Apparatus and method for stimulation of biological tissue and treating disease

Abstract

An apparatus for generating currents in biological tissue is provided. The apparatus comprises an electrical source capable of generating an electric field across a region of tissue and means for altering the impedance of the tissue relative to the electric field, whereby an altered current is generated. The means for altering the impedance may be a chemical source, optical source, mechanical source, thermal source, or electromagnetic source. The system can be used to provide stimulation safely and effectively in human transcranial use. The currents are used for stimulating tissues and treating diseases, such as for example Parkinson's Disease, Chronic Pain, Depression, and / or Opioid Use Disorder.

Description

[0001] APPARATUS AND METHOD FOR STIMULATION OF BIOLOGICAL TISSUE AND TREATING DISEASE

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This patent application claims priority to and the benefit of U.S. Provisional Patent Application Serial Nos. 63 / 529,298, filed on July 27, 2023, 63 / 546,926, filed on November 1, 2023, and 63 / 640,194 filed on April 29, 2024, the contents of which are hereby incorporated by reference herein in their entirety.

[0004] TECHNOLOGICAL FIELD

[0005] The present disclosure relates generally to the field of applying energy to the nervous system to alter neural activity in a manner which can influence behavior and / or treat disease and methods which tune or optimize the process.

[0006] BACKGROUND

[0007] Stimulation of living tissue in humans and other animals is used in several clinical applications as well as in clinical and general biological research. In particular, stimulation of neural tissue has been used in the treatment of various diseases including Parkinson’s disease, depression, chronic pain, stroke, and / or addiction. However, methods used in the clinic today are usually sub-optimal in treating disease. The appropriate energy characteristics (e.g., type of energy, dose of energy, target of energy deposition, duration of energy application) need to be appropriately matched to the target disease and specific symptoms of the disease to be safe and effective for disease management. Furthermore, the method of application needs to be applied and tested in a manner which can withstand regulatory scrutiny to attain widescale use. Additionally, the form and type of stimulation need to be matched to the typical point-of-care of the patient for wide-scale adoption. Identifying best responders to treatment (and / or methods to identify the type of symptoms that respond best to the type of therapy) is also key to optimal stimulation. The present disclosure discloses methods, characteristics, and systems of use in paired energy applications for the treatment of diseases based on clinical metrics and symptoms that had not previously known such as for chronic pain, addiction, Parkinson’s Disease, stroke, and / or depression treatment that can be completed safely and effectively. We furthermore disclose methods for optimizing energy delivery and / or coupled therapies for improving symptoms of disease and / or clinical metrics of the disease. Additionally, we demonstrate methods in which the combined energies can be applied to improve a task, skill, procedure, and / or balance in a patient. Finally, we demonstrate how these methods can be appropriately applied in the general population to improve aspects of motor or cognitive performance, such as for example in a manner which might be used in the elderly to improve balance and prevent falls.

[0008] SUMMARY

[0009] Accordingly, an apparatus for generating currents in biological tissue is provided along with the method for optimally applying the energy to achieve disease improvements. The apparatus according to the disclosure includes an electrical source capable of generating an electric field across a region of tissue and a means for altering the impedance tissue relative to the electric field, whereby the alteration of the tissue permittivity and / or tissue conductivity relative to the electric field generates or alters a displacement current in the tissue and / or ohmic current in the tissues. The means for altering the impedance may include a chemical source, optical source, mechanical source, thermal source, or electromagnetic source. In one embodiment, the apparatus implements an ultrasound source as mechanical means for altering the impedance of the tissues. In another embodiment the apparatus includes a means for altering the conductivity of tissue relative to the electric field, whereby an ohmic current is altered. In another embodiment the apparatus includes a means for altering the permittivity of tissue relative to the electric field, whereby a displacement current is altered and / or generated. In another embodiment the apparatus includes a means for altering the conductivity and permittivity of tissue relative to the electric field, whereby altering the conductivity results in an ohmic current that is altered and altering the permittivity of tissue relative to the electric field results in a displacement current that is altered and / or generated. The method in which the energy is applied, optimized energy patterns, and target symptoms for the disease (and / or clinical metrics) which are impacted are disclosed.

[0010] In one exemplary embodiment, the apparatus includes an electrical source capable of generating an electric field across a broad region of tissue or tissues. The apparatus also includes an ultrasound device that generates a mechanical field focused on the sub-region of tissue whereby the combined effects of the electric field and the mechanical field generate an altered current with a newly generated and / or altered displacement current and / or altered ohmic current within the subregion of tissue, via the alteration of tissue electromagnetic properties. In certain embodiments the altered current can stimulate the targeted tissue.

[0011] The electrical source according to the present disclosure may be applied in a variety of ways to achieve a specified outcome. For example, the electrical source may generate a field that is pulsed, time varying, a sequence of time varying pulses, and / or time invariant (meaning it can be any one of these conditions or any combination thereof). Additionally, the means for altering tissue impedance (i.e., conductivity, permittivity, and / or permeability) may be a pulsed signal, time varying signal, a sequence of time varying pulsed signals, a signal of low frequency pulsed higher frequency signals (for example, pulsing a higher frequency signal (for example above a KHz) on and off at frequency below a KHz (such as for example a waveform that center frequency component of ~2MHz pulsed on and off at a 30Hz pulse frequency, or a for example a waveform that is composed of a center frequency of ~700KHz with a 60Hz pulse frequency)), a signal of low frequency pulsed higher frequency signals with uneven duty cycles, and / or a signal of low frequency pulsed higher frequency signals with even duty cycles. The electrical source and / or means for altering the tissue impedance may be applied non-invasively. For example, electrodes may be configured to be applied to the specified tissue, tissues, or adjacent tissues. As one alternative, the electrical source may be implanted inside the specified tissue, tissues, or adjacent tissues. Generally, the electrical source is current that has a frequency from about DC to approximately 100,000 Hz. The electric field may be applied with time varying fields of different frequencies. The electrical source and / or means of altering the tissue impedance may scan a region, such using a sector probe or phased array ultrasonic source. In certain embodiments, the phased array system could use a linear phased array transducer, an annular phased array transducer, a convex phased array transducer, a square phased array transducer, and / or a circular phased array system. In other embodiments the phased array system can be provided while an MRI system is used and the dose and focus area of the stimulation is controlled with dosing software (such as dosing software described in U.S. Patent Publication No. US2021 / 0322771 the entire disclosure of which is hereby incorporated by reference herein). In another embodiment the electric field may be focused over a deep region, such as by using temporal interference methods, but with the neurostimulation effects enhanced (e.g., focused or amplified) via the means to alter the tissue impedance in the region.

[0012] In one exemplary embodiment, the electric field is applied broadly and the means for altering the tissue impedance is focused on a specific brain structure or multiple structures for therapeutic purposes. The electric field may be applied broadly and the means for altering the tissue impedance may be focused on a structure or multiple structures, such as brain or nervous tissues including dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-52, primary sensory cortex, primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, peripheral nerves, and / or spinal cord. In another embodiment the electric field may be focused over a deep region, such as by using temporal interference methods, but the effects enhanced (e.g., focused or amplified in a region) via the means to alter the tissue impedance in the region.

[0013] The apparatus and method may assist in the treatment of a variety of ailments, such as Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Dystonia, Tics, Spinal Cord Injury, Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving, Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson’s Disease, Parkinsonianism, Depression, Obsessions, Schizophrenia, Bipolar Disorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, Hallucinations, Movement Disorders, Neurodegenerative Disorders, Pain Disorders, Metabolic Disorders, Addictive Disorders, Psychiatric Disorders, Traumatic Nerve Injury, and / or Sensory Disorders. Similarly, the electric field and the means for altering impedance may be focused on specific brain structures to enact procedures such as sensory augmentation, sensory alteration, anesthesia induction and maintenance, brain mapping, epileptic mapping, pre-surgical planning, neuroprosthetic interaction or control with nervous system, stroke and traumatic injury neurorehabilitation, bladder control, assisting breathing, cardiac pacing, muscle stimulation, and / or treatment of pain syndromes, such as those caused by migraine, neuropathies, and low-back pain; or internal visceral diseases, such as chronic pancreatitis or cancer.

[0014] In another embodiment, the apparatus according to the present disclosure includes an electrical source capable of generating an electric field across a region of tissue and a means for altering the permittivity of the tissue relative to the electric field, whereby a displacement current is generated. The apparatus further includes a means for altering the conductivity of the tissue relative to the electric field, whereby the ohmic current is altered. Additionally, the means for altering impedance (i.e., conductivity, permittivity, and / or permeability) may be a pulsed signal, time varying signal, a sequence of time varying pulsed signals, a signal of low frequency pulsed higher frequency signals (for example, pulsing a higher frequency signal (for example above a KHz) on and off at frequency below a KHz (such as for example a waveform that center frequency component of ~2MHz pulsed on and off at a 30Hz pulse frequency, or a for example a waveform that is composed of a center frequency of ~700KHz with a 60Hz pulse frequency)), a signal of low frequency pulsed higher frequency signals with uneven duty cycles, and / or a signal of low frequency pulsed higher frequency signals with even duty cycles.

[0015] A method for stimulating biological tissue is also provided. The method includes applying an electrical source to biological tissue and altering the permittivity of tissue relative to the electrical source by applying a means for altering the permittivity of tissue relative to the electric field. The alteration of the permittivity of the tissue relative to the electric field generates a displacement current in the tissue. The means for altering the permittivity may be a variety of sources including a chemical source, optical source, mechanical source, thermal source, or electromagnetic source. For example, a mechanical source such as an ultrasound source may be applied to mechanically alter the tissue. The tissue can be biological tissue, such as neural tissue, endocrine tissue, electrically receptive tissue, mechanically receptive tissue, muscle tissue, epithelial tissue, dermal tissue, connective tissue, or skeletal tissue. In a further embodiment, the apparatus further includes a means for altering the conductivity of the tissue relative to the electric field, whereby the ohmic current is altered. Additionally, the means for altering impedance (i.e., conductivity, permittivity, and / or permeability) may be a pulsed signal, time varying signal, a sequence of time varying pulsed signals, a signal of low frequency pulsed higher frequency signals (for example, pulsing a higher frequency signal (for example above a KHz) on and off at frequency below a KHz (such as for example a waveform that center frequency component of ~2MHz pulsed on and off at a 30Hz pulse frequency, or for example a waveform that is composed of a center frequency of ~700KHz with a 60Hz pulse frequency)), a signal of low frequency pulsed higher frequency signals with uneven duty cycles, and / or a signal of low frequency pulsed higher frequency signals with even duty cycles.

[0016] In another embodiment the combined energies can be applied in combination with training, occupational therapy, and / or physical therapy to improve training, occupational or physical therapy. Additionally, we demonstrate methods in which the combined energies can be applied to improve a task, skill, procedure, and / or balance in a patient by applying the combined energies in an appropriate manner to improve the subject in the task, skill, procedure, and / or balance. In another embodiment the combined energies can be used as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies.

[0017] In another embodiment, the combined energies can be provided in a manner and tuned by a motion analysis suite, such as those described in the incorporated priority applications and PCT Publication No. WO / 2024 / 086537, the entire disclosure of which is hereby incorporated by reference herein. Such as, for example, the best responders to therapy can be found based on a patients’ baseline state or the system’s prediction of the likelihood of a response to therapy based on predictions and analysis completed by the motion analysis suite (MAS). In another embodiment, the combined energies can be provided in a manner tuned by a quantitative sensory testing (QST), such as for example identifying a potential chronic pain patient’s likelihood of response to treatment based on their conditional pain modulation (CPM) response. In another embodiment, a method for optimizing the patient’s response to therapy based on cost effective analysis (CEA) is also provided. The CEA method can be used to design the combined energies therapeutic dosing for a specific disease state and or combined with the other methods of optimization and dosing control that are described herein (e.g., field dosing via biophysics models, QST, MAS).

[0018] The present disclosure includes, without limitation, the following example implementations. Example Implementation 1: An apparatus for treating neurological disease comprising an electrical source capable of generating an electric field across a region of tissue; and a means for altering the impedance of said tissue relative to said electric field, whereby the alteration of the impedance of said tissue relative to said electric field generates an altered current in said tissue; and the means for altering impedance in tissue is an ultrasonic source with a Mechanical Index of less than 1.9 and a Thermal Index of less than 1.5.

[0019] Example Implementation 2: An apparatus for stimulating neural activity in biological tissue comprising a DC electrical source capable of generating an electric field across a region of tissue; and a means for altering the impedance of said tissue relative to said electric field, whereby the alteration of the impedance of said tissue relative to said electric field generates a displacement current in said tissue and / or the alteration of conductivity in said tissue alters an ohmic current in the tissue; and the means for altering impedance in tissue is an ultrasonic source with a Mechanical Index of less than 1 and a Thermal Index of less than 1.5.

[0020] Example Implementation 3: An apparatus for generating currents in biological tissue comprising an electrical source capable of generating an electric field across a region of tissue; and an ultrasound device which generates a mechanical field focused on a sub-region of tissue, whereby the combined effects of said electric field and said mechanical field generate an altered current with a newly generated displacement current within said region of tissue; and said ultrasonic device operates with a Mechanical Index of less than 1.9 and a Thermal Index of less than 1.5.

[0021] Example Implementation 4: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electrical source is applied non-invasively.

[0022] Example Implementation 5: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said means for altering impedance is applied non-invasively.

[0023] Example Implementation 6: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electrical source is a time varying inductive magnetic field generated from an external source.

[0024] Example Implementation 7: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electrical source is at least one electrode.

[0025] Example Implementation 8: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electric field and said means for altering impedance can be applied to neural tissue to assist in the treatment of any of the ailments disclosed herein.

[0026] Example Implementation 9: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electric field and said means for altering impedance stimulate a structure or multiple structures within the brain or nervous system as disclosed herein.

[0027] Example Implementation 10: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said electrical source is shaped to at least partially enclose said ultrasonic source.

[0028] Example Implementation 11: The apparatus (or a corresponding method thereof) of any preceding example implementation, or any combination of any preceding example implementations, wherein said ultrasonic source is a pulsed signal or the ultrasonic device produces a pulsed signal.

[0029] These and other features, aspects, and advantages of the present disclosure will be apparent from a reading of the following detailed description together with the accompanying figures, which are briefly described below. The present disclosure includes any combination of two, three, four or more features or elements set forth in this disclosure, regardless of whether such features or elements are expressly combined or otherwise recited in a specific example implementation described herein. This disclosure is intended to be read holistically such that any separable features or elements of the disclosure, in any of its aspects and example implementations, should be viewed as combinable, unless the context of the disclosure clearly dictates otherwise.

[0030] It will therefore be appreciated that this Summary is provided merely for purposes of summarizing some example implementations to provide a basic understanding of some aspects of the disclosure. Accordingly, it will be appreciated that the above described example implementations are merely examples and should not be construed to narrow the scope or spirit of the disclosure in any way. Other example implementations, aspects and advantages will become apparent from the following detailed description taken in conjunction with the accompanying figures which illustrate, by way of example, the principles of some described example implementations.

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Having thus described aspects of the disclosure in the foregoing general terms, reference will now be made to the accompanying figures, which are not necessarily drawn to scale, and wherein: Figure 1 is a top view of one embodiment of an apparatus for stimulating biological tissue constructed in accordance with the principles of the present disclosure;

[0033] Figure 2 is a table of recommended dwell time and Thermal Index (TI) ranges for adult transcranial, general abdominal, peripheral vascular, neonatal (except head and spine), and other scanning examinations (except the eye). Dwell times should be reduced by 33% for ARFI and pulsed Doppler examinations when bone is near the transducer focus;

[0034] Figure 3 is a view of a stimulation system depicting electrode sources and an ultrasound source for a C3 (or C4) ultrasound and electrode setup with a contralateral orbital placed electrode;

[0035] Figure 4 depicts Electrosonic Stimulation (ESStim) Parkinson’s Disease (PD) headgear, placement location, and headgear and electrode and ultrasound transducer options (in certain embodiments the headgear can also be used in chronic pain treatments);

[0036] Figure 5 demonstrates example results for Example PD Treatment Course 1. A. Change in walking times from baseline averaged from the last stimulation session through the last follow-up. B. Change in bradykinesia test times from baseline averaged from the last stimulation session through the last follow-up. C. Supplementary Bradykinesia Analysis. Here we depict the mean of the difference in task time improvements relative to baseline for the Active and SHAM conditions (baseline determined from patient evaluation visits prior to the patients’ visits for stimulations). D. Supplementary Walking Analysis: The figure demonstrates walking time improvements at the conclusion of 10 days of stimulation (S10), 1 week (w), 2w, 4w, and 6w post stimulation for Active ESStim + PT vs SHAM ESStim + PT in the Phase I PD PT study. While the study was not designed to assess differences across observation days, emerging trends within the data were used to guide the maintenance schedule (which was further reinforced by data from our other PD studies (without PT) and dose modeling);

[0037] Figure 6 depicts an Integrated Motion Analysis Suite (IMAS) implementation and integration with additional data types (e.g., biospecimen, imaging, etc.) and the ESStim system;

[0038] Figure 7 depicts ESStim treatment for Opioid Use Disorder OUD electrode ultrasound and transducer placement locations;

[0039] Figure 8 depicts EEG changes from a result of treatment correlated with craving: Patients demonstrated significant changes in EEG power and concurrent lowered Opioid Craving on a 10- point Visual Analog Scale (VAS) scale relative to baseline (2.3) via an Opioid Cue Exposure Task. Patients also showed a small (-10%) but significant reduced Opioid use on urine toxicology;

[0040] Figure 9 depicts Diabetic Neuropathic Pain Demographics from an Example Study;

[0041] Figure 10 depicts Relative VAS Pain (at time of assessment) Score Improvement from Baseline for Chronic Low Back Pain Phase II Study Example; Figure 11 depicts Relative VAS Pain (7-day average) Score Improvement from Baseline for Chronic Low Back Pain Phase II Study Example; and

[0042] Figure 12 depicts Relative Conditional Pain Modulation Examples for Chronic Low Back Pain Phase II Study Example.

[0043] DETAILED DESCRIPTION

[0044] Some implementations of the present disclosure will now be described more fully hereinafter with reference to the accompanying figures, in which some, but not all implementations of the disclosure are shown. Indeed, various implementations of the disclosure may be embodied in many different forms and should not be construed as limited to the implementations set forth herein; rather, these example implementations are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.

[0045] Unless specified otherwise or clear from context, references to first, second or the like should not be construed to imply a particular order. A feature described as being above another feature (unless specified otherwise or clear from context) may instead be below, and vice versa; and similarly, features described as being to the left of another feature else may instead be to the right, and vice versa. Also, while reference may be made herein to quantitative measures, values, geometric relationships, or the like, unless otherwise stated, any one or more if not all of these may be absolute or approximate to account for acceptable variations that may occur, such as those due to engineering tolerances or the like.

[0046] As used herein, unless specified otherwise or clear from context, the “or” of a set of operands is the “inclusive or” and thereby true if and only if one or more of the operands is true, as opposed to the “exclusive or” which is false when all of the operands are true. Thus, for example, “[A] or [B]” is true if [A] is true, or if [B] is true, or if both [A] and [B] are true. Further, the articles “a” and “an” mean “one or more,” unless specified otherwise or clear from context to be directed to a singular form.

[0047] It is envisioned that the present disclosure may be used to stimulate biological tissue in-vivo comprising an electrical source that is placed on the body to generate an electric field combined with a means for altering the impedance of tissue relative to the electric field, whereby the alteration of the tissue permittivity relative to the electric field generates or alters a displacement current in the tissue and / or the alteration of tissue conductivity alters the ohmic current in the tissue. The exemplary embodiments of the apparatuses and methods disclosed can be employed in the area of neural stimulation, where amplified, focused, direction altered, and / or attenuated currents can be used to alter neural activity via directly stimulating neurons, depolarizing neurons, hyperpolarizing neurons, modifying neural membrane potentials, altering the level of neural cell excitability, and / or altering the likelihood of a neural cell firing. Likewise, the method for stimulating biological tissue may also be employed in the area of muscular stimulation, including cardiac stimulation, where amplified, focused, direction altered, and / or attenuated currents can be used to alter muscular activity via direct stimulation, depolarizing muscle cells, hyperpolarizing muscle cells, modifying membrane potentials, altering the level of muscle cell excitability, and / or altering the likelihood of cell firing. Similarly, it is envisioned that the present disclosure may be employed in the area of cellular metabolism, physical therapy, drug delivery, and gene therapy.

[0048] Detailed embodiments of the present disclosure are disclosed herein; however, it is to be understood that the described embodiments are merely exemplary of the disclosure, which may be embodied in various forms. Therefore, specific functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed embodiment.

[0049] The components of the tissue stimulation method according to the present disclosure are fabricated from materials suitable for a variety of medical applications, such as, for example, polymeries, gels, films, and / or metals, depending on the particular application and / or preference. Semi-rigid and rigid polymeries are contemplated for fabrication, as well as resilient materials, such as molded medical grade polyurethane, as well as flexible or malleable materials. The motors, gearing, electronics, power components, electrodes, and transducers of the method may be fabricated from those suitable for a variety of medical applications. The method according to the present disclosure may also include circuit boards, circuitry, processor components, etc. for computerized control. One skilled in the art, however, will realize that other materials and fabrication methods suitable for assembly and manufacture, in accordance with the present disclosure, also would be appropriate.

[0050] The following discussion includes a description of the components and exemplary methods for generating and / or altering currents in biological tissues in accordance with the principles of the present disclosure. Alternate embodiments are also disclosed. Reference will now be made in detail to the exemplary embodiments of the present disclosure illustrated in the accompanying figures wherein like reference numerals indicate the similar parts throughout the figures.

[0051] Turning now to Figure 1, which illustrates an exemplary embodiment of an apparatus 10 to alter currents, e.g., amplify, focus, alter direction, and / or attenuate in the presence of an applied electric field or applied current source by the combined application of a mechanical field within a biological material to stimulate the biological cells and / or tissue in accordance with the present disclosure. For example, the apparatus 10 illustrated in Figure 1 according to the present disclosure may be applied to the area of neural stimulation. An initial source electric field 14 results in a current in the tissue. The electric field 14 is created by an electrical source, current or voltage source. As described in further detail below, the impedance (i.e., conductivity, permittivity, and / or permeability) of the tissue is altered relative to the electric field, for example by a mechanical field, thereby generating an altered current (e.g., altered ohmic current, altered displacement current, and / or additional displacement current).

[0052] Electrodes 12 are applied to the scalp and generate a low magnitude electric field 14 over a large brain region. While electrodes 12 are used and applied to the scalp in this exemplary embodiment, it is envisioned that the electrodes may be applied to a number of different areas on the body including areas around the scalp. It is also envisioned that one electrode may be placed proximal to the tissue being stimulated and the other distant, such as one electrode on the scalp and one on the thorax. It is further envisioned that electrical source can be mono-polar with just a single electrode, multi-polar with multiple electrodes, part of a distributed network configuration, and / or different configurations can be combined including the use of sequential activation of electrodes. Similarly, the electrical source may be applied to tissue via any medically acceptable medium. It is also envisioned that means can be used where the electrical source does not need to be in direct contact with the tissue, such as for example, inductive magnetic sources where the entire tissue region is placed within a large solenoid generating magnetic fields or near a coil generating magnetic fields, where the magnetic fields induce electric currents in the tissue. In certain embodiments, a single electrode can be used with a monopolar source. In certain embodiments, the electrodes can be anodal or cathodal. The electrode(s) can connect to an electrical source through a wire(s).

[0053] In certain embodiments, an electrode or electrodes may be approximately U shaped and / or designed to cup or enclose the transducer face of the ultrasound (such as with the component of the electrode cutout to encompass the ultrasound transducer face). In certain embodiments the electrode and ultrasonic stimulator face are joined or merged such as in a single unit or connected unit. In certain embodiments the electrode and ultrasonic stimulator face are a single unit. In certain embodiments the electrodes surround the transducer face. In certain embodiments the electrode is designed to interface with a conductive acoustic gel pad or conductive acoustic coupling materials whereby the electrical source and acoustic source can be coupled to the tissue. The materials are designed to have low electrical and acoustic impedance to the applied fields and allow efficient coupling to the targeted tissues.

[0054] The electrodes can be made of conductive biocompatible material, such as sponge, rubber sponge, hydrogel, silver, carbon, carbon rubber, gold, platinum, and / or any biocompatible conductive material that can be affixed to the skin of the subject to whom stimulation is being delivered. For example, a rubber sponge material may be used which is infused with conductive saline.

[0055] In certain embodiments, an electrode can be composed of multiple elements, such as for example a sponge rubber electrode encasing another conductive element, such as for example carbon rubber material which connects to a source through a wire(s). The wire(s) can connect to the electrode(s) though a port built into the electrode whereby the connecting wire is mostly insulated but exposed to the electrode at the port location.

[0056] In Figure 1, the electrodes are coupled to the skin via a conductor with high biocompatibility 15. In particular embodiments, the conductor 15 is designed to have low acoustic impedance and allow the coupling of a mechanical source such as an ultrasound source 16. The liquid may be saline, such as 0.9% NaCl saline solution. This concentration is designed to match the physiological salt concentration of the body, minimizing potential skin irritation, minimizing discomfort, and / or ensuring better conductivity for the stimulation. In certain embodiments an NaCl saline liquid can be mixed with local anesthetics to further reduce the sensation of stimulation and mixed in a manner to maintain a similar conductivity of 0.9% NaCl. In certain embodiments the electrode can be coupled to the skin with a conductive paste, which generally matched to a similar conductivity of 0.9% NaCl. In certain embodiments the electrode can be coupled to the skin with a conductive paste with high conductivity such as that of carbon, silver, or gold. In certain embodiments the electrode can be coupled to the skin with a conductive material with conductivity between 0.9% NaCl and materials such as that of carbon, silver, or gold. In certain embodiments the electrodes can be coupled with biocompatible fluid, paste, gel, and / or material that has a conductivity similar to that of an NaCl concentration around 0.5% to 1%. In certain embodiments the electrodes can be coupled with biocompatible fluid, paste, gel, and / or material that has a conductivity similar to that of an NaCl concentration around 0 to 0.5%. In certain embodiments the electrodes can be coupled with biocompatible fluid, paste, gel, and / or material that has a conductivity similar to that of an NaCl concentration around 0.5% to 0.75%. In certain embodiments the electrodes can be coupled with biocompatible fluid, paste, gel, and / or material that has a conductivity similar to that of an NaCl concentration around 0.75% to 1%. In certain embodiments the electrodes can be coupled with biocompatible fluid, paste, gel, and / or material that has a conductivity similar to that of an NaCl concentration greater than 1%. The electrodes can come pre-gelled, pre-pasted, pre-coated, pre-applied, and / or hydrated with this NaCl concentration (or other conductive material) or prepared prior to use with solution of similar concentration to ensure optimal electrical conductivity and comfort for the patient. Additionally in certain embodiments, the materials can be designed to minimize skin irritation and allergic reactions, enhancing patient safety and comfort. Advanced formulations may also include antimicrobial agents to reduce the risk of infection, as well as adhesives to provide secure placement. In certain embodiments, the electrode can be comprised almost entirely of fluid and / or gel and contained in an enclosure (such as a cup or reservoir whereby the enclosure is conductive or has a conductive component and / or conductive component that connects a wire that is the source of the electrical energy).

[0057] Sponge rubber electrodes themselves generally have a range in conductivity from 0.5 to 2 S / m conductivity when properly soaked in a saline solution. However, in certain embodiments the conductivity can be higher, such by infusing the sponge rubber material with biocompatible conductor particles (such as carbon, silver, or gold). In other embodiments the electrodes can be even higher in conductivity, wholly or in part. Such as, for example, platinum, gold, and / or silver electrodes having high conductivities, or other materials such as carbon, carbon filled polymers, or hydrogels. And finally, in certain embodiments the electrodes can have conductivity of less than 1 S / m.

