronger amplitude. The right colour bar shows strength of the electric field, measured by volts per meter, induced by the tPCS with an average current intensity of about 0.6 mA and a peak current of about 10.7 mA (other parameters including 400Hz frequency, 140μs pulses, and 5.6% duty cycle), wherein lighter colour indicating stronger induced electric field. As shown in Fig. 6, regions 602 and 604 are located near the electrode attachment areas. In regions 602 and 604, the induced electric field is generally at the strongest range. Region 606 is a brain region that is deeper than regions 602 and 604. The drawing shows that electric field was also induced in this deep region 606, just that the strength of the induced electric field in the deep region 606 of brain is generally weaker than that in regions 602 and 604. That said, the tPCS with the parameters noted above is able to induce electric field not only in superficial brain regions near the electrodes, but also in deeper brainstem regions that involve in sleep-wake regulation.

[0351] Trial of the Pulsed Current Stimulator in Adults with Mild Cognitive Impairment (MCI) and Mild Dementia

[0352] A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to mild cognitive impairment and mild dementia. It is as a single-center, double-blinded, sham-controlled randomized clinical trial. While a total of 31 adults with MCI, aged 55 to 89 years old, have been recruited for joining the trial, only 3 subjects have completed the trial, under the active-tPCS group. The 3 adults with MCI who completed the trial are aged from 78 to 85 years old. Each adult underwent 25 sessions of prefrontal-precuneus tPCS stimulation, at 30 minutes per session, over 5 weeks. Under the active-tPCS group, the adults were treated with tPCS signals applied to their scalp through the first set of surface electrodes 120. During the tPCS treatment, there was a 10-second ramp-up to 0.6 mA at the beginning of each session, followed by treatment with tPCS signal throughout the session, which is in turn followed by a 5-second ramp down to zero for the remainder of the session.

[0353] Fig. 7 illustrates electrode montage adopted in this trial. During the sessions for each adult with MCI, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the left dorsolateral prefrontal cortex (the location for EEG (64-channel): F3), and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the precuneus (the location for EEG (64-channel): Pz).

[0354] The tPCS signal generated and supplied to the first set of surface electrodes 120 has a frequency of about 100Hz, a pulse width of about 500 μs (a duty cycle of about 5%). The tPCS has a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 0.6mA per second while the peak current of each pulse is about 12mA.

[0355] The results were evaluated using three measurements: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) - composite score (Primary outcome); RBANS subdomain scores measuring cognitive domains that includes immediate memory, delayed memory, attention, language and visuospatial abilities; Montreal Cognitive Assessment (MoCA).Table 14 presents the results of RBANS and MoCA after the tPCS treatment, which demonstrates:

[0356] - tPCS signal was associated with consistent post-intervention improvements across multiple cognitive domains, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

[0357] - Following the intervention, all 3 participants demonstrated improvements in overall RBANS composite scores (range: 5.13% - 20.45%), RBANS subdomain scores for immediate memory (range: 6.19% - 27.63%), delayed memory (range: 7.14% - 48.88%), and visuospatial ability (range: 8.26% - 24.59%), while attention remained relatively stable, showing small changes.

[0358] - Notably, delayed memory showed the most pronounced gains across individuals, suggesting a particularly strong effect of the intervention on memory consolidation and retrieval processes. These findings indicate that tPCS may preferentially enhance memory-related cognitive networks in individuals with MCI, functions that are particularly vulnerable in MCI and early neurodegeneration, with secondary benefits in other cognitive domains.

[0359] While not all the recruited adults have completed the trial, the treatment results of the 3 adults who have completed the trial demonstrates significantly improved cognitive functioning.Table 14. Post-treatment outcomes of RBANS and MoCA

[0360] Patient Number 1 2 3 Name AAA BBB CCC Sex female female male Age 78 79 85 Education years >12yrs >12yrs >12yrs Master's Bachelor's Education Level Degree Diploma Degree Right / Left Hand Dominant Right Right Right CDR_BASELINE 0.5 0.5 0.5

[0361] Anodal: F3 Anodal: F3 Anodal: F3 Stimulation Montage Cathodal: Pz Cathodal: Pz Cathodal: Pz MoCA (Baseline) 20 22 21 MoCA (post; different

[0362] version) 20 24 24 Change Pre-Post (MoCA) 0.00% 9.09% 14.29% RBANS Total_Baseline 78 88 99 RBANS Total_Post 82 106 109 Change Pre-Post (RBANS) 5.13% 20.45% 10.10% RBANS Raw Scores

[0363] Total_Baseline 410 459 499 RBANS Raw Scores

[0364] Total_Post 434 527 535 Immediate memory_Baseline 61 76 97 Immediate memory_Post 76 97 103 Change Pre-Post (RBANS

[0365] Immed memory) 24.59% 27.63% 6.19% Visuospatial_Baseline 92 121 102 Visuospatial_Post 102 131 121 Change Pre-Post (RBANS

[0366] Visuospatial) 10.87% 8.26% 24.59%

[0367]

[0368] Language_Baseline 92 92 97Language_Post 90 99 92

[0369] Change Pre-Post (RBANS

[0370] Language) -2.17% 7.61% -5.15%

[0371] Attention_Baseline 109 106 122 Attention_Post 106 106 125

[0372] Change Pre-Post (RBANS

[0373] Attention) -2.75% 0.00% 2.46%

[0374] Delayed memory_Baseline 56 64 81

[0375] Delayed memory_Post 60 94 94

[0376] Change Pre-Post (RBANS

[0377]

[0378] Delayed Memory) 7.14% 46.88% 16.05%

[0379] Trial of the Pulsed Current Stimulator in Adults with Parkinson’s Disease

[0380] A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to Parkinson’s disease. It was conducted as a single-center, double-blinded, sham-controlled randomized clinical trial. 30 adults with Parkinson’s disease, aged 18 to 85 years old, joined and completed the trial. Each adult underwent 20 sessions of tPCS stimulation, at 20 minutes per session, Monday to Friday, over 4 weeks. Under the active-tPCS group, the adults were treated with tPCS signals applied to their scalp through the first set of surface electrodes 120. In the active-tPCS group, there was a 10-second ramp-up to 1.0 mA at the beginning of each session, followed by treatment with tPCS signal throughout the session, which is in turn followed by a 5-second ramp down before the session ends. In the sham group, there was a 10-second ramp-up to 1.0 mA followed by a 5-second ramp down to 0mA, and 0mA was maintained for the remainder of the session. Two stimulation montages were employed, each administered for 10 minutes, with a 5-minute gap in between the two montages, resulting in an actual total stimulation duration of 20-minutes per session.Fig. 8(a) and 8(b) illustrates the two electrode montages adopted in this trial. Fig.

[0381] 8(a) illustrates the first montage targeting at PD motor symptoms and Fig 8(b) illustrates the second montage targeting at PD non-motor symptoms. As shown in Fig 8(a), during the first 10 minutes of each session for each adult with Parkinson’s disease, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the midline motor cortex (the location for EEG (64-channel): Cz), and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the midline cerebellar hemisphere (the location for EEG (64-channel): Iz). As shown in Fig 8(b), during the second 10 minutes of each session for each adult with Parkinson’s disease, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the left dorsolateral prefrontal cortex (the location for EEG (64-channel): F3), and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the right dorsolateral prefrontal cortex (the location for EEG (64-channel): F4).

[0382] The tPCS signal generated and supplied to the first set of surface electrodes 120 has a frequency of about 400Hz, a pulse width of about 140μs (a duty cycle of about 5.6%). The tPCS has a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 1.0 mA per second while the peak current of each pulse is about 17.9 mA.

[0383] The results were evaluated using 13 measurements:

[0384] - Parkinson’s Disease Questionnaire (Primary outcome),

[0385] - Non-Motor Symptoms Scale for Parkinson’s Disease (NMSS)

[0386] - Unified Parkinson’s Disease Rating Scale (UPDRS)

[0387] - UPDRS Motor

[0388] - UPDRS Non-Motor

[0389] - Modified Hoehn and Yahr Staging Scale

[0390] - Schwab and England Activities of Daily Living Scale

[0391] - Hamilton Depression Rating Scale (HAMD)- Parkinson Fatigue Scale (PFS)

[0392] - Timed Up and Go Test (TUG)

[0393] - 10Meter_Walk Test (10MWT)

[0394] - Berg Balance Scale (BBS)

[0395] - Mini-Mental State Examination

[0396] Table 15 presents baseline demographic and clinical characteristics of the adults recruited for this trial, which shows that there is no statistical significance between the sham group and the active group.

[0397] Table 15. Baseline Demographic and Clinical Characteristics

[0398] Group

[0399] Sham- Active- Overall P- Characteristic tPCS tPCS Statistic

[0400] N = 30 value N = 12 N = 18

[0401] Age, Mean ± SD 65 ± 8 62 ± 7 67 ± 9 W = 0.3961

[0402] 87.50

[0403] Sex, n (%) 0.4422Male 19 9 10

[0404] (63.3%) (75.0%) (55.6%)

[0405] Education level, n (%) 0.6152Junior high school or 24 (80%) 8 16

[0406] below (66.7%) (88.8%)

[0407] MMSE, Median (Q1, Q3) 29.0 29.0 29.0 W = 0.6801

[0408] (27.0, (28.0, (26.0, 30. 118.00

[0409] 30.0) 29.5) 0)

[0410] PDQ_SI, Median (Q1, Q3) 15 (8, 14 (10, 21 (8, W = 0.4581

[0411] 30) 25) 31) 90.00 PDQ_Mobility, Median (Q1, 3.5 (0.0, 2.5 (0.5, 5.5 (0.0, W = 0.5211Q3) 9.0) 8.5) 10.0) 92.50

[0412]

