Transcranial Alternating Current Stimulation (TACS)

Description

1 / 44 “Transcranial Alternating Current Stimulation (TACS)” Fundamentals

[001] Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are highly prevalent; in 2020, 48 million Americans were prescribed antidepressant medication and 49 million were prescribed anxiety medication. Furthermore, according to the Centers for Disease Control and Prevention, the rate of clinical depression and anxiety among adults in the U.S. has more than tripled since the start of the COVID-19 pandemic; Boston University reported that about 1 in 3 Americans may now suffer from one or both disorders. Approximately 60% of patients with GAD also have MDD, and nearly half of patients with MDD have GAD; this high level of comorbidity makes treatments that can address both conditions simultaneously advantageous.Of the two conditions, MDD is considered more fatal due to the risk of suicide and the high rate of hospitalizations and other chronic health conditions and disorders, such as substance use disorder, associated with MDD.

[002] For decades, inadequate access to psychiatrists has been recognized as a public health problem for many segments of the US population; most patients with clinical depression who are treated with psychotropic medications receive their prescriptions from their primary care physicians, rather than a board-certified psychiatrist. However, analyses of primary care practices show low utilization of depression care management processes, suggesting that primary care physicians may not be well-equipped to manage depression effectively. Some researchers claim that depression is “significantly undertreated,” particularly in the context of primary care. Other research suggests that antidepressant medications may be overprescribed for patients who are better suited to psychotherapy. Petition 870250108869, dated 11 / 27 / 2025, page 6 / 57 2 / 44 lower risk. There is also a much greater demand for psychotherapy than for therapists who can care for patients in a timely manner.

[003] Common antidepressant medications and psychotherapy generally take many weeks to take effect. The American Psychiatric Association (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder notes that psychotherapeutic approaches should produce at least moderate improvement (e.g., a reduction of more than 20% in symptoms) within 4 to 8 weeks of treatment and recommends that physicians emphasize to patients that 2 to 4 weeks of medication are necessary before beneficial effects can be noticed. However, this long period to achieve symptom improvement can be problematic. Notably, delayed responses to treatment can result in decreased adherence, which affects treatment success, relapse risk, and the cost of the illness.For example, it has been observed that the first 6 weeks of treatment are a particularly critical period for promoting adherence, with increased risks of treatment abandonment, relapse, medication discontinuation, vulnerability to suicide, and greater economic burden among those who demonstrate early non-adherence to antidepressants. Fear and experience of side effects also contribute to patients' non-adherence to medication. Less commonly prescribed controlled substances, such as ketamine and electroconvulsive therapy (ECT), act quickly but are extremely expensive to administer and frequently cause significant side effects.

[004] Consequently, there is a need for fast-acting depression treatments that pose a low risk to patients, promote adherence, are self-administered and inexpensive, and can also significantly reduce anxiety. SUMMARY Petition 870250108869, dated 11 / 27 / 2025, p. 7 / 57 3 / 44

[005] Transcranial Alternating Current Stimulation (tACS) has been investigated as another approach to treat depression. tACS is a form of non-invasive neurostimulation that delivers low-dose alternating current to the brain to induce neuroplasticity. In this way, tACS has shown promise as an effective treatment for depression, as well as anxiety, insomnia, and other neuropsychiatric and cognitive disorders.

[006] tACS devices can be self-administered by the patient and used safely as a standalone treatment or in combination with medication. Although regulated as medical devices, tACS devices are neither complex nor expensive to manufacture. Importantly, there is growing scientific evidence that tACS is safer than medication and, in certain forms, has a rapid onset of action.

[007] A challenge faced in the development of tACS devices has been to discover a method of delivering electrical current that is simultaneously therapeutic, comfortable for the patient, and capable of successfully maintaining blinding in a sham controlled clinical trial. If patients find the stimulation uncomfortable, they may avoid using the device; if participants in a clinical trial can easily differentiate an active device from a sham device (a device that appears to function normally but produces no stimulation), the trial results may not be easily defended.

[008] The present disclosure provides enhanced tACS systems and methods that are suitable for the treatment of depression (e.g., Major Depressive Disorder; MDD), as well as anxiety (e.g., Generalized Anxiety Disorder; GAD), insomnia, and other neuropsychiatric and cognitive disorders. As discussed in greater detail below, a tACS device is provided that has been shown to provide therapeutically effective treatment. Petition 870250108869, dated 11 / 27 / 2025, page 8 / 57 4 / 44 using a rapidly pulsed alternating current (AC) output in the form of a bipolar (bidirectional) square wave that employs a high-frequency carrier and modulates to two lower frequencies, with a current amplitude of 2.2 mA (+ / - 5% manufacturing tolerance). In conducting large-scale, randomized, controlled clinical trials, this combination of amplitude, pulse frequency, waveform, and frequency, applied to the human brain daily for a predetermined treatment time (e.g., approximately 20 minutes), twice a day (once immediately after waking and once before sleeping), via two electrodes placed at specific locations on each side of the head, has been found to provide effective treatment for depression and anxiety. The ability to deliver effective therapy at lower current amplitude substantially reduces or eliminates discomfort experienced by patients.

[009] In one embodiment, a method of transcranial alternating current stimulation (tACS) is provided. The method involves generating and transmitting, by a controller including a processor, an electrical current to be 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 electrical current has a constant average amplitude of about 2.2 mA and a bidirectional square waveform using a carrier waveform with a frequency of about 15 kHz, a first modulating waveform with a frequency of about 15 Hz, and a second modulating waveform with a frequency of about 500 Hz.The generated current includes a plurality of subbursts within a burst duration, the burst duration including an on burst duration of approximately 50 ms including the plurality of subbursts followed by an off burst duration of approximately 16.7 ms without the plurality of subbursts. The current switches polarity after each burst duration. Each subburst includes a plurality of pulses within a subburst duration, a. Petition 870250108869, dated 11 / 27 / 2025, p. 9 / 57 5 / 44 Subburst duration including a subburst of 1 ms duration including the pulse plurality followed by a deactivated burst duration of approximately 1 ms without the pulse plurality. Each pulse of the pulse plurality extends for approximately 33.33 μs, followed by a pause of approximately 33.33 μs.

[010] In another embodiment, each of the two electrodes is positioned in the squamous temporal bone, above the posterior aspect of the zygomatic arch, and held in place during the administration of the therapeutic dose of tACS for the treatment of Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD). The diameter of each electrode is approximately 36 mm. The method also includes the processor retrieving the predetermined treatment time from a memory in communication with the processor, where the predetermined treatment time is approximately 20 minutes. The method also includes measuring a treatment time during which the therapeutic dose of tACS is administered to the patient, comparing the treatment time with the predetermined treatment time; and ceasing the transmission of the generated electrical current when the elapsed time is equal to the predetermined treatment time.

[011] In another embodiment, the method also includes administering the therapeutic dose of tACS to the patient twice a day during the predetermined treatment time, one administration occurring within two hours of waking up and another administration occurring within two hours before sleeping.

[012] In one embodiment, a method of transcranial alternating current stimulation (tACS) is provided. The method involves placing two electrodes in contact with opposite sides of the patient's scalp. The method further involves generating an electrical current using a controller including a processor. The method additionally involves transmitting the generated electrical current to the electrodes to deliver a therapeutic dose of tACS for a predetermined treatment time (e.g., approximately 20 minutes). The generated electrical current has an amplitude of Petition 870250108869, dated 11 / 27 / 2025, page 10 / 57 6 / 44 approximately 2.2 mA. The generated electric current still has a waveform including a carrier waveform having a frequency of approximately 15 kHz, a first modulating waveform having a frequency of approximately 15 Hz, and a second modulating waveform having a frequency of approximately 500 Hz.

[013] In another modality, each of the two electrodes is positioned on the squamous temporal bone, above the posterior aspect of the zygomatic arch, and held in place during stimulation.

