Transcranial alternating current stimulation (tACS)

Abstract

A method of transcranial alternating current stimulation (tACS) is provided. The method includes generating a current and transmitting the current to two electrodes contacting the patient's scalp to deliver a therapeutic dose of tACS for a predetermined treatment time. The current has a constant average amplitude of 2.2 mA and a bidirectional square waveform having a carrier wave at a frequency of 15 kHz, one modulation waveform frequency being 15 Hz and the other modulation waveform frequency being 500 Hz. The current includes a sub-burst within a burst duration including a burst on duration of 50 ms including the sub-burst followed by a burst off duration of 16.7 ms without the sub-burst. After each burst duration, the current switches polarity. Each sub-burst includes a pulse within a sub-burst duration that includes a sub-burst on duration of 1 ms including a pulse followed by a sub-burst off duration of 1 ms without a pulse. Each pulse extends about 33.33 ps, followed by a pause of 33.33 ps.

Description

Background Technology

[0001] Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are very common; in 2020, 48 million Americans were prescribed antidepressants and 49 million were prescribed medication for anxiety disorders. Furthermore, data from the U.S. Centers for Disease Control and Prevention shows that the incidence of clinical depression and anxiety disorders among American adults has more than tripled since the COVID-19 pandemic began; Boston University reports that up to one-third of Americans may now have one or both disorders. Approximately 60% of people with GAD also have MDD, and nearly half of people with MDD have GAD; this high level of comorbidity makes treatments that address both conditions advantageous. Of the two conditions, MDD is considered more life-threatening due to its high suicide risk, high hospitalization rates, and other chronic health conditions and disorders associated with MDD, such as substance use disorder.

[0002] For decades, the under-accessibility of psychiatrists has been considered a public health issue for many segments of the U.S. population; most patients with clinical depression receiving psychotropic medication receive their prescriptions from their primary care physicians, not board-certified psychiatrists. However, analyses of primary care practices reveal low utilization of depression care management processes, suggesting that primary care physicians may not be adequately equipped to manage depression effectively. Some researchers claim a “significant undertreatment” of depression, particularly in primary care settings. Other studies suggest that antidepressants may be overprescribed for patients better suited to low-risk psychotherapy. The demand for psychotherapy also far exceeds the number of therapists available to care for patients promptly.

[0003] Common antidepressants and psychotherapy typically take several weeks to show results. The American Psychiatric Association (APA) Practice Guidelines for the Treatment of Major Depressive Disorder state that psychotherapy should produce at least moderate improvement (e.g., a reduction of more than 20% in symptoms) within 4 to 8 weeks of treatment, and recommend that physicians emphasize to patients that 2 to 4 weeks of medication is needed to notice beneficial effects. However, this long waiting period for symptom improvement can be problematic. Notably, delayed responses to treatment can lead to reduced adherence, which affects treatment success rates, relapse risk, and medical costs. For example, the first 6 weeks of treatment have been observed to be a particularly critical period for promoting adherence; among those who show early non-adherence to antidepressants, the risk of treatment withdrawal, relapse, discontinuation of medication, suicidal tendencies, and increased financial burden is higher. Fear and experience of side effects also contribute to patients' inability to adhere to medication. Less commonly used prescription controlled drugs, such as ketamine and electroconvulsive therapy (ECT), are fast-acting but extremely expensive to administer and often cause significant side effects.

[0004] Therefore, there is a need for a fast-acting treatment for depression that is low-risk to patients, promotes adherence, is self-administered, inexpensive, and can significantly reduce anxiety. Summary of the Invention

[0005] Transcranial alternating current stimulation (tACS) has been investigated as an alternative treatment for depression. tACS is a non-invasive neurostimulation technique that delivers low-dose alternating current to the brain to induce neural plasticity. Therefore, tACS has shown promise as an effective treatment for depression, as well as anxiety disorders, insomnia, and other neuropsychiatric and cognitive disorders.

[0006] The tACS device can be self-administered by the patient and can be safely used as a standalone treatment or in combination with medication. Although classified as a medical device, the manufacturing process of the tACS device is neither complex nor expensive. Importantly, mounting scientific evidence suggests that tACS is safer than medication and, in some forms, takes effect faster.

[0007] The challenge in developing tACS devices is finding a method of delivering electrical current that is both therapeutic and comfortable for patients, and that can be successfully maintained through blinding in sham-controlled clinical trials. If patients find the stimulation uncomfortable, they may avoid using the device; and if clinical trial participants can easily distinguish between effective devices and sham devices (devices that appear to function normally but produce no stimulation), the trial results may not be easily defended.

[0008] Embodiments of this disclosure provide systems and methods for an improved tACS applicable to the treatment of depression (e.g., major depressive disorder; MDD) and anxiety disorders (e.g., generalized anxiety disorder; GAD), insomnia, and other neuropsychiatric and cognitive disorders. As discussed in more detail below, a tACS device is provided that has been shown to provide therapeutically effective treatment using a fast-pulsating alternating current (AC) output in the form of a bipolar (bidirectional) square wave employing a high carrier frequency and modulated to two lower frequencies with a current amplitude of 2.2 mA (+ / - 5% manufacturing tolerance). Through large-scale, randomized, controlled clinical trials, it has been found that this combination of amplitude, pulse rate, waveform, and frequency, delivered to the brain twice daily (once shortly after the patient wakes up and once before sleep) for a predetermined treatment time (e.g., approximately 20 minutes) via two electrodes placed at specific locations on either side of the head, provides effective treatment for depression and anxiety disorders. The ability to provide effective treatment at a lower current amplitude reduces or substantially eliminates discomfort experienced by the patient.

[0009] In one embodiment, a method of transcranial alternating current (tACS) stimulation is provided. The method includes generating and transmitting a current by a controller including a processor, the current being received by two electrodes in contact with opposite sides of a patient's scalp to deliver a therapeutic dose of tACS for a predetermined treatment time. The generated current has a constant average amplitude of approximately 2.2 mA and a bidirectional square wave waveform utilizing a carrier waveform with a frequency of approximately 15 kHz, a first modulation waveform with a frequency of approximately 15 Hz, and a second modulation waveform with a frequency of approximately 500 Hz. The generated current includes multiple sub-bursts within a burst duration comprising a burst-on duration of approximately 50 ms containing the multiple sub-bursts, followed by a burst-off duration of approximately 16.7 ms without the multiple sub-bursts. After each burst duration, the current polarity is switched. Each sub-burst comprises multiple pulses within its duration, comprising a 1 ms sub-burst-on duration containing the multiple pulses, followed by a 1 ms sub-burst-off duration without the multiple pulses. Each of the multiple pulses extends for approximately 33.33 μs, followed by a pause of approximately 33.33 μs.

[0010] In another embodiment, each of the two electrodes is positioned on the squamous bone of the temporal bone, above the posterior part of the zygomatic arch, and remains in place during the delivery of a therapeutic dose of tACS to treat major depressive disorder (MDD) or generalized anxiety disorder (GAD). Each of the electrodes has a diameter of approximately 36 mm. The method also includes retrieving a predetermined treatment time from a memory in communication with the processor, wherein the predetermined treatment time is approximately 20 minutes. The method further includes: measuring the treatment time during which a therapeutic dose of tACS is delivered to the patient, comparing this treatment time with the predetermined treatment time; and stopping the transmission of the generated current when the elapsed time equals the predetermined treatment time.