[0058] The electrical source may be direct current (DC) or alternating current (AC) and may be applied inside or outside the tissue of interest. Additionally, the source may be time varying. Similarly, the source may be pulsed and may be comprised of time varying pulse forms. The source may be an impulse. Also, the source according to the present disclosure may be intermittent. In certain embodiments continuous wave or continuous waves of electromagnetic energy can be used. In certain embodiments, multiple electric fields of the same or different parameters can also be applied, such as for example with temporal interference fields, or for example in providing DC fields, or for providing DC fields with field(s) of varied frequencies or pulse forms. The electric field may be a pulsed signal, time varying signal, a sequence of time varying pulsed signals, a signal of low frequency pulsed higher frequency signals (for example, pulsing a higher frequency signal (for example above a KHz) on and off at frequency below a KHz (such as for example a waveform that center frequency component of ~1.1 KHz pulsed on and off at a 30Hz pulse frequency), a signal of low frequency pulsed higher frequency signals with uneven duty cycles, and / or a signal of low frequency pulsed higher frequency signals with even duty cycles. In certain embodiments, amplitude modulation can be used to vary the strength of the higher frequency signal. Phase shifts between pulses can be implemented. The rise and fall times of the pulses can be adjusted. Additionally, the electrical signals can be synchronized with specific biological rhythms or events, such as cardiac cycles, respiratory cycles, and / or brain oscillations.

[0059] A mechanical source such as an ultrasound source 16 is applied on the scalp and provides concentrated acoustic energy 18, i.e., mechanical field to a focused region of neural tissue, affecting a smaller number of neurons 22 than affected by the electric field 14, by the mechanical field 18 altering the tissue impedance relative to the applied electric field 14, and thereby generating the altered current 20. The mechanical source may be any acoustic source such as an ultrasound device. Generally, such device may be a device composed of electromechanical transducers capable of converting an electrical signal to mechanical energy such as those containing piezoelectric materials, a device composed of electromechanical transducers capable of converting an electrical signal to mechanical energy such as those in an acoustic speaker that implement electromagnets, a device in which the mechanical source is coupled to a separate mechanical apparatus that drives the system, or any similar device capable of converting chemical, plasma, electrical, nuclear, or thermal energy to mechanical energy and generating a mechanical field. In certain embodiments, the electric field and mechanical field can be applied to the same tissue (i.e., where the same number of neurons is affected by both fields, thereby making use to the synergistic effects of the dual energies applied). In other embodiments, the electric field is provided to a more focal area than the mechanical field.

[0060] The mechanical field may be coupled to tissue via a bridging medium, such as a container of saline to assist in the focusing or through gels and / or pastes which alter the acoustic impedance between the mechanical source and the tissue. The coupling can be completed with an acoustic coupling pad. Furthermore, the coupling material can also be made to be capable of coupling electrical energy at the same time, thereby allowing the coupling medium to bridge both the electrical and mechanical energies via one material. In certain embodiments, the conductor with high biocompatibility 15 can also serve as the bridging medium for the mechanical field source (such as with a conductive ultrasound gel). In certain embodiments the bridging mediums can be dual purpose and / or use multiple bridging materials, for example covering an ultrasound gel pad with an electrically conductive fluid so it can function for coupling the electrical and mechanical energies with the scalp and underlying brain targets.

[0061] The mechanical field may be time varying, pulsed, an impulse, or may be comprised of time varying pulse forms. It is envisioned that the mechanical source may be applied inside or outside of the tissue of interest. In certain embodiments the mechanical field frequencies can be less than 1 kHz and / or between 1-10 kHz, 10-100 kHz, 100-500 kHz, 500-1000 kHz, 1-4 MHz, 4-8 MHz, and / or 8-13 MHz. In other embodiments the mechanical field frequencies can be greater than 13 Mhz. These ranges are chosen to cover various operational regimes relevant to different applications. For example, the lower frequencies (3Mz) are particularly suited for applications near or through bone where attenuation will be less in the bone with lower frequencies (but balanced with the desired focus as the higher frequency waves can have greater focality, such as for example 750 KHz could be used in certain transcranial applications with a larger spot size than say a 2.6 MHz frequency (but with more attenuation / shallower penetration)); 4-8 MHz principally for applications through potentially thin bone (e.g., an animal or pediatric transcranial cases where attenuation through bone is less of an issue), though soft-tissues, or for shallow applications through thicker bone; 8-13 MHz principally through soft-tissues; and above 13 MHz through soft- tissues but principally via implant or catheter applications (which all lower can also be applied). Additionally, multiple transducers providing multiple mechanical fields with similar or differing frequencies, and / or similar or different mechanical field waveforms may be used- such as in an array of sources like those used in focused ultrasound arrays. The ultrasound may be a pulsed signal, time varying signal, a sequence of time varying pulsed signals, a signal of low frequency pulsed higher frequency signals (for example, pulsing a higher frequency signal (for example above a KHz) on and off at frequency below a KHz (such as for example a waveform that center frequency component of ~2.6 MHz pulsed on and off at a 30Hz pulse frequency, or a for example a waveform that is composed of a center frequency of ~700KHz with a 60Hz pulse frequency)), a signal of low frequency pulsed higher frequency signals with uneven duty cycles, and / or a signal of low frequency pulsed higher frequency signals with even duty cycles. In certain embodiments the mechanical field center frequency can be less than 1 kHz and / or between 1-10 kHz, 10-100 kHz, 100-500 kHz, 500-1000 kHz, 1-4 MHz, 4-8 MHz, and / or 8-13 MHz as discussed above while the pulse frequency can be less than 1 Hz and / or between 1-5 Hz, 5-10 Hz, 10-20Hz, 20-50 Hz, 50- 100 Hz, 100-200 Hz, and / or 200-500 Hz. In certain embodiments the pulse repetition frequency (PRF) of an ultrasound source can be upwards of 10kHz, but the pulse frequency impacting the tissue is generally withing the range cited above as pulse scanning is performed sequentially along different lines, so even if the PRF is high, the actual number of pulses interacting with any specific tissue region at one time is limited. These frequency ranges are chosen to cover various operational regimes relevant to different applications for human use. The justification of the mechanical field center frequency is as above (e.g., the lower frequencies (e.g., 2.5 MHz, 0.75 MHz, 0.5 MHz) are particularly suited for applications near or through bone, such as transcranial applications). The pulse frequency chosen will be dependent on the electric field frequency. For example, with a DC anodal electrical source, the higher frequency will lead to increased excitability modulation. Furthermore, it will be tuned to the disease state that is being treated (and pulse frequencies of ~20- 40 Hz, scanning a region of cortical tissue with ultrasound combined with an anodal source can be therapeutic in numerous neuropathologies as denoted below). Finally, when the electric field is time varying, the ultrasound can be phase locked to the signal (such as to impact neural oscillations), phase locked with a phase offset, or following a random noise stimulation pattern. The electric field frequency will impact the magnitude of current generated (due to the frequency dependence of the impedance) and the neural response. In certain embodiments, where a DC electrical source is used, the polarity of the signal can be used to control the direction of modulation (e.g., anodal facilitating and cathodal inhibiting). In certain embodiments continuous wave or continuous waves of ultrasound can be used. In certain embodiments, the signal will have an uneven duty cycle. The duty factor (or duty cycle) in ultrasound refers to the fraction of time that the ultrasound system is actively transmitting sound waves during each cycle. It is usually expressed as a percentage and is a crucial parameter in understanding the performance and safety of ultrasound systems. In certain cases, the duty factor can be determined by Pulse Repetition Frequency (PRF) divided by 2 times the center frequency (f_c) times one hundred percent (i.e., PRF / (2 x f_c) x 100%. The National Electrical Manufacturers Association (NEMA) center frequency, calculated in accordance with NEMA UD2 (NEMA Acoustic Output Measurement Standard, of which is hereby incorporated by reference herein), is defined as Fc= (fl + f2) / 2 where fl and f2 are the frequencies at which the transmitted acoustic pressure spectrum is 71% (-3dB) of its maximum value. As disclosed, the system can be effective in stimulation with duty factors of less than 1%. By combining the energies (electrical and ultrasound) a lower ultrasound duty cycle, such as less than 1% can be used for stimulating tissue. In certain embodiments, the duty cycle (aka duty factor) of between 1 and 5% can be used. In other embodiments a duty cycle of between 5% than 10% can be used. These duty cycle ranges are chosen to cover various operational regimes relevant to different applications for human use. Higher duty cycles can be used in other embodiments, such as greater than 10% (e.g., 30-40% and 40-55%), but lower duty factors are considered safer and reduce the risk of tissue heating and cavitation, which are potential hazards in ultrasound. In certain embodiments the pulse duration can be less than 0.01 microseconds, and / or between 0.01-.1 microseconds, 0.1- 0.25 microseconds, 0.25-0.5 microseconds, 0.5-0.75 microseconds, 0.75 - 1 microsecond, 1-2 microseconds, and / or 2-5 microseconds (and is generally related to being approximately equal to the 1 over the center frequency). In certain embodiments, such as in certain cases where the center frequency of the ultrasound is less than 200kHz, can be great than 5 microseconds. Typical intensities used for transcranial applications implement derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal-Average intensities (Ispta.3) between 0.1-1 mW / cmA2, 1-10 mW / cmA2, 10-20 mW / cmA2, 20-30 mW / cmA2, 30-40 mW / cmA2, 40-50 mW / cmA2, 50-60 mW / cmA2, 60-70 mW / cmA2, 70-80 mW / cmA2, 80-90 mW / cmA2, and / or 90-100 mW / cmA2. In certain embodiments, Ispta.3 levels up to 720 mW / cmA2 can be used for human use for short periods of time (e.g., for example at a level of 720mW / cmA2 one would generally want to provide the ultrasound for less than or equal to 30 seconds at a time for stimulation uses). There are other ways in which ultrasound intensity can be expressed and / or measured. The derated Spatial-Peak Temporal-Average intensity (Ispta.3) is one method, representing the time-averaged intensity at the spatial peak, adjusted for tissue attenuation at 0.3 dB / cm / MHz, typically measured in milliwatts per square centimeter (mW / cm2). Another method is the derated Spatial-Peak Pulse- Average intensity (Isppa.3), which represents the average intensity during the pulse duration at the spatial peak, also derated by 0.3 dB / cm / MHz and typically expressed in watts per square centimeter (W / cm2). Additionally, Imax.3 refers to the maximum intensity during a single half-cycle of the ultrasound wave, adjusted for tissue attenuation at 0.3 dB / cm / MHz, measured at the depth where the Pulse Intensity Integral (Pii .3) is maximized. Pii.3 represents the integral of the intensity over the pulse duration, also derated by the same factor. For example, in certain embodiments one could apply Isppa.3 of between 0.1-1 W / cmA2, 1-5 W / cmA2, 5-10 W / cmA2, 10-20 W-cmA2, 20-40 W / cmA2, 40-80 W / cmA2, 80-120 W / cmA2, 120-160 W / cmA2, 160-190 W / cmA2, and / or < 190 W / cmA2. Similarly, in certain embodiments one could apply Imax.3 of between 0.1-1 W / cmA2, 1- 5 W / cmA2, 5-10 W / cmA2, 10-20 W-cmA2, 20-40 W / cmA2, 40-80 W / cmA2, 80-120 W / cmA2, 120- 160 W / cmA2, 160-190 W / cmA2, and / or < 190 W / cmA2. These intensities ranges are chosen to cover various operational regimes relevant to different applications for human use. The choice of the intensity is key to thermal safety (the limits help prevent excessive heating of tissues, reducing the risk of thermal damage which could potentially affect sensitive tissues) and mechanical safety (the limits minimize the risk of cavitation and other mechanical effects that could damage tissue structures). Importantly, one can use the combined energies with the ultrasound applied with an ultrasound Mechanical Indexes (Mis) of less than 1 and Thermal Index for the cranium (TIC) of less than 1.5 for transcranial use, or Mechanical Indexes (Mis) of less than 1 and Thermal Indexes (TI) of soft tissue less than 1.5 for non-transcranial use. In certain embodiments for stimulation higher levels are possible, such as for example Mis of 1.9 or less and / or thermal indices of the cranium at the level and duration per the table provided in Figure 2. These mechanical and thermal index ranges are chosen to cover various operational regimes relevant to different applications for human use. The thermal index is used to predict tissue heating during ultrasound and the mechanical index is used to predict mechanical effects, such as cavitation, occurring in tissues exposed to ultrasound. The thermal index and mechanical index can be calculated as in provided by IEC 62359 (International Electrotechnical Commission “62359 Ultrasonics - Field characterization - Test methods for the determination of thermal and mechanical indices related to medical diagnostic ultrasonic fields” which is incorporated herein). For both indices, higher values are worse and as demonstrated below we have identified values that are safe and effective from the ultrasound when applied in combination with an electrical source. For human use one can use any combination of the above but should be guided first by the mechanical and thermal indices. For, example, in certain embodiments for use in humans, one can use a Spatial -Peak Temporal-Average intensity (Ispta.3) < 94 mW / cmA2, a Spatial-Peak Pulse-Average intensity (Isppa.3) < 190 W / cmA2, and MI < 1.9. As another example, one could use an Ispta.3 between 10 and 35 mW / cmA2, a Isppa.3 of between 50-150 W / cmA2, an Imax.3 of 50-150 W / cmA2, a thermal index of cranium of 0.6-1.5, and a mechanical index of 0.55-0.85. As another example, if one had a Isppa.3 of between 50-150 W / cmA2, an Imax.3 of 50-150 W / cmA2, a mechanical index of 0.55- 0.85, but found a condition where the thermal index was greater than 6 then one would not want to use this as an ultrasound source for combined electrical and ultrasonic based forms of stimulation. Generally, the device ultrasound component would be operated with dwell times described by the American Institute of Ultrasound in Medicine (AIUM) guidelines for dwell time. There is no dwell time limit for TI < 1.5 (see Recommended Maximum Scanning Times for Displayed Thermal Index (TI) Values, Sept. 26, 2022, published by the AIUM, but one should provide the ultrasound in conjunction with the values reproduced below in Figure 2).

[0062] In certain embodiments, one can use imaging-based transducers and / or transducers with energy profiles already approved for transcranial human use as by the USFDA and other regulatory bodies, such sector probes commonly used in imaging and / or phased array ultrasound systems. In certain embodiments, one can use imaging-based transducers and / or transducers with energy profiles already approved for human use as by the USFDA and other regulatory bodies, such sector probes commonly used in imaging and / or phased array ultrasound systems. In certain embodiments, one can use an ultrasound system capable of generating energy profiles already approved for human use as by the USFDA and other regulatory bodies. One could use a system with the range of intensities such as those disclosed above. Although it is not necessary to use the same system intensities as in imaging probes, in certain embodiments one can use typical intensities used for transcranial B-mode imaging. Ranges that can be used for transcranial use example include an Ispta.3 of between 1-50 mW / cmA2, an Isppa.3 of between 75-150 W / cmA3, and / or an Imax.3 of between 75-150 W / cmA3. In another embodiment, ranges that can be used for transcranial use example include an Ispta.3 of less than -100 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2. In another embodiment, ranges that can be used for transcranial use example include an Ispta.3 of less than -100 mW / cmA2, an Isppa.3 between 50-150 W / cmA2, and / or an Imax.3 between 50-150 W / cmA2. Furthermore, one can have a Mechanical Index (MI) of <1 and a Thermal index of the cranium <1.5. See the above paragraph for additional examples and combinations, and as above one should be guided by the thermal and mechanical indexes. In certain embodiments, one can use an imaging sector like probe or an imaging sector probe, such as for example with of Frame Rate (fr) less than 120 frames / sec with ~1 Pulse per line (ppi) with a lines per frame (Ipf) of less than 500, with a with a Pulse Repetition Frequency (PRF) of less than 10,000 (which is determine by calculating the fr x ppi x Ipf, such as for example ~ 7680 pulses / sec (30 fr x 1 ppi x 256 Ipf)), a center frequency of pulsed transmit pattern of less than 5 MHz, a pulse duration of less than 1 microsecond, a Duty factor of less than 1%, an MI<1, and a thermal index of the cranium of less than 1.5. In certain embodiments one can use an imaging sector like probe or an imaging sector probe, such as for example with of Frame Rate (fr) less than 35 frames / sec with less than 5 Pulse per line (ppi) with a lines per frame (Ipf) of <256, with a with a Pulse Repetition Frequency (PRF) of less than 10,000 a center frequency of pulsed transmit pattern of <3 MHz, a pulse duration of <1 microsecond, and a Duty factor of <1%. In certain embodiments can use Ispta.3 of < -720 mW / cmA2, an Isppa.3< -1000 W / cmA2, and / or an Imax.3: < -1000 W / cmA2. For human use one can use any combination of the above but should be guided first by the mechanical and thermal indices.

[0063] In certain embodiments one could use ultrasound that is considered unfocused (although in certain embodiments it still could be applied onto smaller regions of tissue than the electric field) and / or ultrasound that is considered focused.

[0064] In certain embodiments, such as where the acoustic energy is scanned over small regions of non-overlapping tissue or the multiple energy scan lines are generated by sweeping the ultrasound beam across the region of interest that cover different parts of the tissue without significant overlap, one can determine the stimulation effect by calculating the fr multiplied by the ppi, to determine the mechanical energy pulses that are delivered to neural tissue (for example, with 1 ppi and a 60 fr, one can effectively have stimulation pulse frequency impacting a subset of neural cell of 60Hz, which when combined with anodal field along an axon would be excitatory for motor neurons in the motor cortex) and in certain embodiments, if there is not a frame rate (e.g., for example if image processing was not done), then the ppi would be used as the stimulation pulse frequency. One can also have multiple pulses per line, for example with a 60ppl and 1 fr one can effectively have stimulation pulse frequency impacting a subset of neural cell of 60Hz. In certain embodiments the acoustic energy can involve transmitting multiple pulse lines at different angles. These lines intersect within the tissue, allowing increasing the total acoustic energy delivered to the tissue. In three-dimensional (3D) and four-dimensional (4D) ultrasound, pulse lines are systematically directed in multiple planes. In certain embodiments phased array systems are used. In phased array ultrasound systems, pulse lines can indeed intersect within the tissue being imaged due to the technology's beam steering and focusing capabilities. The transducer elements in a phased array can electronically steer the ultrasound beam by adjusting the timing of pulse emissions, directing the beam at various angles and focusing at different depths. This allows for multiple scan lines to intersect within the tissue. These intersections can lead to enhanced energy delivery and focality in particular regions. This method can reduce energy deposition to non- targeted regions. The phased array systems can electronically control the timing of ultrasound pulse emissions, allowing for targeted steering and focusing of the beam. Phased arrays concentrate ultrasound energy on specific tissue points altering tissue impedance in specific brain regions (and can additionally affect membrane permeability and ion channel function), thereby providing therapeutic benefits. The precise control over ultrasound parameters allows phased array systems to deliver safe and effective treatments by minimizing collateral energy deposition and ensuring targeted energy delivery. These systems can be used with imaging modalities to monitor treatments in real-time, further enhancing their safety and efficacy in therapeutic applications. For human use one can use any combination of the above but should be guided first by the mechanical and thermal indices.

[0065] Some embodiments of the disclosure are accomplished by noninvasively providing stimulation to a central nervous system of an awake subject to modulate a signal sent to or from the awake subject’s central nervous system. Generally, the signal will be processed in the subject’s brain. However, the signal may be processed in other parts of the subject’s body, e.g., the spinal cord. In certain embodiments, effects of the stimulation alter neural function past the duration of stimulation. Thus, the effects of the treatment last significantly longer than the period of treatment.

[0066] The parameters of the stimulation can be tuned so that stimulation is provided in a short period of time, allowing for a subject to receive stimulation while awake with little disruption to their day. That is opposed to stimulation protocols that require that stimulation be provided for long periods of time while a subject sleeps. In certain embodiments, the stimulation is provided in a single session that lasts 3 hours or less. For example, a single session may last 2.5 hours or less, 2 hours or less, 1 hour or less, thirty minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less. An exemplary stimulation protocol may involve numerous stimulation sessions over multiple days over multiple days, with no single session lasting more than three hours. For example, a stimulation protocol may be two weeks 5 in length, in which a subject received a single 20 minute session of stimulation each day of the week, or 5 days / week over a two week period (e.g., on weekdays). The stimulation can be tuned such that nothing more than stimulation of the central nervous system is required to improve the subject’s targeted disease symptoms or can be tuned to work in conjunction with other therapies.

[0067] The altered current 20 properties are controlled by the coupled fields. In an application where the electrical source is DC, the timing parameters of the altered current is controlled by the timing of the mechanical source.

[0068] The combined fields, electric and mechanical, may be controlled intermittently to cause specific patterns of spiking activity or alterations in neural excitability. For example, the device may produce a periodic signal at a fixed frequency, or high frequency signals at a pulsed frequency to cause stimulation at pulse frequencies shown to be effective in treating numerous pathologies. Such stimulation waveforms may be those implemented in rapid or theta burst transcranial magnetic stimulation (TMS) treatments, deep brain stimulation treatments, epidural brain stimulation treatments, spinal cord stimulation treatments, or for peripheral electrical stimulation nerve treatments. As an example, one may provide a DC electrical source field and intermittent Burst Frequency: 5 Hz (bursts every 200 ms) with an Intra-Burst Frequency: 50 Hz (3 pulses per burst at 20 ms intervals) for 2 seconds of stimulation (10 bursts) followed by an 8-second rest period for a total duration of approximately 190 seconds (600 pulses in total). As an example, one may provide a DC electrical source field and intermittent Burst Frequency: 5 Hz (bursts every 200 ms) with an Intra-Burst Frequency: 50 Hz applied continuously stimulation for 40 seconds. One could for example vary the Intra-Burst Frequency: 30 Hz to 100 Hz (3 pulses per burst at 10-33 ms intervals) or vary the bursts for example to contain four pulses instead of three. Generally, for such an example one could have a Burst Frequency: 4-7 Hz, an Intra-Burst Frequency: 20-100 Hz, and the Number of Pulses per Burst: 2-6 pulses. In other embodiments, the electric field frequency can also be adjusted, such as detailed in the examples above.

[0069] The ultrasound source may be placed at any location relative to the electrode locations, i.e., within, on top of, below, or outside the same location as the electrodes as long as components of the electric field and mechanical field are in the same region. The electrode(s) for the electrical source may be designed to cup around the ultrasound source, such as in Figure 3, where the electrode 117 is shaped to cup an ultrasound transducer face 114b. The locations of the sources should be relative to each other such that the fields intersect relative to the tissue and cells to be stimulated, or to direct the current alteration relative to the cellular components being stimulated. In certain embodiments the electrical and ultrasonic source are integrated into a single unit.

[0070] An example image of the electrode and ultrasound placement for certain embodiments is further depicted in Figure 3. In this example, the electric field source 116 (terminal 1) and 117 (terminal 2) (e.g., electrodes placed on the scalp of an individual) are shaped and placed in a manner to maximize the intersection of fields, and direct the applied currents to intersect with the applied ultrasonic field resulting in the altered current containing altered ohmic currents and altered displacement currents (note if the initial source electric field was DC, then an altered current would contain an altered ohmic current and a newly generated displacement current). As depicted in the figure, the electrode shape and location are based on the relative targets of the combined fields and placement of the ultrasonic source. In certain embodiments, one can use a DC source with electrodes (anode and cathode, for example at 116 and 117 respectively), and an ultrasound 114 are depicted which show how to impact tissue below the C3 / C4 surface points, corresponding to the primary motor cortex (as described with a 10-20 EEG coordinate system). In this figure, note that the electrode 117 that cups the ultrasound has a larger part more distal to the second electrode, and the second electrode 116 is placed at a location above the contralateral orbital. 118 points to an ultrasonic gel pad and 120 to a headgear system to aid in targeting and securing the electrical and ultrasonic sources. In Figure 4, an example of how C3 or C4 can be localized is demonstrated (and the contralateral orbital), for use with multiple different ESStim mounting options.

[0071] The apparatus and method according to the present disclosure generates capacitive currents via permittivity alterations, which can be significant in magnitude, direction, duration, and / or location, especially in the presence of low frequency applied electric fields. Tissue permittivities in biological tissues are much higher than most other non-biological materials, especially for low frequency applied electric fields where the penetration depths of electric fields are highest. This is because the permittivity is inversely related to the frequency of the applied electric field, such that the tissue permittivity magnitude is higher with lower frequencies. For example, for electric field frequencies below 100,000 Hz, brain tissue has permittivity magnitudes as high as or greater than 10A8 (100,000,000) times the permittivity of free space (8.854* 10A-12 farad per meter), and as such, minimal local perturbations of the relative magnitude can lead to significant displacement current generation. As the frequency of the electric field increases, the relative permittivity decreases by orders of magnitude, dropping to magnitudes of approximately 10A3 times the permittivity of free space (8.854* 10A-12 farad per meter) for electric field frequencies of approximately 100,000Hz. Additionally, by not being constrained to higher electric field frequencies, the method according to the present disclosure is an advantageous method for stimulating biological tissue due to lowered penetration depth limitations and thus lowered field strength requirements. Additionally, because displacement currents are generated in the area of the permittivity change, focusing can be accomplished via the ultrasound alone (or in combination with the electric field generation method). For example, to generate capacitive currents via a permittivity perturbation relative to an applied electric field as described above, broad DC or a low frequency electrical source field well below the cellular stimulation threshold is applied to a brain region but stimulation effects are locally focused in a smaller region by altering the tissue permittivity in the focused region of a mechanical field generated by a mechanical source such as an ultrasound source. This can be done noninvasively with the electrodes and the ultrasound device both placed on the scalp surface such that the fields penetrate the tissue surrounding the brain region and intersect in the targeted brain location, or with one or both of the electrodes and / or the ultrasound device implanted below the scalp surface (in the brain or any of the surrounding tissue) such that the fields intersect in the targeted region. This can be accomplished with methods used to focus an electric field, such as for example with focused and / or deep TMS.

[0072] A displacement current is generated by the modification of the permittivity in the presence of the sub threshold electric field and provides a stimulatory signal. In addition to the main permittivity change that occurs in the tissues, which can elicit stimulation (i.e., the generation of the altered currents for stimulation), a conductivity change can also occur in the tissue, which secondarily alters the ohmic component of the currents and can elicit stimulation. In a further embodiment, the displacement current generation and altered ohmic current components may combine for stimulation. Generally, tissue conductivities vary slightly as a function of the applied electric field frequency over the DC to 100,000 Hz frequency range, but not to the same degree as the permittivities, and increase with the increasing frequency of the applied electric field. Additionally in biological tissues, unlike other materials, the conductivity and permittivity do not show a simple one-to-one relationship as a function of the applied electric field frequency. The permittivity ranges are as discussed above.

[0073] Although the process described may be accomplished at any frequency of the applied electric field, the method in an exemplary embodiment is applied with lower frequency applied electric fields due to the fact the permittivity magnitudes of tissues, as high as or greater than 10A8 times the permittivity of free space, and the electric field penetration depths are highest for low frequency applied electric fields. Higher frequency applied electric fields may be less desirable as they will require greater radiation power to penetrate the tissue and / or a more pronounced mechanical source for permittivity alteration to achieve the same relative tissue permittivity change, i.e., at higher applied electric field frequencies the permittivity of the tissue is lower and as such would need a greater overall perturbation to have the same overall change in permittivity of a tissue as at a lower frequency. Applied electric field frequencies in the range of DC to approximately 100,000 Hz frequencies are advantageous due to the high tissue permittivity in this frequency band and the high penetration depth for biological tissues at these frequencies. In this band, tissues are within the so called ‘alpha dispersion band’ where relative tissue permittivity magnitudes are maximally elevated (i.e., as high as or greater than 10A8 times the permittivity of free space). Frequencies above approximately 100,000 to 1,000,000 Hz for the applied electric fields are still applicable for the method described in generating displacement currents for the stimulation of biologic cells and tissue, however, both the tissue permittivity and penetration depth are limited for biological tissues in this band compared to the previous band, but displacement currents of sufficient magnitude can still be generated for some applications. In this range, the magnitude of the applied electric field will likely need to be increased, or the method used to alter the permittivity relative to the applied electric field increased to bring about a greater permittivity change, relative to the tissue’s permittivity magnitude for the applied electric field frequency. Additionally, due to potential safety concerns for some applications, it may be necessary to limit the time of application of the fields or to pulse the fields, as opposed to the continuous application that is possible in the prior band. For tissues or applications where the safety concerns preclude the technique in deeper tissues, the technique can still be applied in more superficial applications in a noninvasive manner or via an invasive method. Higher frequency applied electric fields, above 1,000,000 to 100,000,000 Hz, can be used in generating displacement currents for the stimulation of biologic cells and tissue. However, this would require a more sufficient permittivity alteration or electromagnetic radiation, and as such is less than ideal in terms of safety than the earlier bands. For frequencies of the applied electric field above 100,000,000 Hz, biologic cell and tissue stimulation may still be possible, but may be limited for specialized applications that require less significant displacement currents.