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

[015] In another embodiment, the therapeutic dose of tACS is sufficient for the treatment of at least one of the following: Major Depressive Disorder (MDD) or Generalized Anxiety Disorder (GAD).

[016] In another embodiment, the method also includes the processor retrieving the predetermined treatment time from a memory communicating with the processor. The method also includes measuring the treatment time during which the therapeutic dose of tACS is administered to the patient. The method also includes comparing the treatment time with the predetermined treatment time. The method also includes interrupting the transmission of the therapeutic dose of tACS to the patient when the elapsed time is equal to or greater than the predetermined treatment time.

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

[018] In another embodiment, the waveform includes a plurality of first square wave subbursts having a first polarity that repeats for a burst duration, followed by a plurality of second square wave subbursts having an opposite second polarity that repeats for the burst duration. Petition 870250108869, dated 11 / 27 / 2025, p. 11 / 57 7 / 44

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

[020] In another embodiment, each of the plurality of first subbursts and second subbursts extends over a subburst duration of about 2 ms which includes an on subburst duration of about 1 ms followed by an off subburst duration of about 1 ms.

[021] In another embodiment, each of the first and second plurality of square wave subbursts includes a plurality of pulses extending a pulse duration of about 66.7 ms, which includes an on pulse duration of about 33.3 ms, followed by an off pulse duration of about 33.3 ms.

[022] In one embodiment, a transcranial alternating current stimulation (tACS) device is provided. The device includes a stimulator comprising a strap and two electrodes attached to the strap. The strap is configured to be fastened to the human 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 the plurality of electrodes and configured to perform a variety of operations. The controller is configured to generate an electrical current. The controller is further configured to transmit the electrical current to the electrodes to deliver a therapeutic dose of tACS for a predetermined treatment time. The generated electrical current has an amplitude of approximately 2.2 mA.The generated electric current has a waveform that includes a carrier waveform with a frequency of approximately 15 kHz, a first modulating waveform with a frequency of approximately 15 Hz, and... Petition 870250108869, dated 11 / 27 / 2025, p. 12 / 57 8 / 44 a second modulating waveform having a frequency of approximately 500 Hz.

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

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

[025] In one embodiment, the controller is further configured to retrieve the predetermined treatment time from a memory in communication with the processor, to measure a treatment time during which the therapeutic dose of tACS is administered to the patient, to compare the treatment time with the predetermined treatment time; and to cease transmission of the therapeutic dose of tACS to the patient when the elapsed time is equal to or greater than the predetermined treatment time.

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

[027] In one embodiment, the waveform includes a plurality of first square wave subbursts having a first polarity that repeats for a burst duration, followed by a plurality of second square wave subbursts having an opposite second polarity that repeats for the burst duration.

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

[029] In one embodiment, each of the plurality of first subbursts and second subbursts extends over a subburst duration of about 2 ms Petition 870250108869, dated 11 / 27 / 2025, p. 13 / 57 9 / 44 which includes an on-subburst duration of approximately 1 ms followed by an off-subburst duration of approximately 1 ms.

[030] In one embodiment, each of the first and second plurality of square wave subbursts includes a plurality of pulses extending a pulse duration of about 66.7 ms, which includes an on pulse duration of about 33.3 ms, followed by an off pulse duration of about 33.3 ms. DESCRIPTION OF THE DRAWINGS

[031] These and other features will be more readily understood from the following detailed description taken in conjunction with the attached drawings, in which:

[032] FIG. 1 is a diagram illustrating an exemplary embodiment of a treatment environment in which a transcranial alternating current stimulation (tACS) device, including a controller and a stimulator, is employed to deliver electrical stimulation to a patient's head;

[033] FIG. 2A is a rear-facing perspective view of the stimulator in FIG. 1;

[034] FIG. 2B is a top-down view of the stimulator in FIG. 1;

[035] FIG. 3A is a schematic diagram of an exterior of the controller of FIG. 1;

[036] FIG. 3B is a block diagram that illustrates the components of the controller in FIG. 1;

[037] FIGS. 4A-4B are schematic illustrations of a constant current waveform generated by the controller for tACS treatment; and

[038] FIG. 5 is a flow diagram that illustrates a treatment method using the tACS device of FIG. 1.

[039] Note that the drawings are not necessarily to scale. The drawings are intended to represent only typical aspects of the subject matter here. Petition 870250108869, dated 11 / 27 / 2025, p. 14 / 57 10 / 44 disclosed and therefore should not be considered as limiting the scope of the disclosure. DETAILED DESCRIPTION

[040] As used herein, a “patient” is a vertebrate, preferably a mammal, most preferably a human. Mammals include, but are not limited to, mice, apes, humans, farm animals, sport animals, and domestic animals.

[041] As used herein, treating or managing a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach to achieving beneficial or desired outcomes, 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 in the extent of the condition, disorder or disease, stabilization of the state of the condition, disorder or disease, prevention of the development of the condition, disorder or disease, prevention of the spread of the condition, disorder or disease, delay or slowing of the progression of the condition, disorder or disease, delay or slowing of the onset of the condition, disorder or disease, improvement or palliation of the condition, disorder or disease state, and partial or total remission."Treating" can also mean inhibiting the progression of the condition, disorder, or disease, slowing the progression of the condition, disorder, or disease temporarily, although in some cases it involves permanently halting the progression of the condition, disorder, or disease.

[042] Here are discussed modalities of systems and corresponding methods for transcranial alternating current stimulation (tACS). These systems and methods can be employed for the treatment of depression (Major Depressive Disorder), as well as anxiety and insomnia for sleep maintenance. However, it can be understood that modalities of dissemination can be Petition 870250108869, dated 11 / 27 / 2025, page 15 / 57 11 / 44 employees to treat other conditions without limits.

[043] FIG. 1 illustrates a treatment environment in which a tACS device is employed to treat a patient. As shown, the tACS device includes a controller in signal communication with a stimulator. As discussed in greater detail below, the stimulator is configured to attach to the patient's head in order to deliver current to the patient's brain. The controller is configured to allow a user (e.g., patient) to control the tACS device and deliver electrical current to the electrodes with a predetermined waveform and controlled, constant amplitude for a defined period of time (a predetermined treatment time).

[044] FIG. 2A-2B shows the stimulator in a rear view (FIG. 2A) and a top-down view (FIG. 2B). As shown, the stimulator includes a strap and a pair of electrodes, each mounted in an electrode compartment that is adjustably attached to the strap.

[045] The strap may be a flexible band that forms a closed loop. In certain embodiments, the strap may be made of an elastic material capable of stretching to fit the patient's head. In other embodiments, the strap may include an adjustment mechanism to adjust the circumference of the closed loop to comfortably fit the patient's head. The adjustment mechanism may take any form that allows the electrodes to be securely positioned in contact with the patient at a selected location (e.g., a strap adjuster, buckles, hook-and-loop fasteners, snap closures, and the like).

[046] In one embodiment, each of the electrode pairs may be removable from its housing. For example, the electrodes may be sponges. The sponges may have a selected diameter suitable for administering a therapeutic dose of tACS. For example, the diameter of the electrodes may be approximately 36 mm (e.g., 36 mm + / - 5%). When moistened with water, the sponges Petition 870250108869, dated 11 / 27 / 2025, page 16 / 57 12 / 44 conduct electricity through water. However, it can be appreciated that electrodes can adopt other configurations that provide clinical performance equivalent to the sponges discussed above, without limitations. For example, the electrode can be non-removable from the cavity and formed from a durable electrically conductive material (e.g., a conductive polymer, metal, etc.).

[047] Each of the pairs of electrode housings can be mounted below the strip on opposite sides. As shown, the electrode housings may include an opening that extends through them (e.g., in a front-to-back direction). The opening can be sized to receive the strip through it.

[048] In certain modalities, the position of the receptacle in relation to the strip can be adjusted. This adjustment is beneficial to ensure that the electrodes are positioned in the correct location on the patient's head.