[0011] In a further embodiment, the method further includes administering a therapeutic dose of tACS to the patient twice daily within a predetermined treatment time, one administration occurring within two hours after waking from sleep and the other administration occurring within two hours before falling asleep.

[0012] In one embodiment, a method of transcranial alternating current (tACS) stimulation is provided. The method includes positioning two electrodes in contact with opposite sides of a patient's scalp. The method also includes generating a current by a controller including a processor. The method further includes transmitting the generated current to the electrodes to deliver a therapeutic dose of tACS for a predetermined treatment time (e.g., about 20 minutes). The generated current has an amplitude of about 2.2 mA. The generated current also has a waveform comprising a carrier waveform with a frequency of about 15 kHz, a first modulated waveform with a frequency of about 15 Hz, and a second modulated waveform with a frequency of about 500 Hz.

[0013] In another embodiment, each of the two electrodes is positioned on the squamous bone of the temporal bone, above the posterior part of the zygomatic arch, and remains in place during stimulation.

[0014] In another embodiment, each of the two electrodes has a diameter of approximately 36 mm.

[0015] In another embodiment, the therapeutic dose of tACS is sufficient to treat at least one of major depressive disorder (MDD) or generalized anxiety disorder (GAD).

[0016] In another embodiment, the method further includes retrieving a predetermined treatment time from a memory in communication with the processor by the processor. The method also includes measuring the treatment time of the tACS (treaty-associated acute syndrome) during which a treatment dose is delivered to the patient. The method further includes comparing the treatment time with a predetermined treatment time. The method also includes stopping the delivery of the treatment dose to the patient by the tACS when the elapsed time is equal to or greater than the predetermined treatment time.

[0017] In another embodiment, the waveform is a pulsed alternating current in the form of a bidirectional square wave.

[0018] In another embodiment, the waveform includes: a plurality of first square wavelet bursts having a first polarity, the first square wavelet bursts repeating for a burst duration; followed by a plurality of second square wavelet bursts having a second opposite polarity, the second square wavelet bursts repeating for a burst duration.

[0019] In another embodiment, the burst duration is approximately 66.7 ms and includes an on duration and a off duration, wherein the on duration is approximately 50 ms and extends from the beginning of the first sub-burst of the burst duration to the end of the last sub-burst of the burst duration, and wherein the off duration is approximately 16.7 s and extends from the end of the last sub-burst of the burst duration to the end of the burst duration.

[0020] In another embodiment, each of the plurality of first and second subbursts extends the subburst duration by approximately 2 ms, including a subburst on duration of approximately 1 ms, followed by a subburst off duration of approximately 1 ms.

[0021] In another embodiment, each of the first and second plurality of square wavelet bursts includes a plurality of pulses that extend for a pulse duration of approximately 66.7 ms, including a pulse-on duration of approximately 33.3 ms followed by a pulse-off duration of approximately 33.3 ms.

[0022] In one embodiment, a transcranial alternating current stimulation (tACS) device is provided. The device includes a stimulator comprising a band and two electrodes coupled to the band. The band is configured to be secured to a person's head and to position the two electrodes in contact with opposite sides of the patient's scalp. The method also includes a controller comprising a processor. The controller is in electrical communication with a plurality of electrodes and is configured to perform various operations. The controller is configured to generate a current. The controller is also configured to transmit the current to the electrodes to deliver a therapeutic dose of tACS for a predetermined treatment time. The generated current has an amplitude of approximately 2.2 mA. The generated current has a waveform comprising a carrier waveform with a frequency of approximately 15 kHz, a first modulated waveform with a frequency of approximately 15 Hz, and a second modulated waveform with a frequency of approximately 500 Hz.

[0023] In one embodiment, the band is configured to hold each of the two electrodes on the squamous bone of the temporal bone, above the posterior part of the zygomatic arch.

[0024] In one embodiment, each of the two electrodes has a diameter of approximately 36 mm.

[0025] In an embodiment, the controller is also configured to retrieve a predetermined treatment time from a memory in communication with the processor, measure the treatment time during which a treatment dose of tACS is delivered to the patient, compare the treatment time with the predetermined treatment time, and stop delivering the treatment dose of tACS to the patient when the elapsed time is equal to or greater than the predetermined treatment time.

[0026] In this embodiment, the waveform is a pulsed alternating current in the form of a bidirectional square wave.

[0027] In an embodiment, the waveform includes: a plurality of first square wavelet bursts having a first polarity, the first square wavelet bursts repeating for a burst duration; followed by a plurality of second square wavelet bursts having a second opposite polarity, the second square wavelet bursts repeating for a burst duration.

[0028] In an embodiment, the burst duration is approximately 66.7 ms and includes an on duration and a off duration, wherein the on duration is approximately 50 ms and extends from the beginning of the first sub-burst of the burst duration to the end of the last sub-burst of the burst duration, and wherein the off duration is approximately 16.7 s and extends from the end of the last sub-burst of the burst duration to the end of the burst duration.

[0029] In an embodiment, each of the plurality of first and second subbursts extends the subburst duration by approximately 2 ms, including a subburst on duration of approximately 1 ms, followed by a subburst off duration of approximately 1 ms.

[0030] In an embodiment, each of the first and second plurality of square wavelet bursts includes a plurality of pulses that extend for a pulse duration of approximately 66.7 ms, including a pulse-on duration of approximately 33.3 ms followed by a pulse-off duration of approximately 33.3 ms. Attached Figure Description

[0031] These and other features will be more readily understood from the following detailed description taken in conjunction with the accompanying drawings, wherein: Figure 1 This is a diagram illustrating an exemplary embodiment of a treatment setup in which an electrical stimulation is delivered to the patient's head using a transcranial alternating current stimulation (tACS) device including a controller and a stimulator; Figure 2A yes Figure 1 A rear perspective view of the stimulator; Figure 2B yes Figure 1 A top view of the stimulator; Figure 3A yes Figure 1 A schematic diagram of the controller's appearance; Figure 3B It is shown Figure 1 A block diagram of the controller components; Figures 4A to 4B This is a schematic diagram of the constant current waveform generated by the controller used for tACS treatment; and Figure 5 It shows the use Figure 1 The flowchart of the treatment method of the tACS device.

[0032] Note that the accompanying drawings are not necessarily drawn to scale. The drawings are intended to depict only typical aspects of the subject matter disclosed herein and should therefore not be considered as limiting the scope of this disclosure. Detailed Implementation

[0033] The term "patient" as used in this article refers to vertebrates, preferably mammals, and more preferably humans. Mammals include, but are not limited to, rodents, apes, humans, farm animals, sporting animals, and pets.

[0034] As used herein, “treating” or “treatment” for a condition, disease, or disorder, or symptoms associated with a condition, disease, or disorder, means a method used to achieve a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to: relief or improvement of one or more symptoms or conditions; reduction of the severity of a condition, disorder, or disorder; stabilization of the state of a condition, disorder, or disorder; prevention of the development of a condition, disorder, or disorder; prevention of the spread of a condition, disorder, or disorder; delay or slowing the progression of a condition, disorder, or disorder; delaying or slowing the onset of a condition, disorder, or disorder; improvement or relief of the state of a condition, disorder, or disorder; and relief, whether partial or complete. “Treatment” may also mean inhibiting the progression of a condition, disorder, or disorder; temporarily slowing the progression of a condition, disorder, or disorder, although in some cases it involves permanently stopping the progression of a condition, disorder, or disorder.