[0413] Group

[0414] Sham- Active- Overall P- Characteristic tPCS tPCS Statistic

[0415] N = 30 value N = 12 N = 18

[0416] PDQ_Activities of Daily 1.5 (0.0, 1.5 (0.0, 1.5 (0.0, W = 0.9481Living, Median (Q1, Q3) 3.0) 4.5) 3.0) 106.00 PDQ_Emotional Well2.0 (0.0, 1.5 (0.0, 2.5 (0.0, W = 0.4011being, Median (Q1, Q3) 4.0) 4.0) 8.0) 88.00 PDQ_Stigma, Median (Q1, 0.0 (0.0, 0.0 (0.0, 0.0 (0.0, W = 0.6071Q3) 0.0) 2.0) 0.0) 117.00 PDQ_Social Support, 0.0 (0.0, 0.0 (0.0, 0.0 (0.0, W = 0.2601Median (Q1, Q3) 0.0) 0.0) 0.0) 96.00 PDQ_Cognition, Median 3.0 (1.0, 2.0 (0.0, 3.0 (2.0, W = 0.2471(Q1, Q3) 5.0) 3.5) 5.0) 80.50 PDQ_Communication, 0.0 (0.0, 0.0 (0.0, 0.0 (0.0, W = 0.6951Median (Q1, Q3) 1.0) 1.5) 1.0) 116.00 PDQ_Bodily Discomfort, 1.5 (0.0, 0.5 (0.0, 3.5 (0.0, W = 0.0641Median (Q1, Q3) 5.0) 2.0) 6.0) 65.00 UPDRS_Total, Median (Q1, 31 (21, 29 (19, 33 (23, W = 0.2351Q3) 44) 34) 66) 79.50 UPDRS_Motor, Median 8.0 (6.0, 8.0 (3.5, 8.0 (7.0, W = 0.4571(Q1, Q3) 12.0) 11.0) 13.0) 90.00 UPDRS_NonMotor, Median 7.0 (3.0, 4.0 (3.0, 9.0 (3.0, W = 0.2591(Q1, Q3) 12.0) 7.5) 14.0) 81.00 NMSS, Median (Q1, Q3) 17 (9, 16 (10, 24 (9, W = 0.5821

[0417] 32) 19) 40) 94.50 HAMD, Median (Q1, Q3) 5 (2, 9) 5 (2, 7) 6 (3, 10) W = 0.2411

[0418] 80.00 H& Y, Median (Q1, Q3) 2.0 (1.5, 2.3 (1.8 1.8 (1.5, W = 0.1871

[0419] 2.0) 2.5) 2.5) 139.00

[0420]

[0421] Group

[0422] Sham- Active- Overall P- Characteristic tPCS tPCS Statistic

[0423] N = 30 value N = 12 N = 18

[0424] S& E, Median (Q1, Q3) 90 (80, 90 (85, 90 (80, W = 0.7811

[0425] 90) 90) 90) 114.50

[0426] PFS, Median (Q1, Q3) 34 (28, 35 (29, 33 (28, W = 0.9831

[0427] 48) 41) 54) 109.00 TUGT, Median (Q1, Q3) 10.4 (9.4, 10.2 (9.1, 10.7 (9.6, W = 0.4913

[0428] 13.2) 12.5) 14.7) 91.00

[0429] 10M, Median (Q1, Q3) 8.3 (7.5, 8.4 (7.5, 8.1 (7.7, W = 0.6571

[0430] 9.3) 9.0) 10.0) 97.00

[0431] BBS, Median (Q1, Q3) 55.0 55.0 55.0 W = 0.8281

[0432] (52.0, (53.0, (51.0, 113.50

[0433] 56.0) 56.0) 56.0)

[0434] FGA, Median (Q1, Q3) 27.0 27.5 26.5 W = 0.4171

[0435] (21.0, (26.0, (20.0, 127.50

[0436] 29.0) 28.5) 29.0)

[0437] Abbreviations:

[0438] MMSE= Mini-Mental State Examination; SD= Standard Deviation; PDQ_SI= Parkinson’s Disease Questionnaire Summary Index; UPDRS = Unified Parkinson’s Disease Rating Scale; NMSS = Non-Motor Symptoms Scale; HAMD = Hamilton Depression Rating Scale; H& Y = Hoehn and Yahr Scale; S& E = Schwab and England Activities of Daily Living Scale; PFS = Parkinson’s Fatigue Scale; TUGT =Timed Up and Go Test, 10M- 10M walk test; BBS = Berg Balance Scale; FGA = Functional Gait Assessment

[0439] P-values were obtained using:1Wilcoxon rank sum test,2Fisher's exact test,3Wilcoxon rank sum exact test

[0440]

[0441] Table 16 presents post-treatment analyses of the results using a rank-based ANCOVA model between the sham group and active group. The results in Table 16 demonstrate significant between-group differences in health-related quality oflife, as assessed by the Parkinson’s Disease Questionnaire-39. Post-treatment, the sham group had a median PDQ SI score of 11.5 (Median IQR: 8.0-14.8), representing a 2.5-point reduction from baseline. In contrast, the active-tPCS group showed a post-treatment median PDQ SI of 6.5 (Median IQR: 2.3-15.0), corresponding to a 14.5-point reduction from baseline. Between-group comparisons were conducted using a rank-based ANCOVA model controlling for baseline PDQ SI. The active-tPCS group demonstrated significantly greater improvement in PDQ SI compared with the sham group (adjusted mean rank difference = -5.8; 95% Cl: -10.5 to -1.1; F = 6.51; p = 0.017; partial η² = 0.19), corresponding to a large effect size. None of the eight PDQ subdomains showed statistically significant between-group differences.

[0442] Significant between-group differences were also observed for the secondary outcomes, in particular, non-motor symptom burden. At post-treatment, the sham group had a median UPDRS Total score of 20.5 (IQR 15.0-28.8), representing an 8.5-point reduction from baseline. The active-tPCS group also had a posttreatment median of 20.5 (IQR 13.5-37.3), but demonstrated a larger median reduction of 12.5 points. Rank-based ANCOVA controlling for baseline showed significantly greater overall improvement in the active-tPCS group compared with the sham group (adjusted mean rank difference = -4.0; 95% Cl -7.2 to -0.9; F = 6.77; p = 0.015; partial η² = 0.20). This effect was primarily driven by changes in non-motor symptoms. Specifically, the sham group showed no meaningful change in UPDRS Non-motor score (median 4.0, IQR 3.8-6.0), whereas the active-tPCS group improved to a median of 3.0 (IQR 1.3-6.8), corresponding to a 6-point reduction from baseline. Between-group rank-based ANCOVA confirmed significantly greater improvement in the UPDRS Non-motor score in the active-tPCS group (adjusted mean rank difference = -5.7; 95% Cl -10.5 to -0.9; F = 5.96; p = 0.022; partial η² = 0.18).The NMSS, an independent measure of non-motor symptom severity, also corroborated this non-motor benefit. The sham group showed no change (median 16.0, IQR 6.8-18.3), whereas the active-tPCS group improved to 12.5 (IQR 2.5-16.0), representing an 11.5-point reduction from baseline. Rank-based ANCOVA again demonstrated significantly greater improvement with active tPCS (adjusted mean rank difference = -5.8; 95% Cl -9.8 to -1.9; F = 9.01; p = 0.006; partial η² = 0.25), consistent with a large effect. No other secondary outcomes showed significant between-group differences at post-treatment.

[0443] This large effect sizes seen in the PQD SI, NMSS and UPDRS-Non-motor scores are clinically meaningful and indicates that the observed improvement in quality of life was supported by a beneficial treatment effect of tPCS on non-motor symptoms in Parkinson’s disease.

[0444] Table 16. Post-treatment RANK ANCOVA between groups

[0445] Outcom Adjusted Effec Adjusted Mean F P e Mean Rank t Median (IQR) Rank1Stati valu measur Diff Btw Grp Size (Meant SE) Stic e1e (95% Cl)

[0446] Sham Active- Sham Active- tPCS tPCS

[0447] 6.5

[0448] 11.50 19.0±1. 13.2±1. -5.8 (-10.5,- 0.01 PDQ SI (2.3- 6.51 0.19

[0449] (8.0-14.8) 8 4 1.1) 7*

[0450] 15.0)

[0451] PDQ_ 2.5 1.0 17.1±2. 14.5±1. -2.6 (-7.8, 0.32

[0452] 1.03 0.04 Mobility (0.0-5.5) (0.0-3.8) 0 6 2.7) 0 PDQ_

[0453] Activitie

[0454] 0.5 0.0 16.1±2. 15.1±1. -1.1 (-7.0, 0.71 s of 0.14 0.01

[0455] (0.0-3.3) (0.0-1.8) 3 8 4.9) 5 Daily

[0456] Living

[0457] PDQ_ 2.0 0.5 17.4±2. 14.3±1. -3.1 (-9.0, 0.29

[0458] 1.17 0.04

[0459]

[0460] Emotion (0.0-2.0) (0.0-2.0) 2 8 2.8) 0al Wellbeing

[0461] PDQ_ 0.0 0.0 16.1±1. 15.1±0. -1.0 (-3.9, 0.46

[0462] 0.54 0.02 Stigma (0.0-0.0) (0.0-0.0) 1 9 1.9)

[0463] PDQ_

[0464] 0.0 0.0 15.5±0. 15.5±0.

[0465] Social 0.0 (-0.0, 0.0) N / A N / A N / A (0.0-0.0) (0.0-0.0) 0 0

[0466] Support

[0467] PDQ_

[0468] 3.0 1.5 17.3±2. 14.3±1. -3.0 (-9.2, 0.32 Cognitio 1.00 0.04

[0469] (0.0-3.3) (0.0-3.8) 3 9 3.2) 8 n

[0470] PDQ_

[0471] 0.0 0.0 17.5±1. 14.2±1. -3.3 (-7.9, 0.15 Comma 2.17 0.07

[0472] (0.0-1.0) (0.0-0.0) 7 4 1.3) 3 nication

[0473] PDQ_

[0474] Bodily 1.0 1.0 16.2±2. 15.1±1. -1.1 (-7.6, 0.72

[0475] 0.13 0.01 Discomf (0.0-2.3) (0.0-4.8) 4 9 5.4) 6 ort

[0476] 20.5

[0477] UPDRS 20.5 17.9±1. 13.9±1. -4.0 (-7.2, - 0.01

[0478] (13.5- 6.77 0.20 _Total (15.0-28.8) 2 0 0.9) 5*

[0479] 37.3)