[0074] The apparatus and method according to the present disclosure alters ohmic currents via conductivity alterations, which can be significant in in magnitude, direction, duration, and / or location as ohmic currents can be the dominant current component during stimulation. Additionally, by not being constrained to higher electric field frequencies, the method according to the present disclosure is an advantageous method for stimulating biological tissue due to lowered penetration depth limitations and thus lowered field strength requirements. Additionally, because altered currents are generated as a result of the conductivity change, focusing can be accomplished via the ultrasound alone (or in combination with the electric field generation method).

[0075] As an example, to generate capacitive currents via a permittivity perturbation relative to an applied electric field as described above, broad DC or a low frequency electrical source field well below the cellular stimulation threshold is applied to a brain region but stimulation effects are locally focused in a smaller region by altering the tissue permittivity in the focused region of a mechanical field generated by a mechanical source such as an ultrasound source. This can be done noninvasively with the electrodes and the ultrasound device both placed on the scalp surface such that the fields penetrate the tissue surrounding the brain region and intersect in the targeted brain location, or with one or both of the electrodes and / or the ultrasound device implanted below the scalp surface (in the brain or any of the surrounding tissue) such that the fields intersect in the targeted region.

[0076] The focus of the electric field(s) and means to alter tissue impedance (e.g., mechanical fields) to generate an altered current according to the present disclosure may be directed to various structures within the brain or nervous system including but not limited to (stimulation applied as a sole therapy, adjunctive with other therapies, and / or in combination with other therapies) such as Substantia Nigra, Ventral Tegmental Area, Locus Coeruleus, Raphe Nuclei, Basal Nucleus of Meynert, Hypothalamus, Amygdala, Hippocampus, Nucleus Accumbens, Periaqueductal Gray, Bed Nucleus of the Stria Terminalis, Medial Septal Nucleus, Olfactory Bulb, Medulla Oblongata, Pons, Anterior Cingulate Cortex, Prefrontal Cortex, Insular Cortex, Thalamus, Pineal Gland, Pituitary Gland, Cerebellum, Red Nucleus, Dorsal Raphe Nucleus, Lateral Hypothalamus, Arcuate Nucleus, Paraventricular Nucleus, Suprachiasmatic Nucleus, Lateral Septal Nucleus, Dorsal Motor Nucleus of the Vagus, Ventromedial Hypothalamus, Posterior Hypothalamus, Parabrachial Nucleus, Nucleus of the Solitary Tract, Superior Colliculus, Inferior Colliculus, Area Postrema, Lateral Habenula, Globus Pallidus, Caudate Nucleus, Putamen, Entorhinal Cortex, Preoptic Area, Tuberomammillary Nucleus, Zona Incerta, Pedunculopontine Nucleus, Interpedunculopontine Nucleus, Spinal Cord, Frontal Cortex, Orbitofrontal Cortex, Motor Cortex, Somatosensory Cortex, Parietal Cortex, Occipital Cortex, Temporal Cortex, Visual Cortex, Auditory Cortex, Association Cortex, Cingulate Gyrus, Dentate Gyrus, Subiculum, Presubiculum, Parasubiculum, Claustrum, Nucleus Basalis, Medial Geniculate Nucleus, Lateral Geniculate Nucleus, Reticular Nucleus, Pulvinar Nucleus, Ventral Posterior Nucleus, Ventral Anterior Nucleus, Ventral Lateral Nucleus, Dorsal Medial Nucleus, Lateral Dorsal Nucleus, Lateral Posterior Nucleus, Intralaminar Nuclei, Parafascicular Nucleus, Centromedian Nucleus, Midline Thalamic Nuclei, Epithalamus, Hypothalamic Supraoptic Nucleus, Hypothalamic Paraventricular Nucleus, Hypothalamic Lateral Preoptic Nucleus, Hypothalamic Medial Preoptic Nucleus, Hypothalamic Ventrolateral Preoptic Nucleus, Hypothalamic Dorsomedial Nucleus, Hypothalamic Posterior Area, Hypothalamic Periventricular Nucleus, Hypothalamic Preoptic Area, Amygdaloid Complex, Central Amygdaloid Nucleus, Medial Amygdaloid Nucleus, Basal Amygdaloid Nucleus, Cortical Amygdaloid Nucleus, Lateral Amygdaloid Nucleus, Basomedial Amygdaloid Nucleus, Thalamic Reticular Nucleus, Paratenial Nucleus, Paraventricular Thalamic Nucleus, Reuniens Nucleus, Rhomboid Nucleus, Subthalamic Nucleus, Habenular Nucleus, Mammillary Bodies, Paraventricular Nucleus of the Hypothalamus, Suprachiasmatic Nucleus, Tuberomammillary Nucleus, Ventrolateral Preoptic Nucleus, Mediodorsal Thalamus, Centromedian Thalamus, Parafascicular Thalamus, Periventricular Thalamus, Periaqueductal Gray, Pontine Nuclei, Reticular Formation, Solitary Nucleus, Inferior Olive, Superior Olive, Vestibular Nuclei, Cochlear Nuclei, Lateral Dorsal Tegmental Nucleus, Parabrachial Nucleus, Medial Dorsal Nucleus, Central Lateral Nucleus, Central Medial Nucleus, Dorsal Hypothalamic Area, Ventral Tegmental Area, Medial Forebrain Bundle, Nucleus of Diagonal Band, Bed Nucleus of the Stria Terminalis, Habenula, Interstitial Nucleus of Cajal, Lateral Dorsal Tegmental Nucleus, Lateral Hypothalamus, Lateral Septal Nucleus, Medial Septal Nucleus, Parafornical Area, Paraventricular Nucleus, Posterior Hypothalamus, Preoptic Area, Reticular Thalamic Nucleus, Subfornical Organ, Supramammillary Nucleus, Ventral Pallidum, Zona Incerta, Primary Motor Cortex, Premotor Cortex, Supplementary Motor Area, Primary Somatosensory Cortex, Secondary Somatosensory Cortex, Primary Visual Cortex, Secondary Visual Cortex, Primary Auditory Cortex, Secondary Auditory Cortex, Prefrontal Cortex, Dorsolateral Prefrontal Cortex, Ventromedial Prefrontal Cortex, Orbitofrontal Cortex, Anterior Cingulate Cortex, Posterior Cingulate Cortex, Medial Prefrontal Cortex, Lateral Prefrontal Cortex, Insular Cortex, Parietal Association Cortex, Temporal Association Cortex, Occipital Association Cortex, Inferior Parietal Lobule, Superior Parietal Lobule, Supramarginal Gyrus, Angular Gyrus, Fusiform Gyrus, Parahippocampal Gyrus, Lingual Gyrus, Cuneus, Precuneus, Broca's Area, Wernicke's Area, Frontal Eye Fields, Supplementary Eye Fields, Dorsal Attention Network, Ventral Attention Network, Default Mode Network, Salience Network, Left Hemisphere Language Network, Right Hemisphere Spatial Attention Network, Ventrolateral Prefrontal Cortex, Dorsomedial Prefrontal Cortex, Ventromedial Prefrontal Cortex, Dorsolateral Prefrontal Cortex, Anterior Insula, Posterior Insula, Primary Gustatory Cortex, Orbitofrontal Cortex, Ventral Striatum, Dorsal Striatum, Medial Temporal Lobe, Lateral Temporal Lobe, Medial Parietal Lobe, Lateral Parietal Lobe, Medial Occipital Lobe, Lateral Occipital Lobe, Central Sulcus, Postcentral Gyrus, Precentral Gyrus, Middle Temporal Gyrus, Superior Temporal Gyrus, Inferior Temporal Gyrus, Middle Frontal Gyrus, Superior Frontal Gyrus, Inferior Frontal Gyrus, Calcarine Sulcus, Brodmann area 1, Brodmann area 2, Brodmann area 3, Brodmann area 4, Brodmann area 5, Brodmann area 6, Brodmann area 7, Brodmann area 8, Brodmann area 9, Brodmann area 10, Brodmann area 11, Brodmann area 12, Brodmann area 13, Brodmann area 14, Brodmann area 15, Brodmann area 16, Brodmann area 17, Brodmann area 18, Brodmann area 19, Brodmann area 20, Brodmann area 21, Brodmann area 22, Brodmann area 23, Brodmann area 24, Brodmann area 25, Brodmann area 26, Brodmann area 27, Brodmann area 28, Brodmann area 29, Brodmann area 30, Brodmann area 31, Brodmann area 32, Brodmann area 33, Brodmann area 34, Brodmann area 35, Brodmann area 36, Brodmann area 37, Brodmann area 38, Brodmann area 39, Brodmann area 40, Brodmann area 41, Brodmann area 42, Brodmann area 43, Brodmann area 44, Brodmann area 45, Brodmann area 46, Brodmann area 47, Brodmann area 48, Brodmann area 49, Brodmann area 50, Brodmann area 51, Brodmann area 52, any component of the basal ganglia, gastric nuclei, brainstem, sub-cortical structures, spinal cord, nerve roots, sensory organs, and peripheral nerves. In certain embodiments the areas can be stimulated directly and / or indirectly (i.e., through connections to another area upstream or downstream from the brain area that was directly stimulated).

[0077] Tissue and / or cells can be stimulated (directly or indirectly) to alter their function, such as for example by providing stimulation to alter neural excitability, alter synaptic plasticity, alter neural connectivity, alter dendritic growth, modulate neurotransmitter release, alter long-term potentiation, alter long-term depression, alter neural oscillations, increase myelination, enhance axonal regeneration, alter synaptic efficiency, alter neural pathways, increase neurogenesis, alter brain network connectivity, reduce neural inflammation, modulate cortical excitability, improve interneuron function, increase synaptic density, modulate resting-state networks, enhance functional connectivity, improve neural synchronization, increase cortical thickness, alter neurovascular coupling, alter neural spike timing, modulate gamma band activity, modulate beta band activity, modulate alpha band synchronization, modulate theta band activity, modulate delta wave regulation, alter neural circuit reorganization, increase oligodendrocyte proliferation, modulate astrocyte activity, enhance microglial function, improve synaptic pruning, increase neuronal survival, impact neurotransmitter release (or production or absorption), modulate ion channel activity, enhance receptor sensitivity, improve glial-neuron interactions, modulate extracellular matrix composition, alter blood-brain barrier integrity, modulate calcium signaling, enhance intracellular communication, increase mitochondrial function, modulate protein synthesis, improve oxidative stress response, enhance autophagy, increase synaptic vesicle recycling, modulate GABAergic signaling, enhance glutamatergic transmission, improve cholinergic function, modulate dopaminergic pathways, enhance serotonergic activity, improve noradrenergic signaling, modulate histaminergic function, enhance purinergic signaling, improve nitric oxide synthesis, modulate endocannabinoid system, enhance peptide neurotransmitter release, improve synaptic homeostasis, increase neural stem cell proliferation, modulate neurotrophic factors, enhance synaptogenesis, improve neuroplasticity, increase interneuron connectivity, modulate pyramidal cell activity, enhance inhibitory control, improve excitatory signaling, modulate brain network hubs, enhance synaptic recruitment, improve neural entrainment, modulate large-scale brain networks, enhance cross-hemispheric communication, improve neural pathway integrity, increase brain-derived neurotrophic factor (BDNF) levels, modulate synaptic plasticity-related genes, enhance epigenetic regulation, improve gene expression profiles, modulate synaptic strength, enhance neural adaptation, improve synaptic transmission fidelity, modulate synaptic integration, enhance neurotransmitter transporter function, improve synaptic vesicle release probability, modulate synaptic latency, enhance synaptic delay variability, improve postsynaptic receptor density, modulate synaptic conductance, enhance synaptic cooperativity, improve synaptic competition, modulate synaptic crosstalk, enhance synaptic tagging, improve synaptic capture, modulate synaptic consolidation, enhance synaptic compartmentalization, improve synaptic heterogeneity, modulate synaptic resource allocation, enhance synaptic efficacy, improve synaptic information storage, modulate synaptic encoding, enhance synaptic decoding, improve synaptic fidelity, modulate synaptic filtering, enhance synaptic precision, improve synaptic reliability, modulate synaptic resilience, enhance synaptic robustness, improve synaptic scalability, modulate synaptic selectivity, enhance synaptic specificity, improve synaptic stability, modulate synaptic variability, enhance synaptic versatility, improve synaptic weighting, modulate synaptic wiring, enhance neural code optimization, and / or improve neural encoding strategies..

[0078] Stimulated tissue(s) may be selected such that a wide variety of pathologies may be treated. Generally, diseases that can result in abnormal levels of tissue excitability and / or network function are treatable. However, symptoms of the disease may also be improved by stimulating parts of the brain and / or nervous system that have compromised function as a result of the pathology. Such pathologies that may be treated include, but are not limited, to Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Dystonia, Tics, Spinal Cord Injury, Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving, Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson’s Disease, Parkinsonianism, Obsessions, Depression, Schizophrenia, Bipolar Disorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, Auditory Hallucinations, Movement Disorders, Neurodegenerative Disorders, Pain Disorders, Metabolic Disorders, Addictive Disorders, Psychiatric Disorders, Traumatic Nerve Injury, Cognitive Disorders, Sensory Disorders, Endocrine Disorders, Syndromic Disorders, Leukodystrophies, Mitochondrial Disorders, Metabolic Disorders, Migraine, Neuropathies, Low-back Pain, Chronic Pancreatitis, Cancer, Huntington's Disease, Cerebral Palsy, Myasthenia Gravis, Guillain-Barre Syndrome, Rett Syndrome, Fragile X Syndrome, Wilson's Disease, Niemann-Pick Disease, Batten Disease, Lafora Disease, Tay-Sachs Disease, Charcot-Marie-Tooth Disease, Friedreich's Ataxia, Wernicke- Korsakoff Syndrome, Restless Legs Syndrome, Meningitis, Encephalitis, Bell's Palsy, Trigeminal Neuralgia, Central Pain Syndrome, Post-Polio Syndrome, Shingles, Postherpetic Neuralgia, Chronic Fatigue Syndrome, Fibromyalgia, Sleep Disorders, Narcolepsy, Insomnia, Sleep Apnea, REM Sleep Behavior Disorder, Parasomnias, Obstructive Sleep Apnea, Somnambulism, Bruxism, Cluster Headaches, Tension Headaches, Hemiplegic Migraine, Vestibular Migraine, Chronic Daily Headache, Idiopathic Intracranial Hypertension, Normal Pressure Hydrocephalus, Subarachnoid Hemorrhage, Subdural Hematoma, Epidural Hematoma, Concussion, Chronic Traumatic Encephalopathy, Anoxic Brain Injury, Hypoxic Brain Injury, Transient Ischemic Attack, Vascular Dementia, Frontotemporal Dementia, Lewy Body Dementia, Progressive Supranuclear Palsy, Corticobasal Degeneration, Primary Lateral Sclerosis, Progressive Bulbar Palsy, Spinal Muscular Atrophy, Kennedy's Disease, Brown-Sequard Syndrome, Syringomyelia, Chiari Malformation, Arnold-Chiari Malformation, Dandy -Walker Syndrome, Spina Bifida, Anencephaly, Encephalocele, Holoprosencephaly, Schizencephaly, Lissencephaly, Polymicrogyria, Pachygyria, Microcephaly, Macrocephaly, Hydrocephalus, Tethered Spinal Cord Syndrome, Cauda Equina Syndrome, Radiculopathy, Myelopathy, Spondylosis, Spinal Stenosis, Disc Herniation, Sciatica, Plexopathy, Mononeuropathy, Polyneuropathy, Autonomic Neuropathy, Small Fiber Neuropathy, Giant Cell Arteritis, Temporal Arteritis, Takayasu's Arteritis, Kawasaki Disease, Buerger's Disease, Thromboangiitis Obliterans, Moyamoya Disease, Central Retinal Artery Occlusion, Central Retinal Vein Occlusion, Retinitis Pigmentosa, Optic Neuritis, Papilledema, Anosmia, Ageusia, Dysgeusia, Hypogeusia, Phantosmia, Parosmia, Agnosia, Agraphia, Alexia, Anomia, Apraxia, Aphasia, Ataxia, Dysarthria, Dysphagia, Dysmetria, Dysdiadochokinesia, Hemiballismus, Myoclonus, Tic Disorders, Tourette Syndrome, Tremor, Essential Tremor, Psychogenic Tremor, Functional Neurological Disorder, Conversion Disorder, Somatic Symptom Disorder, Illness Anxiety Disorder, Body Dysmorphic Disorder, Factitious Disorder, Malingering, Munchausen Syndrome, Munchausen by Proxy, Dissociative Identity Disorder, Depersonalization / Derealization Disorder, Schizoaffective Disorder, Schizophreniform Disorder, Brief Psychotic Disorder, Delusional Disorder, Shared Psychotic Disorder, Paranoid Personality Disorder, Schizoid Personality Disorder, Schizotypal Personality Disorder, Antisocial Personality Disorder, Borderline Personality Disorder, Histrionic Personality Disorder, Narcissistic Personality Disorder, Avoidant Personality Disorder, Dependent Personality Disorder, Obsessive- Compulsive Personality Disorder, Attention-Deficit / Hyperactivity Disorder, Oppositional Defiant Disorder, Conduct Disorder, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, Dermatillomania, Obsessive-Compulsive Spectrum Disorders, Body-Focused Repetitive Behaviors, Hoarding Disorder, Skin Picking Disorder, Hair Pulling Disorder, Anxiety Disorders, Generalized Anxiety Disorder, Panic Disorder, Agoraphobia, Specific Phobia, Social Anxiety Disorder, Separation Anxiety Disorder, Selective Mutism, Anorexia Nervosa, Bulimia Nervosa, Binge-Eating Disorder, Pica, Rumination Disorder, Avoidant / Restrictive Food Intake Disorder, Obesity, Metabolic Syndrome, Diabetes Mellitus, Hypoglycemia, Hyperglycemia, Insulin Resistance, Cushing's Syndrome, Addison's Disease, Hyperthyroidism, Hypothyroidism, Thyroid Storm, Myxedema Coma, Coma, Hyperparathyroidism, Hypoparathyroidism, Adrenal Insufficiency, Pheochromocytoma, Hyperaldosteronism, Hypoaldosteronism, Hypopituitarism, Hyperpituitarism, Diabetes Insipidus, Syndrome of Inappropriate Antidiuretic Hormone, Polycystic Ovary Syndrome, Menstrual Disorders, Premenstrual Syndrome, Premenstrual Dysphoric Disorder, Menopause, Andropause, Sleep-Wake Disorders, Circadian Rhythm Sleep-Wake Disorders, Delayed Sleep-Wake Phase Disorder, Advanced Sleep-Wake Phase Disorder, Irregular Sleep-Wake Rhythm Disorder, Non- 24-Hour Sleep-Wake Disorder, Shift Work Disorder, Parasomnias, Non-Rapid Eye Movement Sleep Arousal Disorders, Sleepwalking, Sleep Terrors, Nightmare Disorder, Rapid Eye Movement Sleep Behavior Disorder, Restless Legs Syndrome, Periodic Limb Movement Disorder, Sleep- Related Hypoventilation, Sleep-Related Hypoxemia, Central Sleep Apnea, Complex Sleep Apnea Syndrome, Hypersomnolence Disorder, Kleine-Levin Syndrome, Idiopathic Hypersomnia, Narcolepsy Type 1, Narcolepsy Type 2, Sleep-Related Eating Disorder, Exploding Head Syndrome, Hypnic Jerks, Sleep Paralysis, Sleep Bruxism, Sleep Enuresis, Sleep-Related Groaning, Sleep-Related Rhythmic Movement Disorder, Sleep-Related Hypertension, Nocturnal Hypertension, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, Neurocardiogenic Syncope, Vasovagal Syncope, Carotid Sinus Hypersensitivity, Reflex Syncope, Situational Syncope, Cardiovascular Dysautonomia, Cardiac Arrhythmias, Atrial Fibrillation, Ventricular Fibrillation, Long QT Syndrome, Short QT Syndrome, Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Wolff-Parkinson-White Syndrome, Atrial Flutter, Supraventricular Tachycardia, Ventricular Tachycardia, Torsades de Pointes, Premature Atrial Contractions, Premature Ventricular Contractions, Sinus Bradycardia, Sinus Tachycardia, Sick Sinus Syndrome, Heart Block, Bundle Branch Block, Trifascicular Block, Hormone disorders, Endocrine Disorders, Infertility, Hypogonadism, Hypergonadism, Gynecomastia, Hirsutism, Virilization, Cerebrovascular Disease, Multiple System Atrophy (MSA), Progressive Multifocal Leukoencephalopathy (PML), Paraneoplastic Neurological Syndromes, Peripheral Neuropathy, Hereditary Spastic Paraplegia (HSP), Neurofibromatosis, Landau-Kleffner Syndrome, Rasmussen's Encephalitis, Primary CNS Lymphoma, Stiff-Person Syndrome, Creutzfeldt-Jakob Disease (CJD), Transverse Myelitis, Neuroacanthocytosis Syndromes, and / or Opsoclonus-Myoclonus Syndrome.

[0079] Furthermore, electric and means for altering tissue impedance mechanical fields to generate an altered current may be focused on specific brain structures, neural structures, and / or tissues of the nervous system to assess or impact system function such as sensory augmentation, sensory alteration, anesthesia induction, brain mapping, epileptic mapping, neural atrophy reduction, neuroprosthetic interaction or control with nervous system, stroke and traumatic injury neurorehabilitation, bladder control, assisting breathing, cardiac pacing, muscle stimulation, motor control restoration, cognitive enhancement, sensory substitution, neural plasticity enhancement, memory enhancement, neurogenesis stimulation, synaptic strength modulation, mood stabilization, anxiety reduction, sleep regulation, arousal regulation, circadian rhythm adjustment, sensory processing improvement, neurodevelopmental support, tremor suppression, autonomic function modulation, neural network modulation, attention regulation, learning facilitation, reflex enhancement, stress response modulation, balance restoration, coordination improvement, motor learning enhancement, neuroinflammation reduction, neuropathic pain modulation, blood-brain barrier modulation, neurotoxin removal, neurovascular coupling improvement, spasticity management, cognitive enhancement, neural connectivity mapping, muscle tone regulation, signal - to-noise ratio improvement, nerve regeneration, axonal growth promotion, synaptic pruning regulation, sensory threshold adjustment, motor threshold adjustment motor planning improvement, neurotransmitter release modulation, electrical activity modulation, bi-directional neural communication, neuro-immune interaction regulation, cerebral blood flow modulation, cerebral edema reduction, intracranial pressure management, white matter integrity preservation, gray matter density enhancement, neural circuit modulation, synaptic vesicle cycling improvement, oligodendrocyte function enhancement, astrocyte modulation, Schwann cell function support, microglial activity regulation, neurotransmitter reuptake modulation, exci totoxi city prevention, oxidative stress reduction, mitochondrial function enhancement, apoptosis regulation, protein misfolding reduction, neurotransmitter synthesis enhancement, ion channel regulation, genetic expression modulation, epigenetic modification, proteostasis maintenance, neural metabolic rate modulation, cortical thickness enhancement, brain volume preservation, neuronal firing rate modulation, neural response normalization, cortical reorganization facilitation, brain reserve capacity improvement, structural connectivity enhancement, functional connectivity enhancement, neuroelectric activity mapping, axonal transport improvement, cerebrospinal fluid dynamics regulation, glial scar formation reduction, synaptic gap modulation, ion gradient maintenance, receptor sensitivity adjustment, synaptic cleft homeostasis, action potential modulation, refractory period regulation, cortical activation balance, neurochemical gradient modulation, neural feedback loop adjustment, synaptic transmission reliability improvement, dendritic spine density enhancement, interhemispheric communication improvement, cognitive load management, neuroendocrine function regulation, treatment of pain syndromes and / or treatment of internal visceral diseases, such as chronic pancreatitis or cancer.

[0080] The focus of the electric field(s) and means to alter tissue impedance (e.g., mechanical fields) to generate an altered current according to the present disclosure may be directed to alter neurotransmitters, such for example when applied to the primary motor cortex it can improve dopamine levels and impact motor symptoms of PD. In other embodiments, it can be directed at the brain targets (via direct or indirect stimulation of areas), to influence the release, production breakdown, and / or reabsorption of other neurotransmitters (such as for example affecting receptor sensitivity modulation, receptor density modulation, transporter activity alteration, synaptic vesicle dynamics, neuromodulator interaction, second messenger system activation, genetic expression changes, epigenetic modifications, enzyme regulation (e.g., esterase activity), hormonal effects, inflammatory responses, precursor molecule availability, cofactor presence, environmental toxin impact, age-related changes, stress-induced alterations, drug interactions, sleep pattern influences, physical activity effects, social interaction impacts, circadian rhythm regulation, injury-induced disruptions, mental health disorder-related changes, receptor upregulation, receptor downregulation, neurotransmitter receptor desensitization, neurotransmitter receptor sensitization, receptor internalization, receptor trafficking, receptor phosphorylation, receptor dephosphorylation, ion channel modulation, synaptic cleft neurotransmitter concentration, neurotransmitter diffusion rates, neurotransmitter gradient maintenance, synaptic plasticity changes, long-term potentiation, long-term depression, dendritic spine formation, dendritic spine elimination, synaptic pruning, neurotransmitter vesicle docking, neurotransmitter vesicle fusion, exocytosis regulation, endocytosis regulation, synaptic bouton formation, synaptic bouton elimination, neurotransmitter spillover, astrocytic uptake, microglial modulation, blood-brain barrier permeability, neurovascular unit interaction) such as for example acetylcholine, dopamine, serotonin, norepinephrine, epinephrine, glutamate, gamma-aminobutyric acid (GABA), glycine, histamine, aspartate, substance P, endorphins, enkephalins, dynorphins, vasopressin, oxytocin, anandamide, nitric oxide, adenosine, cholecystokinin, somatostatin, neuropeptide Y, corticotropinreleasing hormone, melatonin, beta-endorphin, calcitonin gene-related peptide (CGRP), galanin, hypocretin (orexin), neurokinin A, neurokinin B, neurotensin, bombesin, gastrin, ghrelin, glucagon, insulin, neuropeptide Y, peptide YY, pituitary adenylate cyclase-activating polypeptide (PACAP), prolactin, secretin, thyrotropin-releasing hormone (TRH), urocortin, vasoactive intestinal peptide (VIP), angiotensin II, bradykinin, corticotropin, endothelin, interleukins, leptin, and / or growth hormone-releasing hormone (GHRH).