[0035] This document discusses embodiments of systems and corresponding methods for transcranial alternating current stimulation (tACS). These systems and methods can be used to treat depression (major depressive disorder), as well as anxiety disorders and sleep maintenance insomnia. However, it is understood that the embodiments of this disclosure can be used, without limitation, to treat other conditions.

[0036] Figure 1 A treatment setup employing a tACS device to treat a patient is illustrated. As shown, the tACS device includes a controller that signals in communication with a stimulator. As discussed in more detail below, the stimulator is configured to be coupled to the patient's head to deliver electrical current to the patient's brain. The controller is configured to allow a user (e.g., the patient) to control the tACS device and deliver current to electrodes with a predetermined waveform and controlled constant amplitude over a specified time period (predetermined treatment time).

[0037] Figures 2A to 2B Later View ( Figure 2A ) and top view ( Figure 2B The stimulator is presented in the form of a band and a pair of electrodes, each of which is mounted in an electrode housing that is adjustablely fixed to the band.

[0038] The band can be a flexible band forming a closed loop. In some embodiments, the band may be formed of an elastic material capable of stretching to conform to the patient's head. In other embodiments, the band may include an adjustment mechanism to adjust the circumference of the closed loop for a tight fit to the patient's head. The adjustment mechanism can take any form that allows the electrodes to be securely positioned in contact with the patient at a selected location (e.g., band adjuster, buckle, hook and loop fastener, snap, etc.).

[0039] In this embodiment, each of the electrodes is removable from its housing. For example, the electrode may be a sponge. The sponge may have a selected diameter suitable for delivering a therapeutic dose of tACS. For example, the electrode diameter may be approximately 36 mm (e.g., 36 mm + / - 5%). When wetted with water, the sponge conducts electricity via the water. However, it is understood that the electrodes may take on other configurations that provide clinically equivalent performance to the sponge described above without limitation. For example, the electrode may be non-removable from the cavity and formed of a durable conductive material (e.g., conductive polymer, metal, etc.).

[0040] Each of the electrode housings can be mounted on opposite sides below the strip. As shown, the electrode housings may include a hole extending through them (e.g., in the front-to-back direction). The hole can be sized to accommodate the strip passing through it.

[0041] In some embodiments, the position of the insertion port relative to the strap can be adjusted. Such adjustments help ensure that the electrode is positioned correctly on the patient's head.

[0042] In one embodiment, this adjustment can be provided by a frictional fit between the hole and the strip. For example, the thickness of the hole can be slightly less than the thickness of the strip to provide a frictional fit. When a sliding force sufficient to overcome the friction between the electrode housing and the strip is applied, the electrode housing can slide relative to the strip. When the application of the sliding force ceases, the electrode housing remains fixed in place relative to the strip.

[0043] It is understood that other mechanisms can be used without limitation to secure the electrode housing to the strap and provide adjustment of the electrode housing relative to the strap. Examples include, but are not limited to, reusable adhesives, hook and loop fasteners, snaps, etc.

[0044] Alternatively, the stimulator may include a padding strap fixed to the front of the stimulator. This configuration allows the padding to contact the patient's forehead when the stimulator is placed on the patient's head, thereby enhancing patient comfort during stimulator use.

[0045] Figures 3A to 3B An example of the controller is shown. Figure 3A An external view of the controller's housing is shown, while Figure 3BThis is a schematic diagram of the controller's electronics. As shown, the controller includes a power supply, speaker, constant current controller, rotary switch, lamp, controller, and voltage regulator. Each of these components is described in more detail below.

[0046] The power supply provides power to the entire tACS device. In one embodiment, the power supply may be one or more batteries. However, in an alternative embodiment, the controller may be configured to receive mains power after power conditioning.

[0047] The rotary switch is configured to electrically turn on / off and to start / stop the delivery of current to the electrodes for treatment. For example, rotating it a certain distance from the off position to a first position turns on the tACS device and places it in standby mode. Further rotation to a second position causes current to be delivered to the electrodes. In this embodiment, the rotary switch may be a thumbwheel. However, other interface devices (not shown) may be used without limitation. Examples may include, but are not limited to, buttons, sliders, switches, etc.

[0048] The controller may also include one or more lights (e.g., LEDs) to indicate the status of the tACS device (e.g., off, on, standby). For example, when the tACS device is on and in standby mode, one of the lights may be lit and green.

[0049] The tACS device is configured to output a constant current. This output is achieved by a constant current controller. According to Ohm's law, voltage and current are directly related to each other through the load resistance. In the context of the tACS device, the load is a human head. The constant current controller addresses the varying resistance of the human head. The constant current controller adjusts its own resistance so that the human head plus the controller will produce a fixed current for the output voltage. In this way, a constant current amplitude of 2.2 mA within tolerance (e.g., + / - 5%) can be produced using a bidirectional square wave output.

[0050] A voltage regulator is an integrated circuit that provides a constant, fixed output voltage in response to commands from a controller, regardless of changes in load or input voltage. This keeps the supply voltage within a range compatible with other electrical components of the tACS device.

[0051] The speaker is configured to provide audio output to notify the patient / operator that the treatment process has ended or that a power outage has occurred. In this embodiment, a buzzer may be used instead of a speaker.

[0052] The controller includes a processor and may include memory or communicate electrically with a memory device (not shown) and electrodes. The controller can power a lamp to provide visual confirmation that the tACS device is activated. A voltage regulator draws power from a power source and increases the voltage of the output circuitry. The controller generates three frequencies: a carrier frequency and two modulation frequencies, and uses an analog switch to modulate the output. A constant current controller maintains the current through the output using a resistive feedback circuit that changes its own resistance to maintain a constant current output of 2.2 mA + / - 5%, even if there are differences at the output. The controller drives a speaker / buzzer to indicate the end of the treatment procedure.

[0053] Figures 4A to 4B This is a schematic diagram of a constant current waveform generated by the controller. As shown, the waveform is a pulsed alternating current in the form of a bidirectional square wave. The parameters of the waveform discussed below can vary from the stated values ​​within manufacturing tolerances (e.g., + / - 5%).

[0054] like Figure 4A As shown, the waveform includes: a plurality of first square wavelet bursts having a first polarity, which repeat during the burst duration; followed by a plurality of second square wavelet bursts having a second opposite polarity, which repeat during the burst duration.

[0055] The burst duration is approximately 66.7 ms, including both the on and off durations. The on duration is approximately 50 ms and extends from the beginning of the first sub-burst of the burst duration to the end of the last sub-burst of the burst duration. The off duration is approximately 16.7 s and extends from the end of the last sub-burst of the burst duration to the end of the burst duration.

[0056] Each of the multiple first and second subbursts has a subburst duration of approximately 2 ms. The subburst duration includes a subburst on duration of approximately 1 ms, followed by a subburst off duration of approximately 1 ms.