[049] In one embodiment, this fit may be provided by a friction fit between the opening and the strip. For example, the thickness of the opening may be slightly less than the thickness of the strip to provide the friction fit. When a sliding force sufficient to overcome the friction between the electrode housing and the strip is applied, the electrode housing may slide relative to the strip. When the application of the sliding force is stopped, the electrode housing is held in place relative to the strip.

[050] It can be understood that other mechanisms may be employed without limit to secure the electrode housings to the strip and to provide adjustment of the electrode housings to the strip. Examples may include, but are not limited to, reusable adhesives, hook and loop fasteners, snap closures and the like.

[051] Optionally, the stimulator may include a pad attached to the strap on the front side of the stimulator. In this way, the pad can contact the patient's forehead. Petition 870250108869, dated 11 / 27 / 2025, page 17 / 57 13 / 44 when the stimulator is placed on the patient's head, increasing patient comfort during use of the stimulator.

[052] FIGS. 3A-3B illustrate an embodiment of the controller. FIG. 3A illustrates an external view of the controller housing, while FIG. 3B is a schematic diagram of the controller electronics. As shown, the controller includes a power supply, a speaker, a constant current controller, a rotary switch, lights, a controller, and a voltage regulator. Each of these components is discussed in more detail below.

[053] The power source provides power to the entire tACS device. In one embodiment, the power source may be one or more batteries. However, in other embodiments, the controller may be configured to receive power from the mains after power conditioning.

[054] The rotary switch is configured to turn on / off and to start / stop the current supply to the electrodes for treatment. For example, turning it a certain amount from an OFF position to a first position turns the tACS device on and puts it into a standby state. A further turn to a second position causes current distribution to the electrodes. In one embodiment, the rotary switch may be a rotary knob. However, other interface devices (not shown) may be employed without limitation. Examples may include, but are not limited to, buttons, sliders, switches, etc.

[055] 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.

[056] The tACS device is configured to generate a constant current. This output is obtained by the constant current controller. According to Ohm's Law, voltage and current are directly related to each other by the resistance of Petition 870250108869, dated 11 / 27 / 2025, p. 18 / 57 14 / 44 load. In the context of the tACS device, the load is the human head. The constant current controller handles the variability in the resistance of the human head. The constant current controller adjusts its own resistance so that the human head plus the controller produce a fixed current for the output voltage. In this way, a constant current amplitude of 2.2 mA within a manufacturing tolerance (e.g., + / - 5%) can be emitted using a bidirectional square waveform.

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

[058] The speaker is configured to provide audio output to notify the patient / operator that a therapy session has been completed or that there is a power supply interruption problem. In one modality, a buzzer may be used in place of a speaker.

[059] The controller includes a processor and may include a memory or be in electrical communication with a memory device (not shown) and the electrode. The controller may power the lights to provide visual confirmation that the tACS device is on. The voltage regulator receives power from the power source and increases the voltage to the output circuit. The controller produces three frequencies, a carrier frequency and two modulation frequencies, and modulates the output using the analog switch. The constant current controller maintains the current through the output by means of a resistive feedback circuit that varies its own resistance so that the constant current output of 2.2 mA + / - 5% is maintained even if there are differences in the output. The controller will activate the speaker / buzzer to indicate the end of a treatment session. Petition 870250108869, dated 11 / 27 / 2025, page 19 / 57 15 / 44

[060] FIGS. 4A-4B are schematic illustrations of the 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 waveform parameters discussed below may vary within manufacturing tolerances from the stated values ​​(e.g., + / - 5%).

[061] As shown in FIG. 4A, the waveform includes a plurality of first square wave subbursts having a first polarity that repeats for a burst duration, followed by a plurality of second square wave subbursts having an opposite second polarity that repeats for the burst duration.

[062] The burst duration is approximately 66.7 ms and includes an on duration and an off duration. The on duration is approximately 50 ms and extends from the beginning of the first subburst of the burst duration to the end of the last subburst of the burst duration. The off duration is approximately 16.7 ms and extends from the last subburst of the burst duration to the end of the burst duration.

[063] Each of the plurality of first subbursts and second subbursts extends a subburst duration of about 2 ms. The subburst duration includes an on subburst of about 1 ms duration, followed by an off subburst of about 1 ms.

[064] As shown in FIG. 4B, each of the first and second plurality of square wave subbursts includes a plurality of pulses spanning a pulse duration. The pulse duration is about 66.7 ms and includes an on pulse duration of about 33.3 ms, followed by an off pulse duration of about 33.3 ms.

[065] In the discussion above, the constant current waveform is generated by the controller and transmitted to the electrodes. However, in other embodiments, one or more components of the controller circuit may be positioned in Petition 870250108869, dated 11 / 27 / 2025, p. 20 / 57 16 / 44 electrode housing. In certain embodiments, all the components of the controller circuit can be housed in the electrode housing. Lights, speaker and controller switches can also be duplicated in the electrode housing. Thus, the tACS device can include a stimulator that combines the functionality of the stimulator and the controller of FIG. 1.

[066] Configured in this way, the user can control the tACS device in several ways. In one embodiment, user interface devices (e.g., switches, buttons, etc.) can be provided on the electrode to control the tACS device. In another embodiment, the tACS device can be configured to communicate wirelessly with a computing device (e.g., smartphone, tablet, laptop, desktop computer, etc.). The computing device can run one or more programs that virtually replicate the functionality of physical components of the controller (e.g., the lights, the speaker, and / or switches, such as the rotary switch).

[067] FIG. 5 illustrates a treatment method 500 using the tACS device of FIG. 1. As shown, the modalities of method 500 include operations 402 to 416. However, it can be understood that, in alternative modalities, the method may include more or fewer operations and the order of one or more operations may be varied.

[068] In operation 402, the stimulator is positioned on the patient's head. The patient's scalp and hair must be clean to minimize the risk of skin irritation caused by the electrodes. The sponge electrodes must be moist enough to wet the scalp and hair with which they come into contact. This ensures proper electrical contact between the electrodes and the patient's head. The wires are electrically connected to the connector at the terminals and electrically connected to the sponge electrodes.

[069] The band is placed over the patient's head so that the strip stays Petition 870250108869, dated 11 / 27 / 2025, page 21 / 57 17 / 44 above the patient's eyebrows. The moistened electrodes are inserted into the electrode housings with the wires connected. The electrodes are then slid firmly under the headband, directly from the sideburns, so that the bottom of the electrode is lower than the top of the ear, which is behind and not below the electrode. The physiological location for electrode placement is the squamous temporal bone, above the posterior aspect of the zygomatic arch.

[070] In operation 504, once the moist sponge electrodes are positioned, the tACS device is switched on (e.g., by rotating the rotary switch) to generate and transmit the electrical current to the patient via the electrodes to deliver the therapeutic dose of tACS to the patient. The dial is rotated from the OFF to the ON position. The standby light should illuminate. Rotating the dial further causes the fixed current to be generated and distributed to the electrodes. The waveform of the generated current has a predetermined waveform, as discussed above, including the carrier frequency and the two modulation frequencies. The amplitude (of the generated current) is also fixed at 2.2 mA + / - 5%.

[071] In operation 506, the microprocessor measures an amount of time elapsed since the start of the distribution of the generated electrical current (therapeutic dose of tACS) to the electrodes. For example, the processor starts a timer (e.g., a 20-minute timer) simultaneously with the distribution of the generated waveform to the electrodes.

[072] In operation 510, the controller compares an amount of time elapsed since the start of the timer with a predetermined therapy time (e.g., 20 minutes). The predetermined therapy time can be retrieved from a memory in communication with the microprocessor. In one mode, the predetermined therapy time may be 20 minutes. However, in other modes, the predetermined therapy time may take on other values.