[0081] Stimulation (direct or indirect) can alter tissue and / or cellular function, such as to alter or alter or enhance synaptic plasticity, alter or enhance neural connectivity, alter or increase dendritic growth, modulate neurotransmitter release, alter or enhance long-term potentiation, reduce longterm depression, alter neural oscillations, alter or increase myelination, modulate neural network activity, alter or enhance axonal regeneration, alter or enhance synaptic efficiency, strengthen neural pathways, alter or increase neurogenesis, alter brain network connectivity, reduce neural inflammation, modulate cortical excitability, alter or enhance interneuron function, alter or increase synaptic density, modulate resting-state networks, alter or enhance functional connectivity, alter default mode network activity, alter or enhance neural synchronization, alter or increase cortical thickness, modulate subcortical networks, alter or enhance cross-network communication, alter prefrontal cortex activity, alter or enhance hippocampal function, alter or increase thalamocortical connectivity, modulate basal ganglia activity, alter or enhance cerebellar networks, alter or enhance sensorimotor integration, alter or increase corpus callosum integrity, modulate limbic system activity, alter or enhance reward circuitry, alter amygdala connectivity, alter or enhance anterior cingulate cortex function, alter or enhance parietal network activity, modulate temporal lobe networks, alter or enhance occipital lobe function, alter or increase frontal lobe connectivity, alter or enhance brainstem networks, modulate hypothalamic activity, alter or enhance neurovascular coupling, alter neural spike timing, alter or enhance gamma band activity, reduce beta band activity, alter or increase alpha band synchronization, modulate theta band activity, alter or enhance delta wave regulation, alter or enhance neural circuit reorganization, alter or increase oligodendrocyte proliferation, modulate astrocyte activity, alter or enhance microglial function, alter or enhance synaptic pruning, alter or increase neuronal survival, modulate ion channel activity, alter or enhance receptor sensitivity, alter or enhance glial-neuron interactions, modulate extracellular matrix composition, alter or enhance blood-brain barrier integrity, alter or enhance neural metabolic activity, modulate calcium signaling, alter or enhance intracellular communication, alter or increase mitochondrial function, modulate protein synthesis, alter or enhance oxidative stress response, alter or enhance autophagy, alter or increase synaptic vesicle recycling, modulate GABAergic signaling, alter or enhance glutamatergic transmission, alter or enhance cholinergic function, modulate dopaminergic pathways, alter or enhance serotonergic activity, alter or enhance noradrenergic signaling, modulate histaminergic function, alter or enhance purinergic signaling, alter or enhance nitric oxide synthesis, modulate endocannabinoid system, alter or enhance peptide neurotransmitter release, alter or enhance synaptic homeostasis, alter or increase neural stem cell proliferation, modulate neurotrophic factors, alter or enhance synaptogenesis, alter or enhance neuroplasticity, alter or increase interneuron connectivity, modulate pyramidal cell activity, alter or enhance inhibitory control, alter or enhance excitatory signaling, modulate brain network hubs, alter or enhance synaptic recruitment, alter or enhance neural entrainment, modulate large-scale brain networks, alter or enhance cross-hemispheric communication, alter or enhance neural pathway integrity, alter or increase brain-derived neurotrophic factor (BDNF) levels, modulate synaptic plasticity-related genes, alter or enhance epigenetic regulation, alter or enhance gene expression profiles, modulate synaptic strength, alter or enhance neural adaptation, alter or enhance synaptic transmission fidelity, modulate synaptic integration, alter or enhance neurotransmitter transporter function, alter or enhance synaptic vesicle release probability, modulate synaptic latency, alter or enhance synaptic delay variability, alter or enhance postsynaptic receptor density, modulate synaptic conductance, alter or enhance synaptic cooperativity, alter or enhance synaptic competition, modulate synaptic crosstalk, alter or enhance synaptic tagging, alter or enhance synaptic capture, modulate synaptic consolidation, alter or enhance synaptic compartmentalization, alter or enhance synaptic heterogeneity, modulate synaptic resource allocation, alter or enhance synaptic efficacy, alter or enhance synaptic information storage, modulate synaptic encoding, alter or enhance synaptic decoding, alter or enhance synaptic fidelity, modulate synaptic filtering, alter or enhance synaptic precision, alter or enhance synaptic reliability, modulate synaptic resilience, alter or enhance synaptic robustness, alter or enhance synaptic scalability, modulate synaptic selectivity, alter or enhance synaptic specificity, alter or enhance synaptic stability, modulate synaptic variability, alter or enhance synaptic versatility, alter or enhance synaptic weighting, modulate synaptic wiring, alter or enhance neural code optimization, and / or alter or enhance neural encoding strategies.

[0082] Stimulation can also be directed at the peripheral nervous system (through direct stimulation or via connections with other parts of the nervous system directly stimulated) such as for example at peripheral nerves (that carry motor, sensory, and / or autonomic signals), plexuses (networks of intersecting nerves, such as the brachial and lumbosacral plexuses, which serve the limbs), ganglia (clusters of nerve cell bodies in the peripheral nervous system (PNS). Stimulation can also be directed at the autonomic nervous system (through direct stimulation or via connections with other parts of the nervous system directly stimulated) such as for example at the Sympathetic Nervous System (SNS) which is involved in the "fight or flight" response (such as structures such as the sympathetic trunk, various ganglia, and splanchnic nerves), Parasympathetic Nervous System (PNS) which promotes the "rest and digest" functions (such as the vagus nerve, cranial and sacral outflows, and various ganglia like the ciliary and pterygopalatine ganglia), and / or the Enteric Nervous System (ENS) which is often referred to as the "second brain," and controls gastrointestinal functions (such as it includes the myenteric and submucosal plexuses). Stimulation can also be directed at the spinal cord (through direct stimulation or via connections with other parts of the nervous system directly stimulated) such as for example at the anterior horn, posterior horn, lateral horn, central canal, anterior gray column, posterior gray column, lateral gray column, anterior corticospinal tract, lateral corticospinal tract, anterior spinothalamic tract, lateral spinothalamic tract, ventral corticospinal tract, dorsal spinocerebellar tract, ventral spinocerebellar tract, anterior spinothalamic pathway, lateral spinothalamic pathway, dorsal column-medial lemniscus pathway, motor neurons, sensory neurons, autonomic neurons, spinal reflex arcs, ascending tracts, descending tracts, and / or central pattern generators. Stimulation may be directed at cranial nerves, such as for example the vagal nerve to impact function like mood, excitability / seizure threshold, and / or systemic or focused inflammation.

[0083] Stimulation can be provided to a single target or multiple targets and can be provided in combination and / or adjunct to other forms of neuromodulation at the same target or other targets simultaneously and / or sequentially.

[0084] In the focused region of tissue to which the means to alter impedance (e.g., mechanical fields) are delivered, the excitability of individual neurons can be heightened to the point that the neurons can be stimulated by the combined fields, or be affected such as to cause or amplify the alteration of the neural excitability caused by the altered currents, either through an increase or decrease in the excitability of the neurons. Furthermore, this can enhance the effects of ultrasound or electrical stimulation applied alone in a manner that is beyond a simple addition of two different stimulation types, whereby the effects can be greater in magnitude and / or last longer than either of the individual stimulation types added together. Furthermore, the direction of the effects (e.g., facilitatory or inhibitory can be altered). This can be effectively and safely done with the levels and methods disclosed herein. This alteration of neural excitability can last past the duration of stimulation and thus be used as a basis to provide lasting treatment. Additionally, the combined fields can be provided in multiple, but separate sessions to have a summed, or carry-over effect, on the excitability of the cells and tissue. The combined fields can be provided prior to another form of stimulation, to prime the tissue making it more or less susceptible to alternate, follow-up forms of stimulation. Furthermore, the combined fields can be provided after an alternate form of stimulation, where the alternate form of stimulation is used to prime the tissue to make it more or less susceptible to the form of stimulation disclosed herein. Furthermore, the combined fields can be applied for a chronic period of time.

[0085] Tissue impedances can be altered relative to the applied electric fields via a number of methods. Mechanical techniques can be used to either alter the bulk tissue impedance relative to an applied electric field or move tissue components of differing impedances relative to an applied electric field. A second electromagnetic field can be applied to the tissue, at a different frequency than the initial frequency of the applied electromagnetic field, such that it alters the tissue permittivity and / or conductivity at the frequency dependent point of the initially applied electric field. An optical signal can also be focused on the tissues to alter the permittivity and / or conductivity of the tissue relative to an applied electric field. A chemical agent or thermal field can also be applied to the tissues to alter the permittivity and / or conductivity of the tissue relative to an applied electric field. These methods can also be used in combination to alter the tissue permittivity and / or conductivity relative to an applied electric field via invasive and / or noninvasive methods.

[0086] In certain embodiments, the electric field characteristics determine the effect on the targeted neural tissue. In certain embodiments, when the system is used with a cathodal electrical source (inhibitory) and ultrasonic (inhibitory) energies, the combined energies can be used to elicit an inhibitory effect in tissue. In certain embodiments, when the system is used with a cathodal electrical source (inhibitory) and ultrasonic (faciliatory) energies, the combined energies can be used to elicit an inhibitory effect in tissue. In certain embodiments, when the system is used with an anodal electrical source (faciliatory) and ultrasonic (inhibitory) energies, the combined energies can be used to elicit an faciliatory effect in tissue. In certain embodiments, when the system is used with an anodal electrical source (faciliatory) and ultrasonic (facilitatory) energies, the combined energies can be used to elicit an faciliatory effect in tissue.

[0087] In a further embodiment, the method according to the present disclosure is applied in the area of muscular stimulation, where amplified, focused, direction altered, and / or attenuated currents can be used to alter muscular activity via direct stimulation, depolarizing muscular cells, hyperpolarizing muscular cells, modifying membrane potentials, and / or increasing or decreasing the excitability of the muscle cells. This alteration of excitability or firing patterns can last past the duration of stimulation and thus be used as a basis to provide lasting treatment. Additionally, the stimulation can be provided in multiple, but separate sessions to have a summed, or carry-over effect, on the excitability of cells and tissue. Additionally, the stimulation can be provided to prime the tissue by adjusting the muscle cell excitability to make it more or less susceptible to alternate follow up forms of stimulation. The stimulation can be used after another form of stimulation was used to prime the tissue. Furthermore, the stimulation can be applied for a chronic period of time. This embodiment may be useful for altering or assisting cardiac pacing or function, assisted breathing, muscle stimulation for rehabilitation, muscle stimulation in the presence of nerve or spinal cord injury to prevent atrophy or assist in movement, or as substitution for physical exercise.

[0088] In yet another embodiment, the method according to the present disclosure can be applied the area of physical therapy, where amplified, focused, direction altered, and / or attenuated currents can be used to augment or enhance physical therapy. In certain embodiments stimulation may be used to stimulate blood flow, increase or alter neuromuscular response, limit inflammation, speed the breakdown of scar tissue, and speed rehabilitation by applying the focus of the current generation to the effected region in need of physical therapy. It is envisioned that the method according to the present disclosure may have a wide variety in the area of physical therapy including the treatment or rehabilitation of traumatic injuries, sports injuries, surgical rehabilitation, occupational therapy, and / or robot assisted rehabilitation following neural or muscular injury. For instance, following an injury to a joint or muscle, there is often increased inflammation and scar tissue in the region and decreased neural and muscular response. Typically, ultrasound is provided to the affected region to increase blood flow to the region and increase the metabolic re-absorption of the scar tissue while electrical stimulation is provided separately to the nerves and muscles; however, by providing them together, a person can receive the benefit of each individual effect, but additionally amplified stimulatory and metabolic effects through the altered currents. The other methods for generating altered currents discussed within can also be used to assist in physical therapy via the displacement currents that are generated.

[0089] Furthermore, the method according to the present disclosure may be applied to the area of cellular metabolism, where currents can be used to interact with electrically receptive cells or charged membranes to alter the tissue or cellular dynamics. It is envisioned that this embodiment can provide treatment for various diseases where electrically receptive cells respond to the newly generated displacement currents and altered current distribution.

[0090] Furthermore, the method according to the present disclosure may be applied to the area of gene therapy. Amplified, focused, direction altered, and / or attenuated currents can be used to interact with electrically receptive cells or receptors within the cell to influence protein transcription processes and alter the genetic content of the cells. The altered current densities in the tissue can interact with the tissue to stimulate this altered gene regulation. Additionally, the displacement currents generated by the method can further be used to assist in drug delivery and / or gene therapy through the altered current influence on the delivery of agents.

[0091] The electrical source and means to alter a tissue impedance, such as an ultrasound source, may be controlled by a single system of integrated electronics which can control and monitor the output of the system. The system for example can monitor and control the operating conditions of the system, such as for monitoring the thermal aspects of the ultrasound source and be able to stop the delivery of stimulation should the device operate outside of typical thermal ranges (e.g., between 10 degrees C to 40 degrees C, 0 to 40 degrees C, 15- 30 degrees C, or 0 to 15 degrees C). The system can be designed to control the two fields timing, intensity, frequency, duration, and / or location of application, such as for example it could be an Electrosonic stimulation (ESStim) system that implements direct current intensities in a transcranial direct current stimulation mode and ultrasound intensities and temporal pattems / frequencies approved by the FDA for transcranial imaging (such as for example using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1.9, or Mis less than 1 and thermal indices of the cranium of less than 1.5 (which can be applied for extended periods of time), or as in Figure 2). The energies can be provided by first ramping up a transcranial direct current stimulation (tDCS) source from 0 to the desired DC current intensity, such as for example to 2 mA over a 30 second to one minute interval, and then engaging the ultrasound, such as for example with a signal of low frequency pulsed higher frequency signals implanting a duty factor of less than 1% (note the ultrasound can also be ramped up to the desired intensity), with pulses of less than a microsecond in length and pulsed at frequency lower than the center frequency of the pulsed waveform. In certain embodiments an imaging like transducer or imaging transducer can be used (with capability to provide transcranial imaging information (and for example, scan a sector of tissue with a pulse rate per line, lines per frame, and frame rate equal to the total pulse rate frequency which is lower than the center frequency of the pulsed transmit pattern). The ultrasound transducer can be connected to an imaging system, such as for example to confirm or assess an acoustic window prior to or during stimulation. In certain embodiments an imaging system can be used prior to stimulation as part of the placement / targeting procedure. The system itself could be designed for both options.

[0092] The combined ultrasound and electrical form of neuromodulation can be applied to improve neuromodulatory focus, depth, targeting control, amplitude of effect, and / or duration of effect.

[0093] Electrosonic Stimulation (ESStim) is an improved noninvasive brain stimulation (NIBS) modality, with enhanced focality, penetration, and targeting control compared to other NIBS technologies. In the present embodiment disclosed herein, during ESStim with transcranial direct current stimulation and transcranial ultrasonic sources, an ultrasonic field is focused on a select volume of neural tissue that is broadly exposed to a sub-threshold DC electric field (but it should be noted that other field combinations are possible, such as in focus, distribution, and type to enact combined field stimulation with an electrical and ultrasonic source). The ultrasonic field mechanically perturbs the tissue and alters its permittivity (i.e., tissue capacitance) relative to the applied electric field. A displacement current is generated, via this electromechanical coupling in the tissue, that is capable of stimulating or modulating the activity of neurons. Furthermore, an altered ohmic current is generated that can stimulate or modulate the activity of neurons. Furthermore, the neuromodulatory effects of ultrasound can be enhanced. Furthermore, the neuromodulatory effects of the electrical stimulation can be enhanced. Biologically active tissues, like gray matter, demonstrate elevated low frequency dielectric permittivities that are mechanically responsive, making them ideal for this technique. Furthermore, biologically active tissues, like gray matter, also demonstrate conductivities that are mechanically responsive, making them ideal for the technique.

[0094] An ESStim system that implements direct current intensities that are already used safely in transcranial direct current stimulation and ultrasound intensities and temporal patterns / frequencies approved by the FDA for transcranial imaging (such as for example using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1.9, or Mis less than 1 and thermal indices of the cranium of less than 1.5 (which can be applied for extended periods of time), or as in Figure 2). The energies are provided by first ramping up a transcranial direct current stimulation (tDCS) source from 0 to the desired DC current intensity, such as for example 2 mA, and then engaging the ultrasound, such as for example with a signal of low frequency pulsed higher frequency signals implanting a duty factor of less than 1% (note the ultrasound can also be ramped up to the desired intensity), with pulses of less than a microsecond in length and pulsed at frequency lower than the center frequency of the pulsed waveform. In certain embodiments an imaging like transducer or imaging transducer can be used (with capability to provide transcranial imaging (and for example scan a sector of tissue with a pulse rate per line, lines per frame, and frame rate equal to the total pulse rate frequency which is lower than the center frequency of the pulsed transmit pattern). The ultrasound transducer can be connected to an imaging system, such as for example to confirm or assess an acoustic window prior to or during stimulation. In certain embodiments an imaging system can be used prior to stimulation as part of the placement / targeting procedure. For animal use, stimulation characteristics, particularly that of the ultrasound can be reduced for transcranial use as an animal skull is typically thinner than the human skull and stimulation characteristics that are effective in animals are not always effective in humans. Furthermore, the head can be much smaller (or larger) depending on the animal and the energy deposition patterns and effects can be quite different. For example, the thermal index and mechanical indices are not comparable and what can be done safely in an animal or human are not interchangeable. This present disclosure focuses on the discovery of the appropriate field characteristics and methods of implementation that are safe and effective for human use and focused on treating numerous neuropathologies that can be improved with stimulation.

[0095] The methods described above outline a range of values and characteristics that can be implemented in combined energy forms of stimulation. It should be noted we demonstrated combinations and ranges that can be used as above in any permutation of those disclosed. In certain embodiments, ranges and values are provided that can be used safely and effectively for human use and stimulation of the targets in the central nervous system. Below we provide specific examples of various methods of the disclosure that may be used to improve movement disorders, chronic pain, addiction, mood, and / or fall risk in patients.

[0096] Parkinson’s Disease (PD): The methods herein, such as the combined ultrasound and electrical form of neuromodulation can be applied in multiple indications to improve disease symptoms or clinical metrics of the diseases such as for example Parkinson’s Disease.

[0097] The past decade has seen a rapid increase in the application of neurostimulation methods to treat PD. Present stimulation techniques make the tradeoff between invasiveness and efficacy, where the most effective techniques require surgical procedures to implant stimulation devices within the nervous system. Thus, the most widely used stimulation methods are invasive, such as deep brain stimulation (DBS). These techniques rely on implanted devices that stimulate brain tissue by injecting electrical currents directly into the tissue. Although both the stimulating electrode and targeted tissues influence the final stimulating current density distributions, the major limiting factor is not the technology or physics of stimulation, but the potential for surgical complications. These invasive methods are most effective due to their focality, ability to stimulate deeper locations, and ability to precisely target neural tissue. However, because of their associated costs and risks the therapeutic need for noninvasive options is enormous. Noninvasive methods have been developed to provide stimulation without the risks associated with the surgical based stimulation methods. These techniques are notable for not just their online effects (i.e., during stimulation), but also for offline effects, in which therapeutic effects persist past the period of stimulation if the appropriate stimulation parameters are applied, in certain embodiments over multiple sessions on consecutive days. The two most common noninvasive techniques, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), take advantage of different electromagnetic principles to induce or inject currents into cortical tissue. However, these same fundamental electromagnetic principles limit the focality, penetration, and targeting control of the stimulating currents, translating into limited therapeutic effect. Although TMS and tDCS have exhibited some potential in the treatment of PD, they have shown minimal and / or inconsistent effects on PD symptoms.

[0098] “Non-electromagnetic” stimulation methods have also been explored with limited to no clinical success, including mechanical / acoustic, optical, and thermal methods. For instance, Fry (Year: 1958 Title: Production of reversible changes in the central nervous system by ultrasound Journal: Science), and more recently others, have proposed Transcranial Ultrasound Stimulation (TUS). The technique has demonstrated some success with potential improvements in focality and penetration compared to TMS and tDCS. However, the technique has yet to show a long lasting neuromodulatory clinical effect, due possibly to the fact that electrical currents are not generated. Furthermore, many noninvasive electromagnetic techniques can elicit offline therapeutic effects with sub-threshold stimulation intensities (i.e., without inducing an action potential), but there is no evidence that mechanical methods can induce comparable effects to electrical effects (and vice versa).

[0099] Thus there remains a significant unmet clinical need, across multiple classes of disease, for a noninvasive stimulation technique that can match the effects of invasive DBS, improve the impact of DBS, offer a noninvasive alternative, reduce and / or enhance the impact of PD pharmacological therapies when provided adjunct to therapy, and / or be coupled with other therapies (such as Physical Therapy (PT), Occupational Therapy (OT), Balance Training, Speech Therapy). This need is particularly evident for those patients suffering from PD. In upwards of 10-20% of PD cases, drug therapy is marked with debilitating side effects, particularly levodopa-induced motor complications (which becomes increasingly common with an extended duration of use). In many of these patients, DBS stimulation can elicit significant therapeutic effects. For instance, stimulation of the ventral intermediate nucleus of the thalamus can dramatically relieve tremor, and stimulation of the subthalamic nucleus can substantially reduce bradykinesia, rigidity, tremor, and some gait difficulties in people with PD (especially for patients with advanced disease with limited response to dopaminergic drugs). However, the rate of complications with DBS can be quite high. DBS post-op complications can be significant, including intracranial bleeds (12%), seizures (3%), headache (25%), and infection (6%). Device malfunctions are reported at rates upwards of 20%, including lead migration, lead fracture, and pulse generator malfunction

[0048] , Additionally, over 10% of DBS implantations can result in misplaced stimulation leads, resulting in limited efficacy and unwanted side effects.

[0100] ESStim is an improved noninvasive brain stimulation (NIBS) modality, with enhanced focality, penetration, and targeting control compared to other NIBS technologies. It combines independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue. In an embodiment disclosed herein, during ESStim with transcranial direct current and ultrasonic sources, an ultrasonic field is focused on a select volume of neural tissue that is broadly exposed to a sub-threshold DC electric field (but it should be noted that other field combinations are possible, such as in focus, distribution, and type to enact combined field stimulation). The ultrasonic field mechanically perturbs the tissue and alters its permittivity (i.e., tissue capacitance) relative to the applied electric field. A displacement current is generated, via this electromechanical coupling in the tissue, which is capable of stimulating or modulating the activity of neurons. Furthermore, an altered ohmic current is generated that can stimulate or modulate the activity of neurons. Furthermore, the neuromodulatory effects of ultrasound can be enhanced. Furthermore, the neuromodulatory effects of the electric fields can be enhanced. Biologically active tissues, like gray matter, demonstrate elevated low frequency dielectric permittivities that are mechanically responsive, making them ideal for this technique. Furthermore, biologically active tissues, like gray matter, also demonstrate conductivities that are mechanically responsive, making them ideal for the technique.

[0101] The physical principles that govern this technique do not suffer from the same electromagnetic constraints as the other non-invasive methods like TMS and tDCS. Electrically driven stimulation can be accomplished, even with low intensity fields, because at the DC electric field frequency used for ESStim, tissue permittivities are considerably elevated due to “alpha dispersion’Vcounterion effects and are capable of sustaining significant displacement currents. Thus, ESStim can make use of the inherently high capacitance of biologically active tissues with a simple electromechanical technique, with much lower field intensities and frequencies than other techniques, to non-invasively generate new stimulating displacement currents in the brain tissue. ESStim stimulation can be electromagnetic in nature, and thus in theory can accomplish the same effects as deep brain stimulation (DBS), spinal cord stimulation (SCS), and other noninvasive electromagnetic modalities. The second advantage is that focusing can be accomplished through the acoustic field while subthreshold DC currents can be broadly applied to the tissue via scalp surface electrodes, in a manner similar to tDCS. Ultrasound, used for non- stimulatory applications, can be incredibly focal, and our electromechanical coupling models demonstrate electrosonic focality ESStim systems can reach ~10mm3, which is orders of magnitude more focal than other non-invasive electromagnetic stimulation methods. The third advantage is that a subcortical electrical focus can also be achieved via the acoustic field (e.g., generated with conventional focused ultrasound arrays and / or acoustic lenses) coupled with the sub-threshold electric field (that can penetrate subcortically with large surface electrodes). TMS and transcranial electrical stimulation (TES) non-invasive electrical techniques are generally restricted to maximum cortical effects. Deep TMS is also limited, as it can stimulate deeply, but at the expense of focality. Techniques in development, such as temporal interference, suffer from similar electromagnetic limitations that can potentially limit translation beyond rats into the clinic. Furthermore, targeting with temporal interference can be limited, as can its focality. For ESStim, phased array ultrasound systems allow for beam steering and real-time, multi-node targeting. Additionally, electromagnetic techniques are constrained by the electromagnetic tissue properties of targeted tissue, whereas the electrosonic approach allows one to modulate the electromagnetic tissue properties for more effective control of stimulation field distributions. Finally, ESStim implements acoustic powers up to lOx lower or more than pure transcranial ultrasound stimulation (and orders of magnitude lower power than ablative and past combined methods). Accordingly, ESStim can be applied for extended durations, well within established ultrasound and electrical guidelines (such as those of the FDA), and with greater than purely electrical or mechanical methods. See the incorporated priority applications for more details.

[0102] Primary Motor Cortex Stimulation (and adjacent or connected tissues) for treating PD: TMS and tDCS have shown some positive effects on motor function in PD, most effectively via stimulation of the primary motor cortex (Ml) which can sometimes lead to offline clinical improvements in PD motor symptoms based on long-lasting neuroplastic modifications (i.e. stimulation effects can outlast the period of stimulation and lead to significant results from days to months following stimulation, see details below in the Preliminary Data Section). Although these techniques are sometimes effective, they often elicit suboptimal responses in magnitude and duration of clinical effect. It has been postulated that the inconsistent, suboptimal clinical effects result from the limited focality, penetration, and targeting control of TMS and tDCS, further highlighting the need for improved noninvasive techniques for PD treatments. See the incorporated priority applications for more details.

[0103] Elaborating on the above, TMS and tDCS are limited in focality, depth, and targeting control, which in turn can result in a limited magnitude and duration of effects following PD treatments. Given ESStim’s advantages over these techniques, we disclose how ESStim can be used for PD therapy. We disclose how to apply the technique to be more effective than its noninvasive counterparts in treating PD. In this example, we disclose the effects of Ml directed stimulation. ESStim as it is known that the Ml is a reliable therapeutic target for offline PD benefits. The offline effects of Ml stimulation are beneficial to PD patients. Furthermore, we disclose a number of dosing procedures to optimize improvements in clinical effect, and further limit the potential for the inconsistent effects seen with the other techniques.

[0104] As outlined above, ESStim is an improved noninvasive brain stimulation (NIBS) modality, with enhanced focality, penetration, and targeting control compared to other NIBS technologies. In the present embodiment disclosed herein, during ESStim with transcranial direct current stimulation and transcranial ultrasonic sources, an ultrasonic field is focused on a select volume of neural tissue that is broadly exposed to a sub-threshold DC electric field (but it should be noted that other field combinations are possible, such as in focus, distribution, and type to enact combined field stimulation). The ultrasonic field mechanically perturbs the tissue and alters its permittivity (i.e., tissue capacitance) relative to the applied electric field. A displacement current is generated, via this electromechanical coupling in the tissue, that is capable of stimulating or modulating the activity of neurons. Furthermore, an altered ohmic current is generated that can stimulate or modulate the activity of neurons. Furthermore, the neuromodulatory effects of ultrasound can be enhanced. Furthermore, the neuromodulatory effects of the electric fields can be enhanced. Biologically active tissues, like gray matter, demonstrate elevated low frequency dielectric permittivities that are mechanically responsive, making them ideal for this technique. Furthermore, biologically active tissues, like gray matter, also demonstrate conductivities that are mechanically responsive, making them ideal for the technique. An ESStim system that implements direct current intensities that are already used safely in transcranial direct current stimulation and ultrasound intensities and temporal patterns / frequencies approved by the FDA for transcranial imaging (such as for example using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1.9, or Mis less than 1 and thermal indices of the cranium of less than 1.5, or per table in Figure 2) can be effective for treating PD. The energies are provided by first ramping up the tDCS from 0 to the desired DC current intensity ( such as for example up to 0.1 mA, 0.5 mA, 1 mA, 2 mA, or 10mA, but in certain embodiments it can range from between l-3mA) and then engaging the ultrasound, such as for example with a signal of low frequency pulsed higher frequency signals implanting a duty factor of less than 1% (note the ultrasound can also be ramped up to the desired intensity), with pulses of less than a microsecond in length and pulsed at frequency lower than the center frequency of the pulsed waveform. Furthermore, in other embodiments the ultrasound can be engaged prior to the electrical source or at the same time. Typical intensities used for the application such as the derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal -Average intensity (mW / cmA2) can be less than 1 mW / cmA2, 2 mW / cmA2, 10 mW / cmA2, 20 mW / cmA2, 30 mW / cmA2, 40 mW / cmA2, 50 mW / cmA2, 75 mW / cmA2, and / or 100 mW / cmA2 (although levels up to 720 mW / cmA2 can be used for human use for short periods of time (e.g., less than 30 seconds)) as discussed above, and in some situations even higher levels can be used and / or durations of application can be provided). In certain embodiments, one can use Ispta.3 of < -100 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2. As another example, one could use an Ispta.3 between 10 and 35 mW / cmA2, a Isppa.3 of between 50-150 W / cmA2, and / or an Imax.3 of 50-150 W / cmA2, a thermal index of cranium of 0.6-1.5, and a mechanical index of 0.55-0.9. One can use the combined energies with ultrasound Mechanical Indexes (Mis) of less than 1 and Thermal Indexes for the cranium (TIC) of less than 1.5 (although higher levels are possible, such as for example Mis of 1.9 or less and thermal indices of the cranium of per the table of Figure 2). One can use an imaging sector like probe or an imaging sector probe, such as for example with of Frame Rate (fr) < 120 frames / sec with -1 Pulse per line (ppi) with a lines per frame (Ipf) of <500, with a with a Pulse Repetition Frequency (PRF) of <10,000 (such as for example - 7680 pulses / sec (30 fr x 1 ppi x 256 Ipf),acenter frequency of pulsed transmit pattern of <5 MHz, a pulse duration of <1 microsecond, and a Duty factor of <1%. One can use an imaging sector like probe or an imaging sector probe, such as for example with of Frame Rate (fr) < 40 frames / sec with -1 Pulse per line (ppi) with a lines per frame (Ipf) of <300, with a with a Pulse Repetition Frequency (PRF) of <10,000 (such as for example - 7680 pulses / sec (30 fr x 1 ppi x 256 Ipf), a center frequency of pulsed transmit pattern of <2.5 MHz, a pulse duration of <1 microsecond, and a Duty factor of <1%. In certain embodiments, such as where the acoustic energy is scanned over small regions of non-overlapping tissue or the multiple energy scan lines are generated by sweeping the ultrasound beam across the region of interest that cover different parts of the tissue without significant overlap, one can determine the stimulation effect by calculating the fr times the ppi, to determine the mechanical energy pulses that are delivered to neural tissue (for example, with 1 ppi and a 60 fr, one can effectively have stimulation pulse frequency impacting a subset of neural cell of 60Hz, which when combined with anodal field along an axon would be excitatory for motor neurons in the motor cortex or for example with a 60ppl and 1 fr one can effectively have stimulation pulse frequency impacting a subset of neural cell of 60Hz) and in certain embodiments, if there is not a frame rate (e.g., for example if image processing was not done), then the ppi would be used as the stimulation pulse frequency. These are just examples that can be effective with PD (but see above for a wide range of options that can be used for treatment).