[0057] like Figure 4B As further shown, each of the first and second plurality of square wavelet bursts includes a plurality of pulses with extended pulse durations. The pulse duration is approximately 66.7 ms and includes a pulse on-time of approximately 33.3 ms, followed by a pulse off-time of approximately 33.3 ms.

[0058] In the above discussion, a constant current waveform is generated by the controller and transmitted to the electrodes. However, in alternative embodiments, one or more circuit components of the controller may be located within the electrode housing. In some embodiments, all circuit components of the controller may be housed within the electrode housing. The controller's lamp, speaker, and switch may also be replicated on the electrode housing. Therefore, the tACS device may include a combination of... Figure 1 The stimulator and controller are functional stimulators.

[0059] With this configuration, the user can control the tACS device in several ways. In one embodiment, a user monitoring device (e.g., a switch, button, etc.) can be provided on the electrodes to control the tACS device. In another embodiment, the tACS device can be configured to communicate wirelessly with a computing device (e.g., a smartphone, tablet, laptop, desktop computer, etc.). The computing device can execute one or more programs that virtually replicate the functionality of the controller's physical components (e.g., lights, speakers, and / or switches such as rotary switches).

[0060] Figure 5 It shows the use of Figure 1 The treatment method 500 of the tACS device. As shown in the figure, an embodiment of method 500 includes operations 402-416. However, it will be understood that in alternative embodiments, the method may include more or fewer operations, and the order of one or more of the operations may be changed.

[0061] In operation 402, the stimulator is positioned on the patient's head. The patient's scalp and hair should be kept clean to minimize the risk of skin irritation caused by the electrodes. The sponge electrode should be sufficiently moistened to wet the scalp and hair, and this sponge electrode is positioned to contact the scalp and hair. This ensures proper electrical contact between the electrode and the patient's head. Leads are electrically connected to connectors at terminals and to the sponge electrode.

[0062] Place the headband on the patient's head so that it is above the patient's eyebrows. Insert the moistened electrode into the electrode housing with the attached wire. Then, slide the electrode securely upwards from the temple directly under the headband so that the bottom of the electrode is now below the top of the ear, with the top of the ear behind, not below, the electrode. The physiological position of the electrode is the squamous bone of the temporal bone above and behind the zygomatic arch.

[0063] In operation 504, once the moistened sponge electrode is in place, the tACS device is turned on (e.g., by rotating a rotary switch) to generate a current and transmit that current via the electrode to the patient, thereby delivering a therapeutic dose of tACS to the patient. The dial is rotated from the off position to the on position. The standby light should illuminate. Further rotation of the dial causes a fixed current to be generated and delivered to the electrode. The waveform of the generated current has a predetermined waveform as described above, including a carrier frequency and two modulation frequencies. The amplitude (of the generated current) is also fixed at 2.2 mA + / - 5%.

[0064] In operation 506, the microprocessor measures the amount of time elapsed from the start of delivering the generated current (tACS therapeutic dose) to the electrode. For example, the processor starts a timer (e.g., a 20-minute timer) while delivering the generated waveform to the electrode.

[0065] In operation 510, the controller compares the amount of time elapsed since the timer started with a predetermined treatment time (e.g., 20 minutes). The predetermined treatment time can be retrieved from memory that communicates with the microprocessor. In an embodiment, the predetermined treatment time may be 20 minutes. However, in alternative embodiments, the predetermined treatment time may take other values.

[0066] In operation 512, the controller determines whether the elapsed time equals the predetermined treatment time. If not, method 500 returns to operation 506. If yes, the controller stops outputting waveforms to the electrodes at operation 412, thereby stopping tACS treatment.

[0067] In a further embodiment, tACS termination can be configured to determine whether treatment has been interrupted. If so, the timer tracking treatment can be paused and subsequently restarted upon resumption of treatment (unless the tACS device is turned off). Alternatively, if the tACS device is turned off, the timer can be reset to a predetermined treatment time (e.g., 20 minutes).

[0068] The method may also include administering a therapeutic dose of tACS to the patient multiple times daily at predetermined treatment times (e.g., about 20 minutes) (e.g., twice daily treatment). For example, the first daily treatment may be administered at a predetermined time at the start of the patient's daily routine—such as within two hours after waking from sleep. For example, the second daily treatment may be administered at a predetermined time before the end of the patient's daily routine—such as within two hours before falling asleep.

[0069] result Trial 1 – Treatment of Major Depressive Disorder (MDD) Overview A triple-blind, randomized, sham-controlled trial was conducted to demonstrate the efficacy of the tACS device presented in this study for the treatment of major depressive disorder (MDD) in adults. The patient population in this study consisted of participants meeting the criteria for moderate to severe depressive disorder (DSM-5), as diagnosed by practicing psychiatrists and mental health care professionals in the study. Patients' baseline Beck Depression Scale (BDI-II) scores ranged from 20 to 63 (moderate to severe).

[0070] Participants self-administered treatment at home using either a working tACS device or a sham tACS device, performing two 20-minute sessions daily, once upon waking during the day and once before bedtime, for four (4) weeks. The primary outcome was the change in BDI-II scores from baseline to week 2 in the intention-to-treat analysis, followed by analyses of participants who adhered to the protocol (“treatment adherents” or “use compliant”). Secondary analyses examined changes at week 1 and week 4, response rates, subgroup analyses, and safety.

[0071] 255 participants were randomly assigned to effective treatment or sham treatment; 185 women and 70 men aged 21–65 years residing in 47 U.S. states were enrolled. In the general population, approximately twice as many women as men received MDD treatment. In the intention-to-treat analysis, significantly greater improvement was observed with the tACS device at week 1 and a greater response rate at week 4. Importantly, protocol analysis determined that effective tACS treatment was significantly superior to sham tACS treatment at all time points. Women experienced significantly greater improvement. A small percentage of participants reported side effects, which were mild and transient.

[0072] Studies have demonstrated that the tACS device discussed in this article provides rapid and significant improvement in depression in adults with MDD, particularly women. Compared to other depression treatments, the tACS device offers advantages such as rapid and clinically meaningful therapeutic effects, patient self-administration, and a low frequency and minimal severity of adverse events.

[0073] Participants were randomly assigned (approximately 1:1) to receive either the effective treatment or the sham treatment. Participants, assessors, and funders were all unaware of the study details (triple blinding). The James blinding index was used to assess participants' awareness of whether they were using the effective or sham device (subject blinding). The sham device appeared to function like the effective device but produced zero electrical output. This study was conducted in accordance with good clinical practice (ISO 14155-2020).

[0074] Adults diagnosed by a clinical investigator, meeting the DSM-5 criteria, and possessing moderate to severe severity on the Beck Depression Inventory-II (BDI-II) are eligible to participate. Eligibility criteria are: age 21 to 65; U.S. resident; able to read / write English; able to adhere to the treatment plan; no history of suicide attempts or planned or intentional suicidal ideation in the past 30 days; no hospitalization for mental health conditions in the past year; no use of neuromodulation in the past year; no changes in prescribed neurological medications in the past 30 days; no use of recreational substances, hypnotics, steroids, and / or cannabis products in the past 30 days; no alcohol or substance abuse problems in the past 12 months; no mental health disorders other than MDD; no known history of heart disease or trigeminal neuralgia; no pacemaker or any form of medical electronic device. Sexually active women of childbearing age must commit to using at least one method of contraception during Trial 1.