[073] In operation 512, the controller determines if the elapsed time is equal Petition 870250108869, dated 11 / 27 / 2025, page 22 / 57 18 / 44 to the predetermined therapy time. Otherwise, method 500 returns to operation 506. If so, the controller interrupts the waveform output to the electrodes in operation 412, ceasing tACS treatment.

[074] In other modalities, the tACS device can be configured to determine if therapy is interrupted. If so, the timer that tracks therapy can pause and restart when therapy is resumed (unless the tACS device is switched off). Additionally, in circumstances where the tACS device is switched off, the timer can be reset to the predetermined therapy time (e.g., 20 minutes).

[075] The method may also include administering the therapeutic dose of tACS to the patient several times a day (e.g., twice-daily treatment) during a predetermined treatment time (e.g., about 20 minutes). For example, a first daily treatment may be performed at a predetermined time at the beginning of the patient's daily routine, such as two hours after waking up. A second daily treatment may be performed at a predetermined time at the end of the patient's daily routine, such as two hours before bedtime. RESULTS Essay 1 - Treatment of Major Depressive Disorder (MDD) Overview

[076] A triple-blind, randomized, placebo-controlled study was conducted to demonstrate the efficacy of the tACS device incorporated herein for the treatment of Major Depressive Disorder (MDD) in adults. The study patient population consisted of subjects who met the criteria for moderate to severe Major Depressive Disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition - DSM-5), as diagnosed by the study's clinical team, composed of licensed psychiatrists and psychiatric mental health nurses. Patients had a Beck Depression Inventory score. Petition 870250108869, dated 11 / 27 / 2025, page 23 / 57 19 / 44 (BDI-II) baseline between 20 and 63 (moderate to severe).

[077] Participants self-administered treatment at home using either an active tACS device or a sham tACS device for two daily 20-minute treatment sessions, once after waking and a second time before sleeping, for four (4) weeks. The primary outcome was the change in baseline BDIII score to the week 2 time point in an intention-to-treat analysis, followed by pre-protocol participant analyses (“treatment adherent” or “compliant to use”). Secondary analyses examined changes in week 1 and week 4 time points, response rates, subgroup analyses, and safety.

[078] 255 participants were randomized to active or sham treatment; 185 women and 70 men, aged 21 to 65 years, residing in 47 US states, were enrolled. In the general population, approximately twice as many women as men are treated for MDD. In the intention-to-treat analysis, there was significantly greater improvement at week 1 and greater response at week 4 using the tACS device. Importantly, per-protocol analyses determined that active tACS treatment was significantly superior to sham tACS treatment at all time points. Improvements were significantly greater for female participants. Side effects were reported by a small percentage of participants and were mild and temporary.

[079] The study demonstrated that the tACS device discussed here provides rapid and significant improvement in depression in adults with MDD, particularly in women. Compared to other therapies for depression, the tACS device offers advantages of rapid and clinically significant treatment effect, patient self-administration, and low frequency and minimal nature of adverse events. Petition 870250108869, dated 11 / 27 / 2025, page 24 / 57 20 / 44

[080] Subjects were randomly assigned (approximately 1:1) to active or sham treatment. Subjects, assessors, and sponsors were all blinded to the study conditions (triple-blind). James's Concealment Index was used to assess the degree to which participants believed they were using an active or sham device (subject concealment). The sham device appeared to function like the active device but did not produce electrical output. This study was conducted in accordance with good clinical practice (ISO 14155-2020).

[081] Adults who meet the DSM5 criteria for MDD, diagnosed by a study clinician, with moderate to severe severity on the Beck Depression Inventory (BDI-II) could participate.The eligibility criteria were: age between 21 and 65 years; resident in the USA; able to read / write in English; able to commit to the treatment protocol; no history of suicide attempt or active suicidal ideation with a plan or intent in the last 30 days; no prior hospitalization for mental health problems in the past year; no use of neuromodulation in the past year; no changes in prescription medications for the nervous system in the past 30 days; no use of recreational substances, hypnotics, steroids and / or marijuana products in the past 30 days; no history of alcohol or substance abuse in the past 12 months; no history of mental health disorders other than MDD; no known history of heart disease or trigeminal neuralgia; no pacemaker or any type of electronic medical device.Sexually active women with the potential to become pregnant were required to commit to practicing at least one method of contraception during experiment 1.

[082] All data were entered into the Clinical Research Organisation (CRO) managed electronically reported patient outcomes (ePRO) clinical trial software platform. Potential participants completed an online pre-screening process. Participants Petition 870250108869, dated 11 / 27 / 2025, page 25 / 57 21 out of 44 eligible participants met virtually with the research team, who reviewed the purpose of the experiment, the procedures, the risks and benefits, the compensation, and the confidentiality of the data. Interested participants completed the informed consent form electronically.

[083] Participants began a 14-day preparation period (no treatment was initiated), after which they reassessed self-assessments and completed a computer-administered MINI (Mini International Neuropsychiatric Interview (MINI): The MINI is an assessment tool for major psychiatric disorders. In the experiment, the MINI was used in a participant-self-administered format and was confirmed during participants' telemedicine consultation with a physician to determine if any comorbid diagnosis might disqualify the participant from proceeding to the treatment phase of the study.

[084] A BDI-II score between 20 and 63 was required at both the initial pre-screening and baseline to participate. The purpose of this introduction was to eliminate participants with transient depression that could potentially distort the study results. Given the timing of these assessments, participants should have been experiencing depression for at least one month prior to the start of treatment. During a clinical interview with a clinician, participants were assessed using the DSM-5 diagnostic criteria for MDD and other psychiatric disorders, and MINI responses were reviewed for final eligibility determination.

[085] Eligible participants were randomized to the active treatment group (active tACS device) or to the control group (sham tACS device) by a non-blinded investigative team member who had no contact with the participants and did not discuss group allocation with other investigative team members. Randomization assignments were made Petition 870250108869, dated 11 / 27 / 2025, page 26 / 57 22 / 44 sequentially. There were no restrictions or other information determining the randomization order for the initial 250 randomizations required by the protocol. Excess randomizations above 250 used a table with equal allocations between the active and sham arms in each block of 10.

[086] The active tACS device used by the experiment participants was a modality of the tACS device discussed above. The tACS device included an electrical pulse generator, operated by a controller that included a processor that produces and transmits an electrical current to two electrodes (or sensor electrodes) in contact with the patient's scalp. The diameter of each electrode was approximately 36 mm. The active tACS device generates a pulsed, alternating, constant current. A third-party device testing laboratory confirmed that the devices produced a current amplitude between 2.1 mA and 2.2 mA, which was within a tolerance of ±5% of 2.2 mA.The device used a bidirectional square waveform (also called rectangular) with a carrier frequency of 15 kHz (+ / - 5% manufacturing tolerance), a first modulated frequency of 15 Hz (+ / - 5% manufacturing tolerance), and a second modulated frequency of 500 Hz (+ / - 5% manufacturing tolerance). The current, supplied in a series of bursts over a burst duration, including an on-burst duration of 50 milliseconds and an off-burst duration of 16.7 milliseconds, then changed polarity (direction). Each 50-millisecond burst included a series of sub-bursts. Each sub-burst had a 1-millisecond on duration, followed by a 1-millisecond off duration. Each 1-millisecond sub-burst further included a plurality of pulses. Each pulse had a duration of 33.33 μs (pulse-on duration), followed by a pause of 33.33 μs (pulse-off duration).The active tACS device provided a predetermined treatment duration of 20 minutes, timed from a memory communicating with the processor, and then switched off. Petition 870250108869, dated 11 / 27 / 2025, p. 27 / 57 23 / 44 automatically, ending the treatment sessions.