[0105] In certain embodiments an imaging like transducer or imaging transducer can be used (with capability to provide transcranial imaging (and for example scan a sector of tissue with a pulse rate per line, lines per frame, and frame rate equal to the total pulse rate frequency which is lower than the center frequency of the pulsed transmit pattern). The ultrasound transducer can be connected to an imaging system, such as for example to confirm or assess an acoustic window prior to or during stimulation. In certain embodiments an imaging system can be used prior to stimulation as part of the placement / targeting procedure (either using a single system with imaging and stimulation capabilities, two systems with a single transducer that is interchangeable between the systems, and / or two systems with two different transducers) such as for example using the ultrasound imaging system to confirm the proper placement (e.g., location, pitch, roll, yaw) of the transducer and identifying an appropriate acoustic window by assessing the image received (such as for example using the system to visualize deeper to contralateral bones of the skull when placing the transducer over a potential brain target, which could confirm the ability to transmit noninvasively to the desired target). In certain embodiments, the energy patterns for transcranial ultrasound imaging confirmation can be the same energy characteristics used for stimulation. In other embodiments, the energy patterns for transcranial ultrasound imaging confirmation can use different energy characteristics than those used for stimulation, but by confirming the placement with the same transducer (shape, location, etc.) for both imaging and stimulation (as for example the same intensities or focal pattern to visualize a contralateral bone of the skull might not be implemented during the stimulation procedure).

[0106] Stimulation as described can be provided for extended durations of time safely and effectively, such as for example for 5 minutes, 10, minutes, 20 minutes, 1 hour, and onwards. The stimulation can also be provided for shorter periods of time, or in staggered or continuous intervals. In certain embodiments the stimulation or part of the stimulation can be briefly stopped, such as for example providing the electrical stimulation over 20 minutes during a session but briefly stopping the ultrasound, such as in 5 minute intervals. This can be done for example to briefly check or reapply the ultrasonic and / or electrical bridging medium. Furthermore, stimulation can be provided across multiple days on different sessions, such as for example providing stimulation for 20 minutes a day over a 5 day or 10 day period. Furthermore, stimulation can be provided in a manner to initiate a stimulation effect during an induction phase (such as for example providing stimulation for 20 minutes a day 10 times over a two week period) and then providing maintenance stimulation (such as biweekly stimulation over a month period). Even when the stimulation is stopped, the effects can last for days, weeks, or months after.

[0107] In certain embodiments, the targeting for stimulation is controlled by headgear placement and localizing C3 or C4 targets with the transducer (as exemplified below) to affect the primary motor cortex and other associated brain areas. The ultrasound transducer is positioned coincident on the scalp with the tDCS electrode location in a 10-20 EEG coordinate system, depending on the desired treatment outcome. For example, treatment for gait disturbances and postural instability in PD patients, patients are treated with the energy localized over the patient’s primary motor cortex (Ml) (i.e., the C3 or C4 electrode location in an 10-20 EEG coordinate system). See Figures 3 and 4. The electrodes cover a surface area of the scalp, such as for example approximately Ixlcm, 5x5cm, or 5x7 cm rectangular shaped (with a cut out for the location of the ultrasound transducer where the ultrasound gel is conductive or made out of materials that can serve the role of a bridging medium for both the electrical and mechanical energy).

[0108] The target location is determined using the 10-20 EEG coordinate measurement and identification procedure, described here and in the figures below for C3 placement. This process begins by identifying several fixed landmarks on the participant's head: the nasion (the depression between the forehead and nose), the inion (the bony protrusion at the base of the skull), and the left and right preauricular points (the points just in front of the ear canals), as shown in Figure 4 when done manually or with a semi -automated or automated methods such as depicted in Figure 3 herein and the methodology of which is detailed in U.S. Patent Publication No. US2020 / 0054414, the entire disclosure of which is hereby incorporated by reference herein (see, for example, Figures 10-13 of that application, the detailed description of the document, and the description of the methods pertaining to the figures for additional details and methods of placement which are incorporated herein by reference). In other embodiments, described below, imaging such as MRI, can be used with a frameless stereotactic system, or pre-stimulation targeting system without a frameless stereotactic system, to localize the electrode(s) and ultrasound placement. Note, in certain embodiments, the ultrasound source and at least one electrode are integrated into a single unit.

[0109] For placement with implementing a 10-20 system, to locate the Cz position (at the skull's vertex), one would measure the distance between the nasion and inion and divide it by 2. Next, one would find the line that intersects the left and right preauricular points and crosses the midpoint between the inion and nasion. The Cz is situated at the intersection of these measures (see Figure 4).

[0110] The C3 (and C4) location is found along the line that intersects the left and right preauricular points through the Cz (depicted as the skull’s vertex in Figure 4), at 20% of the distance measured from left to right preauricular points, starting from the Cz, as depicted in Figure 4. The C3, which is used to target the stimulation of the left primary motor cortex (Ml), is illustrated in Figures 4. The C4 is the target of the right Ml. For applications where patients have one sides disease, the C3 will be targeted for patients with right-side dominant disease (and vice-versa, C4 for left side dominant disease). For Parkinson’s Disease patients without a clearly defined disease side dominance, the dominant hand side will be used can be used determine stimulation side (e.g., right hand dominant patients will receive left brain side stimulation). Finally, the cathode electrode is localized above the contralateral brow line slightly lateral to the midline. In certain embodiments, the cathode electrode is placed ~1.5 cm (typically ranging between 1-3 cm) above the contralateral brow line and -1.25 cm lateral to the of the midline (typically ranging between 0.5 to 2 cm) for typical head sizes. In certain embodiments, the electrode can be placed bordering the brow line and at the midline.

[0111] In another embodiment, stimulation can be provided to both the C3 and C4 simultaneously and / or sequentially. Additionally, one can still be effective in providing treatment to just one consistent side, such as for example one can stimulate the left side brain for left side dominant disease and still have a beneficial impact due to the redundancy in the system (e.g., transcallosal connections) and the transsynaptic effects of stimulation on the network impacted by PD.

[0112] The tDCS electrodes and ultrasound transducer can be held in place using either a “manual” method, “semi-automated” method, or “automated” (see Figure 4). In the “manual” method the localization is made as above per the 10-20 coordinate system. In certain instances, the location for the electrode(s) and ultrasound transducer(s) are marked in advance directly on the patient’s scalp with a non-conductive wax / grease pencil or similar item. The electrode is held down via the strapping mechanism pictured in Figure 4, allowing for a fixed electrode location throughout the procedure. The electrode face is structured such that the ultrasound transducer interface can only be placed in one location within the electrode interface (not one on top of each other, but the transducer is placed within the boundary outline of the electrode, see Figure 4) allowing for consistency of placement once the coordinate system is confirmed. The operator can manually hold the ultrasound transducer and electrode interface in place at the identified location. In the semiautomated method, the same 10-20 based localization method is used with the same electrode / transducer interface that assures electrode and transducer placement, but the ultrasound transducer is held in place via the assistive headgear (see Figure 4). The electrode is held down via the headgear mechanism pictured below, allowing for a fixed electrode location throughout the procedure. The electrode interface assures the proper placement of the transducer at the identified location, resulting in equivalent application compared to the manual approach. The “automated” approach for the 10-20 coordinate localization and electrode / transducer placement is made directly through the headgear in Figure 4 and in Figure 3 and the fitting procedure using the methodology of which is detailed in U.S. Patent Publication no. US2020 / 0054414 (incorporated above) (see, for example, Figures 10-13, the detailed description of the document, and the description of the methods pertaining to the figures for additional details and methods of placement). The headgear has fixed anatomical marker locators (e.g., for the inion, tragus, and nasion) which when aligned to the patient, as part of fitting the headgear on the patient, allows one to establish a 10-20 coordinate system and localize the electrode and transducer to the appropriate location. The system allows one to establish the same coordinate system and localization as determined manually during the other approaches (but having the measurement system built into the headgear) and apply the stimulation to the same location.

[0113] In certain embodiments ESStim delivered to the patients Ml via the PD setups can be combined with Physical Therapy (PT), such as balance focused training.

[0114] ESStim can be used to improve postural instability and / or gait disturbances. Current PD treatments, including pharmacological (e.g., levodopa) and surgical (e.g., Deep Brain Stimulation (DBS)) approaches, are not specifically designed to improve postural instability, and as such their effects on postural instability are limited at best. In fact, dopamine therapy’s effect on balance and gait is controversial, and is characterized by waning effects and increasing side effects with prolonged use. Similarly, DBS effects on gait and balance are not clear, and may even aggravate symptoms. PT for PD was proposed years ago. Initial PT approaches were based on empirical experience, with poor knowledge of the underlying mechanisms, and thus were not commonly employed. Today, PT for PD is increasingly being employed as a means to induce exercisedependent plasticity that can result in significant benefits for patient gait and balance [9], However, PT is still untailored to each patient need, and is not optimized to work synergistically with other therapies in PD (and / or other therapies are not optimized for PT). In recent years, there has been an increase in the use of NIBS devices for the treatment of PD. These therapies have proven desirable, as they do not suffer from the side effects associated to drugs and / or invasiveness of surgical methods, but they are still suboptimal compared to ESStim. In the past few years, the number and quality of clinical trials assessing the efficacy of PT in PD have increased significantly, and a growing body of evidence from bench and translational research now suggests that PT / physical exercise has a far greater effect on PD symptoms than previously believed. Animal models of PD suggest that exercise / activity dependent processes modulate an interplay between degenerative and regenerative mechanisms, influence dopaminergic and glutamatergic neurotransmission, and can ultimately alter cortically driven hyper-excitability. In humans, it has been shown that exercise is associated with neuroplasticity of dopaminergic signaling and a number of studies have documented exercise-induced (balance training) brain plasticity correlated with improvements in gait characteristics (e.g.; speed) and / or balance in PD patients. Also, our preliminary studies in healthy subjects and patients with other disorders have shown that motor training -induced plasticity in combination with NIBS can be superior to PT alone. Furthermore, ESStim demonstrated its superiority in duration and magnitude of effect over TMS, tDCS, and TUS and that ESStim can induce a significant lasting effect on PD symptoms, including gait and balance (see below). Furthermore, ESStim provided in conjunction with PT, in a synergistic manner can maximally improve a patient’s postural instability (see below and the incorporated priority applications for more details).

[0115] ESStim can be applied to improve patients’ PD symptoms either as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies (e.g., medication and / or PT), such as for example PD patients’ Intellectual Impairment, Thought Disorder (hallucinations, delusions), Depression, Motivation / Initiative, Speech, Salivation, Swallowing, Handwriting, Cutting food and handling utensils, Dressing, Hygiene, Turning in bed and adjusting bedclothes, Falling (unrelated to freezing), Freezing when walking, Walking, Tremor (for ADLs), Sensory complaints related to Parkinsonism, Speech, Facial expression, Tremor at rest, Action or postural tremor of hands, Rigidity, Finger taps, Hand movements, Rapid alternating movements of hands, Leg agility, Arising from chair, Posture, Gait, Postural stability, Body bradykinesia and hypokinesia, Duration of Dyskinesias, Disability from Dyskinesias, Painful dyskinesias, Presence of early morning dystonia, Predictability of “off’ periods, Unpredictability of “off’ periods, “Off’ periods related to medication wearing off, “On-off’ phenomenon, Freezing of gait, Sleep disturbances, Schwab and England Activities of Daily Living Scale (independence in daily activities), likelihood of fall, independence, mobility, quality of life, drug side effects, amount of drugs needed to treat symptoms, ‘On’ symptom management, ‘Off symptom management, waxing and waning variability, increasing ‘On’ and / or minimizing ‘Off period durations, dexterity, speed of movement, movement accuracy, smoothness of movement, variability in movement, instability during balance testing, stride length, and / or stride speed. While this is a sample of symptoms and metrics that can be improved in PD patients (in addition to further movement, mood, cognition, pain, quality of life, coordination, and general health symptoms that can be improved).

[0116] ESStim PD Treatment Course Examples:

[0117] Example PD Treatment Course 1 :

[0118] ESStim delivered to the patients Ml and / or adjacent or connected tissues via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above (e.g., Figure 4), implementing energy patterns described above in this section and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Parkinson’s Disease. Stimulation effects are present well past the duration of stimulation (months past the period of stimulation). The effects of stimulation grow with continued sessions and there is a cumulative effect of stimulation on the Parkinson’s Disease symptoms and / or clinical metrics used to evaluate the patients. Stimulation as provided can improve Parkinson’s Disease symptoms and / or clinical metrics used to evaluate the patients.

[0119] For example, in 24 patients (randomized between an Active and Sham (Placebo) groups, 12 Active, 12 SHAM) receiving this course of stimulation the stimulation was proven to be safe and effective. Patient follow-ups took place 1 week, 2 weeks, 4 weeks, and 6 weeks after the last stimulation session. As proposed, all patients were provided stimulation and evaluated in their ‘ON’ state (i.e., state where symptoms are well controlled with their medications). In these patients, stimulation took place when patients were in the ‘ON’ state (but in alternative embodiments stimulation can be delivered in the patients’ ‘OFF’ states, or in PD patients that not on a course of L-Dopa or equivalent medications)

[0120] The subject inclusion and exclusion criteria were as follows:

[0121] Inclusion Criteria: Documentation of PD diagnosis from their clinician by either a letter or verification through their medical record; Research criteria of “possible” or “probable” PD, as defined by Gelb et al (Gelb D, Oliver E, Gilman S. Diagnostic Criteria for Parkinson Disease. Arch Neurol.1999;56:33-39); Age 40 or over; Taking stable medications for at least 30 days.

[0122] Exclusion Criteria: Features suggestive of other causes of parkinsonism / Parkinson’s-plus syndromes; History of deep brain stimulation or ablation surgery, mass brain lesions; History of schizophrenia, schizoaffective disorder, other psychosis, episode of bipolar illness, alcohol / drug abuse within the past year; Need for rapid clinical response due to conditions such as initiation, psychosis, or suicidal; Contraindications to transcranial brain stimulation or TUS, i.e. metal in the head, implanted brain medical devices, etc.; Unstable medical conditions (e.g. uncontrolled diabetes, uncompensated cardiac issues, heart failure, pulmonary issues, or chronic obstructive pulmonary disease); Pregnancy; Epilepsy or disorders that increase likelihood of seizures including: moderate or severe traumatic brain injury, congenital birth defects leading to seizures, brain tumor, metabolism disorders associated with seizures, and non-lacunar stroke.

[0123] The enrolled subjects consisted of 13 males and 11 females with an average age 64 (range: 51- 83). All subjects were Caucasian.

[0124] Stimulation was safe: There were no serious adverse events (SAEs) resulting from ESStim; There was no significant neurocognitive decline for either Active or SHAM stimulation, or when comparing them. In fact, we observed signs of small improvements in patient mood (as indexed by VAS depression and VAS stress measures) when comparing Active ESStim to SHAM ESStim. All other measures were unremarkable (including VAS anxiety, VAS sleepiness, SCOPA-cog, working memory, and 4-choice reaction times); There was no pathological EEG activity that demonstrated any seizure activity caused by stimulation when comparing both Active and SHAM groups and before and after 10 days of stimulation; Patients’ neurological exams were absent of any new neurological signs or symptoms of disease following stimulation.

[0125] Efficacy: As mentioned above, evaluations were completed during patient ‘On’ periods. Patients showed improvements in the time for patients to walk 10m relative to their baseline performance (baseline determined from the average of walking times taken at two separate patient visits prior to patients’ visits for stimulation; baseline average across the patients was 9.11 seconds). A comparison of the Active and SHAM groups demonstrated significant improvement in walking times, with 1107 ms vs. 410 ms improvements, respectively, averaged following the last stimulation session through the last follow-up (up to ~6 weeks post stimulation) compared to baseline (p<0.05, unpaired t-test of differences, see Figure.5 A). A bradykinesia test evaluating patient times necessary to perform a set of upper limb motion tasks (consisting of hand opening and closing, extension and flexion of the elbow, and squeezing and releasing a ball) showed significant improvements in the time for patients to perform the movements relative to baseline (baseline average across the patients was 26.4 seconds to perform all the tests). A comparison of the Active and SHAM groups demonstrated significant improvements in the bradykinesia test times, with 7.36s vs 4.8s improvements, respectively, following the last stimulation session through the last follow-up compared to baseline (p<0.05, unpaired t-test of differences, see Figure.5B). The results of the Unified Parkinson’s Rating Scale (UPDRS) assessment (Parts I-IV) demonstrated a statistically significant 3-point improvement in assessed metrics for the Active group compared to the SHAM group from baseline averaged from last stimulation session through the last follow-up (p<0.05, unpaired t-test of differences). The average of the subjects’ baseline UPDRS total was 30.8 points.

[0126] Overall, the study results demonstrated that ESStim treatment significantly improves motor function in patients with PD. There were no safety concerns reported or measured from stimulation during the treatments or throughout the study follow-up. The effects of ESStim were clinically meaningful, especially given that ESStim was applied as an adjunctive therapy to patients’ current phy sical / pharmacol ogi c therapi es .

[0127] In certain embodiments, ESStim can be provided to impact patients with bradykinesia and rigidity (such as a bradykinesia and rigidity subtype), for example in 20 patients provided ESStim with the above protocol Given that we gathered measurements of the changes in performance (from baseline) following the first stimulation session (Post 1), following the 5thstimulation session (Post 5), following the 10thstimulation session (Post 10), at the first follow-up visit 1 week post stimulation (FU1), at the second follow-up visit 2 weeks post stimulation (FU2), at the third followup visit 1 month post stimulation (FU3), and at the last follow-up visit (FU4) 6 weeks post stimulation (see Figure 5C), we also ran 2 way-ANOVA (Dependent: Improvement in Bradykinesia Test Time from Baseline / Independent: Visit, Stimulation Type). It demonstrated a significant result for the main effect of Stimulation Type (p<0.001) and Visit (p=0.0085). In this embodiment with the example patients, bradykinesia and rigidity symptoms were most improved by our method. Essentially in certain embodiments, bradykinesia and rigidity can be more easily overcome than the other symptoms of PD in certain patients via though an increase in the excitability of motor cortex, the principal target of our ESStim in this example. Thus, we carried out a 3 way-ANOVA (Dependent: Improvement in Bradykinesia Test Time from Baseline / Independent: Visit, Stimulation Type, and Patient Pairing (paired based on baseline UPDRS Part III Bradykinesia and Rigidity starting scores)). It demonstrated a significant result for the main effects of Stimulation Type (p<0.001), Visit (p<0.001), Pairing (p<0.001), and interaction effect for Pairing and Stimulation Type (p<0.001). This interaction effect between stimulation type and pairing demonstrates that ESStim may be particularly effective, relative to SHAM stimulation, in a subpopulation of patients, defined by their baseline UPDRS Part III Bradykinesia and Rigidity scores (i.e., patient UPDRS Part III Bradykinesia and Rigidity scores determined at patient evaluation visits prior to the patients’ visits for stimulations). Specifically, we found that patients with larger baseline UPDRS Part III Bradykinesia and Rigidity scores were more likely to demonstrate a greater improvement in Bradykinesia Test Times with ESStim, relative to SHAM stimulation. The Bradykinesia and Rigidity baseline scores proved effective pairing criteria across the other motor evaluations explored in this example (i.e., Walking Times and UPDRS). Walking Time Improvements compared to baseline via a 2-way ANOVA (Dependent: Improvement in Walking Time from Baseline / Independent: Visit, Stimulation Type) and demonstrated a significant effect for Stimulation Type (p<0.001), see Figure 5d. A paired analysis where patients were paired based on their baseline UPDRS Part III Bradykinesia and Rigidity scores via a 3 -way ANOVA (Dependent: Improvement in Walking Time from Baseline / Independent: Visit, Stimulation Type, and Patient Pairing) and demonstrated a significant effect for Stimulation Type (p<0.001), Visit (p=0.018), Pairing (p<0.001), and interaction effects for Pairing and Stimulation Type (p<0.001). This interaction effect between stimulation type and pairing suggests that ESStim may be particularly effective, relative to SHAM stimulation, in a subpopulation of patients, based on their baseline UPDRS Part III Bradykinesia and Rigidity scores (i.e., patient UPDRS Part III Bradykinesia and Rigidity scores determined at patient evaluation visits prior to the patients’ visits for stimulations). We demonstrated that patients with larger baseline UPDRS Part III Bradykinesia and Rigidity scores were more likely to demonstrate a greater improvement in walking time with ESStim, relative to SHAM stimulation. We found similar results with a comparable assessment of the UPDRS Part III Improvements compared to baseline (2 -way ANOVA demonstrated significant effects for Stimulation Type (p=0.02) and the 3-way ANOVA with the same patient pairing criteria (i.e., UPDRS Part III Bradykinesia and Rigidity scores) demonstrated significant effects for Stimulation Type (p<0.001), Pairing (p<0.001), and interaction effects for Pairing and Stimulation Type (p<0.001)). This methodology exemplifies a way to identify patient types and / or symptoms, for whom ESStim therapy is most likely to be immediately effective and a method to pair them to the appropriate stimulation course of treatment. Other mood and sleep based metrics also improved, for example in we examined Visual Analog Score (VAS) scores in 20 patients for sleep, depress and We demonstrated a change in VAS Depression between Active and SHAM stimulations, with a 1.19 decrease and a 0.20 score decrease between baseline and the last day of stimulation, respectively for Active and SHAM stimulation (note- decrease in scores indicate that the patient is less depressed). We demonstrated a change in VAS Stress between Active and SHAM stimulations, a 1.94 decrease and a 1.00 score decrease between baseline and the last day of stimulation, respectively for Active and SHAM stimulation - (note- decrease in scores indicate that the patient is experiencing less stress). We demonstrated a change in VAS Sleep between Active and SHAM stimulations, with a 0.81 decrease and a 0.41 score between baseline and the last day of stimulation, respectively for Active and SHAM stimulation (note- decrease in scores indicate that the patient is experiencing less levels of sleepiness

[0128] In addition to ANOVA based quantitative analysis other computational methods can be used, such as those disclosed in the incorporated priority applications and those described in PCT Publication No. WO / 2024 / 086537 (incorporated above) and U.S. Patent Publication No. US2021 / 0322771 (incorporated above). For example, one could use methods such as mixed effects models, ANOVA, t-test, elastic net regularization, linear regression, logistic regression, Poisson regression, survival analysis, Cox proportional hazards model, Kaplan-Meier estimator, chi-square test, Mann-Whitney U test, Kruskal-Wallis test, Wilcoxon signed-rank test, paired t-test, repeated measures ANOVA, multivariate analysis of variance (MANOVA), principal component analysis (PCA), factor analysis, cluster analysis, discriminant analysis, canonical correlation analysis, multilevel modeling, structural equation modeling (SEM), partial least squares regression, ridge regression, lasso regression, Bayesian inference, generalized estimating equations (GEE), time series analysis, autocorrelation analysis, Granger causality test, mediation analysis, moderation analysis, hierarchical linear modeling, propensity score matching, difference-in-differences, synthetic control method, instrumental variables analysis, quantile regression, bootstrap resampling, jackknife resampling, permutation tests, meta-analysis, network analysis, spatial analysis, geostatistical analysis, Moran's I, Geary's C, spatial regression, spatial econometrics, Markov chain Monte Carlo (MCMC), Gibbs sampling, Monte Carlo simulations, permutation entropy, survival curves comparison, hazard ratio comparison, proportional odds model, cumulative link models, ordinal logistic regression, nominal logistic regression, zero-inflated models, hurdle models, latent class analysis, mixture models, item response theory, growth curve modeling, path analysis, covariance structure analysis, confirmatory factor analysis, exploratory factor analysis, weighted least squares regression, generalized linear models (GLM), generalized additive models (GAM), Tobit models, Heckman correction, dose-response analysis, receiver operating characteristic (ROC) analysis, area under the curve (AUC) analysis, precision-recall curves, decision tree analysis, random forests, support vector machines, k-nearest neighbors, neural networks, deep learning, reinforcement learning, causal inference, directed acyclic graphs (DAGs), fuzzy logic, text mining, sentiment analysis, natural language processing (NLP), topic modeling, hidden Markov models, autoregressive integrated moving average (ARIMA), generalized autoregressive conditional heteroskedasticity (GARCH), time-varying coefficient models, panel data analysis, longitudinal data analysis, cross-sectional analysis, bootstrapped confidence intervals, likelihood ratio tests, deviance tests, information criteria (AIC, BIC), goodness-of-fit tests, and / or Hosmer-Lemeshow test).

[0129] This course of treatment, implementing ESStim delivered to the patients Ml via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section (such as using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1 with derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal- Average intensity (mW / cmA2) can be less than 40 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2 (where the Ispta.3 can be between 10-40 mW / cmA2, Isppa.3 can be between 50-175 W / cmA2, and the Imax.3 between 50-175 W / cmA2), and with a PRF less than 10,000 (such as 30 fr x 1 ppi x 256 Ipf) based on ultrasound scanning methods detailed above, and tDCS currents of less than 2.5 mA (using 5x7 cm electrodes with an area for the ultrasound transducer on the anode, see Figure 3) and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Parkinson’s Disease symptoms or clinical metrics (such as those outlined above in this PD section). The treatment effects can last from weeks to months where certain patients had improvements lasting for months from the 10 days of stimulation. See the incorporated priority applications for more details or examples. Treatment can be provided either as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies it can also be used to improve other symptoms of PD as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies.

[0130] Example PD Treatment Course 2:

[0131] ESStim delivered to the patients Ml and / or adjacent tissues or connected tissues via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Parkinson’s Disease The safety and effectiveness of ESStim (tDCS+ TUS) to improve motor symptoms in patients with PD is superior to equivalently dosed tDCS, Transcranial Ultrasound Stimulation (TUS), or SHAM applied individually. In a double-blind, randomized, parallel, factorial, double-dummy design study that included 48 subjects randomized to: 12 active ESStim, 12 sham tDCS+ sham TUS; 12 active tDCS+sham TUS; and 12 sham tDCS+active TUS.

[0132] The study eligibility criteria in in this example were essentially the same as the above example (although it should be noted that a slight number of patients were assessed that were not on any L- Dopa therapy, who were also responsive to ESStim).

[0133] The enrolled and randomized subjects consisted of 35 males and 13 females with an average age of 63.5 (range: 40-82). Forty-six of the subjects were white and two were Asian. Safety Results:

[0134] Similar to the above example, there were no significant safety issues resulting from ESStim. No SAEs were reported resulting from ESStim, tDCS, TUS, or SHAM stimulation. Non-serious AEs related to stimulation were expected and transient (e.g., tingling sensation directly at the scalp transducer location, skin redness). Subject neurological exams were absent of any new signs or symptoms following stimulation. On EEG, there was NO evidence of seizure activity, or any other pathological EEG activity related to stimulation. There was no evidence of neurocognitive decline from stimulation on any of the administered tests.

[0135] Efficacy Results:

[0136] Primary Efficacy: A 2-way ANOVA (Dependent variable: change in UPDRS3 from Baseline to the last stimulation; Independent variables: stimulation type and visit) demonstrated a significant effect of stimulation type (F3, 325=12.75, p<0.001) that persisted over time (see Figure 2 of the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above)). Baseline measures were made 1 week pre-stimulation (UPDRS3 average across patients in ‘ON’ state: 22.5, with no significant difference between groups). A subsequent comparison of the means (with a least squares difference (LSD) correction, with significance set as p< 05) demonstrated a significant difference between ESStim and all other techniques. Additionally, neither tDCS nor TUS were significantly different than SHAM.