[0480] UPDRS 8.0 6.0 17.6±1. 14.1±1. -3.5 (-8.2, 0.14

[0481] 2.32 0.08 _Motor (4.0-11.0) (3.3-11.0) 8 4 1.2) 0 UPDRS

[0482] 4.0 3.0 18.9±1. 13.2±1. -5.7 (-10.5, - 0.02 _NonMo 5.96 0.18

[0483] (3.8-6.0) (1.3-6.8) 8 5 0.9) 2* tor

[0484] 16.0 12.5 19.0±1. 13.2±1. -5.8 (-9.8, - 0.00 NMSS 9.01 0.25

[0485] (6.8-18.3) (2.5-16.0) 5 2 1.9) 6*

[0486] 3.5 4.5 15.1±2. 15.8±1. 0.79 HAMD 0.7 (-5.1, 6.6) 0.07 0.00

[0487] (2.0-5.3) (2.0-6.8) 2 8 8 2.0 1.5 15.4±1. 15.6±1. 0.91 0.00 H& Y 0.2 (-3.5, 4.0) 0.01

[0488] (1.0-2.5) (1.0-2.0) 4 1 0 90.0 90.0

[0489] 14.8±1. 16.0±1. 0.64 S& E (80.0- (90.0- 1.2 (-4.0, 6.3) 0.21 0.01

[0490] 9 6 9 100.0) 90.0)

[0491] 33.5

[0492] 39.0 17.3±2. 14.3±1. -3.0 (-8.5, 0.26 PFS (30.3- 1.32 0.05

[0493] (27.8-49.5) 1 7 2.4) 1

[0494] 37.0)

[0495] 9.1 9.7 15.5±1. 15.5±1. 0.97 TUGT 0.2 (-4.5, 4.6) 0.00 0.00

[0496]

[0497] (8.6-10.5) (8.6-13.8) 7 4 88.0 8.2 16.1±1. 15.1±1. -1.0 (-5.9, 0.67 10M 0.18 0.01

[0498] (7.5-8.8) (7.6-10.5) 9 5 3.9) 9

[0499] 55.5

[0500] 55.0 14.5±1. 16.2±1. 0.51 BBS (52.5- 1.6 (-3.5, 6.7) 0.43 0.02

[0501] (54.0-56.0) 9 6 8

[0502] 56.0)

[0503] 27.5

[0504] 27.5 14.1±2. 16.4±1. 0.41 FGA (26.0- 2.3 (-3.4, 7.9) 0.67 0.02

[0505] (25.8-29.3) 1 7 9

[0506] 29.0)

[0507] Abbreviations:

[0508] SE= Standard Error; Cl= Confidence Interval; PDQ_SI= Parkinson’s Disease Questionnaire Summation Index; UPDRS = Unified Parkinson’s Disease Rating Scale; NMSS = Non-Motor Symptoms Scale; HAMD = Hamilton Depression Rating Scale; H& Y = Hoehn and Yahr Scale; S& E = Schwab and England Activities of Daily Living Scale; PFS = Parkinson’s Fatigue Scale; TUGT =Timed Up and Go Test, 10M= 10M walk test; BBS =Berg Balance Scale; FGA- =Functional Gait Assessment

[0509] P-values were obtained using:1RankANCOVA, Holm-Bonferroni correction was applied for the 8 PDQ subdomains

[0510] Holm-Bonferroni correction was applied across the eight PDQ subdomains, the PDQ_SI was analyzed separately without adjustment, as it represents a composite summary measure. Statistical analysis for the “PDQ_Social Support” subscale could not be performed due to zero variance, as all subjects in both groups scored zero, outcome indicated as “Not Application (N. A)”.

[0511] Effect sizes represent partial η². Partial η² effect size:

[0512] • Small effect = ~0.01

[0513] • Medium effect =~0.06

[0514] • Large effect = 0.14

[0515]

[0516] Table 17 presents within-group changes in the sham-tPCS group. Table 18 presents within-group changes in the active tPCS group.

[0517] Within-group pre-post analyses in the active-tPCS group demonstrated significant improvements across several clinical outcomes. The PDQ SI decreased significantly from a baseline to a post-treatment (median A = 14.0; Z = 3.30; p = 0.001), indicating a significant improvement in health-related qualityof life (HRQoL). At the PDQ subdomain level, significant improvements were observed in PDQ emotional well-being scores (median A = 2.0; Z = 2.71; p = 0.007) and the PDQ cognition scores (median A = 1.50; Z = 2.79; p = 0.005). Significant improvements were also observed in the NMSS (median A = 11.5; Z = 3.21; p = 0.001), UPDRS Non-Motor scores (median A = 6.0, Z = 3.24; p = 0.001), UPDRS total score (median A = 12.5; Z = 3.38; p = 0.001), indicating reduced overall disease severity, HAMD scores indicating reduced depressive symptoms (median A = 1.0, Z = 2.14; p = 0.032) and the TUGT scores (median A = 1.0; Z = 2.07; p = 0.038) reflecting improved functional mobility.

[0518] In contrast, within-group pre-post analyses in the sham-tPCS group did not demonstrate statistically significant changes from baseline to post-treatment across all the assessed outcomes. Although a statistically significant change was observed in the UPDRS total score (p = 0.001), this finding should be interpreted with caution, as neither the UPDRS motor nor UPDRS non-motor subscale scores showed significant pre-post differences. The apparent significance of the total score may reflect a potential aggregation phenomenon, whereby statistical significance in the composite measure may occur despite the absence of detectable changes within individual domains.

[0519] These findings indicate moderate to large effect sizes, reflecting clinically meaningful improvements in quality of life, non-motor symptom burden, mood, functional mobility, and overall disease impact following active tPCS.

[0520] In summary, active tPCS was associated with clinically meaningful and statistically robust improvements in health-related quality of life and non-motor symptom burden in individuals with Parkinson’s disease. Between-group rankbased analyses demonstrate significant advantages of active tPCS over sham stimulation, with consistent moderate effect sizes observed across key non-motor outcomes. The pattern of results was further supported by broad within-group improvements exclusively observed in the active tPCS group, spanning patient-reported outcomes, clinician-rated non-motor symptoms, mood, and functional mobility.

[0521] Table 17. Within-Group Pre-Post Outcomes, Sham-tPCS Group (N=12)

[0522] Outcome Baseline Post-treatment Median A Z-value P- Measure Median (IQR) Median (IQR) (T1-T0) value1

[0523] 13.5 (10.3- PDQ_SI 11.50 (8.0-14.8) 2.0 1.47 0.151

[0524] 23.8)

[0525] PDQ_Mobility 2.5 (0.8-8.3) 2.5 (0.0-5.5) 0.0 0.42 0.719 PDQ_Activities

[0526] 1.5 (0.0-3.8) 0.5 (0.0-3.3) 1.0 0.26 0.859 of Daily Living

[0527] PDQ_Emotional

[0528] 1.5 (0.0-4.0) 2.0 (0.0-2.0) -0.5 0.92 0.414 Well-being

[0529] PDQ_Stigma

[0530] 0.0 (0.0-1.0) 0.0 (0.0-0.0) 0.0 1.34 0.500 PDQ_Social

[0531] Support 0.0 (0.0-0.0) 0.0 (0.0-0.0) 0.0 0.00 1.000 PDQ_Cognition 2.0 (0.0-3.3) 3.0 (0.0-3.3) -1.0 0.24 0.875 PDQ_Communi

[0532] cation 0.0 (0.0-1.3) 0.0 (0.0-1.0) 0.0 1.23 0.250 PDQ_Bodily

[0533] Discomfort 0.5 (0.0-2.0) 1.0 (0.0-2.3) -0.5 -0.34 0.781

[0534] 29.0 (19.8- UPDRS_Total 20.5 (15.0-28.8) 8.5 2.94 0.0012

[0535] 34.0)

[0536] UPDRS_Motor 8.0 (3.8-10.5) 8.0 (4.0-11.0) 0.0 0.10 0.936 UPDRS_NonMo

[0537] 4.0 (3.0-7.3) 4.0 (3.8-6.0) 0.0 0.97 0.354 tor

[0538] 15.5 (10.3- NMSS 16.0 (6.8-18.3) -0.5 1.02 0.334

[0539] 19.0)

[0540] HAMD 5.0 (1.8-7.0) 3.5 (2.0-5.3) 1.5 1.13 0.289 MH& Y 2.3 (1.9-2.5) 2.0 (1.0-2.5) 0.3 2.07 0.063

[0541] 90.0 (87.5- 90.0 (80.0- S& E 0.0 0.96 0.344

[0542] 90.0) 100.0)

[0543] 35.0 (30.5- PFS 39.0 (27.8-49.5) -4.0 -0.85 0.424

[0544]

[0545] 40.5)TUGT 10.2 (9.2-12.1) 9.1 (8.6-10.5) 1.1 1.88 0.062 10M 8.4 (7.5-9.0) 8.0 (7.5-8.8) 0.4 -0.16 0.910

[0546] 55.0 (53.5- Berg Balance 55.0 (54.0-56.0) 0.0 0.14 0.977

[0547] 56.0)

[0548] 27.5 (26.0- FGA 27.5 (25.8-29.3) 0.0 0.05 0.977

[0549] 28.3)

[0550] Abbreviations:

[0551] MMSE= Mini-Mental State Examination; SD= Standard Deviation; PDQ= Parkinson’s Disease Questionnaire; UPDRS = Unified Parkinson’s Disease Rating Scale; NMSS = Non-Motor Symptoms Scale; HAMD = Hamilton Depression Rating Scale; H& Y = Hoehn and Yahr Scale; S& E = Schwab and England Activities of Daily Living Scale; PFS = Parkinson’s Fatigue Scale; TUGT= Timed Up and Go Test, 10M= 10M walk test; BBS= Berg Balance Scale; FGA= Functional Gait Assessment

[0552] 1P-values were obtained using Wilcoxon rank sum test due to small dataset and non-normal distribution

[0553] * p<0.05 ** p<0.01

[0554] 2The discrepancy between the significant UPDRS total score and the non-significant subscale of UPDRS_Motor and UPDRS_NonMotor analyses suggests a potential aggregation phenomenon.

[0555] When correlated subcomponents are combined, variance may be reduced relative to the cumulative signal, increasing the likelihood of statistical significance. However, the absence of significance within individual domains raises questions regarding the clinical specificity of the observed total score effect.