[087] Before participants began their first treatment session, the study team conducted a training session with each participant via videoconference. Participants assembled the device during the training and practiced its use under the team's supervision. Each of the two electrodes was moistened with tap water and positioned on the scalp, placing it under a headband included in the device kit; each electrode was placed on each side of the head, over the squamous temporal bone, located above the posterior aspect of the zygomatic arch. Participants were instructed to self-administer a 20-minute treatment twice a day, once upon waking and a second time before bedtime.

[088] After the training session, participants responded to the James Concealment Index, a standardized and validated questionnaire developed to detect the success or failure of participant blinding (whether a participant knows which arm of the study they are part of), which asked what type of experimental device they believed they had received (active or control device) and selected from five options to indicate the strength of that belief. An analysis of the results of the James Concealment Index determined that the concealment was successful, confirming the participants' inability to distinguish an active device from a sham device.

[089] Every day after device training, participants reported whether they used the tACS device as instructed and any changes in their health status or medications. After one, two, and four weeks of treatment, participants completed clinical outcome measures and reported any adverse events or changes in concomitant medications.

[090] The Beck Depression Inventory, Second Edition (BDI-II) was the Petition 870250108869, dated 11 / 27 / 2025, page 28 / 57 The 24 / 44 is the main instrument used to assess the severity of depression. The BDI-II is a validated and commonly used self-report, multiple-choice inventory that assesses the severity of depression. The BDI-II contains 21 items on a 4-point scale of 0 to 3 for a total score of 0 to 63. The BDI-II is commonly used in clinical research and in the mental health field to assess psychiatric disorders and is particularly useful for measuring the effectiveness of patient-administered treatments. Statistical Analysis

[091] The sample size for Experiment 1 was based on the primary outcome measure of change in the BDI-II. Sample size calculations were based on a planned sample size of 250 evaluable subjects with a 1:1 allocation. Experiment 1 provided 80% power, assuming a population mean difference between groups of 3.2 and a common standard deviation of 9, based on a two-sample two-sided t-test with an alpha of 0.05. Previous data suggested that the standard deviation for improvement at 2 weeks would be approximately 6.5; however, a conservative estimate of 9 was used for these calculations.

[092] All analyses were performed using SAS® Version 9.4. The primary outcome analysis was performed at a one-sided alpha level of 0.025, with all other analyses based on a nominal two-sided alpha level of 0.05. Confidence intervals and p-values ​​for secondary outcomes and subgroup analyses were not adjusted for multiple comparisons. Primary analyses used an intention-to-treat (ITT) as a more conservative estimate of treatment effects. Subsequently, selected analyses of subjects who reported complete twice-daily treatment adherence were conducted to determine whether the active treatment was significantly superior to the sham treatment when participants in both the active and sham groups followed the instructions for use. Petition 870250108869, dated 11 / 27 / 2025, page 29 / 57 25 / 44

[093] The primary efficacy outcome was defined as the change in BDI-II score at week 2 compared to baseline in the active treatment versus control arm. The analysis was performed using a linear regression model for change, adjusted for each subject's baseline value. Missing data for the primary outcome only were addressed through 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 by treatment group. Several sensitivity analyses were performed. They were of a supportive nature and employed nominal confidence levels. The primary outcome was replicated using the As Treated and As Protocol (adherent to use) populations. The same statistical methods used for the primary outcome were employed.Secondary analyses were conducted for the week 1 and 4 time points and for the PHQ-9 and QIDS-SR at all time points, adjusting for baseline scores. One secondary analysis compared the BDI-II response rate at weeks 1, 2, and 4, with response defined as a 50% or greater improvement in baseline score. Subgroup analysis of the primary outcome was performed on the ITT analysis set for subgroups defined by sex, race, and baseline BDI-II (moderate (20-28) vs. severe (29-63)) using an interaction between the treatment arm and the subgroup. The interaction term with a p-value < 0.15 was examined in more detail according to the pre-specified analysis plan. No adjustment for multiple comparisons was performed. An exploratory analysis examined whether concomitant use of antidepressant medications affected the treatment outcome. Participant Characteristics

[094] Baseline demographic and clinical characteristics are summarized in Table 1. Petition 870250108869, dated 11 / 27 / 2025, page 30 / 57 26 / 44 Table 1 - Characteristics of the Participants. Intention-to-treat sample (N=255) Assessments Active Treatment N = 126 Control Treatment N = 129 Total N = 255 p-value Age (year) N 126 129 255 0.7182 Mean 39.6 40.1 39.8 SD 10.04 10.90 10.47 Median 38.5 39 39 Min. 21 21 21 Max. 63 63 63 Biological sex (n (n%)) Female 96 (76.19%) 89 (68.99%) 185 (72.55%) 0.1978 Male 30 (23.81%) 40 (31.01%) 70 (27.45%) Race / Ethnicity (n (n%)) White 92 (73.02%) 99 (76.74%) 191 (74.90%) 0.9280 Asian 4 (3.17%) 5 (3.88%) 9 (3.53%) Black or African American 9 (7.14%) 7 (5.43%) 16 (6.27%) Hispanic or Latino 9 (7.14%) 7 (5.43%) 16 (6.27%) Other 12 (9.52%) 11 (8.53%) 23 (9.02%)

[095] Based on baseline BDI-II scores, 32.6% and 67.5% of the sample reported moderate and severe depression symptoms, respectively, as shown in Table 2. Table 2 - Baseline clinical characteristics Assessments Active Treatment N = 126 Control Treatment N = 129 Total N = 255 p-value Beck Depression Inventory-II Scores (BDI-II) N 126 129 255 0.8562 Mean 34.1 33.9 34.0 SD 8.88 8.99 8.92 Petition 870250108869, dated 11 / 27 / 2025, page 31 / 57 27 / 44 Median 33 33 33 Min. 20 20 20 Max. 57 59 59 Beck Depression Inventory-II (BDI-II) clinically based categories Minimum 0 (0.00%) 0 (0.00%) 0 (0.00%) 0.4244 Mild 0 (0.00%) 0 (0.00%) 0 (0.00%) Moderate 44 (34.92%) 39 (30.23%) 83 (32.55%) Severe 82 (65.08%) 90 (69.77%) 172 (67.45%) Simultaneous use of antidepressant medication 55 (43.7%) 47 (36.4%) 102 (40.0%) 0.3623

[096] James's Blinding Index (0.718, 95% CI [0.668 to 0.768]) showed a lower confidence limit above 0.5 and is considered successful blinding. Overall, 56% and 45% in the active and control groups, respectively, did not believe they knew the assigned treatment. Self-reported adherence was high, with 85.1% of participants reporting twice-daily use during the first 14 days. When divided by group, 86.5% of subjects in the active group made full use during 14 days and 83.7% in the sham group. Outcome Measurements

[097] Tables 3, 4 and 5 present the results of the primary and secondary efficacy outcomes related to the change in BDI-II score in the population by protocol (full use of the device). Table 3 - Primary efficacy outcome: Change in BDI-II score in Week 2 Variable Treatment Estimate 95% range p-value Petition 870250108869, dated 11 / 27 / 2025, page 32 / 57 28 / 44 Change in Beck Depression Inventory II Score at Week 2 Active 17.15 15.040-19.253 By protocol analyses (n = 198) Control 13.62 11.439-15.802 Difference 3.72 1.103-6.340 0.005 Active 16.65 14.691 -18.610 ITT analyses (n = 248) Control 14.36 12.244-16.476 Difference 2.04 -0.476 -4.549 0.056 Table 4 - Change in Baseline BDI-II through Week 1 Treatment Arm n Mean 95% Confidence Interval p-value Active 97 -15.00 -16.79, -13.21 Control 101 -10.77 -12.53, -9.02 Difference (Active Control) -4.23 -6.73, -1.72 0.001 Estimates come from a baseline-fitted linear regression model for BDI-II. Change = Week 1 - Baseline. Negative numbers indicate improvement. 28 days of 2x daily use. Table 5 - Change in BDI-II from Baseline to Week 4 Treatment Arm n Mean 95% Confidence Interval p-value Active 97 -20.67 -22.84, -18.51 Control 101 -16.38 -18.51, -14.26 Difference (Active Control) -4.29 -7.32, -1.25 0.006 Estimates come from a linear regression model fitted to baseline BDI-II. Change = Week 4 - Baseline. Negative numbers indicate improvement. 28 days of 2x daily use (full device use). Petition 870250108869, dated 11 / 27 / 2025, page 33 / 57 29 / 44

[098] Analysis of participants with full adherence to use in the first 14 days showed a significantly greater improvement in BDI-II in the active treatment group compared to the control group at 2 weeks (difference: 3.72, p=0.005, CI [1.103 to 6.340]), while the difference between groups in the intention-to-treat population fell short of statistical significance at six thousand (0.006) one-point (difference of 2.04; one-sided p=0.056, 95% CI [-0.476 to 4.549]). There were significant effects at the secondary 1-week time point in the ITT population; effects in the per-protocol population were significant at all time points. These results validate the tACS device as rapidly effective and safe.