[0137] Bradykinesia: A 2-way ANOVA (Dependent variable: relative change in mean time to perform elbow flexion / extension 10 times; Independent variables: stimulation type and visit) demonstrated a highly significant effect of stimulation type (F3, 231=8.48, p<0.001) that persisted over time (see Figure 3 of the sub-section titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above)). No significant changes were found in bradykinesia assessments focused on hand opening / closing or tremor.

[0138] Postural Sway: A 2-way ANOVA (Dependent variable: relative change in postural sway (change in the path length of a patients’ Center of Pressure (CoP) relative to baseline assessed via a force plate during a Romberg test over 15 sec); Independent variables: stimulation type and visit) demonstrated a highly significant effect of stimulation type (F3,231= 9.99, p<0.001) that persisted over time (see Figure 4 of the sub-section titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above)). The postural sway improvements were most effective in patients with larger balance deficits at the baseline, indicative that patients with the Postural Instability and Gait Difficulty (PIGD) subtype and / or symptoms of postural instability and gait abnormalities can respond to ESStim. As above, this provides a method to identify potential best responders to therapy.

[0139] Walking Times: Patient walking times (assessed in times to walk 10 meters) were significantly improved for ESStim, tDCS, and TUS compared to SHAM.

[0140] Activities of Daily Living: The ESStim treatment group showed a significant improvement compared to all the other forms of stimulation in the Functional Independent Measure (FIM)-based ADL scale (averaging ~5% better than each of the other conditions).

[0141] ESStim showed significant improvements in function resulting from ESStim therapy for patients with PD (e.g., see the JANUS2 study results from Provisional Patent Application No. 63 / 529,298 for more results and demonstrations of the device efficacy and symptoms ESStim can improve). This study demonstrates that ESStim therapy provides significantly better improvements not only compared to SHAM but also to either tDCS or TUS alone and that these improvements persisted over the 6-week follow-up period (i.e., when no stimulation was given). Additionally, although the bulk of patients that received ESStim in the ‘On’ period, patients in ‘Off state also reported improvements. Additionally, patients that were not on L-Dopa also respond to ESStim in a similar manner. The significant improvement in postural sway, UPDRS3, walking, and Bradykinesia tests, combined with the continued lack of any significant safety issues, together provide strong evidence that ESStim therapy provides clinical benefit with low risk to improve motor symptoms of patients with Parkinson’s Disease. In each of the studies, evaluations were conducted when subjects were in their ‘ON’ state, i.e., in a period when their symptoms were ‘controlled’ with their medications and thus the ESStim benefits were in addition to those of their conventional therapies (e.g., ESStim can boost the effects of drug therapy and / or other treatments). Furthermore, there were case reports from the patient cohort that indicted lasting patient improvements (as long as 6-8 months post stimulation for certain symptoms, particularly for postural instability and gait indicative of ESStim’ s ability to impact the Postural Instability and Gait Difficulty (PIGD) subtype in patients) and / or the improvement of other symptoms not directly measured including micrographia and pain.

[0142] This course of treatment, implementing ESStim delivered to the patients Ml via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section (such as using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1 with derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal- Average intensity (mW / cmA2) can be less than 40 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2 (where the Ispta.3 can be between 10-40 mW / cmA2, Isppa.3 can be between 50-175 W / cmA2, and the Imax.3 between 50-175 W / cmA2), with a PRF less than 10,000 (such as 30 fr x 1 ppi x 256 Ipf) based on ultrasound scanning methods detailed above, tDCS currents of less than 2.5 mA (using 5x7 cm electrodes with an area for the ultrasound transducer on the anode, see Figure 3), and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Disease symptoms or clinical metrics (such as those outlined above in this PD section). . The treatment effects can last from weeks to months where certain patients had improvements lasting for months from the 10 days of stimulation. See the incorporated priority applications for further examples and results (e.g., JANUS2 study in Provisional Patent No. 63 / 529,298). Treatment can be provided either as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies it can also be used to improve other symptoms of PD as a sole therapy, in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies.

[0143] Example PD Treatment Course 3:

[0144] ESStim delivered to the patients Ml and / or adjacent tissues or connected tissues via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section, and provided 20 minute / day sessions, for 10 of the days, over a 2-week in conjunction with physical therapy (PT) can safely improve PD symptoms in patients with PD.

[0145] We demonstrated this in double-blind, sham-controlled study design with 18 patients randomized to Active (n=9) or SHAM (n=9) ESStim therapy. In addition to the ten, 20-minute treatments over 2 weeks (Active or SHAM per randomization assignment) ESStim stimulation, all subjects, Active and SHAM, had six sessions of balanced-focused physical therapy (PT) spaced three times per week during the two stimulation weeks (PT administered after ESStim therapy although in certain embodiments ESStim can be delivered after PT or during PT). Follow-up visits were at -1, 2, 4, and 6 weeks after the last ESStim session.

[0146] Safety evaluations included recording adverse events at each visit and using the following battery of electrophysiology, cognitive, and neurological safety markers to assess any changes from baseline of EEG; Neurological Exam; Short Portable Mental Status Questionnaire (SPMSQ); and Scales for Outcomes in PD-Cognitive (SCOPA-Cog).

[0147] Efficacy evaluations includedjmprovement in motor symptoms as evaluated using UPDRS3 (primary); Balance as measured by Postural sway - change in the path length of a patients’ center of pressure (CoP) assessed via a force plate during a Romberg test (decreased path length = improved balance) over a fixed time (30 seconds) and Movement Smoothness and Spine Angle during balance testing - smoothness of postural sway (mean jerk) and spinal angle as measured using a motion analysis system during the Romberg test; Gait as measured by Walking time - Change in time to walk 10m and Biomechanics - stride count, stride length, and velocity as measured using a motion analysis system during the 10m walk test; and Quality of Life (QOL) as measured by the Parkinson's Disease Questionnaire (PDQ-39).

[0148] Subject eligibility requirements were:

[0149] Inclusion Criteria: Diagnosis of “probable” or “possible” PD, as defined by the current clinical criteria (Gelb D, Oliver E, Gilman S. Diagnostic Criteria for Parkinson Disease. Arch Neurol. 1999;56:33-39) as confirmed by co-investigator neurologist, or confirmation via medical records or a letter from patient physician; Complaints about balance impairment or postural instability due to PD (self-report); Age from 40 to 90 years old; and taking stable medications for PD for at least 30 days.

[0150] Exclusion Criteria: Features suggestive of other causes of Parkinsonism / Parkinson’s-plus syndromes; History of deep brain stimulation or brain ablation surgeries, malignant mass brain lesions; History of schizophrenia, bipolar illness; history of alcohol / drug abuse within the past 6 months; Need for rapid clinical response due to conditions such as initiation, psychosis, or suicidality; Contraindications to transcranial brain stimulation or TUS, i.e. metal in the head, implanted brain medical devices, etc.; Unstable medical conditions (e.g., uncontrolled diabetes, uncompensated cardiac issues, heart failure, uncompensated pulmonary disease, or chronic obstructive pulmonary disease); Pregnancy; Epilepsy or disorders that significantly increase likelihood of seizures including: severe traumatic brain injury, congenital birth defects leading to seizures, brain tumor, metabolic disorders associated with seizures, intracranial or subarachnoid hemorrhage, and non-lacunar stroke; Recent (<= 2 months) or planned enrollment in an additional physician prescribed physical therapy program specific for balance and postural instability for Parkinson’s disease during their time in the trial; Presence of another disorder that might have a significant impact on balance (as assessed by a co-investigator neurologist); Bed or wheelchairbound.

[0151] The enrolled subjects consisted of 16 males and 2 females with an average age of 66.7 (range: 44-83). 17 were white and 1 was Asian.

[0152] Safety Results: Similar to the above example, there were no significant safety issues resulting from ESStim. There were: No serious adverse events (SAEs) resulting from treatment in either group; No demonstration of seizure activity related to stimulation as defined by epileptiform discharges and any other pathological EEG activity such as spikes or sharp waves; No clinically significant neurocognitive decline caused by treatment as indexed by SCOPA-Cog and SPMSQ testing; and no development of any new neurological signs or symptoms of disease caused by treatment as shown on neurological examinations.

[0153] Efficacy Results:

[0154] UPDRS3: Both Active and SHAM groups demonstrated improvements, however, the Active group showed clinically meaningful improvement that was statistically greater than that shown in the SHAM group (i.e., both groups responded to the Physical Therapy (PT), but the Active group responded in a significantly greater manner). Specifically, the UPDRS3 baseline average was 20.1. The effect for the Active group was largest 1 week following the last stimulation session, with improvements of 7.6 vs 4.3 points for Active vs SHAM (p<0.05), effect size 0.8 (Cohen’s d)). For the period following the last stimulation, improvements of 6.3 vs 4.3 points for Active vs SHAM were observed (p<0.05, effect size 0.48 (Cohen’s d)), see Figure 5 of the sub-section titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above).

[0155] Balance - Postural Sway (change in the path length of a patients ’ center of pressure (CoP)f. The sway baseline average was -171.7 cm across the aggregate of the Eyes Open (EO) and Eyes Closed (EC) portion of the test. For this metric, the effect was largest following the last stimulation session, with improvements of 20.3 vs 6.2 cm (i.e., reduction in CoP sway pathlength) for Active vs SHAM, respectively, (improvement effect size 0.43 (Cohen’s d), where the effects were largely driven by improvements in the EC (14.5 vs 2.5 cm improvement, effect size 0.51 (Cohen’s d)) vs EO (5.8 vs 3.7 cm improvement, effect size 0.17 (Cohen’s d)) portion of the task. During the follow-up period, (i.e., following last stimulation through last follow-up), we observed -5.0 vs +4.8 cm change in CoP sway pathlength for Active vs SHAM, respectively, (p=0.07, improvement effect size 0.32 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above). The CoP sway effects were again largely driven by the EC portion of the test (p<0.05, improvement effect size 0.35 (Cohen’s d)), where the EO portion was mostly unchanged (p>0.05, improvement effect size<0.2 (Cohen’s d)).

[0156] Balance - Movement Smoothness and Spine Angle during balance testing: Significant improvements from last stimulation to end of follow-up were measured in:

[0157] Mean jerk during sway, assessed via back worn accelerometers during both EO (baseline: 1-0.9 x 10-2 g / s; improvement during the period following the last stimulation: 3.4 x 10-2 g / s (Active) vs 0.5 x 10-2 g / s (SHAM), p<0.01, improvement effect size 0.59 (Cohen’s d), and EC (baseline: 11.2 x 10-2 g / s; improvement for the period following the last stimulation: 1.2 vs 0.2 x 10-2 g / s, p<0.05, improvement effect size 0.4 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above).

[0158] Reduced neck flexion angle during the EC portion of the balance task (baseline: -12.2; improvement for the period following the last stimulation: 1.8 vs 0.7 degrees, p<0.05, improvement effect size 0.48 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above). The effects were not significant during the EO portion of the test.

[0159] Gait - Walking time: The baseline average 10m walk time for patients was -12.3 s. For the period following the last stimulation, 1.7 vs 0.9 s reduced walking times were observed for Active vs SHAM patients, respectively, (p<0.01, improvement effect size 0.64 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above). The walking time reductions continued in both groups following therapy, where at 1 month post therapy improvements of 1.70 vs 0.81 s (p=0.08, effect size 0.67 (Cohen’s d)) were observed.

[0160] Gait - Biomechanics: significant improvements from baseline were seen in the following:

[0161] Stride count (baseline: -9.97); improvement (i.e., reduced number of strides) for the period following the last stimulation: 0.97 vs 0.33 strides Active and SHAM, respectively, (p<0.05, effect size 0.75 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above); maximum effect 1 week post stimulation: -1.03 vs -0.06, p<0.05, improvement effect size 0.88 (Cohen’s d)).

[0162] Stride length (baseline -1.04 m); improvement (i.e., increased stride length) for the period following the last stimulation: +9.5 vs + 3.8 cm, p<0.05 improvement effect size 0.68 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above); maximum effect 4 weeks post stimulation: +9.3 vs 1 cm, p<0.01, effect size: 1.4 (Cohen’s d)) Speed (baseline: -0.82 m / s); improvement for the period following the last stimulation: +0.13 vs +0.07 m / s, p<0.05, effect size: 0.52 (Cohen’s d), see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above); maximum effect 2 weeks post stimulation: +0.16 vs +0.9 m / s, p=0.08, effect size 0.67 (Cohen’s d))

[0163] PDQ-39: ESStim combined with PT improves patients’ quality of life as indexed by the PDQ- 39 (consistent with the idea that improving patient postural instability positively impacts their quality of life, as interrelated with the biomechanical changes we observed)- see Figure 5 in the subsection titled “APPENDIX DOCUMENT” of the section titled “Confidential Highland Instruments Project Proposal Response Data” from previous studies in Provisional Patent Application No. 63 / 546,926 (incorporated above). Furthermore, while the PDQ-39 Mobility and ADL sub-scores demonstrated large improvements, we also noted significant effects in Emotional sub-scores (improvement effect size: 0.57 (Cohen’s d)).

[0164] The study results showed that there were no significant safety issues caused by stimulation when combining ESStim treatments with balance-focused PT in these PD patients. Non-serious AEs related to stimulation were expected and transient (e.g., tingling sensation at the scalp transducer location, skin redness). Patients’ neurological exams remained unchanged following stimulation. On EEG, there was no evidence of seizure activity, or any other pathological EEG activity related to stimulation. Finally, there was no evidence of neurocognitive decline from stimulation. The results of this study demonstrated that ESStim therapy combined with balance- focused PT (Active group) resulted in clinically meaningful and statistically significant improvements in motor symptoms in patients with PD as compared to balance-focused PT alone (SHAM group). Statistically better results were observed following the last stimulation session and throughout follow-up in the Active group on the primary study endpoint (UPDRS3). These results were supported by the positive results on the study secondary efficacy endpoints of balance (reduction in postural sway, movement smoothness, and spine angle during balance testing) and gait (improved speeds and improvement in biomechanical responses during walking).

[0165] ESStim delivered to the patients Ml and / or adjacent or connected tissues via the PD setups outlined above via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Parkinson’s Disease when combined with balance training focused Physical Therapy (PT). This course of treatment, implementing PT coupled with ESStim delivered to the patients Ml via the electrode setup whereby an anodal DC source and ultrasound source are placed above the C3 or C4 via the methods outlined above and a cathode placed approximately over the contralateral orbital as described above, implementing energy patterns described above in this section (such as using ultrasonic energies with thermal indices of the cranium of less than 1.5 and Mis less than 1 with derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal-Average intensity (mW / cmA2) can be less than 40 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2(where the Ispta.3 can be between 10-40 mW / cmA2, Isppa.3 can be between 50-175 W / cmA2, and the Imax.3 between 50-175 W / cmA2), with a PRF less than 10,000 (such as 30 fr x 1 ppi x 256 Ipf) based on ultrasound scanning methods detailed above, tDCS currents of less than 2.5 mA (using 5x7 cm electrodes with an area for the ultrasound transducer on the anode), and provided 20 minute / day sessions, over a 2-week period, for 10 of the days can be safe and effective for improving Parkinson’s Disease symptoms or clinical metrics (such as those outlined above in this section). The treatment effects can last from weeks to months where certain patients had improvements lasting for months from the 10 days of stimulation. The stimulation can further improve the effects of PT, increasing the speed at which PT becomes effective, extending the duration of effects of PT, reducing pain during PT sessions, improving patient motivation and compliance with PT and / or other therapies, increasing range of motion, enhancing muscle strength, reducing inflammation, improving circulation, speeding up recovery time, reducing muscle spasms, improving balance and coordination, enhancing flexibility, increasing endurance, reducing the need for medications, improving mental health, decreasing stress and anxiety, enhancing overall well-being, reducing scar tissue, promoting tissue regeneration, improving sleep quality, boosting immune function, increasing patient adherence to PT protocols, reducing the risk of re-injury, improving quality of life, enhancing functional independence, providing more personalized treatment plans, increasing the variety of exercises, improving patient satisfaction, reducing the number of PT sessions needed, enhancing neuroplasticity, improving joint health, reducing stiffness, promoting overall physical fitness, and / or increasing the effectiveness of home exercise programs. Treatment can be provided either as the combined therapy (ESStim and PT), in combination with another therapy or therapies, and / or adjunctive to another therapy or therapies. While this is a sample of symptoms and metrics that can be improved (in addition to further movement, mood, cognition, pain, quality of life, coordination, and general health symptoms that can be improved), See the incorporated priority applications for further examples and results (e.g., JANUS3 study in Provisional Patent Application No. 63 / 529,298). While this example demonstrated the ESStim delivered to the patients Ml and adjacent or connected tissues via the PD setups outlined above combined with balance focused PT can be effective in improving patients PD symptoms of postural instability and / or gait disturbances other forms of therapy and / or PD symptoms such as those outlined herein can be improved by combining ESStim with forms of therapy such as manual therapy, therapeutic exercises, balance training, gait training, hydrotherapy, electrotherapy, ultrasound therapy, cryotherapy, heat therapy, massage therapy, strength training, flexibility exercises, cardiovascular conditioning, proprioceptive training, functional mobility training, postural training, vestibular therapy, neuromuscular reeducation, joint mobilization, soft tissue mobilization, myofascial release, lymphatic drainage, dry needling, cupping therapy, kinesiology taping, therapeutic yoga, Pilates-based rehabilitation, aquatic therapy, biofeedback therapy, chronic pain management, ergonomic training, adaptive equipment training, energy conservation techniques, home modification recommendations, cognitive rehabilitation, hand therapy, sensory integration therapy, scar management, wound care, vocational rehabilitation, sports rehabilitation, pediatric therapy, geriatric therapy, women’s health therapy, orthotic and prosthetic training, pulmonary rehabilitation, cardiac rehabilitation, driver rehabilitation, community reintegration therapy, rhythmic auditory stimulation, functional electrical stimulation, reducing stiffness, promoting overall physical fitness, increasing the effectiveness of home exercise programs, LSVT BIG therapy, LSVT LOUD therapy (Lee Silverman Voice Treatment), Big and Loud Therapy, dance therapy, music therapy, tai chi, speech therapy for Parkinson’s, occupational therapy for daily living skills, resistance training, functional task training, dual-task training, Nordic walking, and / or martial arts training.

[0166] In other embodiments, ESStim can be combined with forms of voice therapy or speech therapy for Parkinson, including Lee Silverman Voice Treatment, Respiratory Muscle Training, Articulation Exercises, Prosody Training, Swallowing Therapy, Pacing and Rate Control, Pitch and Volume Exercises, Breath Support Techniques, and / or techniques that use biofeedback.

[0167] In other embodiments, ESStim can be combined with other forms of therapy for improving facial expression, or hypomimia, which is a common symptom of Parkinson's disease that can affect communication and social interactions. These forms of therapy include Facial Muscle Exercises, Mirror Therapy, and / or Mindfulness and Relaxation Techniques. Additionally, ESStim can be used adjunct to Dopaminergic Medications and / or Botulinum Toxin Injections for improving facial movements and reduce facial muscle stiffness.

[0168] In other embodiments, ESStim can be combined with other forms of therapy for improving stooped posture. These forms of therapy can include Strengthening Exercises such as Core Strengthening and Upper Body Strengthening, and / or Posture Correction Exercises such as Wall Angels and Chin Tucks. Additionally, ESStim can be used to augment the effect of Assistive Devices such as Posture Braces and Walking Aids.

[0169] In other embodiments, ESStim can be provided with vibration therapy as part of a comprehensive rehabilitation program for improving gait patterns, reducing gait freezing and postural instability. Vibration therapy can be delivered to specific body parts, such as the feet or legs, using vibrating insoles, pads, handheld devices, or wearable devices such as ankle or calf bands, or to whole body, for example using platforms where patient stands on that deliver vibrations to the entire body, through the feet and up the legs, which can improve overall muscle function and balance.

[0170] In other embodiments, ESStim can be provided in combination with mindfulness and relaxation techniques for improving posture. These can include breathing exercises like diaphragmatic breathing and progressive muscle relaxation for tensing and relaxing different muscle groups to reduce overall muscle tension and promote better posture.

[0171] In other embodiments, ESStim can be used in combination with levodopa and a dietary plan to stabilize off and on fluctuations. As intake of certain foods limit levodopa absorption, which in turn may affect off and on fluctuations, one may coordinate meal, medication, and ESStim timing to optimize management of off and on fluctuations.

[0172] In other embodiments, ESStim can be used in combination with respiratory therapy for managing breathing difficulties and enhancing respiratory function in Parkinson for example to improve lung function, achieve better airway clearance, and increased respiratory muscle strength. Respiratory therapy can include for example breathing exercises and chest physiotherapy.

[0173] Further PD Information and Examples:

[0174] In addition to the Ml and / or adjacent tissue other areas can be stimulated directly or indirectly for treating PD (stimulation applied as a sole therapy, adjunctive with other therapies, and / or in combination with other therapies) such as for example the subthalamic nucleus, globus pallidus interna, thalamus, pedunculopontine nucleus, substantia nigra, striatum, locus coeruleus, cerebellum, prefrontal cortex, nucleus basalis of Meynert, ventral tegmental area, red nucleus, caudate nucleus, putamen, and / or the entopeduncular nucleus.

[0175] The target of ESStim (stimulation applied as a sole therapy, adjunctive with other therapies, and / or in combination with other therapies) in addressing PD symptoms can be tuned or combined with external measures or treatments, such as with imaging, other forms of neuromodulation, and electro-physiological studies. For example, for posture and gait there is an extensive body of literature focused on the involvement of specific cortical areas in gait and posture (see, for example, the incorporated priority applications for further examples). For example, high-density EEG and source localization work described Ml (as well as premotor motor cortex (PMA), supplementary motor cortex (SMA), cingulate cortex, primary somatosensory cortex and the somatosensory association cortex) involvement in stepping movements in an upright position. As such these can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode or connected to the directly stimulated target and indirectly stimulated via connections). Another study found EEG electrocorti cal sources localized to the sensorimotor cortex (and prefrontal cortex, anterior cingular cortex, and posterior parietal cortex) during walking on a treadmill. As such these can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode or connected to the directly stimulated target and indirectly stimulated via connections). In addition, extensive literature identifies a critical role of higher cortical areas in posture control. Ml’s role in postural control is supported by functional near-infrared spectroscopy combined with surface electromyography work, and also by electrocorti cographic grid recordings over the interhemispheric Ml area. Specifically, Ml primarily encodes high-level gait motor control and likely interacts with subcortical / spinal networks, which are responsible for low-level motor control, to produce normal human walking. Research, including data from human patients and animal studies, contributes to the growing body of evidence. Individuals, both human and animal, with lesions in the sensorimotor cortex display abnormal postural control in daily life functional tasks (such as perturbed and unperturbed standing), body sway, etc. As such the Ml, adjacent areas, and / or connected regions can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode, or connected to the directly stimulated target and indirectly stimulated via connections). Furthermore, studies characterizing the Ml role in movement via single-cell and field potential recordings correlate with midbrain degenerative changes during PD. Finally, fMRI studies have shown altered connectivity between the Ml and other cortical and subcortical motor control areas in PD patients, with a recent study providing evidence that individuals with PD depend more on cortical motor areas for dynamic balance, while healthy older adults favor subcortical control during such tasks. As such the Ml, adjacent areas, and / or connected regions can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode or connected to the directly stimulated target and indirectly stimulated via connections).

[0176] Many motor symptoms of PD arise from reduced dopaminergic neurons in the substantia nigra pars compacta, decreasing cortical excitability through disruptions in the direct (reducing movement facilitation) and indirect (increasing movement inhibition) pathways. This impacts the motor cortex, causing movement preparation and execution challenges in PD patients. ESStim can target the motor cortex to improve PD motor symptoms by prompting dopamine release in the basal ganglia through the activation of specific corticostriatal fibers.

[0177] Combined stimulation targeting the Ml has been reviewed herein. The dysregulation of the basal ganglia circuitry in PD, especially the imbalance between the direct and indirect pathways, reduces the excitatory drive to the Ml, leading to issues in initiating and controlling voluntary movements, which can be improved via ESStim Ml stimulation (such as for compensatory balance reactions to prevent loss of balance). Rate based models further support this hypothesis, particularly as subthreshold cortical stimulation has been shown to increase the spontaneous firing of targeted cells as a function of subthreshold current orientation relative to the target cells axes(which has been optimized for ESStim based on biophysical field models as described in U.S. Patent Publication No. US2021 / 0322771 (incorporated above) (e.g., acoustic and electric field models derived with anatomical, neural, electrical, and / or mechanical properties of the tissue aligned with the neural activation models of stimulation)). As such, one can tune the stimulation based on such results and / or biophysical models.

[0178] For effecting balance, beyond direct Ml effects, the functional processing of posture / gait control by the basal ganglia in relation to PD relies on the connections between cerebellum, basal ganglia, and motor cortical areas, which include the Ml, SMA, and PMC. In response to alterations in conditions (e.g., motor or sensory challenges), the capacity to generate motor programs may be compromised due to heightened inhibitory signals from the basal ganglia directed at thalamocortical pathways. Consequently, alongside deficits in sensory processing within the temporoparietal cortices, diminished excitability in the motor cortical regions can contribute to disruptions in motor programming. As such these can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode or connected to the directly stimulated target and indirectly stimulated via connections). On this direction, improvements in gait and balance can be mediated by Ml based stimulation modulating neuronal activity across the cortico-basal ganglia-thalamo-cortical motor loop in PD patients.

[0179] Furthermore, the cerebellum has a central role in the control of posture, balance, and movement by adjusting the force, rate and timing of muscle groups activated during postural adjustment and locomotion, thereby direct or indirect stimulation of the area with ESStim (and / or other forms of stimulation) can impact these symptoms. The Ml sends strong projections to the cerebellum via pontine nuclei where the motor signal is integrated with visual, proprioceptive, and vestibular sensory signals; the output is sent to Ml through the motor thalamus to adjust and refine movement commands in Ml. In addition, the cerebellum sends output to diverse brainstem regions including midbrain regions such as the pedunculopontine tegmentum, and reticular formation nuclei to provide a direct influence on locomotion and postural circuits, respectively. Therefore, direct or indirect stimulation of these areas with ESStim (and / or other forms of stimulation) can impact these symptoms. Based on its close interrelationship with the Ml and its role in posture and postural stability, the cerebellum has been identified as a possible region that can compensate for motor dysfunction in the initial phases of PD. Indeed, PD patients with postural instability and gait disorders exhibit decreased volumes but increased task-related cerebellar activation in the cerebellum, and increases in cerebellar volume occur after successful balance training in PD patients. Thus, Ml activation, by itself or in conjunction with PT, may recruit and strengthen this compensatory role of the cerebellum, and thereby produce improvement in balance and gait. As such these can be potential targets for stimulation (or in the path of current flow, such as directed from the path of current flow of an anode and a cathode, or connected to the directly stimulated target and indirectly stimulated via connections)

[0180] Our work has demonstrated that ESStim can facilitate rehabilitation strategies, such as PT or occupational therapy techniques, to be more effective in priming the activation of areas such as the primary motor cortex to improve physical function. In addition, ESStim can modulate neural activity, improving the brain's ability to adapt to PT and motor learning in PD. Several additional studies demonstrate the therapeutical benefits of stimulation applied to Ml plus PT on posture and gait on healthy subjects and patients including older individuals and PD patients (See the incorporated priority applications for more details), whereby one can use the safe and effective forms of ESStim as outlined herein to achieve superior results than demonstrated earlier.