[0556]

[0557] Table 18. Within-Group Pre - Post Outcomes, Active-tPCS Group (N=18)

[0558] Outcome Baseline PostMedian Z- P- Measure Median (IQR) treatment Change value value1

[0559] Median (IQR) (T1-T0)

[0560] PDQ_SI 20.5 (8.8-30.8) 6.5 (2.3 -15.0) 14.0 3.30 0.001** PDQ_Mobility 5.5 (0.5-9.8) 1.0 (0.0-3.8) 4.5 2.42 0.016* PDQ_Activities of

[0561] 1.5 (0.3-3.0) 0.0 (0.0-1.8) 1.5 1.42 0.156 Daily Living

[0562] PDQ_Emotional

[0563] 2.5 (0.3-7.0) 0.5 (0.0-2.0) 2.0 2.71 0.007**

[0564]

[0565] Well-beingPDQ_Stigma

[0566] 0.0 (0.0-0.0) 0.0 (0.0-0.0) 0.0 1.60 0.109 PDQ_Social

[0567] Support 0.0 (0.0-0.0) 0.0 (0.0-0.0) 0.0 1.34 0.180

[0568] PDQ_Cognition 3.0 (2.0-5.0) 1.5 (0.0-3.8) 1.5 2.79 0.005** PDQ_Communicati

[0569] on 0.0 (0.0-0.8) 0.0 (0.0-0.0) 0.0 1.51 0.131

[0570] PDQ_Bodily

[0571] Discomfort 3.5 (0.3-6.0) 1.0 (0.0-4.8) 2.5 1.86 0.063

[0572] 33.0 (23.8- 20.5 (13.5- UPDRS_Total 12.5 3.38 0.001**

[0573] 63.8) 37.3)

[0574] UPDRS_Motor 8.0 (7.0-12.5) 6.0 (3.3-11.0) 2.0 1.88 0.061 UPDRS_NonMoto

[0575] 9.0 (3.0-13.5) 3.0 (1.3-6.8) 6.0 3.24 0.001** r

[0576] NMSS 24.0 (9.3-38.0) 12.5 (2.5-16.0) 11.5 3.21 0.001** HAMD 5.5 (3.0-9.8) 4.5 (2.0-6.8) 1.0 2.14 0.032* MH& Y 1.75 (1.5-2.4) 1.5 (1.0-2.0) 0.25 2.07 0.038*

[0577] 90.0 (80.0- 90.0 (90.0- S& E 0.0 -1.54 0.124

[0578] 90.0) 90.0)

[0579] 32.5 (28.5- 33.5 (30.3- PFS -1.0 0.79 0.433

[0580] 52.5) 37.0)

[0581] TUGT 10.7 (9.7-14.2) 9.7 (8.6-13.8) 1.0 2.07 0.038* 10M 8.1 (7.7-9.8) 8.2 (7.6-10.5) -0.1 1.20 0.246

[0582] 55.0 (51.5- 55.5 (52.5- Berg Balance -0.5 -1.53 0.126

[0583] 56.0) 56.0)

[0584] 26.5 (20.3- 27.5 (26.0- FGA -1.0 -1.77 0.077

[0585] 29.0) 29.0)

[0586] Abbreviations:

[0587] MMSE= Mini-Mental State Examination; SD= Standard Deviation; PDQ= Parkinson’s Disease Questionnaire; UPDRS = Unified Parkinson’s Disease Rating Scale; NMSS = Non-Motor Symptoms Scale; HAMD = Hamilton Depression Rating Scale; H& Y = Hoehn and Yahr Scale; S& E - Schwab and England Activities of Daily Living Scale; PFS = Parkinson’s Fatigue Scale; TUGT= Timed Up and Go Test, 10M= 10M walk test; BBS= Berg Balance Scale; FGA= Functional Gait Assessment

[0588]

[0589] P-values were obtained using:1Wilcoxon rank sum test due to small dataset and non-normal distribution.

[0590] * p<0.05 ** p<0.01

[0591] Holm-Bonferroni correction was applied across the eight PDQ subdomains, the PDQ_SI was analyzed separately without adjustment, as it represents a composite summary measure. After correction, improvements remained significant in the Cognition (p = 0.005) and Emotional well-being (p = 0.007) domains, Mobility

[0592]

[0593] (p=0.016) was no longer significant.

[0594] Various advantages of the present invention can be appreciated from the foregoing description. Generally, with the stimulus generator 102 being configured to generate tPCS signal with the special combination of parameters described above (high frequency (100Hz to 500Hz), narrow pulse width (50µs-800µs) and high peak current value (8mA to 60mA), the pulsed current stimulator 100 is advantageous in delivering high-frequency, temporally discrete pulse trains with elevated peak currents to induce targeted cortical electric fields, enabling modulation of axonal conduction and alteration of neuronal firing probability in a cell-type-dependent manner, thereby achieving more precise neuromodulation than the diffuse, subthreshold effects of tDCS and tACS.

[0595] On the one hand, the frequency and peak current values ensure the tPCS to be good enough to pass through the layers to reach the cortex more effectively. Specifically, as described above, tPCS is specially configured to have a narrow pulse width (50µs to 800µs) in combination of the high frequency of 100Hz to 500 Hz, which produces higher instantaneous fields due to a rapid rise in current amplitude within microseconds. Such tPCS characteristics enable enhanced penetration of the scalp, skull, cerebrospinal fluid, and meninges, and enables the signal to reach the cerebral cortex with sufficient magnitude to achieve effective modulation of neurons and other brain cells. It has been found that tPCS delivered at high frequency of 100Hz to 500Hz may allow more cell-specific modulation by influencing axonal conduction, synaptic integration, and spike timing in selected neuronal populations. For example,inhibitory Purkinje cells in the cerebellar cortex possess intrinsic membrane properties and synaptic filtering that allow them to reliably follow high-frequency inputs up to few hundred hertz, high-frequency tPCS preferentially modulates their firing and thereby strengthen inhibitory control over downstream cerebellar and brainstem targets. This approach may be particularly advantageous in brain disorders characterized by impaired inhibitory signalling, especially conditions with cerebellar dysfunction such as ASD, ADHD, dystonia, chronic insomnia and selected neurodegenerative diseases, including Parkinson’s disease, cerebellar ataxia, MSA-C, mild cognitive impairment and Alzheimer’s disease.

[0596] The advantages of the present invention may be further appreciated when compared to the conventional solutions. For example, when a signal is configured to have a low frequency of 10Hz (instead of 100Hz) with a 5% duty cycle generating a pulse width of 5000μs, at an average current of 2mA per second, this would mean a peak current amplitude of 40mA. The general understanding is that exposing brain tissue to a peak amplitude of 40mA for such a lengthy period of 5000μs is considered potentially unsafe and intolerable for users. As a similar example, with a low frequency pulsed current of 10Hz plus a duty cycle more than 8% and above 800μs, a burst of power would be created and safety would be compromised as the brain tissue is exposed to a burst that would be too long. Fig. 9 illustrates an example of a transcranial direct current stimulation (tDCS) signal that conventional solutions may use for stimulating cortex. The tDCS signal is a continuous, non-fluctuating electrical current. The constant current value is 0.6mA. Thus, it has an average current intensity of 0.6mA, and a peak current amplitude of 0.6mA which is unlikely to achieve penetration that is sufficiently deep for realizing the abovementioned enhanced treatment effectiveness of tPCS. Fig. 10 illustrates an example of a transcranial alternating current stimulation (tACS) signal that conventional solution uses for stimulating cortex. The tACS signal is a continuous, sinusoidal current waveform with a frequency component that is typically below 80Hz and without a duty cycle. The tACS waveform is therefore without any burst of power and has a peak currentamplitude of 0.6mA. With tACS, the treatment may not be effective given that the entire duration of the current is unlikely to be strong enough to penetrate the scalp and skull resistance to affect the brain tissues including neurons. For any of the examples, if it is needed to increase current amplitude for better penetration, given their continuous output, the average current intensity would exceed the safety limitation (e.g. an average current intensity of 2mA - 4mA per second). In contrast, the tPCS of the present invention penetrates the biological tissue at low risks to the user. The pulsed current stimulator 100 can achieve the abovementioned enhanced penetration without increasing the average current delivered to the user beyond safety limits, and as shown by the experimental data, the parameters of the tPCS used are safe and tolerable to the users.

[0597] It can be appreciated from the above that, when the demonstrated conventional tES (tDCS and tACS) and tPCS have the electrical stimulus applied to users at the same average current intensity, tPCS has a much higher peak current amplitude. It is envisaged that, with other conditions remaining the same, a higher peak current amplitude can be achieved when the pulse width is shortened (e.g. by introducing a frequency waveform and a duty cycle). For example, if the frequency is adjusted to 100Hz, pulse width is adjusted to 200μs, duty cycle is adjusted to 2%, but the total current is maintained at 0.6mA per second then the peak current amplitude of the pulse may be as high as 30mA. With the special configuration of the stimulus generator 102 in generating the tPCS, penetration by the stimulus signal in the user’s brain would be enhanced due to higher peak current but without posing additional safety risk given the average current is maintained in the safety range of 2mA to 4mA.

[0598] Nonetheless, greater current reaching the cortex does not automatically translate into greater neuromodulatory efficacy. Surprisingly, results have shown that the tPCS with a high frequency, a short duty cycle, narrow pulse width is able to modulate Inhibitory neurons (l-NEURONS) such as cerebellar Purkinje cells more efficiently / intensely during stimulation compared to conventional transcranialelectrical stimulation. By modulating more l-NEURONS, the tPCS helps to improve the reorganization of excitation-inhibition networks and enhance the efficacy of treating or improving symptoms and disabilities of certain neurological, psychiatric, neuropsychiatric and / or medical conditions, especially those in which inhibitory signalling is impaired.

[0599] By shaping the pulse train (duty cycle, burst length, and amplitude), the induced electric fields can be tuned to preferentially drive cerebellar Purkinje cells, increasing their firing rates and thereby boosting cerebellar inhibitory output. In contrast, the same high-frequency pulses produce only brief, subthreshold membrane depolarizations in cortical pyramidal neurons, whose relatively long membrane time constants are less likely to track high-frequency stimulation in the same way as Purkinje cells, curbing excessive excitatory activity. This present invention can bias local microcircuits toward stronger inhibition and reduce network hyperexcitability while retaining a relatively focal, cell-type-biased effect.

[0600] As an example, Figure. 11(a) illustrates an image of the cerebellum and nearby brain regions and how the induced electric field spreads through them when tPCS is applied bilaterally over the cerebellar hemispheres with the following parameters: 400 Hz frequency, 5.6% duty cycle, 140 μs pulse width, 0.6 mA average current, and 10.7 mA peak current. The induced electric field is the main factor that can change Purkinje cell firing rate and pyramidal neuron polarization. Fig. 11(b) illustrates the simulation to estimate the effect of how Purkinje cells respond to trains of tPCS pulses, by using a detailed biophysical Purkinje cell model, for example, the model may come from ModelDB (e.g. model #229585), which may be adapted with NEURON’S extracellular mechanism so it could be driven by a pulsed extracellular potential. For field strengths similar to the strongest tPCS-induced fields by current density at pulse peak in the cerebellum under the stimulation parameters, the model shows that these stimulation parameters can alter the cells’ spontaneous firing, with changes of up to about±5 Hz from the baseline firing rate of 69 Hz, depending on the strength and orientation of the applied field.