[099] Finally, in the response analyses at week 4, the active treatment group showed a significantly higher response rate than the control group in the ITT population (65.08% vs. 52.71%, p=0.045), as well as in the per-protocol population, as shown in Table 6. Table 6 - BDI-II respondents with at least 50% improvement in BDI-II by point in time By protocol (Full Device Usage) Sex Time Point Active Arm Control Arm 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)

[0100] Concomitant use of antidepressant medication was quite common, with 43.7% of the active treatment group and 36.4% of the sham group reporting use (Table 2). In the active treatment group, there were no differences in outcome at week 2 between those who took antidepressant medication and those who did not (p=0.543). Safety Results

[0101] The number of adverse events was small. 19 subjects in the active group. Petition 870250108869, dated 11 / 27 / 2025, page 34 / 57 30 / 44 (15.1%) reported 34 events and 10 subjects (7.8%) in the control group reported 13 events. No serious adverse events were reported. Only one AE (skin discomfort) led to discontinuation of the device.

[0102] In conclusion, the experiment validated the active tACS device as a fast, effective, and safe treatment for Major Depressive Disorder; further research is needed to establish results in male patients as completely as this study established results in female patients. Study 2 - Treatment of Anxiety

[0103] A second experiment was conducted to demonstrate the effectiveness of the tACS device for the treatment of Generalized Anxiety Disorder in first responders. The tACS devices used in this experiment were from the same manufacturing batch as those used in the MDD experiment summarized earlier. The device specifications and method of use were identical; as in the MDD trial, participants in the GAD trial were instructed to self-administer the tACS twice daily for 20 minutes, once at the beginning and once at the end of each day.

[0104] This was a randomized, waitlist-controlled clinical trial. After qualification, participants were randomly assigned to the immediate or delayed groups. Both arms received an active device and identical treatment instructions. The immediate group started treatment immediately after enrollment. The waitlist (delayed) group received treatment after a scheduled delay of ten (10) days in the shipping logistics process and up to four (4) days in transit (scheduled delay of fourteen (14) days). 220 participants were enrolled. A score >7 on the Beck Anxiety Inventory (BAI) was included as an inclusion criterion. Scores and participation were monitored in near real-time (via CRO, Climb Technologies) and reassessed weekly. The primary outcome was the change in BAI score from baseline to Week 2. Petition 870250108869, dated 11 / 27 / 2025, page 35 / 57 31 / 44 comparing the Immediate and Delayed Treatment groups.

[0105] Inclusion Criteria: 1) Reading and writing English; 2) Employed by the organization First Responder; 3) Not having used a "brain stimulation device" in the last year; 4) Commit to performing 2 (two) 20-minute sessions per day, one in the morning and one at night, for up to 8 weeks; 5) Wishing to use a ReadiBand actigraph and share data with the study; 6) Not having a pacemaker, or electronic stent, or having / using any other electronic implant / using it regularly for your health; 7) You have not started or are not planning to start any new medical treatment or health program (including a new weight loss or fitness program) in the next 8 weeks; 8) He / She has not thought about suicide in the last year; 9) He was not institutionalized due to mental health problems; 10) Not under medical supervision for a serious medical condition (sleep apnea, restless legs syndrome, mental health problems and / or heart disease); 11) Do not currently take any medication that affects the nervous system (e.g., psychiatric medications); 12) Not allergic to nickel; 13) Not currently participating in, or planning to participate in within the next 8 weeks, any other study on insomnia, anxiety, or other mental health efforts (including the NIJ Fatigue Study); 14) Not being pregnant or planning to become pregnant in the next 10 weeks; 15) Baseline Beck Anxiety Inventory score > 7.

[0106] Subjects were randomized into the immediate treatment group, which Petition 870250108869, dated 11 / 27 / 2025, page 36 / 57 32 / 44 received active treatment, or were in the deferred treatment group, which first waited a period of two weeks before starting active treatment. The Beck Anxiety Inventory was administered to subjects at enrollment, at week 2, and at week 4. Those who consented to extend treatment were observed until week 8.

[0107] Table 7, below, provides details of the subject's arrangement in experiment 2. Table 7 - Subject's disposition Subject Disposition Immediate Deferred Triaged 358 Randomized 110 110 Treated* 105 (95.5%) 95 (86.4%) Treatment discontinued Loss to follow-up 28 (26.7%) 25 (26.3%) Voluntary withdrawal 6 (5.7%) 7 (7.4%) Non-first responder 1 (0.9%) 0 Withdrawal due to side effects 2 (1.9%) 1 (1.1%) Consenting for more than 4 weeks 50 (47.6%) 51 (53.7%)

[0108] A total of 358 subjects were screened for the study, of whom 220 met the inclusion criteria. Eligible subjects were randomized equally into two groups (110 each). In the immediate group, 105 (95.5%) subjects received treatment, while in the deferred group, 95 (86.4%) subjects received treatment. At week 4, there were 28 (26.7%) losses to follow-up in the immediate group, while 25 (26.3%) in the deferred group. There were 6 (5.7%) subjects with voluntary withdrawal in the immediate group, while 7 (7.4%) in the deferred group. Two (1.9%) subjects from the immediate group dropped out due to side effects, while 1 (1.1%) dropped out for the same reason from the deferred group. Among the treated subjects, 50 (47.6%) from the immediate group demonstrated willingness to continue beyond week 4, while 51 (53.7%) subjects from the deferred group demonstrated willingness to continue longer. Petition 870250108869, dated 11 / 27 / 2025, page 37 / 57 33 / 44

[0109] Table 8 shows the descriptive statistics of the characteristics of the subjects in two groups. Table 8 - Descriptive statistics for subject characteristics Statistical Characteristics Group Mean difference 95% Confidence Interval p-value Immediate Deferred Age (years) N ​​110 110 1.13 -1.44 3.69 0.388* Mean 42.39 43.52 Standard deviation 9.49 9.85 Median 41.00 41.00 Minimum 20.00 25.00 Maximum 67.00 73.00 Sex Male 73 (66.4) 54 (49.1) 0.009 Female 37 (33.6) 56 (50.9) Height (inches) N 110 110 -1.37 -2.47 0.27 0.015* Mean 69.45 68.07 Standard deviation 4.14 4.15 Median 70.00 68.00 Minimum 61.00 60.00 Maximum 80.00 80.00 Weight (Ibs.) N 110 110 -10.42 -22.75 1.92 0.097* Mean 197.90 187.48 Standard Deviation 48.67 44.05 Median 199.00 180.00 Minimum 120.00 110.00 Maximum 350.00 310.00 *Obtained using the t-test for independent samples. §Obtained using Pearson's chi-square test. P-values ​​in bold indicate statistical significance.