[0181] In the above PD examples, we chose the 20-minute stimulation session duration for daily sessions and the 10 sessions as it is not over burdensome to patients and supported by substantial clinical evidence in patients of effectiveness and safety. In other embodiments shorter durations of the daily sessions, such as for example 1-5, 5-10, 10-15, 15-20 minute durations are possible as are longer sessions such as 20-30, 30-45, or 45-60, or 60+ minute sessions are possible as determined by dosing evaluations and the patient’s response to stimulation per the targeted symptoms. Furthermore, in other embodiments, the number of daily sessions can also be modified. Although the 10 daily 20-minute stimulation sessions over two weeks, with weekends off, have proven effective, other paradigms are also possible. These include examples such as 5 daily sessions of 20 minutes of stimulation, 20 minutes of stimulation every other day for 2 weeks, bi-weekly stimulation for a month, 10 daily 20-minute sessions over a 3 -week period, 20 minutes of stimulation on weekdays for a month, alternating days of stimulation for a specified period, three times a week for a month, twice a week for six weeks, weekly sessions over a longer duration, and / or combinations of these approaches. The specific paradigm can be tailored based on the patient’s availability, convenience, and compliance and the desired impact on the patients’ symptoms. Such decisions can be made in conjunction with the other tuning and / or optimization methods described herein (e.g., biophysical dosing models, imaging, health economics models, motion analysis suite-based optimization). In other embodiments, induction and maintenance paradigms can also be effective, whereby an induction period is applied (for example, 10 daily 20- minute sessions) followed by a maintenance period. This maintenance period can include various combinations such as for example 1 month of bi-weekly stimulation, 2 months of weekly stimulation, six months of two bi-weekly stimulation sessions (2 per week twice per month), monthly sessions over an extended period, alternating weeks of stimulation, three times a week for a set duration, twice a week for several months, and / or combinations of these approaches. In certain embodiments, repeated stimulation sessions, at reduced session frequency, following an initial induction period, can provide an extended duration of neuromodulatory effect. The specific paradigm can be tailored based on the patient’s availability, convenience, and compliance and the desired impact on the patients’ symptoms. Such decisions can be made in conjunction with the other tuning and / or optimization methods described herein (e.g., biophysical dosing models, imaging, health economics models, motion analysis suite-based optimization). The way in which adjunct therapy and / or combined is delivered can also be varied. For example, stimulation can be given during a patient's 'On' periods when receiving L-Dopa medications and / or PD drugs such as Sinemet (carbidopa / levodopa), Stalevo (carbidopa / levodopa / entacapone), Madopar (benserazide / levodopa), or dopamine agonists like Mirapex (pramipexole), Requip (ropinirole), Neupro (rotigotine), and Apokyn (apomorphine). Other drugs used for Parkinson's disease that can be considered include MAO-B inhibitors like Azilect (rasagiline) and Eldepryl (selegiline), COMT inhibitors like Comtan (entacapone) and Tasmar (tolcapone), and anticholinergics like Artane (trihexyphenidyl) and Cogentin (benztropine). The stimulation can be given during “Off’ periods, or during specific waxing and waning cycles. In certain embodiments stimulation is given between 45-90 minutes after medication is given, based on when a patient reaches their ‘On’ state. Other examples are possible with other forms of adjunct and / or combined therapy. While above we demonstrated the benefits of combining balance focused physical therapy delivered 6 times over a two-week period with 20 minutes of stimulation given daily over 10 days in the two week period (with weekend off for both) other PT and stimulation paradigms are possible in other embodiments. Such as for example stimulation can be provided for 5 daily sessions of 20 minutes of stimulation, 20 minutes of stimulation every other day for 2 weeks, bi-weekly stimulation for a month, 10 daily 20-minute sessions over a 3 -week period, 20 minutes of stimulation on weekdays for a month, alternating days of stimulation for a specified period, three times a week for a month, twice a week for six weeks, weekly sessions over a longer duration, or combinations of these approaches while PT can be provide lx weekly, 2x weekly, 3 weekly, 4x weekly, 5 x weekly on the same days of stimulation (before, after, or during), and / or combinations of these approaches. In certain embodiments ESStim and PT can be provided in an induction and maintenance protocol , such as for example ESStim + PT can be effective when provided over a 12-week period for 18 total stim sessions and 14 total PT sessions comprising a 2-week induction phase (5x stim / week for 20 min / day + 3x PT / week) will be followed by a 10-week maintenance phase (2 biweekly / month stim + PT sessions). Maintenance therapy can start right away or after a period of time, such as for example can start at approximately 4-weeks after the end of the induction phase, at which point one would start providing stimulation + PT 2x / week, for 2 weeks per month, through 3 months (i.e., ~90 days), and / or combinations of these approaches. In general, the induction and maintenance strategies outlined above for ESStim (as a sole therapy) can be implemented now with adding PT adjunctly and / or in combination on select days as outlined above. In certain embodiments, one can provide a 2-week “burst” of PT (coupled with ESStim), and maintenance in a biweekly “spaced” manner to match the benefits of PT spacing with those seen in neuromodulation (see incorporated Provisional Patent Application No. 63 / 546,926 for additional discussion of the benefits of spacing PT in PD patients to maintain the benefits of therapy). Finally, ESStim coupled with PT plans can be designed for 90 days of optimal effect for patients receiving care that requires regulatory review every 90 days.

[0182] The methods of dosing ESStim (and / or other therapies that can be provided in individually or in conjunction with ESStim) and / or patient identification for potential best responders can be completed with a motion analysis suite, biophysical modeling, big data, and / or quantitative methods described in the incorporated priority applications and PCT Publication No. WO / 2024 / 086537 (incorporated above) and U.S. Patent Publication No. US2021 / 032277I(incorporated above). In certain embodiments, our Integrated Motion Analysis Suite (IMAS) system, IMAS, includes multiple sensing modalities (e.g., 3D motion capture camera, inertial sensors, and force plate); a set of computational algorithms for data reduction, modeling, and prediction; and a patient-tracking database (see Fig. 2 of incorporated Provisional Patent Application No. 63 / 640,194 in Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in Parkinson’s Disease Management section ). It is known that movement disorder specialists assess PD motor systems in their entirety, with pattern recognition capabilities that non-expert clinicians lack (see incorporated Provisional Patent Application No. 63 / 640,194 in Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in Parkinson’s Disease Management section for further information). IMAS mirrors this process by acquiring a broad picture of the disease state by combining multiple sensing modalities across multiple joints. However, it is not sufficient to simply collect data from multiple sensor types; a full picture of the disease state requires careful analysis to integrate and distill information across sensors. To this end, the sensing sources are coupled with algorithms for signal pre-processing and machine learning for data reduction and prediction / classification for a variety of purposes including clustering patients and predicting outcomes. IMAS can provide objective motor evaluations, be coupled with ESStim for treating PD (and other disease states such as chronic pain), its algorithms can evaluate, track, and / or predict outcome of various treatments (e.g., PT administered as a single treatment or in combination with neuromodulation). Finally, the patient-tracking database, characterized by a Big Data architecture, can record and visualize patient improvements through time as well as exploration of data clusters and identification of trends (e.g., groups of patients who respond well to a certain treatment) (see incorporated Provisional Patent Application No. 63 / 640,194 in Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in Parkinson’s Disease Management section).

[0183] IMAS has capabilities beyond those of existing systems: 1) combination of multi-modal sensors to overcome the limitations of each sensing modality and acquire a more comprehensive picture of the disease state across multiple joints; 2) prediction of clinical scales widely used in clinical practice (e.g., UPDRS-III, demonstrated herein) to adhere to data representations that are readily interpretable by clinicians; 3) use of sensor-based metrics alongside predictions of traditional clinical scales data to allow further analysis such as classification / prediction; 4) a Big Data architecture that not only helps clinicians understand which treatments are likely to be most effective for patients with similar profiles but also supports personalized treatment planning and facilitates integration with current clinical practices and patient flow, ranging from Electronic Health Records (EHRs) to data fusion (including imaging data and biospecimens); and 5) a streamlined, modular, and robust design to enable IMAS to integrate new technologies, as well as facilitate use outside of clinical settings (e.g., the home).

[0184] Example of IMAS Combination:

[0185] Below, we present a study conducted with IMAS, aimed at assessing: 1) the dimensional complexity of the IMAS dataset, specifically its variable diversity and structural intricacies in PD patients; 2) the efficacy of predictive UPDRS-III modeling, utilizing elastic net regression for its robust variable selection capabilities, which leverage the intrinsic properties of the dataset; and 3) the dataset’s capability for segmentation into distinct clusters, as demonstrated through the use of a Self-Organizing Map (SOM), followed by hierarchical clustering. While these experiments are not exhaustive representations of IMAS full capabilities, they serve to illustrate how a multi-modal sensor system, when integrated with a computational framework, can implement Big Data strategies to improve prognosis, treatment optimization, and care of PD. These methods can be used to identify patient symptoms that best respond to ESStim, multiple energy stimulation methods, and / or stimulation coupled with other therapy and / or therapies as described herein and / or coupled with other methods to tune, optimize, plan, or dose stimulation (e.g., biophysical analysis, cost effective analysis, quantitative sensory testing). Other methods for therapies that IMAS can be used in the PD treatment include, but are not limited to, examples such as Neuromodulation, L- Dopa based medications, Dopamine agonists, MAO-B inhibitors, COMT inhibitors, Anticholinergics, Amantadine, Physical therapy, Occupational therapy, Speech therapy, Exercise programs, Nutritional interventions, Cognitive therapies, Supportive therapies, Surgical interventions, Assistive devices, Deep Brain Stimulation (DBS), Temporal Interference, Transcranial Magnetic Stimulation (TMS), Transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS), Levodopa / Carbidopa, Levodopa / Benserazide, Controlled-release Levodopa / Carbidopa, Pramipexole, Ropinirole, Rotigotine, Apomorphine, Selegiline, Rasagiline, Safinamide, Entacapone, Tolcapone, Opicapone, Trihexyphenidyl, Benztropine, Biperiden, Amantadine HC1, Extended-release Amantadine, Gait training, Balance exercises, Strength training, Flexibility exercises, Aquatic therapy, Treadmill training, Resistance training, Tai Chi, Yoga, Pilates, Dance therapy, Boxing therapy, Nordic walking, High-intensity interval training (HIIT), Functional Electrical Stimulation (FES), Acupuncture, Massage therapy, Chiropractic care, Aromatherapy, Herbal supplements, Omega-3 fatty acids, Coenzyme Q10, Creatine, Vitamin D, Vitamin E, Curcumin, Green tea extract, Probiotics, Medical cannabis, Neuroprotective drugs, Gene therapy, Stem cell therapy, Platelet-rich plasma (PRP) therapy, Fetal cell transplantation, Adult cell transplantation, Exosome therapy, Autophagy enhancers, Mitochondrial enhancers, Lysosomal enhancers, Anti-inflammatory drugs, Immunotherapy, Anti-synuclein antibodies, Calcium channel blockers, Glutamate receptor antagonists, Serotonin receptor antagonists, GABA receptor agonists, Adenosine receptor antagonists, Iron chelators, Zinc supplements, Magnesium supplements, Ketogenic diet, Intermittent fasting, Low-protein diet, Gluten-free diet, Mediterranean diet, DASH diet, Antioxidant-rich diet, Cognitive training programs, Virtual reality therapy, Biofeedback, Light therapy, Hydrotherapy, Psychotherapy, Peer support groups, Caregiver education programs, Respite care, Home modifications, Wearable technology, Mobile health apps, Robotic-assisted therapy, Telemedicine, Clinical trials, Alternative medicine, Integrated medicine, Behavioral interventions, Lifestyle modifications, Stress management techniques, Sleep hygiene strategies, Social engagement activities, and / or pain treatments. We conducted a study with the IMAS to collect a dataset as part of the baseline assessments for a randomized controlled trial investigating ESStim for the treatment of PD (the second example study provided above). Not all the patients examined herein entered the main trial, and the dataset was developed from the first 50 patients that underwent baseline assessments. As part of the study, subjects’ UPDRS -III motor scores (UPDRS QI 8-31) were assessed and summed for the total score. Evaluations were performed during ‘On’ periods. Subjects were then asked to perform a series of motor tasks designed to assess bradykinesia, ability to perform complex movements, tremor, postural instability, and gait, while their movements were tracked using our IMAS. For the forgoing analysis, IMAS assessments focused on subjects most affected side.

[0186] Patients were asked to perform a series of 7 motor tasks: 1) elbow flexion-extension, 2) hand opening-closing, 3) sequence of hand opening-and-closing and elbow flexion / extension, 4) hand touch nose, 5) handheld still, 6) modified Romberg, 7) 10 m walks. The specific details of these tasks were completed as follows: 1A) continuous elbow flexion / extension movements: subject was instructed to move as fast as possible, keeping the wrist stable, palm up, beginning at level of waist / hip, going up to shoulder without touching it or overextending, and keeping the elbow stable but not pressed to the side (10 repetitions); IB) discrete elbow flexion / extension movements: similar to 1 A), but stopping for 2 s at the end of each movement without letting the hand flop, and going as fast as possible in between; 2A) hand opening / closing at shoulder level: subject was instructed to fully open and close their hand fully in a fist (not clenching hard) as fast as possible, keeping the hand at the shoulder level (10 repetitions) starting with the hand open; 2B) hand opening / closing at hips / waist level: similar to the test described in 2A); 3) complex motor sequence involving multi -joint movements: subject was instructed to perform the hand opening / closing movements at the waist / hip and shoulder, and the flexion / extension movements as fast as possible in between with the hands open (10 repetitions); 4) hand-to-nose: keeping the arm / elbow at shoulder level, subject was asked to bring their hand (horizontal, palm down) almost to their nose without touching it and to extend it all the way to the side again, beginning with the arm outstretched and moving at their natural pace (10 repetitions); 5A) hand resting on table: subject was asked to rest their hand and forearm on a table, with the arm relaxed, for 30 s while fixating the evaluator’s index finger swinging back and forth; 5B) hand resting in front of face: with arm / elbow at shoulder level, subject was asked to take their hand close to their nose and keep the hand there for 15 s while fixating the evaluator’s index finger swinging back and forth; 6) balance test: with feet positioned in the middle of each side of a Wii board (i.e., feet about shoulder width apart) subject was asked to maintain an upright position for 30 s test was performed twice, once with eyes open (while fixating a pre-defined landmark) and once with eyes closed; 7) walking test: subject was asked to walk for 10 m at their usual pace (4 repetitions). Tests 1-5 were performed in seated position. Subjects wore hospital-provided, non-slip gripper socks throughout tests 6-7. Subjects’ motor performances during all tests were monitored by IMAS.

[0187] A subset of the 50 patients, N=11, who were part of the main study’s placebo group had data available from a second session. In the second session, both IMAS and UPDRS-III data were again collected, about 1 week after the first session (130).

[0188] The IMAS version used in these experiments (see Fig. 2 of incorporated Provisional Patent Application No. 63 / 640,194 in Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in Parkinson’s Disease Management section) included a commercial Kinect portable camera-based system (Microsoft, Redmond WA; 30 Hz sampling rate), wearable three-axis gyroscope / three-axis accelerometer inertial measurement units (IMU) (64 Hz sampling rate), a portable force plate (Nintendo, Redmond, WA; 98 Hz sampling rate), and a remote controller for event marking. The camera system included an embedded infrared sensor for measuring depth, i.e., recording in 3D, and commercial software for segmenting the human body from background, modeling the body as a 20-joint skeleton (hip center, spine, shoulder center, head, left and right shoulders, elbows, wrists, hands, hips, knees, feet, and ankle joints), and tracking 3D positions of the 20 joints.

[0189] The IMUs were attached to the subject’s body with Velcro straps or elastic cloth material that cuffed the body segment, with anatomical landmarks guiding the positioning (however they can be attached by other methods such as those described in PCT Publication No. WO / 2024 / 086537 (incorporated above) and U.S. Patent Publication No. US2020 / 0060602, the entire disclosure of which is hereby incorporated by reference herein) For example, in the IMAS assessments discussed herein, the primary IMU’s placement was as follows: for tests 1-5, an IMU was placed on the top side of the patient’s index finger; for the balance tests, it was positioned on the subject’s back, at the level of L5, near the body’s center of mass; for the walking tests, patient’s movement was tracked with two IMUs, one on L5 and another on the right ankle using the lateral malleolus as a landmark for the first 2 repetitions; for the last 2 repetitions, each ankle (right and left malleoli) was tracked with a separate IMU. A remote controller allowed the experimenter to mark recordings; the marker signal was set whenever an event occurred (e.g., beginning or end of each motor task) and was null otherwise. The number of IMUs and locations for each test were chosen as a trade-off between time maximizing completeness of information, minimizing overall IMAS- testing duration, and minimizing number changes of sensor configuration (note, these assessments were part of a clinical trial that included other evaluations). All motor tests were tracked with the camera system, except for the walking tests. For the balance test, patients were asked to stand on the force plate. Throughout the experiments, camera, force plate, and subject’s chair (when used) were kept in fixed positions to minimize set-up times between sessions, prevent errors due to equipment re-positioning, and maintain consistency between participants. Custom C# routines were written to synchronize the recordings from all the IMAS sensors and the remote controller.

[0190] IMAS metrics were extracted from the IMAS signals recorded during the above motor tests. For each test, the total task time was determined as the time from the first and last time the marker signal became positive. Then, the following metrics were calculated. For the elbow flexion / extension and hand-to-nose tests, wrist movements speed profiles v were calculated from the first order derivative of the 3D wrist trajectories smoothed with a 10 Hz low-pass FIR filter, segmented, and used to compute movement mean speed, max speed, duration, smoothness (ratio between mean speed and max speed), and number of movements. The path length traveled by the wrist in space was also calculated. For the hand opening / closing tests, angular velocity signals from the gyroscope (Xrot, Yrot, Zrot) were filtered with a 4thorder low-pass Butterworth filter (5 Hz cut-off). Metrics included movement time (total time divided by the number of movements) and inter-peak interval (interval between consecutive times when the hand was fully open, as marked by positive peaks in the angular velocity component Xrot). Analysis of the complex movement focused on total time to complete the task. Resting and postural tremor were extracted from the accelerometer data recorded during the hand resting tasks. Resting tremor was calculated as the ratio of power in the 3-6 Hz band and total power, where power was evaluated with multi -taper spectral analysis from acceleration amplitude, which was calculated from the 3 components of acceleration (other methods were also explored, i.e., mean of the power in the 3-6 Hz frequency band and mean of total power and calculation of both metrics using Fast Fourier Transform; a similar method was used to assess postural tremor (5-8Hz). As for the balance tasks, the length of the path traveled by the subjects’ body CoP as measured by the board was calculated. Postural sway was further characterized with standard deviation of CoP components and axes length and area of an ellipse fitting CoP oscillations; also, the mean and peak values of jerk (first-order derivative of acceleration) amplitude were calculated from the acceleration measured by the IMU placed on L5 along the antero-posterior and medio-lateral directions similar to (55, 78) in order to characterize postural sway smoothness. Separate values for the eyes open and eyes closed tests were calculated. For gait, besides total task duration, the following metrics were calculated from the IMU recordings after signals were filtered (4thorder Butterworth low-pass filter, 5 Hz cutoff). For walks 1-2, movement smoothness was calculated as normalized jerk (mean jerk magnitude divided by mean speed) where jerk amplitude was calculated from the first order derivatives of the filtered components of the signals recorded from the accelerometer mounted on L5, smoothed with a 4thorder low-pass (5 Hz cutoff) Butterworth filter. For walks 3-4, the peaks of the Zrot gyroscope signals (the angular velocity component where movements were most evident) were identified to assess when strides occurred; then, we calculated the distance between successive peaks (stride duration) and stride count. For all tests that required multiple movements, mean and standard deviation were calculated. Custom MATLAB routines were written to extract the metrics from the IMAS recordings. See Provisional Patent Application No. 63 / 640,194 (incorporated above) for further information on the metrics in this example.

[0191] Principle Component Analysis (PCA) was used to examine the correlation structure in the UPDRS-III and IMAS metrics and to estimate the effective dimensionality of both data sets. Each measure in each data set was standardized by removing its mean and dividing by its standard deviation and PCAs analyses were conducted for the set of UPDRS-III and IMAS measures, separately and together. Elastic net regularization was used to identify a sparse set of predictors from the IMAS dataset and build linear regression models to predict the UPDRS-III. The elastic net penalty parameters were systematically varied using a grid search approach to find the best combination with highest R-squared value with the model Degrees of Freedom (DFs) capped at 50% of the patient group size. The number of DFs was capped to further reduce model complexity. Model performance was assessed with Leave One Out Cross Validation (LOOCV) to evaluate the model's predictive accuracy, quantified by R2and MAE metrics. To further evaluate the methods generalization ability, we tested a model trained on day 1 observations to predict day 2 UPDRS- III scores from the IMAS metrics extracted from the dataset of N=l l subjects (see above). Prediction errors were compared with published values of inter-rater and intra-rater variability of UPDRS-III. Several clustering techniques were applied to the IMAS dataset to gain insights into its data structure. First, we employed t-Distributed Stochastic Neighbor Embedding (t-SNE). Then, clustering was performed using a SOM, followed by hierarchical clustering on neuron weights extracted from the SOM using the Ward method and a random forest classifier was used to assess the importance of different features with respect to the higher-level clustering. Experiments were conducted with different SOM grid sizes, number of epochs, and initial neighborhood sizes. For the hierarchical clustering with the Ward method, experiments were conducted with different numbers of desired groups. A dominance algorithm was used to evaluate feature dominance across clusters. Initially, one-way ANOVA identified significant mean differences among clusters for each feature (p<0.05). Bonferroni-corrected post-hoc tests determined which specific pairs of clusters differed. For each feature within these pairs, the median value for each cluster was calculated, and a feature was deemed dominant in a cluster if it had the highest median value within that pair. Note, dominance was quantified by aggregating the counts of instances where a feature's median was the highest across its significant pairwise comparisons. Finally, the resulting clusters were input into the elastic net regression model to evaluate if they can enhance prediction accuracy. Then, these clusters were compared to those obtained using previously reported clinical subgroup calculations based on UPDRS-III score groupings of tremor-dominant, akinetic-rigid, and mixed subtypes. Analyses were performed using custom routines written in MATLAB (Mathworks, Natick, MA).

[0192] Data from all 50 patients was analyzed (36 males, 14 females, mean age 64.5 yrs. (9.8), mean UPDRS-III 22.7 points (9.6) assessed during ‘On’ periods. IMAS evaluations were also conducted during ‘On’ periods). For each subject and evaluation day, a total of 62 metrics descriptive of motor behavior was extracted from the IMAS recordings.

[0193] Fig. 4 of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section shows exemplary IMAS-derived data for two PD patients with UPDRS-III scores of 21 (Fig. 4B of Provisional Patent Application No. 63 / 640, 194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section) and 9 (Fig. 4A of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section), where a higher score indicates a higher impairment. The wrist speed profiles of patient with score 21 are indicative of elbow flexion / extension movements that are slower and less smooth compared to profiles of patient with score 9 (mean speed=0.37 m / s (0.06) vs. 1.6 m / s (0.21), standard deviation in parentheses; max speed=0.81 m / s (0.23) vs. 2.5 m / s (0.33), and movement duration=0.61s (0.12) vs. 0.30s (0.06); movement smoothness=0.48 (0.09) vs. 0.64 (0.07)). Similarly, compared to the patient with UPDRS-III of 9, the patient with UPDRS-III of 21 moved more slowly during the hand opening / closing tests (average movement duration=0.65s vs 0.47s for the first test of this class, and 1.08s vs 0.46s for the second; took longer for completing the complex, multi-joint motor tasks (26.7s vs 20.06s respectively); and performed the hand-to-nose movements less easily (movement smoothness of 0.41 vs 0.53; mean speed of 0.34 m / s vs 0.89 m / s; max speed of 0.81 m / s vs 1.69 m / s, in average). Additionally, the patient with the UPDRS-III of 21 showed a more prominent resting tremor, with 74.5% greater power than the patient with the UPDRS-III of 9 (1.54 vs. 0.88) as well as poorer postural control as shown by the CoP oscillations in Fig. 5 of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section (for eyes open testing: path length=142.7 cm vs. 23.57 cm; mean jerk=0.14 m / s3and max jerk= 0.55 m / s3vs mean jerk=0.03 m / s3and max jerk=0.13 m / s3; for eyes closed testing: path length= 91.87 cm vs 23.58 cm; mean jerk=0.09 m / s3and max jerk=0.29 m / s3vs 0.03 m / s3and 0.10 m / s3) and greater walking impairment (average total walking times of 13s vs. 7.25s, most affected leg average stride times of 1.27s vs. 1.04s, stride lengths of 1.0m vs. 1.67m, and stride velocity of 0.78 m / s vs. 1.6 m / s).

[0194] Fig. 6 of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section shows the PCA results. Each line represents the percentage of the total variability among the given set of standardized signals as a function of the number of PC retained. The red line shows the PCA results for the set of UPDRS-III measures. The 1stPC captured around 40% of the variability in the data. An analysis of the PCs showed that the 1stPC had large positive contributions from all the UPDRS-III measures except for the two related to tremor (Q20, Q21), postural stability (Q30), and arise from chair (Q27). The posture and rise from chair were the largest positive contributors to the 2ndPC and the tremor questions to the 3rdPC. Additionally, the first 5 PCs captured -80% of the variability. Although the UPDRS-III total score is the gold- standard for PD motor assessments, not surprisingly, these results provide evidence that there is additional variability in the UPDRS-III measures that is not explained by this score alone. The green line shows the PCA results for the IMAS metrics. The 1st PC alone explains -20% of the total variability in these measures. An analysis of the PCs associated to the IMAS metrics showed that the 1st PC had the largest positive contributions from task time in continuous elbow flexion / extension, complex sequence of movements, and both hand opening / closing tasks and large negative contributions from the mean speed and peak speed during the hand to nose test and mean speed of discrete elbow flexion / extension movements. About 12 PCs were required to capture -80% of the variability in these measures. This suggests that the effective number of independent dimensions associated with the IMAS measures is larger than that of the UPDRS-III measures. The blue line shows the PCA results when the UPDRS-III and IMAS measures are combined. The plot for the variance explained as a function of dimension for the combined dataset is consistently close to that of the IMAS alone, suggesting that adding data from the IMAS increases the number of independent measures beyond what is available from the UPDRS-III alone, but that adding the UPDRS-III data might not increase the number of independent measures from what is available from the IMAS data alone. Examining the 1st PC of the combined dataset, we found the weights associated with the UPDRS-III measures were close to the 1st PC of the UPDRS-III data alone, and that the weights associated with the IMAS measures were close to the 1st PC of the IMAS measures alone. This suggests that the combination of IMAS measures along which variability is maximal may be linearly predictive of the sum UPDRS-III measure. The simplest prediction model, based on the elastic net regression, demonstrated an R2of 0.54 and an MAE of 5.2 points of the total UPDRS-III score on the LOOCV evaluation. The key predictors identified from the elastic net based on the IMAS dataset included a mix of metrics from the 5 key movements (elbow flexion / extension (6 metrics), hand opening / closing (2 metrics), handtouch-nose (6 metrics), tremor (5 metrics), modified Romberg (2 metrics), and walking (3 metrics)). IMAS signals with the largest weights in the elastic net model included peak speed of continuous elbow flexion / extension, movement duration and variability in movement mean speed of the hand-touch-nose task, path length of CoP oscillations during balance task with eyes closed, and path length of discrete elbow flexion / extension. For the assessments of N=l l patients evaluated on day 2, the prediction results demonstrated an MAE of 4.32 points of the total UPDRS- III score and R2=0.75. Notably, the mean errors across our models are lower than past published values of inter-rater variability (23), which compared typical clinical staff to movement disorder experts and demonstrated mean errors in UPDRS-III evaluations of up to 5.4 points (see below for further examples).

[0195] Taken together, the PCA and modeling analysis suggest that the IMAS signals contain much of the information present in the UPDRS-III data and can predict the UPDRS-III score. The IMAS signals contain additional information not present in the UPDRS-III data which can be useful in identifying symptom patterns not typically captured in classic exams.