[0075] All data were entered into the electronic patient-reported outcomes (ePRO) clinical trial software platform managed by the clinical research organization (CRO) Climb Technologies. Potential participants completed an online pre-screening process. Eligible participants had virtual meetings with investigators who reviewed the trial's purpose, procedures, risks and benefits, compensation, and data confidentiality. Interested participants then completed informed consent forms electronically.

[0076] Participants began a 14-day introductory period (without initiating treatment), after which they re-performed self-report assessments and computer-assisted MINI ( Mini International Neuropsychiatric Interview ) (MINI) The MINI is an assessment tool for major mental disorders. In the trial, the MINI was used in a self-administered form by the participants and confirmed during telemedicine visits between the participants and their clinicians to determine if any comorbid diagnoses might disqualify the participants from entering the study treatment phase.

[0077] Participants must have a BDI-II score between 20 and 63 at both the initial pre-screening and baseline stages. This induction aims to exclude participants with transient depressive disorder, which could potentially bias the study results. To accommodate the timing of these assessments, participants must have experienced at least one month of depression prior to the start of treatment. Participants are assessed using the DSM5 diagnostic criteria for MDD and other mental disorders during clinical interviews with clinicians, and their MINI responses are reviewed to finalize eligibility.

[0078] Eligible participants were randomly assigned to the effective treatment group (effective tACS device) or the control group (sham tACS device) by an unblinded investigator without contacting the participants or discussing the group assignments with other members of the investigation team. Randomization was sequential. For the initial 250 randomizations required by the protocol, no restrictions or other inputs determined the order of randomization. For over 250 additional randomizations, a table was used, with 10 participants per block, and each block equally allocated between the effective and sham groups.

[0079] The effective tACS device used by participants in the trial was an embodiment of the aforementioned tACS device. The tACS device included an electrical pulse generator operated by a controller, which included a processor that generated current and transmitted it to two electrodes (or sensor electrodes) in contact with the patient's scalp. Each electrode was approximately 36 mm in diameter. The effective tACS device generated a pulsed, alternating, constant current. Third-party device testing laboratories confirmed that these devices generated current amplitudes between 2.1 mA and 2.2 mA (within a ±5% tolerance of 2.2 mA). The device utilized a bidirectional square (also known as a rectangular) waveform with a carrier frequency of 15 kHz (+ / - 5% manufacturing tolerance), a first modulation frequency of 15 Hz (+ / - 5% manufacturing tolerance), and a second modulation frequency of 500 Hz (+ / - 5% manufacturing tolerance). The current was delivered in a series of bursts over a burst duration that then switched polarity (direction), the burst duration including a 50 ms on burst duration and a 16.7 ms off burst duration. Each 50 ms burst consisted of a series of sub-bursts. Each subburst has an on duration of 1 millisecond, followed by an off duration of 1 millisecond. Each 1-millisecond subburst further comprises multiple pulses. Each pulse has a duration of 33.33 μs (on pulse duration), followed by a pause of 33.33 μs (off pulse duration). The effective tACS device delivers a predetermined treatment duration of 20 minutes, timed according to a memory communicated with the processor, and then automatically shuts down, ending the treatment process.

[0080] Before participants began their first treatment, researchers provided training to each participant via video conference. During the training, participants assembled the device and practiced using it under staff supervision. Each of the two electrodes was moistened with tap water and positioned on the scalp by placing it under the headband included in the device kit; each electrode was placed on either side of the head, on the squamous bone of the temporal bone, above and behind the zygomatic arch. Participants were instructed to self-administer the treatment for 20 minutes twice daily, once upon waking during the day and the second time before bedtime.

[0081] Following the training, participants were administered the James Blinding Index—a standardized and validated questionnaire designed to detect the success or failure of blinding (whether participants knew which research group they were part of). The questionnaire asked participants what type of research apparatus they believed they received (valid apparatus or control apparatus) and asked them to choose from five options to indicate the strength of that belief. Analysis of the James Blinding Index results determined that blinding was successful, thus confirming that participants were unable to distinguish between valid and dummy apparatuses.

[0082] Each day following device training, participants reported whether they used the tACS device as instructed and whether there were any changes in their health status or medications. After one, two, and four weeks of treatment, participants completed clinical outcome measurements and reported any adverse events or changes in accompanying medications.

[0083] Beck Depression Inventory, Second Edition (BDI-II) The Body Mass Index (BDI-II) is a primary tool for assessing the severity of depression. It is a validated and commonly used multi-choice self-report scale for assessing the severity of depression. The BDI-II contains 21 items on a 4-point scale from 0 to 3, with a total score of 0 to 63. The BDI-II is frequently used in clinical research and the field of mental health to assess mental disorders, and is particularly useful for measuring the effectiveness of treatments administered by the patient themselves.

[0084] Statistical analysis The sample size for Trial 1 was based on the primary outcome measure of change in BDI-II. The sample size was calculated based on a planned sample size of 250 evaluable subjects, allocated 1:1. Trial 1 provided 80% power, assuming a difference of 3.2 in the overall means and a common standard deviation of 9 between groups, based on a two-tailed, two-sample t-test with α = 0.05. Previous data suggested a standard deviation of approximately 6.5 for improvement at 2 weeks; however, these calculations used a conservative estimate of 9.

[0085] All analyses were performed using SAS. ® Version 9.4 was used. The primary endpoint analysis was performed at a one-sided 0.025 alpha level, with all other analyses based on a nominal two-sided 0.05 alpha level. Confidence intervals and p-values ​​for secondary endpoints and subgroup analyses were not adjusted for multiple comparisons. The primary analysis used intention-to-treat (ITT) as a more conservative estimate of treatment efficacy. A selection analysis was then performed on participants who reported complete adherence to twice-daily treatment to determine whether effective treatment was significantly superior to sham treatment when both the effective and sham groups adhered to the usage guidelines.

[0086] The primary efficacy endpoint was defined as the change in BDI-II score at week 2 compared to baseline in the effective treatment and control groups. Analysis of change was performed using linear regression models, adjusted for baseline values ​​for each subject. Missing data for the primary endpoint were handled via multiple imputation based on a fully conditional specification, with the following covariates: age, sex, baseline BDI-II, week 1 BDI-II, and available follow-up BDI. Imputation was performed separately for each treatment group. Several sensitivity analyses were performed. These analyses were supportive in nature and employed nominal confidence levels. The primary endpoint was replicated using both treatment and protocol (using adherent) cohorts. The same statistical methods used for the primary endpoint were employed. Secondary analyses were performed at week 1 and week 4, and at all time points, for PHQ-9 and QIDS-SR, adjusted for baseline scores. Secondary analyses compared BDI-II response rates at weeks 1, 2, and 4, where response rate was defined as a score improvement of 50% or more from baseline. By leveraging interactions between treatment groups and subgroups, subgroup analyses were performed on the primary endpoint within the ITT analysis set for subgroups defined by sex, race, and baseline BDI-II (moderate (20–28) and severe (29–63)). Interactions with p-values ​​<0.15 were further examined according to the pre-specified analysis protocol. No adjustments were performed for multiple comparisons. Exploratory analyses examined whether concomitant use of antidepressants affected treatment outcomes.