[0110] The average age of the subjects in the immediate group was 42.39 years (SD: 9.49 years), while that of the deferred group was 43.52 years (SD: 9.85 years), and the Petition 870250108869, dated 11 / 27 / 2025, p. 38 / 57 The difference in means between 34 and 44 was not statistically significant (p=0.388). Regarding gender, there were 66.4% men in the immediate group, compared to 49.1% in the deferred group, while the proportion of women was lower in the immediate group (33.6%) compared to the deferred group (50.9%). The gender distribution was significantly different in the two groups, as indicated by a p-value of 0.009. The overall mean height of the subjects in the immediate group was 69.45 inches (SD: 4.14 inches), while that of the deferred group was 68.07 inches (SD: 4.15 inches), and the difference in means was statistically significant with a p-value of 0.015. The mean weight of the subjects in the immediate group was 197.90 lbs. (SD: 48.67 lbs.), while in the deferred group it was 187.48 lbs. (44.05 lbs.), and the difference in means was not statistically significant (p=0.097).

[0111] Table 9 provides descriptive statistics for the Beck Anxiety Inventory (BAI) scores in two groups at different points in time. Table 9 - Descriptive statistics for Beck Anxiety Inventory scores in two groups according to time__________________________ Visit Statistics Group p-value Immediate Deferred Baseline N 105 95 0.905 Mean 20.14 19.80 Standard Deviation 10.45 9.40 Median 19.00 18.00 Minimum 1.00 5.00 Maximum 48.00 43.00 Week 2 N 81 87 < 0.001 Mean 12.79 19.24 Standard Deviation 7.86 9.29 Median 11.00 18.00 Minimum 0.00 5.00 Maximum 44.00 45.00 Week 4 N 73 77 0.024 Mean 10.64 13.08 Standard Deviation 6.93 7.10 Median 10.00 11.00 Minimum 0.00 0.00 Petition 870250108869, dated 11 / 27 / 2025, page 39 / 57 35 / 44 Maximum 39.00 35.00 *Obtained using the Mann-Whitney U test. Bold p-values ​​indicate statistical significance.

[0112] At baseline, the parameter violated the normality assumption, as per the Shapiro-Wilk test, and therefore a non-parametric assessment was performed to compare scores between the two groups. At baseline, the mean BAI score for the immediate group was 20.14 (SD: 10.45) and the median was 19, while for the deferred group it was 19.80 (SD: 9.40) and the median was 18. The difference in median scores was not statistically significant (p=0.905). In week 2, the mean BAI in the immediate group was 12.79 (SD: 7.86) and the median was 11, while in the deferred group, the mean was 19.24 (SD: 9.29) and the median was 18. The difference in median BAI scores between the two groups in 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 for the deferred group it was 13.08 (SD: 7.10) with a median of 11, and the difference between the medians was statistically significant with a p-value of 0.024.

[0113] Table 10 provides descriptive statistics for the change in BAI scores from baseline to week 2. Table 10 - Comparison of the change in BAI (D) scores from baseline to week 2 between two groups_____________________________________ Statistics Group p-value Immediate Deferred Baseline for Week 2 N 81 87 < 0.001 Mean 6.33 0.38 Standard Deviation 7.83 7.67 Median 5.00 0.00 Minimum -11.00 -29.00 Maximum 29.00 29.00 *Obtained using the Mann-Whitney U test. Bold p-values ​​indicate statistical significance.

[0114] The comparison of the change in scores revealed that, in the week Petition 870250108869, dated 11 / 27 / 2025, pp. 40 / 57 36 / 44 2, the mean change in score in the immediate group was 6.33 (SD: 7.83) and a median of 5, while in the deferred group it was 0.38 (SD: 7.67) and a median of 0. The difference in medians between the groups was statistically significant with p < 0.001.

[0115] Table 11 is the cross-tabulation showing the frequencies of subjects in each BAI category at baseline and week 2 for the immediate group. Table 11 - Change in anxiety level from baseline to week 2 in the immediate group based on BAI score categorization______________ IMMEDIATE Category BAI: Week 2 Total <=21 (Low) 22-35 (Moderate) >=36 (Severe) Category BAI: Baseline <=21 (Low) 53 1 0 54 (66.7%) 22-35 (Moderate) 13 7 0 20 (24.7%) >=36 (Severe) 4 2 1 7 (8.6%) Total 70 (86.4%) 10 (12.3%) 1 (1.2%) 81 P < 0.001 using marginal homogeneity test

[0116] There were 54 (66.7%) subjects in the low category at baseline, of whom 53 remained in the low category at week 2, while 1 moved to the moderate category. There were 20 (24.7%) subjects in the moderate category at baseline, of whom 13 moved to the low category, 7 remained moderate. Additionally, of 7 (8.6%) subjects with the severe category at baseline, 4 moved to the low category, 2 to the moderate category, and 1 remained in the severe category. At week 2, there were 70 (86.4%) subjects in the low category, 10 (12.3%) in the moderate category, and 1 (1.2%) in the severe category.

[0117] The marginal distribution changed significantly from baseline to week 2, as indicated by p < 0.001, with a significantly higher proportion of subjects in the low category in week 2 compared to baseline. Petition 870250108869, dated 11 / 27 / 2025, pp. 41 / 57 37 / 44

[0118] Table 12 is the cross-tabulation showing the frequencies of subjects in each BAI category at baseline and at week 2 for the deferred group. Table 12 - Change in anxiety level from baseline to week 2 in the deferred group based on BAI score categorization_______________ DEFERRED Category BAI: Week 2 Total <=21 (Low) 22-35 (Moderate) >=36 (Severe) Category BAI: Baseline <=21 (Low) 46 6 1 53 (60.9%) 22-35 (Moderate) 7 18 3 28 (32.2%) >=36 (Severe) 2 3 1 6 (6.9%) Total 55 (63.2%) 27 (31.0%) 5 (5.7%) 87 P=0.590 using marginal homogeneity test

[0119] There were 53 (60.9%) subjects in the low category at baseline, of whom 46 remained in the low category at week 2, while 6 moved to the moderate category and 1 to the severe category. There were 28 (32.2%) subjects in the moderate category at baseline, of whom 7 moved to the low category, 18 remained moderate, and 3 moved to the severe category. Additionally, of 6 (6.9%) subjects with a severe category at baseline, 2 moved to the low category, 3 to the moderate category, and 1 remained in the severe category. At week 2, there were 55 (63.2%) subjects in the low category, 27 (31.0%) in the moderate category, and 5 (5.7%) in the severe category. The marginal distribution did not change significantly from baseline to week 2 in the deferred group (p=0.590).

[0120] The willingness to continue beyond four weeks was indicated by 53 subjects from the immediate group and 50 from the different group. Therefore, a subset analysis of these subjects was performed and the parameters were compared at week 8 between the two groups, as shown in Table 13. Table 13 - Descriptive statistics for different scores in week 8 Petition 870250108869, dated 11 / 27 / 2025, pp. 42 / 57 38 / 44 In two study groups: Parameter Statistic Group p-value Immediate Deferred Week 8 BAI Score N 53 50 0.010* Mean 8 11.72 Standard Deviation 6.47 7.96 Median 6 10 Minimum 0 0 Maximum 35 28 *Obtained using the Mann-Whitney U test. Bold p-values ​​indicate statistical significance.

[0121] Table 13 reveals that the BAI score showed a difference in medians / means between the two groups (p > 0.05) at week 8. The BAI score at week 8 in the immediate groups was significantly lower than that of the deferred group (p=0.010).

[0122] Thus, this study achieved its primary objective and validates the tACS device as rapidly effective for the treatment of Generalized Anxiety Disorder (GAD). Comparative Study - Disqualifying 1 mA of tACS as a Therapeutic Dose

[0123] In 2015, the results of an MDD study conducted at Harvard Medical School determined that using an earlier version of the tACS device that produced an average amplitude of 1 mA (half the amplitude of the tACS incorporated here) and administering 1 mA of tACS to patients only once a day, five days a week, was ineffective. The study summary follows.