[0601] More surprisingly, tPCS selectively enhances the activity of inhibitory interneurons while simultaneously suppressing the activity of excitatory neuronal populations. Such dual effect, i.e. strengthening inhibitory signalling and dampening excessive excitatory drive, is especially beneficial in neurological and neuropsychiatric disorders characterized by reduced inhibitory signalling and disrupted excitation-inhibition balance.

[0602] In summary, a combination of high frequency, short duty cycle, and narrow pulse width as described above yields a stimulation regime that:

[0603] • enhances electric current penetration through scalp and skull compared to conventional techniques (e.g. continuous stimulation in transcranial electrical stimulation), and improves modulation of cortical and subcortical targets;

[0604] • enhances user safety compared with low-frequency stimulation techniques with an equivalent duty cycle;

[0605] • maintains user comfort and safety within accepted limits while achieving therapeutic effects via cell-specific targeting.

[0606] The results of the trials conducted thus far as provided and discussed above corroborate the advantageous of the pulsed current stimulator 100. For example, with the positive improvements for children with ASD, using 400 Hz tPCS, 140μs pulse width, 5.6% duty cycle, 0.7mA average current and 12.5 mA peak current, the anode electrode of over the right cerebellum and the cathode electrode over the left dorsolateral prefrontal cortex, may contribute to the positive results by modulating dysfunctional ASD-relevant prefrontal-cerebellar circuits involved in sociocommunicative and sleep functions, rebalancing excitatory-inhibitory balance in relevant brain networks in ASD, enhancing contralateral frontal-posterior connectivity and thereby improving social functioning and sleep, whichmay reveal a realization of efficient electrical current transmission to the cortex and an obtain of effective neuronal responsiveness.

[0607] This effect cannot be predicted by conventional transcranial electrical stimulation theory and represents a significant technical advancement in the field of non-invasive neuromodulation.

[0608] Further, by utilizing a digital encoder for precision control of variable pulse current output, the pulsed current stimulator 100 allows changes in current output without increasing voltage error commonly seen with mechanical potentiometers and enhances current output stability which significantly reduces potential harms to the human body.

[0609] Fig. 12 illustrates a block diagram of a pulsed current stimulator according to a second embodiment of the present invention. The pulsed current stimulator according to the second embodiment is mostly the same as the pulsed current stimulator 100 according to the first embodiment described above. Thus, Fig. 12 adopts the same reference numerals for the same elements of the pulsed current stimulator 100 in Fig. 1. Only the difference between the two embodiments will be described below.

[0610] As illustrated in Fig. 12, the head harness 104 is further configured to comprise a second set of surface electrodes 122. The pulse module 114 of the stimulus generator 102 is further configured to generate transcutaneous pulsed current stimulation (tcPCS) and supply the tcPCS to the second set of surface electrodes 122. The second set of surface electrodes 122 is attachable to the user’s postcranial body for peripheral stimulation, including stimulating the user’s Vagus nerve. The pulse module 114 is configured to generate tcPCS with a frequency in a range of 100Hz to 500Hz, a pulse width in a range of 50μs-800μs and a peak current value in a range of 10mA to 200mA. Due to the combination of signals being generated, the pulsed current stimulator 100 may be called a combinedtranscranial and transcutaneous pulsed current stimulator. Also, in view of the ‘high frequency’ being used in the context of this invention, just like the first embodiment, the stimulator may also be referred to as a combined high frequency (hf) transcranial pulsed current, and transcutaneous pulsed current (hf-tPCS + tcPCS) stimulator.

[0611] Fig. 13 illustrates some locations for attaching the second set of surface electrodes 122, which are around spine area. Locations 1302 are where the second set of surface electrodes 122 may be attached to the user. Locations 1304 are other possible locations where the second set of surface electrodes 122 may be attached to the user. Attaching the second set of surface electrodes 122 around spine area allows realisation of spinal cord stimulation and stimulation of the Vagus nerve or of other extracranial neural systems structures.

[0612] More specifically, the second set of surface electrodes 122 may be attached near the user’s spinal cord, or via the peripheral nervous system of the user’s body. More generally, the second set of the surface electrodes 122 may be attached to the user’s postcranial body for peripheral stimulation i.e. the rest of the body that is caudal to the user’s head. The extra-cranial (peripheral) stimulation may include stimulation of the spinal cord, nerve roots, peripheral nerves or extracranial portions of the Vagus nerve or any cranial nerve. As an example, the second set of surface electrodes 122 is strategically attached to the user’s spine area and, when the pulsed current stimulator is operational or in use, the second set of surface electrodes 122 is configured to stimulate an extracranial portion of the Vagus nerve.

[0613] The second set of surface electrodes 122 may also be suitably and selectively attached to other strategic locations of the user’s body that are able to provide peripheral stimulation in a non-invasive manner, such as limbs, chest or stomach. It is also envisaged that more surface electrodes may be provided by the pulsed current stimulator 100 so that the surface electrodes may be attached to differentparts of the body to provide peripheral stimulation such as the stimulation of the spinal cord, the nerve roots, the peripheral nerves or extracranial portions of any cranial nerve. For example, the head harness 104 may comprise a third set of surface electrodes in addition to the first set of surface electrodes 120 and second set of surface electrodes 12, the third set of surface electrodes may be attached to the user’s stomach or lower limb in addition or as an alternative to the second set of surface electrodes 122 that is attached to the spine area.

[0614] Fig. 14 illustrates a flowchart of a pulsed current stimulating method based on the pulsed current stimulator 100 of Fig. 12, for alleviating or improving a neurological, psychiatric, neuropsychiatric, and / or medical condition. The method comprises step 1402 of attaching the first set of surface electrodes 120 of the head harness 104 to a user’s scalp for brain stimulation and the second set of surface electrodes 122 of the head harness 104 to the user’s postcranial body for peripheral stimulation, and step 1404 of generating tPCS and tcPCS using the stimulus generator 102 and providing the tPCS to the first set of surface electrodes 120 and tcPCS to the second set of surface electrodes 122.

[0615] In the second embodiment, frequency and duty cycle of the pulsed current (similar to the tPCS of the first embodiment) generated for the second set of surface electrodes 122 is the same as the corresponding parameters of the pulsed current generated for the first set of surface electrodes 120 i.e. similar to the tPCS signal discussed in the first embodiment above. A difference is the maximum or cap average current amplitude and / or peak current value of the pulsed current generated for the first set of surface electrodes 120 and the second set of surface electrodes 122.

[0616] Just like the tPCS signal of the first embodiment, the pulsed current generated for the first set of surface electrodes 120 (for stimulating the brain) in this embodiment has an average current of about 0.5mA to 0.6mA per second (and not exceeding the maximum of an average current of about 2mA to 4mA persecond), with a peak current value that will be further discussed below. In contrast, the pulsed current generated for the second set of surface electrodes 122 for stimulating the Vagus nerve has an average current of about 1mA per second and not exceeding an average current of about 10mA per second (although tcPCS waveform is similar to the tPCS waveform, e.g. the waveform illustrated in Fig. 2 of the first embodiment), with a peak current value that will be further discussed below.

[0617] In some examples, the average tcPCS current value may be in the range of 1 mA to 10mA, it may also be in the ranges of 1 mA to 9mA, 1 mA to 8mA, 1 mA to 7mA, 1 mA to 6mA, 1 mA to 5mA, 1 mA to 4mA, 1 mA to 3mA, 1 mA to 2mA, 2mA to 10mA, 2mA to 9mA, 2mA to 8mA, 2mA to 7mA, 2mA to 6mA, 2mA to 5mA, 2mA to 4mA, 2mA to 3mA, 3mA to 10mA, 3mA to 9mA, 3mA to 8mA, 3mA to 7mA, 3mA to 6mA, 3mA to 5mA, 3mA to 4mA, 4mA to 10mA, 4mA to 9mA, 4mA to 8mA, 4mA to 7mA, 4mA to 6mA, 4mA to 5mA, 5mA to 10mA, 5mA to 9mA, 5mA to 8mA, 5mA to 7mA, 5mA to 6mA, 6mA to 10mA, 6mA to 9mA, 6mA to 8mA, 6mA to 7mA, 7mA to 10mA, 7mA to 9mA, 7mA to 8mA, 8mA to 10mA, 8mA to 9mA, 9mA to 10mA, or any specific and discrete current value within any of these ranges, such as 2 mA, 3mA, 9mA etc.

[0618] In some examples, the peak tcPCS current value may be in the range of 10mA to 200mA. For example, it may be in the ranges of peak current value of the tPCS described in the first embodiment, it may also be in the ranges of 60mA to 200mA, 61mA to 199mA, 62mA to 198mA, 63mA to 197mA, 64mA to 196mA, 65mA to 195mA, 66mA to 194mA, 67mA to 193mA, 68mA to 192mA, 69mA to 191mA, 70mA to 190mA, 71mA to 189mA, 72mA to 188mA, 73mA to 187mA, 74mA to 186mA, 75mA to 185mA, 76mA to 184mA, 77mA to 183mA, 78mA to 182mA, 79mA to 181mA, 80mA to 180mA, 81mA to 179mA, 82mA to 178mA, 83mA to 177mA, 84mA to 176mA, 85mA to 175mA, 86mA to 174mA, 87mA to 173mA, 88mA to 172mA, 89mA to 171mA, 90mA to 170mA, 91mA to 169mA, 92mA to 168mA, 93mA to 167mA, 94mA to 166mA, 95mA to 165mA, 96mA to 164mA,97mA to 163mA, 98mA to 162mA, 99mA to 161mA, 100mA to 160mA, 101mA to 159mA, 102mA to 158mA, 103mA to 157mA, 104mA to 156mA, 105mA to 155mA, 106mA to 154mA, 107mA to 153mA, 108mA to 152mA, 109mA to 151mA, 110mA to 150mA, 111mA to 149mA, 112mA to 148mA, 113mA to 147mA, 114mA to 146mA, 115mA to 145mA, 116mA to 144mA, 117mA to 143mA, 118mA to 142mA, 119mA to 141mA, 120mA to 140mA, 121mA to 139mA, 122mA to 138mA, 123mA to 137mA, 124mA to 136mA, 125mA to 135mA, 126mA to 134mA, 127mA to 133mA, 128mA to 132mA, 129mA to 131mA or any other range within the range of 10mA to 200mA, or any specific and discrete current value within any of these ranges, such as 25 mA, 43mA, 89mA, 155mA, 172mA, 199mA etc.