[0087] Participant characteristics Table 1 summarizes the baseline demographics and clinical characteristics.

[0088] Table 1 - Participant Characteristics and Intention to Treatment Sample (N=255)

[0089] Based on baseline BDI-II scores, 32.6% and 67.5% of the samples reported moderate and major depressive symptoms, respectively, as shown in Table 2.

[0090] Table 2 - Baseline Clinical Characteristics

[0091] The James Blinding Index (0.718, 95% CI [0.668 to 0.768]) indicated a lower limit of confidence above 0.5, considered successful blinding. Overall, 56% and 45% of participants in the effective and control groups, respectively, believed they were unaware of the treatment assigned to them. Self-reported adherence was high, with 85.1% of participants reporting twice-daily use for the first 14 days. When broken down by group, 86.5% of subjects in the effective group and 83.7% in the sham group used the treatment completely within 14 days.

[0092] Result Measurement Tables 3, 4, and 5 present the results of the primary and secondary effectiveness endpoints related to changes in BDI-II scores in the scheme (fully utilized device) group.

[0093] Table 3 - Primary efficacy endpoint: Change in BDI-II score at week 2

[0094] Table 4 – Changes in BDI-II from baseline to week 1

[0095] Table 5 – Changes in BDI-II from baseline to week 4

[0096] Analysis of participants who fully adhered to the treatment for the first 14 days showed that at 2 weeks, the effective treatment resulted in a significantly greater improvement in BDI-II than the control group (difference: 3.72, p = 0.005, CI [1.103 to 6.340]), while the difference between groups in the intention-to-treat group was not statistically significant, at 0.006 per thousand (difference: 2.04; one-sided p = 0.056, 95% CI [-0.476 to 4.549]). In the ITT group, significant effects were observed at the minor week 1 time point; in the protocol-compliant group, significant effects were observed at all time points. These results validate the tACS device as rapid, effective, and safe.

[0097] Finally, in the responder analysis at week 4, the response rate in the effective treatment group was significantly higher than that in the ITT group (65.08% vs. 52.71%, p=0.045) and the protocol-based group, as shown in Table 6.

[0098] Table 6 - BDI-II at least 50% improvement for BDI-II respondents at each time point according to protocol (full device use) gender Time point Effective grouping control group p-value all Week 1 40.2% (39 / 97) 26.7% (27 / 101) Week 2 53.6% (52 / 97)_ 40.6% (41 / 101)_ Week 4 70.1% (68 / 97) 53.5% (54 / 101)

[0099] Concomitant use of antidepressants was quite common, reported by 43.7% in the effective treatment group and 36.4% in the sham treatment group (Table 2). Within the effective treatment group, there was no difference in outcomes between subjects taking and discontinuing antidepressants at week 2 (p=0.543).

[0100] Security Results The number of adverse events was low. In the effective group, 19 subjects (15.1%) reported 34 events, while in the control group, 10 subjects (7.8%) reported 13 events. No serious adverse events were reported. Only one AE (skin irritation) led to device discontinuation.

[0101] In summary, this trial validates the effective tACS device as a rapid, effective, and safe treatment for major depressive disorder; further studies are needed to confirm the outcomes in male patients, just as this study has confirmed the outcomes in female patients.

[0102] Study 2 – Treatment of Anxiety Disorders A second trial was conducted to demonstrate the effectiveness of the tACS device in treating generalized anxiety disorder in first responders. The tACS devices used in this trial were from the same manufacturing batch as those used in the previously summarized MDD trial. Device specifications and usage were identical; as in the MDD trial, participants in the GAD trial were instructed to self-administer tACS twice daily for 20 minutes each time, once at the beginning and once at the end of each day.

[0103] This was a randomized, waitlist-controlled trial. Upon eligibility, participants were randomly assigned to either the “immediate” or “delayed” group. Both groups received the effective device and the same treatment instructions. The immediate group began treatment immediately upon enrollment. The waitlist group (delayed) received treatment after a planned delay of ten (10) days in the logistics process and a maximum of four (4) days in transit (a target delay of fourteen (14) days). A total of 220 participants were enrolled. A Beck Anxiety Scale (BAI) score ≥7 was included as an inclusion criterion. Scores and participation were monitored in near real-time (via CRO, Climb Technologies) and reassessed weekly. The primary endpoint was the change in BAI score from baseline to week 2, compared between the immediate and delayed treatment groups.

[0104] Inclusion criteria: 1) Reading and writing English; 2) Employed by an emergency medical services organization; 3) Has not used a "brain stimulation device" in the past year; 4) Commit to performing the process twice a day for 20 minutes, once in the morning and once in the evening, for a maximum of 8 weeks; 5) Willing to wear the ReadiBand activity recorder and share data with researchers; 6) Does not have a pacemaker, electronic stent, or any other electronic implant / regular use for health reasons; 7) No new medical treatments or health programs (including new weight loss or fitness programs) have been started or are not planned to be started within the next 8 weeks; 8) Has not considered suicide in the past year; 9) Did not receive institutional treatment for mental health problems; 10) Not under medical supervision for serious medical conditions (sleep apnea, restless legs syndrome, mental health problems and / or heart disease); 11) Currently not taking any medications that affect the nervous system (e.g., psychiatric medications); 12) Not allergic to nickel; 13) I am not currently participating in or plan to participate in any other studies related to insomnia, anxiety, or other mental health (including the NIJ Fatigue Study) within the next 8 weeks; 14) Not pregnant or not planning to become pregnant within the next 10 weeks; 15) Baseline Beck Anxiety Scale score >7.

[0105] Participants were randomly assigned to either the immediate treatment group (receiving effective treatment) or the delayed treatment group (waiting two weeks before starting effective treatment). The Beck Anxiety Scale was administered to participants at enrollment, week 2, and week 4. Participants who agreed to extend treatment were observed until week 8.

[0106] Table 7 below provides details of the subjects in Experiment 2.

[0107] Table 7 - Subject Arrangement

[0108] A total of 358 participants were screened for the study, of whom 220 met the inclusion criteria. Eligible participants were randomly assigned to two groups (110 participants in each group). In the immediate group, 105 participants (95.5%) received treatment, while in the delayed group, 95 participants (86.4%) received treatment. At week 4, 28 participants (26.7%) in the immediate group were lost to follow-up, compared to 25 participants (26.3%) in the delayed group. Six participants (5.7%) in the immediate group voluntarily withdrew, compared to 7 participants (7.4%) in the delayed group. Two participants (1.9%) withdrew due to side effects, compared to 1 participant (1.1%) in the delayed group for the same reason. Among those treated, 50 participants (47.6%) in the immediate group expressed a willingness to continue treatment for more than 4 weeks, while 51 participants (53.7%) in the delayed group expressed a willingness to continue treatment further.

[0109] Table 8 shows descriptive statistics of the characteristics of the two groups of subjects.

[0110] Table 8 - Descriptive statistics of subject characteristics Obtained using the independent samples t-test . The results were obtained using a Pearson chi-square test. The bolded p-value indicates statistical significance. .