[0124] “We examined the efficacy and safety of a specific cranial electrical stimulator (CES) device in a fixed setting in subjects with treatment-resistant major depressive disorder (MDD). Thirty subjects (57% women, mean age 48.1 ± 12.3 years) with MDD and inadequate response to standard antidepressants were randomized to 3 weeks of CES treatment. Petition 870250108869, dated 11 / 27 / 2025, pp. 43 / 57 39 / 44 (15 / 500 / 15,000 Hz, symmetrical biphasic rectangular current of 1-4 mAmp, 40 V) or sham CES (device off) for 20 minutes, 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 Inventory (PRISE). Completion rates were 88% for CES and 100% for sham. Both treatment groups demonstrated improvement of approximately 3 to 5 points on HAM-D-17 scores (p < 0.05 for both), and no significant difference was observed between groups. Remission rates were 12% for CES and 15% for sham, a non-significant difference. CES was considered safe, with good tolerability; Low concentration and malaise were the only distressing adverse events that differed significantly between the CES and the sham (p = 0.019 and p = 0.043, respectively).Limitations include a small sample size and the lack of an active comparator therapy. Although both treatment groups improved significantly, this CES in the chosen scenario did not break away from the simulation in this sample. Therefore, we cannot rule out that the benefit of this configuration used in this specific form of CES was due to placebo effects. As this form of CES has other configurations, future studies should test these settings and compare them with other CES devices. In conclusion, this comparative study disqualifies 1 mA of tACS, administered once daily for five days a week, for the treatment of MDD. The MDD and GAD studies summarized above validated the use of modalities of the tACS device incorporated herein, which targets a mean amplitude of 2.2 mA (+ / - 5% manufacturing tolerance) and uses twice-daily, seven-day-a-week treatment.

[0125] Certain exemplary embodiments have been described to provide a general understanding of the principles of structure, function, manufacture and use of Petition 870250108869, dated 11 / 27 / 2025, pp. 44 / 57 40 / 44 systems, devices 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, devices and methods specifically described herein and illustrated in the accompanying drawings are exemplary, non-limiting embodiments and that the scope of the present invention is defined solely by the claims. The features illustrated or described in relation to an exemplary embodiment may be combined with the features of other embodiments. Such modifications and variations are intended to be included within the scope of the present invention. Furthermore, in the present disclosure, similarly named components of the embodiments generally have similar characteristics and, thus, within a particular embodiment, each feature of each similarly named component is not necessarily fully elaborated.

[0126] The matter described herein may be implemented in analog electronic circuits, digital electronic circuits and / or in computer software, firmware or hardware, including the structural means disclosed in this descriptive report and structural equivalents thereof, or combinations thereof. The matter described herein may 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 propagated signal, for execution by, or to control the operation of, data processing apparatus (e.g., a programmable processor, a computer or multiple computers).A computer program (also known as a program, software, software application, or code) can be written in any form of 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. Petition 870250108869, dated 11 / 27 / 2025, pp. 45 / 57 41 / 44 appropriate unit for use in a computing environment. A computer program does not necessarily correspond to a file. A program can be stored in a part of a file that contains other programs or data, in a single file dedicated to the program in question, or in several coordinated files (for example, files that store one or more modules, subprograms, or code segments). A computer program can be implemented to run on one computer or on multiple computers in one location or distributed across multiple locations and interconnected by a communication network.

[0127] The processes and logical flows described in this specification, including the steps of the method of the subject described herein, may be executed by one or more programmable processors executing one or more computer programs to perform functions of the subject described herein, operating on input data and generating output. The processes and logical flows may also be executed by, and the apparatus of the subject described herein may be implemented as, special-purpose logic circuits, for example, an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit).

[0128] Processors suitable for running a computer program include, for example, general-purpose and special-purpose microprocessors, and any one or more processors of any type of digital computer. In general, a processor will receive instructions and data from read-only memory or random-access memory or both. The essential elements of a computer are a processor to execute instructions and one or more memory devices to store instructions and data. Generally, a computer will also include, or be operationally coupled to receive or transfer data to, or both, one or more mass storage devices to store data, for example, magnetic disks, magneto-optical disks, or optical disks. The Petition 870250108869, dated 11 / 27 / 2025, pp. 46 / 57 42 / 44 Suitable information storage media for incorporating computer program instructions and data include all forms of non-volatile memory, including, for example, semiconductor memory devices (e.g., EPROM, EEPROM, and flash memory devices); magnetic disks (e.g., internal hard disks or removable disks); magneto-optical disks; and optical disks (e.g., CD and DVD discs). The processor and memory may be supplemented by, or incorporated into, special-purpose logic circuitry.

[0129] To provide interaction with a user, the subject described herein may be implemented on a computer with a display device, for example, a CRT (cathode ray tube) or LCD (liquid crystal display) monitor, to display information to the user, and a keyboard and a pointing device (for example, a mouse or a trackball), by which the user may provide input to the computer. Other types of devices may also be used to provide interaction with the user. For example, the feedback provided to the user may be of any form of sensory feedback, for example, visual feedback, auditory feedback, or tactile feedback; and the user input may be received in any form, including acoustic, speech, or tactile input.

[0130] 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. At a minimum, however, modules should not be interpreted as software that is not implemented in hardware, firmware, or recorded on a non-transient, processor-readable, writable storage medium (i.e., modules are not software themselves). In fact, “module” should always be interpreted as including at least some non-transient physical hardware, such as a part of a processor or computer. Two different modules may share the same Petition 870250108869, dated 11 / 27 / 2025, pp. 47 / 57 43 / 44 physical hardware (for example, two different modules may use the same processor and network interface). The modules described herein may be combined, integrated, separated, and / or duplicated to support various applications. Furthermore, a function described herein as being executed in a specific module may be executed in one or more other modules and / or by one or more other devices instead of or in addition to the function executed in the specific module. Additionally, modules may be implemented in multiple devices and / or other components, either locally or remotely from each other. Furthermore, modules may be moved from one device and added to another device and / or may be included in both devices.

[0131] Approximate language, as used in this document throughout the descriptive report and claims, may be applied to modify any quantitative representation that may vary permissively without resulting in an alteration of the basic function to which it relates. Consequently, a value modified by a term or terms, such as about, approximately, and substantially, should not be limited to the exact value specified. In at least some cases, the approximation language may correspond to the precision of an instrument for measuring the value or a manufacturing tolerance. For example, the specified value can 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, the manufacturing tolerance can be ±5%.Here and throughout the descriptive report and claims, range limitations may be combined and / or interchanged; such ranges are identified and include all sub-ranges contained therein, unless the context or language indicates otherwise.

[0132] One skilled in the art will appreciate additional features and advantages of the invention based on the embodiments described above. Consequently, the present application will not be limited by what has been particularly Petition 870250108869, dated 11 / 27 / 2025, pp. 48 / 57 44 / 44 shown and described, except as indicated by the appended claims. All publications and references cited in this document are expressly incorporated by reference in their entirety. Petition 870250108869, dated 11 / 27 / 2025, pp. 49 / 57

Claims

2 / 2 Generalized Anxiety Disorder (GAD); wherein the diameter of each of the electrodes is approximately 36 mm; and further comprising retrieving, by the processor, the predetermined treatment time from a memory in communication with the processor, wherein the predetermined treatment time is approximately 20 minutes; measuring a treatment time during which the therapeutic dose of tACS is delivered to the patient; comparing the treatment time with the predetermined treatment time; and ceasing transmission of the generated electrical current when the elapsed time is equal to the predetermined treatment time.

3. Method, according to claim 2, CHARACTERIZED in that it further comprises administering the therapeutic dose of tACS to the patient twice daily for the predetermined treatment time, wherein one administration occurs within two hours or less after waking from sleep and another administration occurs within two hours or less before going to sleep. Petition 870250088308, dated 09 / 29 / 2025, p. 7 / 9

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