[0619] As a specific example for children with cerebral palsy, it is proposed to use a dosage of tPCS with a peak current value in the range of 10mA to 40mA, in combination with a dosage of tcPCS with a peak current in the range of 30mA to 70mA.

[0620] In another specific example for children with dystonia, it is envisaged that the stimulation parameters may be tPCS frequency of about 400Hz, pulse width of 140μs, an average current intensity in the range of about 0.80mA -1.5mA, with a peak current value in the range of 14mA - 27mA, in combination with a dosage of tcPCS with average current intensity in the range of about 2.5mA - 4mA per second and a peak current in the range of about 44mA - 72mA.

[0621] As another specific example for adults with stroke, it is recommended to use a dosage of tPCS with a frequency of about 100Hz, pulse width of about 500μs, tPCS and tcPCS having a monophasic rectangular pulse waveform, tPCS having an average current intensity of about 0.8mA per second and a peak current of about 16mA, in combination with a dosage of tcPCS with a peak current value in the range of 20mA to 100mA. More specifically, the recommended tPCS and tcPCS have a frequency of about 100Hz, a pulse width of about 500μs, and thetPCS has an average current intensity of about 0.8mA per second and a peak current of about 16mA, and the tcPCS has an average current intensity of about 3mA per second and a peak current of about 60mA.

[0622] As another specific example for adults with Multiple Systems Atrophy (MSA), it is recommended to use a dosage of tPCS and tcPCS with a frequency of about 400Hz, pulse width of about 140μs, tPCS and tcPCS having a monophasic rectangular pulse waveform, tPCS having an average current intensity of about 0.8mA per second and a peak current of about 14.3mA, and tcPCS having an average current intensity of about 4mA and a peak current amplitude of about 71.4mA.

[0623] As another specific example for patients with Multiple System Atrophy (MSA), it is proposed to configure the stimulus generator 102 to generate a dosage of tPCS with a frequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 0.8 mA per second, and a peak current of about 14.3mA. In addition, a concurrent dosage of tcPCS over the spinal cord cervical (C7) and lumbar (L5) vertebrae with a frequency of about 400Hz, a pulse width of about 140 µs, duty cycle of 5.6%, an average current intensity of about 4.0 mA per second, and a peak current of about 71.4mA. Both tPCS and tcPCS having a monophasic rectangular pulse waveform.

[0624] As further examples, for both children and adults, it is preferred to have a tcPCS dosage for each of the following areas at:

[0625] - spinal area: an average current value of about 3mA and a peak current value of about 60mA and a frequency of about 400Hz;

[0626] - stomach area: an average current value of about 2.5mA and a peak current value of about 50mA and a frequency of about 400Hz;

[0627] - upper limbs: an average current value of about 1.5mA and a peak current value of about 30mA and a frequency of about 400Hz;- lower limbs: an average current value of about 2mA and a peak current value of about 40mA and a frequency of about 400Hz.

[0628] To be used together with the recommended tcPCS dosage described above, the corresponding tPCS is proposed to have a dosage as follows:

[0629] - for children with ASD: an average current value of about 0.7mA, a peak current value of about 12.5mA, duty cycle of 5.6%, and a frequency of about 400Hz;

[0630] - for children with dystonia: an average current value of about 1 mA, a peak current value of about 17.9 mA, duty cycle of 5.6%, and a frequency of about 400Hz;

[0631] - for adults with Parkinson’s Disease: an average current value of about 1.0mA, a peak current value of about 17.9 mA, duty cycle of 5.6%, and a frequency of about 400Hz;

[0632] - for adults with stroke: an average current value of about 0.8mA, a peak current value of about 16mA, duty cycle of 5.0%, and a frequency of about 100Hz;

[0633] - for adults with Multiple Systems Atrophy (MSA): an average current value of about 0.8mA, a peak current value of about 14.3 mA, duty cycle of 5.6%, and a frequency of about 400Hz;

[0634] - for adults with mild cognitive impairment (MCI) and mild dementia: an average current value of about 0.6mA, a peak current value of about 12mA, duty cycle of 5.0% and a frequency of about 100Hz.

[0635] While the above recommended specific dosages or proposed ranges of dosages are described as being used preferably for the respective specific conditions / diseases, it is envisaged that such proposed ranges may serve as a guide so that the same or similar dosages (or combination of dosages) may be used or adapted accordingly for similar or other conditions / diseases, for example the conditions mentioned in the first embodiment above, or the conditions further mentioned below. Likewise, the recommended specific dosages described in the first embodiment may be used similarly.Surprisingly, it has been found that stimulating the brain using hf-tPCS in combination or concurrently with extracranial (peripheral) stimulation such as the extracranial portion of the Vagus nerve using high frequency transcutaneous pulsed current stimulation may boost effects of improving cognition, including complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition, of patients with one or more neuroimmunological diseases that lead to inflammation and demyelination and neuronal damage, such as

[0636] • Multiple Sclerosis

[0637] • Autoimmune Encephalitis

[0638] • Neuromyelitis Optica

[0639] • CNS vasculitis

[0640] • Cerebral small vessel disease

[0641] • Parkinson’s disease

[0642] • Mild cognitive impairment

[0643] • ASD

[0644] • ADHD

[0645] • Cerebral Palsy

[0646] • Dementia

[0647] • Alzheimer’s disease,

[0648] • Post-surgery cognitive loss

[0649] • Traumatic Brain Injury

[0650] • Stroke

[0651] • Spasticity

[0652] • Dystonia

[0653] • Lupus

[0654] Indeed, it is envisaged that the proposed solution in the second embodiment may also be useful to improve / treat / alleviate the medical / neurological / neuropsychiatric conditions as discussed in the first embodiment, including diseases that involve alterations of inflammatory cascades. It should likewise be appreciated that the solution proposed in the second embodiment may likewise be applicable to the medical conditions etc. described in the first embodiment; and similarly, the solution proposed in the first embodiment may be used to treat or improve any of the medical conditions etc., described in the second embodiment.

[0655] For example, in a specific experiment, surface electrodes positioned strategically at the following four separate locations has led to improvement in cognition of patients with small vessel diseases:

[0656] Head + spine + upper limb + lower limb

[0657] with the respective tPCS and tcPCS dosages as provided above.

[0658] Indeed, the surface electrodes to be attached to the body may be strategically placed at various or any location as long as the tcPCS signal delivered by the surface electrodes can provide peripheral stimulation of the postcranial body, while another set of surface electrodes stimulates the brain of the user using tPCS.

[0659] Various trials have been or is being conducted to verify the safety and efficacy of the present invention in alleviating or improving symptoms in relation to neurological, psychiatric, neuropsychiatric, and / or medical conditions. Generally, it has been found that the combination of using tPCS and tcPCS could be particular useful for improving / treating / alleviating at least one symptom of a condition as described above. Results of some trials will be discussed in detail as below.

[0660] Trial of the Pulsed Current Stimulator in Adults with Multiple Systems Atrophy (MSA)A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to Multiple Systems Atrophy (MSA). It was conducted as an open label study. 3 adults with MSA underwent 20 sessions, at 30 minutes per session of tPCS and tcPCS, over 4 weeks.

[0661] Fig. 15(a) and Fig. 15(b) illustrate electrode montage adopted in this trial. During the sessions for each adult with MSA, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the motor cortex (the location for EEG (64-channel): Cz) (see Fig. 15(a)), and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the right cerebellar hemisphere (2cm right lateral to inion) (see Fig.

[0662] 15(a)). The second set of surface electrodes comprises an anode electrode 1502 and a cathode electrode 1504. The anode electrode 1502 was attached to the adult’s postcranial body over the base of cervical vertebrae (location for transcutaneous pulsed current stimulation (tcPCS): C7), and the cathode electrode 1504 was attached to the adult’s postcranial body over lumbar vertebrae (location of transcutaneous pulsed current stimulation (tcPCS): L1) (see Fig. 15(b)).

[0663] The tPCS signal generated and supplied to the first set of surface electrodes 120 and the tcPCS signal generated and supplied to the second set of surface electrodes 122 both have the same frequency of about 400Hz, same pulse width of about 140μs (thus same duty cycle of 5.6%). The tPCS and tcPCS have a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 0.8mA per second while the peak current of each pulse is about 14.2 mA. The tcPCS signal generated and supplied to the second set of surface electrodes 122 has an average current intensity of about 4mA and a peak current amplitude of about 71.4 mA.

[0664] The outcome was processed using the following measures:- Scale for the Assessment and Rating of Ataxia (SARA)

[0665] - Purdue Peg Board Test

[0666] - Berg Balance Scale (BBS)

[0667] - Short formed 36 Version 2 (SF-36v2)

[0668] - Depression Anxiety Stress Scales (DASS)

[0669] - Timed Up and Go (TUG)

[0670] - Neuro-psychological assessments (including Mini-Mental State Examination (MMSE), Colour Trail, Stroop etc.)

[0671] - BOLD (fMRI)

[0672] Table 19 presents the treatment results of this trial evaluated using the various measures. Base line data T0 represents an average of results of the three participating adults before treatment, T1 represents an average of results of the three participating adults after one week’s treatment, T2 represents an average of results of the three participating adults after two weeks’ treatment, T3 represents an average of results of the three participating adults after three weeks’ treatment, T4 represents an average of results of the three participating adults after four weeks’ treatment. Treatment results demonstrate significantly improved motor scores, measured by the Scale for the Assessment and Rating of Ataxia (SARA) (p<0.05) and Berg balance scale (BBS) (p<0.05). No significant changes were observed in their fine motor assessment (Purdue Peg Board, P>0.05) and gait assessment (7m Timed Up and Go, p>0.05). Significant improvement in overall emotional state was observed as measured by DASS (p<0.05). While quality of life showed no significant changes (SF-36v2, p>0.05) and cognitive function remains relatively the same after treatment, improvement was observed in different areas, such as physical functioning, bodily pain, social functioning, role-emotional and mental health, and physical functioning.