[0111] The mean age of participants in the immediate group was 42.39 years (SD: 9.49 years), while the mean age of participants in the deferred group was 43.52 years (SD: 9.85 years), and the difference in means was not statistically significant (p=0.388). Regarding sex, 66.4% of the participants in the immediate group were male, compared to 49.1% in the deferred group. The percentage of females in the immediate group was lower (33.6%) than in the deferred group (50.9%). The sex distribution was significantly different between the two groups, as indicated by a p-value of 0.009. The mean height of participants in the immediate group was 69.45 inches (SD: 4.14 inches), while the mean height of participants in the deferred group was 68.07 inches (SD: 4.15 inches), and the difference in means was statistically significant (p=0.015). The mean weight of participants in the immediate group was 197.90 pounds. (SD: 48.67 lbs), while the delayed group weighed 187.48 lbs (44.05 lbs), and the difference in means was not statistically significant (p=0.097).

[0112] Table 9 presents descriptive statistics for the Beck Anxiety Scale (BAI) scores of the two groups at different time points.

[0113] Table 9 - Descriptive statistics of Beck Anxiety Scale scores for two groups based on time. Obtained using the Mann-Whitney U test. The bolded p-value indicates statistical significance.

[0114] At baseline, the parameter violated the normality assumption according to the Shapiro-Wilk test, and therefore a nonparametric assessment was performed to compare the scores between the two groups. At baseline, the mean BAI score in the immediate group was 20.14 (SD: 10.45) with a median of 19, while the mean BAI score in the delayed group was 19.80 (SD: 9.40) with a median of 18. The difference in median scores was not statistically significant (p = 0.905). At week 2, the mean BAI score in the immediate group was 12.79 (SD: 7.86) with a median of 11, while the mean BAI score in the delayed group was 19.24 (SD: 9.29) with a median of 18. The difference in median BAI scores between the two groups at week 2 was statistically significant, with p < 0.001. Furthermore, in week 4, the mean for the immediate group was 10.64 (SD: 6.93), with a median of 10, while the mean for the delayed group was 13.08 (SD: 7.10), with a median of 11, and the difference in medians was statistically significant, with a p-value of 0.024.

[0115] Table 10 provides descriptive statistics on the change in BAI scores from baseline to week 2.

[0116] Table 10 - Comparison of BAI score changes (D) from baseline to week 2 between the two groups Obtained using the Mann-Whitney U test. The bolded p-value indicates statistical significance.

[0117] Comparison of score changes revealed that in week 2, the mean score change in the immediate group was 6.33 (SD: 7.83) with a median of 5, while the mean score change in the delayed group was 0.38 (SD: 7.67) with a median of 0. The difference in medians between the groups was statistically significant, with p < 0.001.

[0118] Table 11 is a cross-tabulation showing the frequency of subjects in each BAI category in the immediate group at baseline and week 2.

[0119] Table 11 - Changes in anxiety levels from baseline to week 2 in the immediate group based on BAI score categories. P < 0.001, use the marginal homogeneity test .

[0120] At baseline, 54 (66.7%) participants were in the low-grade category; of these, 53 remained in the low-grade category in week 2, while 1 moved to the moderate category. At baseline, 20 (24.7%) participants were in the moderate category; of these, 13 moved to the low-grade category, and 7 remained in the moderate category. Furthermore, of the 7 (8.6%) participants who were in the severe category at baseline, 4 moved to the low-grade category, 2 moved to the moderate category, and 1 remained in the severe category. In week 2, 70 (86.4%) participants were in the low-grade category, 10 (12.3%) were in the moderate category, and 1 (1.2%) were in the severe category.

[0121] The marginal distribution changed significantly from baseline to week 2, as shown by p<0.001, with a significantly higher proportion of subjects in the low-degree category in week 2 compared to baseline.

[0122] Table 12 is a cross-tabulation showing the frequency of subjects in each BAI category in the extension group at baseline and week 2.

[0123] Table 12 - Changes in anxiety levels from baseline to week 2 in the postponement group based on BAI score categories. P=0.590, using the marginal homogeneity test .

[0124] At baseline, 53 (60.9%) participants were in the low-grade category; of these, 46 remained in the low-grade category in week 2, 6 moved to the moderate category, and 1 moved to the severe category. At baseline, 28 (32.2%) participants were in the moderate category; of these, 7 moved to the low-grade category, 18 remained in the moderate category, and 3 moved to the severe category. Furthermore, of the 6 (6.9%) participants who were in the severe category at baseline, 2 moved to the low-grade category, 3 moved to the moderate category, and 1 remained in the severe category. In week 2, 55 (63.2%) participants were in the low-grade category, 27 (31.0%) were in the moderate category, and 5 (5.7%) were in the severe category. The marginal distribution of the extended group did not change significantly from baseline to week 2 (p=0.590).

[0125] There were 53 participants in the immediate group and 50 participants in the extended group who indicated a willingness to continue for more than four weeks. Therefore, a subset analysis was performed on these participants, and parameters at week 8 were compared between the two groups, as shown in Table 13.

[0126] Table 13 - Descriptive statistics of different scores in week 8 for the two learning groups Obtained using the Mann-Whitney U test. The bolded p-value indicates statistical significance.

[0127] Table 13 reveals that the BAI scores between the two groups at week 8 showed a difference in median / mean (p>0.05). The BAI score in the immediate group was significantly lower than that in the delayed group at week 8 (p=0.010).

[0128] Therefore, this study met its primary endpoint and validated the rapid efficacy of the tACS device in treating generalized anxiety disorder (GAD).

[0129] Comparative study - disqualification of 1 mA tACS as a therapeutic dose In 2015, the MDD study conducted by Harvard Medical School determined that using a previous version of the tACS device that produced an average amplitude of 1 mA (only half the amplitude of the tACS presented in this article) and administering 1 mA tACS to patients only once a day, five days a week, was ineffective. The following is a summary of the study.

[0130] "We investigated the efficacy and safety of a specific cranial stimulator (CES) device in a fixed setting in subjects with treatment-resistant major depressive disorder (MDD). Thirty subjects with MDD who had an inadequate response to standard antidepressants (57% female, mean age 48.1 ± 12.3 years) were randomized to either 3 weeks of CES treatment (15 / 500 / 15,000 Hz, 1–4 mAmp, 40 V symmetrical rectangular biphasic current) or sham CES." (Device off) Treatment, 20 minutes each time, 5 days a week. The primary outcome measure was improvement on the 17-item Hamilton Depression Rating Scale (HAM-D-17). Adverse effects (AEs) were assessed using the Patient-Related Side Effects Scale (PRISE). The completion rate for CES was 88%, and for sham CES it was 100%. Both treatment groups showed improvements of approximately 3–5 points on the HAM-D-17 score (both p < 0.05), and no significant difference was observed between the groups. The remission rate for CES was 12%, while the remission rate for sham CES was 15%, with no significant difference. CES was considered safe and well-tolerated; inattention and discomfort were the only significantly different disturbing AEs between the CES and sham CES groups (p = 0.019 and p = 0.019, respectively). (0.043). Limitations included a small sample size and a lack of effective control therapy. Although both treatment groups showed significant improvement, the CES in the selected setting was indistinguishable from the sham CES in this sample. Therefore, we cannot rule out that the benefit of this setting used in this particular form of CES is due to a placebo effect. Since other settings exist for this form of CES, future studies should test these settings and compare them with other CES devices. In summary, this comparative study disqualifies the use of 1 mA tACS administered once daily, five days a week, for the treatment of MDD. The MDD and GAD studies summarized above validate the use of the embodiment of the tACS device embodied herein, targeting an average amplitude of 2.2 mA (+ / - 5% manufacturing tolerance) and using treatment twice daily, seven days a week.