[0673] The results demonstrate that a combination treatment of tPCS and tcPCS is safe and effective in improving mobility and balance in ataxia patients (with someeffects lasting up to 2 months after treatment), which also helps in improving patent’s mood and daily life.

[0674] Table 19. Post-treatment results (aggregated 3 patients)

[0675] Assessments

[0676] TO T1 T2 T3 T4 20.33 ± 13.67 ± 12.83 ± 13.17 ± 12.67 ± SARA (Total score) 2.08 1.53* 1.26* 1.44* 1.26* Purdue Pegboard

[0677] test (Sum of all 18.45 ± 17.11 ± 18.89 ± 19.11 ± 18.56 ± pins) 1.57 1.71 3.10 2.34 4.55 Berg balance Scale 33.33 ± 34.67 37.33 (Total score) 21 ± 2.65 7.23* ±4.93** 38 ± 2** ±1.53** Motor 45.39 ± 58.86 ± 66.69 ± 63.11 ± 93.75 ± TUG (Time taken) 12.88 30.52 34.48 37.50 86.53 51 ± 33 ± 34.33 ± 26.67 ± 23.33 ± DASS 27.62 31.76* 38.99 24.17* 20.40 SF-36v2 (Physical

[0678] Component 34.65 ± 36.31 ± 37.63 ± 38.86 ± Summary) 1.75 7.10 6.88 9.98 39 ± 7.96 SF-36v2 (Mental

[0679] NonComponent 39.55 ± 43.33 ± 38.24 ± 36.91 ± 43.05 ± Motor Summary) 16.92 17.02 13.04 12.97 14.73 27.67 ± 28.33 ± 28.33 ± 27.67 ± MMSE 2.08 0.58 29 ± 1 2.89 1.53

[0680] 1.05 ± 0.78 ± 1.04 ± 0.89 ± 0.81 ± Colour trail 0.43 0.28 0.33 0.59 0.64 Cogniti 3.23 ± 3.14 ± 2.82 ± 2.59 ± ve Stroop 1.25 0.78 0.37 2.7 ± 1.07 0.89 *P < 0.05 **P < 0.01

[0681]

[0682] Trial of the Pulsed Current Stimulator in Adults with Stroke

[0683] A trial study has been conducted to investigate safety and efficacy of using the pulsed current stimulator 100 in alleviating or improving symptoms in relation to stroke. Notably, for this trial, three sets of surface electrodes are used. It was conducted as a single-center, double-blinded, sham-controlled randomized clinical trial. 100 patients with Hemiplegic Stroke (Subacute to Chronic stage), aged 21 to 80 years old were recruited for this trial. Each patient would need to undergo 20 sessions, at 30 minutes per session, over 1 month. 6 out of the 100 patients have completed the trial so that the following discussion will be based onthe results of these 6 patients (3 in active group, 3 in sham group). In the active group, the patients were treated with tPCS signals applied to their scalp through the first set of surface electrodes 120 and tcPCS applied to their body through the second set of surface electrodes 122 and a third set of surface electrodes.

[0684] In the active group, there was a 10-second ramp-up to 0.8 mA at the beginning of each session, followed by treatment with tPCS signal throughout the session, which is in turn followed by a 5-second ramp down at the end. In the sham group, there was a 10-second ramp-up to 0.8 mA followed by a 5-second ramp down to 0mA, and 0mA was maintained for the remainder of the session.

[0685] Figs. 16(a), 16(b) and 16(c) illustrate electrode montages adopted in this trial. During the sessions for each adult with stroke, the anode electrode 402 of the first set of surface electrodes 120 was attached to the adult’s scalp over the ipsilesional M1, and the cathode electrode 404 of the first set of surface electrodes 120 was attached to the adult’s scalp over the contralesional M1, subject to the location of the lesion (see Fig. 16(a)). The second set of surface electrodes 122 comprises a second anode electrode 1602, a second cathode electrode 1604 (see Fig. 16(b)). The third set of surface electrodes comprises a third anode electrode 1606 and a third cathode electrode 1608 (see Fig. 16(c)). During the sessions for each adult with stroke, the second anode electrode 1602 is attached to the back of the patients over the spine L1, the second cathode electrode 1604 is attached on the back of the patients over the spine L5 (see Fig.

[0686] 16(b)); the third anode electrode 1606 is attached to the lower limb of the patients over adductor longus of paretic limb, the third cathode electrode 1608 is attached on the lower limb of the patients over adductor magnus of paretic limb (see Fig.

[0687] 16(c)).

[0688] The tPCS signal generated and supplied to the first set of surface electrodes 120 and the tcPCS signal generated and supplied to the second and third sets of surface electrodes have the same frequency of about 100Hz and same pulsewidth of about 500µs (same duty cycle of 5%). Both tPCS and tcPCS have a monophasic rectangular pulse waveform. The average current intensity of the tPCS signal is about 0.8mA per second while the peak current of each pulse is about 16mA. The average current intensity of the tcPCS signal is about 2mA per second while the peak current of each pulse is about 40mA.

[0689] The outcome of this trial was evaluated using the following measures:

[0690] Primary Objectives (lower limb motor function recovery)

[0691] • Gait Analysis as objective measurement.

[0692] • lower extremity portion of Fugl-Meyer Assessment (LE-FMA),

[0693] • Time Up and Go (TUG),

[0694] • 10-meter walk test (10MWT),

[0695] • 6-minute walk test and Berg Balance Scale (BBS).

[0696] • National Institutes of Health Stroke Scale (NIHSS)

[0697] • Modified Rankin Scale will be recorded

[0698] Secondary Objectives (lower limb spasticity, functional independence, pain, mood and QoL)

[0699] • Pain numeric rating scale (NRS),

[0700] • Hospital Anxiety Depression Scale (HADS).

[0701] • Functional Independence Score (FIM)

[0702] • EQ5D-5L

[0703] Table. 20 presents baseline demographics and clinical characteristics of the six participants who have completed this ongoing randomized controlled trial for stroke rehabilitation, including three participants in the sham-tPCS group and three in the active-tPCS group. Table 21 presents baseline and post-treatment outcomes for each group. As can be seen from the tables, baseline demographic and clinical characteristics were generally comparable between groups with respect to age, sex, disability level (modified Rankin Scale, mRS), and neurological deficit severity (NIHSS).Given the extremely small sample size, formal statistical comparisons between groups were not performed. At this stage, post-treatment data are available for non-motor outcomes, including pain, mood, functional independence, and health-related quality of life.

[0704] At post-treatment assessment, both groups demonstrated improvements across several clinical outcomes. For pain severity measured by the Numeric Rating Scale (NRS), the sham group showed a slight increase in pain scores (baseline: 1.00 ± 1.73; post-treatment: 2.33 ± 3.21), whereas the active-tPCS group demonstrated improvement (baseline: 4.33 ± 4.04; post-treatment: 1.33 ± 2.31). Similarly, greater reductions in depressive symptoms (HADS-Depression change: -5.66 vs -2.00) and anxiety symptoms (HADS-Anxiety change: -4.33 vs -1.00) were observed in the active-tPCS group compared with the sham group. A similar pattern was observed in the EQ-5D subdomains of pain and anxiety / depression, with larger improvements in the active-tPCS group.

[0705] Overall, at least based on the currently available limited results, larger reductions in pain and mood-related symptoms were observed in the active-tPCS group than sham group, which shows that the pulsed current stimulator 100 is helpful to patients with stroke.

[0706] Table 20. Baseline Demographics and Clinical Characteristics Characteristic Sham tPCS Active-tPCS

[0707] N = 3 N = 3

[0708] Sex, n (%)

[0709] male 2 (66.67%) 3 (100.00%) Age, Mean ± SD 61.3 ± 6.7 63.7 ± 9.6 Modified Ranking Scale, n(%)

[0710] Score: 3-5 ( functionally dependent) 3 (100%) 3 (100%) NIHSS, n(%)

[0711] Score: 1-4 ( minor stroke) 2 (66.67%) 1 (66.67%)

[0712]

[0713] Score: 5-15 ( moderate stroke) 1 (33.33%) 2 (33.33%)Table 21. Baseline and Post-treatment Outcomes

[0714] Outcome Measures Sham tPCS Sham tPCS Active tPCS Active tPCS (Baseline) (Post(Baseline) (Posttreatment) treatment) Pain NRS, n(%) 1.00 ± 1.73 2.33 ± 3.21 4.33 ± 4.04 1.33 ± 2.31 HADS Depression,

[0715] 10.33 ± 4.16 8.33 ± 11.02 7.33 ± 6.66 1.67 ± 1.15 n (% improve)

[0716] HADS Anxiety,

[0717] 3.67 ± 2.08 2.67 ± 2.52 4.33 ± 3.21 0.00 ± 0.00 n (% improve)

[0718] FIM, n (% improve) 66.00 ± 31.51 100.00 ± 4.58 66.67 ± 23.01 85.67 ± 26.63 EQ5D-5L

[0719] Mobility 4.33 ± 1.15 2.33 ± 0.58 4.67 ± 0.58 2.33 ± 0.58 Self-care 3.00 ± 2.00 1.33 ± 0.58 4.33 ± 1.15 2.00 ± 0.00 Usual activities 4.33 ± 1.15 3.33 ± 1.53 4.67 ± 0.58 3.00 ± 0.00 Pain / discomfort 1.67 ± 1.15 2.00 ± 1.00 2.67 ± 1.53 1.33 ± 0.58

[0720]

[0721] Anxiety / Depression 2.33 ± 2.31 2.33 ± 2.31 1.67 ± 1.15 1.00 ± 0.00

[0722] Various advantages can be appreciated from the foregoing description of the second embodiment, and the trial results.

[0723] First of all, as the second embodiment comprises features of the first embodiment, the second embodiment would have all the corresponding advantages of the first embodiment.

[0724] Secondly, compared to the first embodiment, the second embodiment introduces peripheral stimulation to be performed concurrently or simultaneously to brain stimulation using respective tPCS + tcPCS signals. This is particularly useful for treating or improving patients suffering from neuroimmunological diseases i.e. the diseases that are due to both neurological and immunological causes. Results so far for such non-invasive stimulations have been encouraging with improvements to patients’ cognition.Further, the present invention demonstrates that therapeutic neuromodulation is significantly enhanced when central neural circuits (via hf-tPCS) and peripheral sensory-autonomic feedback loops (via tcPCS) are modulated simultaneously at the same frequency and duty cycle. This coordinated stimulation promotes resonance matching between brain and body networks, closed-loop amplification of neuroplasticity, improved homeostatic regulation, and whole-system stabilization. That said, with the second embodiment, the present invention identifies a shared optimal operating window of approximately 100Hz to 500 Hz, wherein both central and peripheral nervous systems are maximally responsive. Delivering hf-tPCS and tcPCS at the same frequency and duty cycle produces maximal system-level integration and accelerates therapeutic response, in particular to neurological and neuroimmune conditions characterized by inflammation, demyelination, and neuronal network dysfunction.