[0131] Certain exemplary embodiments have been described to provide a comprehensive understanding of the principles of the structure, function, manufacture, and use of the systems, apparatuses, and methods disclosed herein. One or more examples of these embodiments are illustrated in the accompanying drawings. Those skilled in the art will understand that the systems, apparatuses, and methods specifically described herein and illustrated in the accompanying drawings are non-limiting exemplary embodiments, and that the scope of the invention is defined only by the claims. Features illustrated or described in conjunction with an exemplary embodiment may be combined with features of other embodiments. Such modifications and variations are intended to be included within the scope of the invention. Furthermore, in this disclosure, components with the same names in embodiments often have similar features, and therefore, in a particular embodiment, it is not necessary to fully describe every feature of every component with the same name.

[0132] The subject matter described herein can be implemented in analog electronic circuits, digital electronic circuits, and / or computer software, firmware, or hardware (including the structural components disclosed herein and their equivalents) or any combination thereof. The subject matter described herein can be implemented as one or more computer program products, such as one or more computer programs tangibly embodied in an information carrier (e.g., in a machine-readable storage device) or embodied in a propagating signal, for execution or control of the operation of a data processing device (e.g., a programmable processor, a computer, or multiple computers). A computer program (also referred to as a program, software, software application, or code) can be written in any programming language (including compiled or interpreted languages) and can be deployed in any form, including as a standalone program or as a module, component, subroutine, or other unit suitable for a computing environment. A computer program does not necessarily correspond to a file. A program can be stored in a portion of a file containing other programs or data, in a single file dedicated to the program in question, or in multiple co-located files (e.g., a file storing one or more modules, subroutines, or code portions). A computer program can be deployed to execute on a single computer or on multiple computers (located in one location or distributed across multiple locations and interconnected via a communication network).

[0133] The processes and logic flows described in this specification, including the method steps of the subject matter described herein, can be executed by one or more programmable processors that execute one or more computer programs to perform the functions of the subject matter described herein by manipulating input data and generating output. These processes and logic flows can also be executed by special-purpose logic circuitry, and the devices of the subject matter described herein can be implemented as special-purpose logic circuitry, such as FPGAs (Field-Programmable Gate Arrays) or ASICs (Application-Specific Integrated Circuits).

[0134] For example, processors suitable for executing computer programs include both general-purpose and special-purpose microprocessors, as well as any one or more processors in any type of digital computer. Typically, a processor receives instructions and data from read-only memory or random access memory, or both. The basic components of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Typically, a computer will also include, or be operatively coupled to, receiving data from or transferring data to one or more mass storage devices (e.g., magnetic disks, magneto-optical disks, or optical disks) for storing data, or both. Information carriers suitable for embodying computer program instructions and data include all forms of non-volatile memory, such as semiconductor memory devices (e.g., EPROM, EEPROM, and flash memory devices); magnetic disks (e.g., internal hard disks or removable magnetic disks); magneto-optical disks; and optical disks (e.g., CDs and DVDs). The processor and memory may be supplemented or incorporated into dedicated logic circuitry.

[0135] To provide interaction with the user, the subjects described herein can be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user, and a keyboard and pointing device (e.g., a mouse or trackball) through which the user can provide input to the computer. Other types of devices can also be used to provide interaction with the user. For example, feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including acoustic, speech, or tactile input.

[0136] The techniques described herein can be implemented using one or more modules. As used herein, the term "module" refers to computing software, firmware, hardware, and / or various combinations thereof. However, at least a module should not be construed as software not implemented in hardware, firmware, or documented on a non-transitory processor-readable and recordable storage medium (i.e., a module). itself(Not software). In fact, a "module" should be interpreted as always including at least some physical, non-transitory hardware, such as a processor or part of a computer. Two different modules can share the same physical hardware (e.g., two different modules can use the same processor and network interface). The modules described herein can be combined, integrated, separated, and / or replicated to support a variety of applications. Furthermore, instead of functions performed at a particular module, or in addition to functions performed at a particular module, the functions described herein that perform at a particular module can be performed at one or more other modules and / or by one or more other devices. Moreover, these modules can be implemented across multiple devices and / or other components, locally or remotely to each other. Additionally, modules can be moved from one device and added to another, and / or can be included in two devices.

[0137] The approximate language used in the specification and claims may be used to modify any quantitative expression that allows for variation without causing a change in the essential function associated with it. Therefore, values ​​modified by one or more terms such as “about,” “approximately,” and “substantially” are not limited to specified exact values. In at least some cases, approximate language may correspond to the precision of the instruments used to measure values ​​or manufacturing tolerances. For example, specified values ​​may vary by ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%. For example, a manufacturing tolerance may be ±5%. Scope limitations may be combined and / or interchanged herein and throughout the specification and claims; such scopes are defined and include all subscopes contained herein, unless otherwise indicated by context or language.

[0138] Based on the above embodiments, those skilled in the art will understand further features and advantages of the present invention. Therefore, except as indicated in the appended claims, this application is not limited to the content already specifically shown and described. All publications and references cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A method of transcranial alternating current stimulation (tACS) comprising: generating and transmitting, by a controller comprising a processor, an electrical current received by two electrodes in contact with opposite sides of a patient's scalp to deliver a therapeutic dose of tACS for a predetermined treatment time; wherein the generated electrical current has a constant average amplitude of about 2.2 mA and a bi-directional square wave waveform that utilizes a carrier waveform having a frequency of about 15 kHz, a first modulation waveform having a frequency of about 15 Hz, and a second modulation waveform having a frequency of about 500 Hz; wherein the generated electrical current comprises a plurality of sub-bursts for a burst duration that includes a burst-on duration of about 50 ms comprising the plurality of sub-bursts followed by a burst-off duration of about 16.7 ms without the plurality of sub-bursts; wherein the electrical current switches polarity after each burst duration; wherein each sub-burst comprises a plurality of pulses for a sub-burst duration that includes a sub-burst-on duration of 1 ms comprising the plurality of pulses followed by a sub-burst-off duration of about 1 ms without the plurality of pulses; wherein each pulse of the plurality of pulses extends for about 33.33 μβ followed by a pause of about 33.33 μβ.

2. The method of claim 1, wherein each of the two electrodes is positioned on the squamous part of the temporal bone, superior to the posterior part of the zygomatic arch, and maintained in place during delivery of the therapeutic dose of tACS to treat major depressive disorder (MDD) or generalized anxiety disorder (GAD); wherein each of the electrodes has a diameter of about 36 mm; and further comprising retrieving, by the processor, the predetermined treatment time from a memory in communication with the processor; measuring a treatment time during which the therapeutic dose of tACS is delivered to the patient; comparing the treatment time to the predetermined treatment time; and stopping transmission of the generated electrical current when the elapsed time equals the predetermined treatment time.

3. The method of claim 2, further comprising: administering the therapeutic dose of tACS to the patient for the predetermined treatment time twice daily, wherein one administration occurs within two hours or less after waking from sleep and the other administration occurs within two hours or less before falling asleep.

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