[0725] Further, the stimulator may comprise two or more sets of surface electrodes. This enables simultaneous stimulation of both the scalp and the body with completely synchronized frequency and duty cycle, while ensuring the outputs of each channel do not interfere with each other during operation. By setting the tPCS and tcPCS with different peak current value, the stimulator is able to balance among the requirements of sufficient penetration, effective treatment and safety (or well tolerance).

[0726] Indeed, peripheral stimulation delivered by transcutaneous pulsed current stimulation (tcPCS), particularly within the frequency range of approximately 100Hz to 500 Hz, robustly engages peripheral sensory-autonomic afferent pathways, including both vagal afferents and spinal afferents. Further, tcPCS applied to the peripheral pathways can indirectly influence central brain activity and, in turn, modulate descending neural signalling throughout the nervous system that mediate symptoms. While peripheral tcPCS alone can produce localized neuromodulatory effects, such effects may be limited indurability when applied in isolation. The combination of use of tPCS helps to address this issue.

[0727] While it is provided in the above embodiments that the surface electrodes are provided in the head harness, it is envisaged that the surface electrodes may be provided in other manners or a suitable device. As an example, a helmet may be provided comprising one or more sets of surface electrodes, and the surface electrodes may be placed on an inner surface of the helmet so that the surface electrodes are connected to the user’s scalp when the user is wearing the helmet. As another example, the surface electrodes may not be attached to each other, so that each electrode can be independently attached to the user’s scalp. Indeed, as it may not be necessary that all surface electrodes are attached to the user’s head, so that the head harness may not be narrowly interpreted as limiting the device to exclude the body surface electrodes.

[0728] While different specific preferred examples are provided with different combinations of parameters or combinations of ranges of parameters, it is envisaged that the parameters or ranges of parameters may be mixed and matched to achieve the desired effect. For example, ranges of frequency and duty cycle of tPCS described in an example may be combined with ranges of pulse width and current value (whether peak current value or average current intensity) of tPCS described in another example.

[0729] While the signal used in the trials is monophasic, it is envisaged that other types of current signal may also be used, such as biphasic, triphasic or multiphasic current signals.

[0730] It is envisaged that the tPCS or tcPCS generated by the stimulus generator 102 may have a waveform selected from a group comprising a rectangular pulse waveform, cosine-squared pulse waveform, Dirac pulse waveform, sine pulsewaveform, Gaussian pulse waveform, sawtooth waveform and a triangular waveform.

[0731] The described embodiments provide various exemplary values of the average current intensity for tPCS and tcPCS respectively. Depending on the application, it is envisaged that the average current of the tPCS may not exceed 2mA, and the average current for tcPCS may not exceed 10mA.

[0732] It is envisaged that the present invention may be realized using The AscenZ Stimulator series of devices, or Yiqi Stimulator series of devices from Beijing Yiqi Biotechnology Co. Ltd and Henan Yiqi Biotechnology Co. Ltd., or similar devices with hardware configured with the same functions.

[0733] Although therapeutic effects may be achieved, the invention primarily relates to a technical system and control architecture for generating and controlling stimulation signals.

[0734] Having now described the invention, it should be apparent to one of ordinary skill in the art that many modifications can be made hereto without departing from the scope as claimed.

Claims

CLAIMS1. A pulsed current stimulator to alleviate or improve at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition, comprising:a first set of surface electrodes attachable to a user’s scalp and configured to stimulate the user’s brain; anda stimulus generator configured to generate transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes, the tPCS having a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle in a range of about 1 % to about 8% and a peak current value in a range of about 8mA to about 60mA.

2. The pulsed current stimulator according to claim 1, wherein the peak current value of the tPCS is in a range of about 10mA to about 60mA.

3. The pulsed current stimulator according to claim 1 or 2, wherein the peak current value of the tPCS is in a range of about 12mA to about 60mA.

4. The pulsed current stimulator according to any preceding claim, further comprising a second set of surface electrodes attachable to the user’s postcranial body for peripheral stimulation,wherein the stimulus generator is further configured to generate transcutaneous pulsed current stimulation (tcPCS) to the second set of surface electrodes, the frequency of the tcPCS has a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle in a range of about 1 % to about 8% and a peak current value in a range of about 10mA to about 200mA.

5. The pulsed current stimulator according to any preceding claim, wherein the frequency of the tPCS is more than about 120Hz but no more than about 500Hz.

6. The pulsed current stimulator according to any preceding claim, wherein the frequency of the tPCS is more than about 200Hz but no more than about 500Hz.

7. The pulsed current stimulator according to any preceding claim, wherein the peak current value of the tPCS is in the range of about 10mA to about 40mA.

8. The pulsed current stimulator according to any preceding claim, wherein the tPCS pulse width is in a range of about 50ps to about 500µs.

9. The pulsed current stimulator according to any preceding claim, wherein the tPCS has a waveform selected from a group comprising a rectangular pulse waveform, cosine-squared pulse waveform, Dirac pulse waveform, sinc pulse waveform, Gaussian pulse waveform, sawtooth waveform and a triangular waveform.

10. The pulsed current stimulator according to any preceding claim, wherein the neurological, psychiatric, neuropsychiatric, and / or medical condition includes diseases or disorders that involve alterations of inflammatory cascades.

11. The pulsed current stimulator according to any preceding claim, wherein the neurological, psychiatric, neuropsychiatric, and / or medical condition includes one of multiple sclerosis; autoimmune encephalitis; neuromyelitis optica; post-infectious syndromes including long-COVID, Paediatric Acute-onset Neuropsychiatric Syndrome (PANS); neoplastic and paraneoplastic syndromes; central nervous system (CNS) vasculitis; cerebral small vessel disease; Parkinson’s disease; Multiple System Atrophy (MSA); mild cognitive impairment(MCI); dementia; Alzheimer’s disease; autism spectrum disorder (ASD); cerebral palsy; attention deficit hyperactive disorder (ADHD); depression; psychosis; mania; sleep disorders; cerebellar ataxia; peri-operative delirium and postsurgery cognitive loss; traumatic brain injury; stroke; spasticity; dystonia; and lupus.

12. A pulsed current stimulating method for alleviating or improving at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition, comprising:attaching a first set of surface electrodes to a user’s scalp; and generating pulsed current stimulation (tPCS) to the first set of surface electrodes to stimulate the user’s brain, wherein the tPCS has a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs, a duty cycle in a range of about 1 % to about 8% and a peak current value in the range of about 8mA to about 60mA.

13. A pulsed current stimulator to alleviate or improve at least one symptom in relation to a neurological, psychiatric, neuropsychiatric, and / or medical condition, comprising:a first set of surface electrodes attachable to a user’s scalp and configured to stimulate the user’s brain, and second or more sets of surface electrodes attachable to the user’s postcranial body for peripheral stimulation; anda stimulus generator configured to generate transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes and transcutaneous pulsed current stimulation (tcPCS) to the second set of surface electrodes, wherein the tPCS and tcPCS each having a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs and a duty cycle in a range of about 1% to about 8%; wherein the tPCS has a peak tPCS current value in a range of about 8mA to about 60mA, and the tcPCS has a peak tcPCS current value in a range of about 10mA to about 200mA.

14. The pulsed current stimulator according to claim 13, wherein the peak tPCS current value is in a range of about 10mA to about 60mA.

15. The pulsed current stimulator according to claim 13 or 14, wherein the peak tPCS current value is in a range of about 12mA to about 60mA.

16. The pulsed current stimulator according to any of claims 13 to 15, wherein the frequency, pulse width and duty cycle of the tPCS for the first set of surface electrodes are the same as the frequency, pulse width and duty cycle of the tcPCS for the second set of surface electrodes.

17. The pulsed current stimulator according to any of claims 13 to 16, wherein the peak tPCS current value for the first set of surface electrodes is different from the peak tcPCS current value for the second set of surface electrodes.

18. The pulsed current stimulator according to any of claims 13 to 17, wherein the peripheral stimulation includes stimulation of the spinal cord, nerve roots, peripheral nerves or extracranial portions of the vagus nerve or any cranial nerve.

19. The pulsed current stimulator according to any of claims 13 to 18, wherein stimulating the user’s brain includes the user’s cortex and connected brain regions.

20. The pulsed current stimulator according to any of claims 13 to 19, wherein the neurological, psychiatric, neuropsychiatric, and / or medical condition includes diseases or disorders that involve alterations of inflammatory cascades.

21. The pulsed current stimulator according to any of claims 13 to 20, wherein the neurological, psychiatric, neuropsychiatric, and / or medical condition includes one of multiple sclerosis; autoimmune encephalitis; neuromyelitis optica; post-infectious syndromes including long-COVID, PANS; neoplastic andparaneoplastic syndromes; CNS vasculitis; cerebral small vessel disease; Parkinson’s disease; MSA; mild cognitive impairment; dementia; Alzheimer’s disease; ASD; cerebral palsy; ADHD; depression; psychosis; mania; sleep disorders; cerebellar ataxia; peri-operative delirium and post-surgery cognitive loss; traumatic brain injury; stroke; spasticity; dystonia; and lupus.

22. A pulsed current stimulating method for alleviating or improving at least one symptom in relation to neurological, psychiatric, neuropsychiatric, and / or medical condition, comprisingattaching a first set of surface electrodes to a user’s scalp and second or more sets of surface electrodes to the user’s postcranial body; and generating transcranial pulsed current stimulation (tPCS) to the first set of surface electrodes to stimulate the user’s brain and generating transcutaneous pulsed current stimulation (tcPCS) to the second or more sets of surface electrodes for peripheral stimulation, the tPCS and tcPCS each having a frequency in a range of about 100Hz to about 500Hz, a pulse width in a range of about 50μs to about 800μs and a duty cycle in a range of about 1% to about 8%; wherein the tPCS has a peak tPCS current value in the range of about 8mA to about 60mA, and the tcPCS has a peak tcPCS current value in a range of about 10mA to about 200mA.

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