[0196] Fig. 7 of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section panels A-C depicts illustrative results of the clustering procedure. Various SOM configurations were systematically explored, including different grid sizes, numbers of epochs, and initial neighborhood sizes, and their impact on the quantization error was assessed. The optimal grid size of 6x6 was identified based on the lowest error, and subsequently trained 10 times to evaluate the model’s stability. The most effective SOM configuration was selected based on the lowest quantization error. The Ward method was then employed for hierarchical clustering. These clustering results are in line with the PCA results. Clusters based on IMAS measures (a dataset richer than the UPDRS-III data set, as indicated by PCA) are more separable / distinct than those based on UPDRS-III. The higher discriminative power of the IMAS-based clusters indicates that the IMAS-based features capture meaningful differences across the dataset, which might facilitate personalization of treatments as patients within each cluster are more homogeneous in terms of how they might respond to a specific treatment. A random forest algorithm was used to explore the IMAS features that most contributed to each cluster. The algorithm was trained across 10 iterations, each with a different random seed to ensure variability, using out-of-bag predictor importance to assess the stability of feature importance scores. The top ten most important features were selected based on having the highest average importance scores. Fig. 7 of Provisional Patent Application No. 63 / 640,194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section, panel D displays these features in the context of the clusters selected by the Ward algorithm, specifically for 2, 3, and 4 clusters. The dendrogram visualizes how these clusters are related and their separation based on the IMAS features. Notably, the clustering effectively distinguishes between patient groups characterized by postural instability, tremor, and bradykinesia metrics. These clusters align with recognized symptom patterns of PD, while also potentially providing insights for treatment planning. Clinical subgroup classifications often distinguish between tremordominant and akinetic-rigid patients, relegating patients without tremor or bradykinesia / rigidity as dominant traits, to a mixed group. However, the IMAS-based clusters highlight the importance of postural instability subgroups, which might provide a basis for tailoring treatments. While postural instability was believed to herald a late-stage PD, it is now known to be a dominant phenotypical trait in early PD. Its early diagnosis may be elusive in clinical exams and hinders PD patients’ wellbeing. Although research initiatives focused on CoP or center of gravity measures alone have not been adopted in clinical practice, this finding might find a more direct application because postural and gait instability cause PD patients to fall, which is a main driver for morbidity and has become the main culprit raising health care expenditures amongst PD motor symptomatology. Additionally, of note is the evolving clinical definition of bradykinesia and the potential for IMAS clustering to identify testing metrics for patient subgroup classification. Finally, the prediction model built on different clusters showed improved prediction accuracy compared to the simple prediction model described above. For example, a prediction model based on the 3 clusters achieved an MAE of 4.34 points and an R2of 0.7 and a model based on the 4 clusters achieved an MAE of 4.17 and an R2of 0.65 via LOOCV.

[0197] As demonstrated in this example, and in the above examples (Example PD Treatment Course 2 (e.g., metrics including those describing tremor, bradykinesia testing, postural instability, and gait) and Example PD Treatment Course 3 (e.g., metrics including those describing tremor, bradykinesia testing, postural instability, rise from chair, and gait) and further described in Provisional Patent Application No. 63 / 640,194 (incorporated above), PCT Publication No. WO / 2024 / 086537 (incorporated above), and those described in U.S. Patent Publication No. US2021 / 0322771 (incorporated above) the IMAS system can be used to identify patient response to ESStim as described herein, multiple energy stimulation methods, and / or stimulation coupled with other therapy or therapies as described herein and / or coupled with other methods to tune, optimize, plan, or dose stimulation (e.g., biophysical analysis, cost effective analysis, quantitative sensory testing). The IMAS can identify patient symptoms, class, progression, temporal dynamics of symptoms and be used to dose stimulation. For example, the system can be used pre, during, and / or post ESStim as described herein and identify the symptoms that best respond to treatment in a class of patients and the dose of stimulation and / or adjunct therapy or combination therapy can be adjusted accordingly (e.g., PT or drugs). The system can be used to tune the stimulation parameters that are used such as for example the intensity, frequency, timing, and or location of the stimulation source.

[0198] In addition to being used with neuromodulation, in certain embodiments the IMAS can be integrated in the PD care pathway in numerous other ways as the IMAS is specifically designed to systematically collect voluminous datasets of motor behavioral data during patient assessments. Assessments are a crucial part of the PD care continuum, and IMAS is engineered to integrate at various stages within this continuum. During periodic assessments, IMAS can aid in patient evaluation and can also be trained to output traditional evaluation scores. While we have reported results for UPDRS-III, the algorithms can be trained to generate other clinical scores, such as MDS- UPDRS-III. Other notable features of IMAS include the capability of its learning core to be trained on different evaluators (such as a specific senior movement disorder expert at a clinical practice), and the potential for its integration with telemedicine, which enables assessments of patients in remote locations orthose lacking access to specialists. Treatment selection or adjustment is another stage of the care continuum where IMAS can have a significant impact. Traditional methods often rely on trial and error and clinical subgroup classifications based on the UPDRS scores or clinical history, such as those described in Provisional Patent Application No. 63 / 640, 194 in the Integrating Big Data, Motion Analysis, and Artificial Intelligence for Emerging Applications in the Parkinson’s Disease Management section. However, these types of classifications share the same limitations as UPDRS, providing only coarse clustering. IMAS-based clusters can be further enhanced by integrating additional data types, such as for example features extracted from neuroimaging (e.g., EEG, MRI, PET, CAT Scan, Xray, DAT Scan, Magnetic Resonance Imaging (MRI), Functional MRI (fMRI), Diffusion Tensor Imaging (DTI), Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Computed Tomography (CT), Magnetoencephalography (MEG), Electroencephalography (EEG), Near-Infrared Spectroscopy (NIRS), Optical Coherence Tomography (OCT), Arterial Spin Labeling (ASL), Functional NearInfrared Spectroscopy (fNTRS), Photon Emission Tomography (PET-MRI), High-Resolution MRI, Structural MRI, Perfusion MRI, Susceptibility-Weighted Imaging (SWI), Magnetic Resonance Spectroscopy (MRS), Proton Density Imaging, Blood Oxygen Level Dependent Imaging (BOLD), Resting-State fMRI, Task-Based fMRI, Dynamic Contrast-Enhanced MRI (DCE-MRI), Diffusion- Weighted Imaging (DWI), Voxel-Based Morphometry (VBM), Cortical Thickness Mapping, Tractography, Fiber Tracking, Quantitative Susceptibility Mapping (QSM), Gradient Echo Imaging, Time-of-Flight (TOF) Imaging, Phase-Contrast Imaging, Black Blood Imaging, White Matter Hyperintensity Imaging, Brain Volumetry, Hippocampal Volumetry, Gray Matter Volume Analysis, Neurovascular Imaging, Vessel Wall Imaging, MR Angiography, CT Angiography, PET-CT, Ultra-High Field MRI, 7-Tesla MRI, 3-Tesla MRI, 1.5-Tesla MRI, Low-Field MRI, Diffusion Kurtosis Imaging (DKI), Susceptibility -Weighted Angiography, Intracranial Vessel Wall Imaging, Dopamine Transporter Scan (DAT scan), Perfusion CT, and / or Functional Connectivity Analysis), biospecimen, and / or autonomic data (e.g., blood pressure, pupillary response). The system can aid in developing personalized treatment plans tailored to specific patient symptoms and likelihood of disease progression. As new treatments (e.g., neuromodulation techniques) and more traditional treatments (e.g., PT) are developed or further explored, they can facilitate understanding of how these interventions impact the motor system over time and help build methods for optimizing such interventions- See Figure 6. Finally, with the evolving understanding of PD, and the continued identification of clinical subtypes and disease processes, IMAS cannot just help with treatment selection but will be able enhance our fundamental understanding of the disease and / or be used as a tool to aid initial diagnosis.

[0199] While our approach focused examples on PD and was based on IMAS, validated herein for PD motor assessments, it can be generalized to other contexts where integration issues arise (of note, we have demonstrate that IMAS can function in stroke and chronic pain conditions (such as diabetic neuropathic pain, carpal tunnel syndrome pain, and lower back pain). See, for example, the incorporated priority applications and PCT Publication No. WO / 2024 / 086537 (incorporated above) and U.S. Patent Publication No. US2021 / 0322771 (incorporated above).

[0200] ESStim optimization and / or tuning via pharmacoeconomic methods and / or decision-support techniques:

[0201] In certain embodiments ESStim can be used with software and / or computational based methods for determining its optimized use or a cost-effective paradigm for its use as a treatment. The methods outlined herein can also be used for other optimizing the use of ESStim for use with methods and treatments discussed in this application , such as for example those discussed in the IMAS section above. The methods can be combined with other methods discussed herein such as for example the IMAS methods, QST methods, imaging, biospecimen collection, biophysical and / or modeling.

[0202] Pharmacoeconomic methods and / or decision-support techniques are employed to guide decisions that maximize limited resources with the highest value to patients, providers, payers, and society for the evaluation health effects of RCTs. Methods employed include cost-benefit analysis (CBA), cost-effectiveness analysis (CEA), cost-utility analysis (CUA), and others. Such methods are becoming more common place in the practice of medicine, for example cost effectiveness assessments are integral to National Institute for Health and Care Excellence (NICE) Guidelines [https: / / www.nice.org.uk / process / pmg6 / chapter / assessing-cost-effectiveness]. CEA defines health benefits in natural units, costs in monetary units, and compares health gains of medical procedures via the same outcome measures.

[0203] ESStim optimization and / or tuning via pharmacoeconomic methods and / or decision-support techniques generally relate to a system, methods, and / or software for optimizing the delivery of treatment for maximum cost effectiveness. Generally, the disclosure provides software and computational based methods for a CEA Based therapy delivery, focused on: 1. Defining the research question (e.g., how effective is ESStim at a certain dose to impact patients’ UPDRS3 scores); 2. Defining effectiveness (what change in UPDRS3 is considered clinically effective); 3. Identifying the treatment States and costs; 4. Discounting (cost and effectiveness); 5. Modeling the stochastic nature of a particular treatment paradigm; 6. Performing a sensitivity analysis; 7. Analyzing Results; and 8. Recommending treatment. These steps can be employed as a whole or in part. The methods can be employed in advance to design a treatment, during the treatment to improve it, and / or after a treatment to better optimize the treatment paradigm, evaluate past treatment paradigms, and / or to design future treatment paradigms.

[0204] The methods, and / or software can be implemented on any computational device and be administered via any computational device such as directly via the device, via a network (e.g., external device (s)), and / or cloud-based computing. The software is designed such that the treatment design variables can be entered via data entry methods, such as into the computational process directly (such as through a keyboard, voice input, and / or a touch screen system), via external software (e.g., Matlab, Excel, database software (census data, data from internet)), and / or via external files (e.g., electronic text files). The particular treatment paradigm variables can include any design variable that can be altered in the design of a particular treatment paradigm, including but not limited to the location of stimulation, duration of stimulation, intensity of stimulation field(s), frequency of stimulation source(s) and / or field(s), pulse width of stimulation source(s) and / or field(s), duty cycle of stimulation source(s) and / or field(s), mechanical index of a stimulation source(s) and / or field(s), TI of stimulation source(s) and / or field(s), and / or individual phases, states, and / or individual elements and / or procedures, cost of a particular treatment paradigm elements and / or individual phases, states, and / or individual elements and / or procedures, number of personnel, skill set of personnel, advertising used for recruitment, equipment available, institution properties (e.g., see stimulation parameters outlined above), potential patient qualities (e.g., gender, age, number, degree and rate of disability), expected treatment effects (e.g., size, duration, side effects, outcome measures), and / or analysis methods (e.g., computational methods). The particular treatment paradigm can be based on any definition of effectiveness and / or an inventory of effectiveness criteria, which can include elements of the particular treatment paradigm variables. The results analysis can be focused on any standard way of reporting particular treatment paradigm data and cost effectiveness data (e.g., discounted costs, discounted effectiveness, cost effectiveness ratios (CERs), incremental cost effectiveness ratios (ICERs), tornado diagrams, costeffectiveness planes) and can be based on discrete, a range of results or probabilistic report of data. The design recommendations can be based on post design analysis or real-time alteration of particular treatment paradigm criteria and give a discrete or probabilistic report of recommendations. Elements of the results analysis and other software modules can be found in references including: (Jean-Michel Josselin and Benoft Le Maux “Statistical Tools for Program Evaluation: Methods and Applications to Economic Policy, Public Health, and Education”); (MIT Critical Data “Secondary Analysis of Electronic Health Records”); ( “WHO GUIDE TO COSTEFFECTIVENESS ANALYSIS”);( www.communities.gov.uk “Multi -criteria analysis: a manual”); (“Markov Models in Medical Decision Making: A Practical Guide” FRANK A. SONNENBERG, MD, J. ROBERT BECK, MD); (THE GREEN BOOK CENTRAL GOVERNMENT GUIDANCE ON APPRAISAL AND EVALUATION); (“Handbook of Markov Chain Monte Carlo”);(“ Average Cost-Effectiveness Ratio with Censored Data” Heejung Bang and Hongwei Zhao);(“ Medical Decision Making” Harold C. Sox, Michael C. Higgins and Douglas K. Owens); (“Cost Effectiveness Analysis in Health A Practical Approach” Peter Muennig); (“ Overview of Cost-effectiveness Analysis” Gillian D. Sanders, PhD; Matthew L. Maciejewski, PhD; Anirban Basu, PhD ); and (Cost-Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run- In Period. (2022). Principles and Practice of Clinical Research, 8(2), 31-

[0205] 42.

[0206] Software and computational modules can effectively work via first defining the question (goal of trial) and metric that will be used to assess the effectiveness of the trial design, this can include number of patient observations and / or type completed, a particular treatment paradigm effect power, cost limits, screening criteria, levels of statistical significance of observed treatment, efficacy goal of treatment, and / or their combination. Computationally one can use this to establish criteria to evaluate and design the trial, such as in the additional paper included herein (in additional files section), or via computational methods such as in (Jean-Michel Josselin and Benof t Le Maux “Statistical Tools for Program Evaluation: Methods and Applications to Economic Policy, Public Health, and Education”); (MIT Critical Data “Secondary Analysis of Electronic Health Records”); (“Fundamentals of Biostatistics” Bernard Rosner). These can be programmed in standard programming languages and implemented via standard programming methods and / or implemented via standard computational methods. Following the identification of the Question and Effectiveness Measure, one will enter variables of a particular treatment paradigm into the computational system or as variables in the software used to conduct the program. Variables can include any aspect of a particular treatment paradigm being evaluated and compared (e.g., intensities, cost elements, time durations). These variables can be entered as discrete base values, as a range of variables, equations, with / without confidence intervals, and / or as a probability distribution. During this stage one enters all of the variables associated with a particular treatment paradigm, the phases and states and the way in which they are connected, the costs and durations of the states and phases, and the way in which they are connected. One can do this for every base scenario they want to analyze and compare. Next one will define the way in which the costs and measures of effectiveness are discounted, these can be defined in any typical manner discounting is employed and can be entered as discrete base values, as a range of variables, equations, with / without confidence intervals, and / or as a probability distribution (one can also choose to not discount anything). To assess the random nature of a particular treatment paradigm, one can enter transition probabilities to transition from one state to the other states and simulate a particular treatment paradigm via Markov models and monte Carlo simulations or simulate the flow of a particular treatment paradigm processes via other simulation methods. The software and / or computational methods can be employed to model the randomized processes, such as via neural networks, Markov models, monte Carlo simulations, stochastic processes, and / or via methods outlined in the (“Encyclopedia of Statistical Sciences” Samuel Kotz Campbell B. Read N. Balakrishnan Brani Vidakovic Norman L. Johnson);(“ The Concise Encyclopedia of Statistics” https:. / doi.org / 10. 1007 / 978-0-387-32833-1 2 ; ); (“Simulation Modeling and Analysis (Mcgraw- Hill Series in Industrial Engineering and Management)” Averill Law);(“ Stochastic Modeling: Analysis and Simulation (Dover Books on Mathematics)” B Nelson);(“ Network Modeling, Simulation and Analysis in MATLAB: Theory and Practices” D Le); (“Introduction to the Modeling and Analysis of Complex Systems” H Sayama); (“Theory and Practical Exercises of System Dynamics: Modeling systems for analysis and optimization (Modeling and Simulation 2020)” by Juan Martin Garcia and John Sterman), and / or any general modeling method. If one ran the initial program analysis on Base Models one can follow the assessment with a sensitivity analysis, based on assessing discrete variable and / or probabilistic variables as entered earlier and demonstrated in the additional paper included herein (in additional files section) or the references included in this application. Following the analysis, one can use the software to report a particular treatment paradigm CEA and / or optimization results automatically, or to provide graphical feedback to serve as a tool in the analysis of the results (the results type data that comes from the software is depicted in the additional paper included herein (in additional files section), for example in the figures). Finally, the software module can make a recommendation of a particular treatment paradigm that should be implemented through methods outlined above.

[0207] Additionally, while the system, software, and computational based methods is presented herein as a forward predicting system, it can also work in an inverse manner as a whole or in part (e.g., one would start with a desired Cost of a particular treatment paradigm component and work the process backward). The software can work by requiring input from a user, be semi-automated, and / or fully automated. The analysis can also be completed or optimized using any machine learning and / or artificial intelligence such as those in (“Encyclopedia of Machine Learning and Data Mining” Claude Sammut and G. Webb); (“Deep Learning (Adaptive Computation and Machine Learning series)” Ian Goodfellow et. al,); (“Artificial Intelligence: A Modern Approach (4th Edition)” S. Russell and P. Norvig); (“Deep Learning (The MIT Press Essential Knowledge series)” J Kelleher).

[0208] The hardware system can be a single computer system with integrated software containing the above modules, multiple systems with individual software modules (or some combination), and / or via a host / client network approach (e.g., cloud based computing). The hardware used can be a computer(s) and / or a mobile device(s) (e.g., phones, tablets). The hardware can include monitors, data entry devices (e.g., mouse, keyboard, touch screen monitor), computational processors, memory units, graphical processing units, and general computational components.

[0209] The software can be used to optimize an RCT design, which can effectively lower costs and maximize efficient or optimize other forms of treatment described in this application, like neuromodulation, drug therapy, PT, or occupational therapy (see incorporated Provisional Patent Application No. 63 / 640,194 Systems, Methods, and Software for Optimizing a Project section and for further details and examples of potential output of the software for an RCT see Cost- Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run-In Period. (2022). Principles and Practice of Clinical Research, 8(2), 31-42. h ps: / / doi org. / 10.218Q j / ppc? ,2022.82,5, the entire disclosure of which is hereby incorporated by reference herein).

[0210] Other Example Uses of ESStim and / or combined energy stimulation methods and / or optimization or tuning methods:

[0211] Opioid Use Disorder (OUD):

[0212] The methods herein, such as the combined ultrasound and electrical form of neuromodulation can be applied in multiple indications to improve disease symptoms or clinical metrics of the diseases such as for example Opioid Use Disorder, other forms of addiction, and / or craving.

[0213] Opioid-related overdose deaths increased from 21,089 in 2010 to 47,600 in 2017, remained stable through 2019, then surged to 68,630 in 2020 and 80,411 in 2021. Of the deaths in 2021, 70,601 involved synthetic opioids other than methadone, primarily fentanyl. Overall, the alarming increase in opioid use, addiction, and overdose has led to a national epidemic. Conventional addiction treatments include pharmacological (e.g., methadone) and psychosocial interventions. Unfortunately, these treatments are characterized by limited efficacy, ceiling effects, and / or serious side effects. Individuals suffering from addiction develop specific brain network states, known to be associated with symptoms and behaviors related to addiction, which are not directly targeted by current therapies. Therefore, better treatments are needed to specifically target the brain alterations induced by addiction.

[0214] Our novel form of noninvasive brain stimulation, ESStim, is safe and effective in the treatment of OUD. It can be used to improve OUD symptoms and signs such as for example cravings, overuse or use of drugs, polysubstance use, unsuccessful attempts to quit, withdrawal symptoms, drowsiness, confusion, nausea, vomiting, constipation, slurred speech, impaired coordination, mood swings, euphoria, anxiety, depression, irritability, agitation, paranoia, hallucinations, delusions, unconsciousness, coma, insomnia, muscle aches, runny nose, diarrhea, abdominal cramps, chills, fever, restlessness, tremors, fatigue, hyperalgesia, anhedonia, dysphoria, cognitive impairment, memory problems, menstrual irregularities, seizures, overdose, frequent hospital visits, impulsivity, lack of self-control, compulsive drug-seeking behavior, impaired decisionmaking, increased risk-taking, emotional instability, feeling of hopelessness, guilt, shame, suicidal thoughts or behaviors, impaired cognition. OUD and / or its signs and symptoms can be improved such as for example by ESStim delivered to the patients Dorsolateral Prefrontal Cortex and / or adjacent tissues (directly or indirectly), deeper reward centers such as the Ventral Tegmental Area (VTA) and Nucleus Accumbens via direct or indirect stimulation and / or other areas including for example those seen in the Figure titled “Fig. A. l. Project Overview in the Option 3 section of Provisional Patent Application No. 63 / 640,194 .

[0215] ESStim stimulation can be provided as a sole treatment, in combination with other therapies, and / or adjunct to other therapies including but not limited to Neuromodulation, Medication- Assisted Treatment (MAT), behavioral therapy, methadone, buprenorphine, Suboxone, naltrexone, naloxone, cognitive-behavioral therapy (CBT), contingency management, motivational interviewing, group therapy, individual counseling, family therapy, 12-step facilitation therapy, antidepressants, antipsychotics, mood stabilizers, dialectical behavior therapy (DBT), residential treatment programs, intensive outpatient programs (IOP), partial hospitalization programs (PHP), sober living homes, peer support groups, acceptance and commitment therapy (ACT), relapse prevention therapy, medical detoxification, trauma-focused therapy, integrated treatment for cooccurring disorders, exposure therapy, mindfulness-based stress reduction (MB SR), solution- focused brief therapy, harm reduction strategies, acupuncture, chiropractic care, biofeedback, neurofeedback, massage therapy, exercise therapy, Transcranial Magnetic Stimulation (TMS), Transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Temporal Interference, and / or auricular stimulation.

[0216] OUD Treatment Course Example:

[0217] ESStim delivered to the patients Dorsolateral Prefrontal Cortex and adjacent tissues, deeper reward centers such as the Ventral Tegmental Area (VTA) and Nucleus Accumbens via direct or indirect stimulation, such as via an the electrode setup whereby an anodal DC source and ultrasound source are placed above the F3 (see Figure 7) and a cathode placed approximately over the contralateral orbital, implementing energy patterns such as those described above and provided 20 minute / day sessions, over a 5-day period, can be safe and effective for improving Opioid Use Disorder (OUD). It can be effective provide as a sole therapy, in combination with other therapies, and / or adjunct to other therapies.

[0218] For example, in 26 patients, randomized between active and SHAM stimulation, we demonstrated the effectiveness of ESStim on OUD where tDCS and transcranial ultrasonic energy were provided using an F3 anodal DC current and ultrasound location with a contralateral orbital placed cathode (see Figure 7). The tDCS portion of ESStim was delivered via a DC source adjustable to deliver <2.5 mA through sponge rubber electrode (anode and cathode shaped similar to those used in PD (e.g., Figure 3) positioned in contact with the scalp in the ESStim headpiece, resulting in a very low current density of <0.1 mA / cmA2. The ultrasound energies were as above (e.g., energies with thermal indices of the cranium of less than 1.5 and Mis less than 1 with derated (at 0.3 dB / cm / MHz) Spatial-Peak Temporal -Average intensity (mW / cmA2), less than 40 mW / cmA2, an Isppa.3< -200 W / cmA2, and / or an Imax.3: < -200 W / cmA2 (where the Ispta.3 can be between 10-40 mW / cmA2, Isppa.3 can be between 50-175 W / cmA2, and the Imax.3 between 50-175 W / cmA2), with a PRF less than 10,000 (such as 30 frx 1 ppi x 256 Ipf)) based on ultrasound scanning methods detailed above, and tDCS currents of less than 2.5 mA (using 5x7 cm electrodes with an area for the ultrasound transducer on the anode). Stimulation was provided 20 minute / day, over a 1-week period, for 5 of the days.

[0219] To set up the system and identify the target area, the participants were first seated in a comfortable chair. Before positioning the headgear, which includes the electrodes and transducer, the scalp is thoroughly examined and cleaned as necessary. The target location is determined using the 10-20 EEG coordinate measurement and identification procedure, exemplified here for F3 placement. This process begins by identifying several fixed landmarks on the participant’s head: the nasion (the depression between the forehead and nose), the inion (the bony protrusion at the base of the skull), and the left and right preauricular points (the points just in front of the ear canals). To locate the Cz position (at the skull’ s vertex), measure the distance between the nasion and inion and divide it by 2. Next, find the line that intersects the left and right preauricular points and crosses the midpoint between the inion and nasion. The Cz is situated at the intersection of these measures. The C3 location is found along the line that intersects the left and right preauricular points through the Cz, at 20% of the distance measured from left to right preauricular points, starting from the Cz. To localize the F3, which is used to target the stimulation of the dorsolateral prefrontal cortex (DLPFC), continue the measurements as illustrated in Figure 7. The F3 is positioned anteriorly from the Cz, 20% of the distance along the parasagittal line. Finally, the cathode electrode is placed ~1.5 cm above the right brow line and ~1.5 cm to the right of the midline (see Figure 7). As above the stimulation localization and electrode / transducer fixing can be completed with a manual, semiautomated, and / or automated system (such as depicted in Figure 4, but different than a C3 target location such is sued in PD, one would use the system with an F3 target. As above the system used bridging medium to couple the electrodes and ultrasonic source to the scalp.

[0220] Patients were recruited with the following Inclusion Criteria: 1. Providing informed consent to participate in the study; 2. 18 to 85 years old, inclusive; 3. Having a diagnosis of OUD a. OUD of more than 6 months duration as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and a positive urine toxicology screen; or b. OUD patients who still feel craving or have not received more than 60 mg of methadone / day from the Methadone program; and 4. Lives in immediate area with no plans to relocate. They had the following Exclusion Criteria: 1. Subject is pregnant; 2. Recently started on antiepileptic drug therapy; 3. History of illegal stimulant use as demonstrated by urine toxicology; 4. Ingestion of poppy seeds or herbal teas containing Papaveris fructus (may cause a positive opiate test for morphine, codeine); 5. History of neurological disorders involving stroke, brain tumors or epilepsy as self-reported (note patients will also be evaluated via electroencephalography (EEG) at baseline 1 week prior to stimulation and any patient showing abnormal EEG activity will be removed); 6. History of unexplained fainting spells as self-reported; 7. History of head injury resulting in more than a momentary loss of consciousness as self-reported; 8. History of brain surgery as self-reported; 9. Contraindications to tDCS applied in conjunction with TUS: a. Metal in the head; or b. Implanted brain medical devices; 10. Suffering from severe depression with a score of >30 in the Beck Depression Inventory (BDI), PHQ-9>10; 11. Active malignancy; 12. History of suicidal behavior or suicide attempts.

[0221] Enrolled subjects were randomized to receive either active or sham ESStim treatments applied to the left dorsolateral prefrontal cortex (DLPFC), 20 minutes per day over 5 consecutive days (14 Active, 12 SHAM). Both study subjects and the evaluating investigators were blinded as to the treatment group assignments. The following evaluations were conducted of all subjects at baseline prior to the first ESStim treatment and during the trial: Addiction Assessments: Addiction Questionnaires (NIDA-Modified ASSIST (NM ASSIST), and 15-item Barrett Impulsivity scale; Behavioral / Computer Assessments: ultimatum game, risk task, inhibitory control task, and opioidcue exposure task for craving; Safety evaluations: Abbreviated Neurological Exam (OUD specific) including: MoCA and Stroop test, Montreal Cognitive Assessment (MOCA) (NIH CDE instrument), Visual Analog Mood Scale (VAMS), PHQ-9 Depression Scale, Urine pregnancy exam (if applicable); EEG; VAS pain intensity; Toxicology screening (urine screening) and Hair follicle toxicology screening (if available); Completion of medication diary (American Pain Foundation Pain and Medication Diary), done at home.

[0222] Subjects received the 20-minute ESStim treatment according to their group assignment at each of the next five visits scheduled over five consecutive days and had follow-ups up to a month post stimulation. Urine toxicology (UT) screening demonstrated significantly reduced drug use in the Active group compared to the SHAM group (p<0.05, Fisher’s Exact Test). Note that UT testing was only conducted during clinic visits and therefore does not indicate whether drug use was reduced during the follow-up period between visits or how it varied between the 2 pre-stimulation baseline assessments (therefore we counted any baseline positive measure as a positive baseline).

[0223] Results of the behavioral measures from baseline through the follow-up period indicate that Active ESStim was more effective in normalizing behavior over SHAM ESStim: Significant reduction in the Craving score (as measured using the Opioid Cue-Exposure Task for Craving Assessment) compared to baseline in Active vs Sham groups (1.6 vs 0.67 points on a 0 to 10-point VAS scale, p<0.05 (ANOVA (Dependent: Change in Craving VAS from Baseline; Independent: Stimulation Group, Visit)) in the period from the last stimulation session through the last followup. In the Ultimatum Game (UG), an assessment of impulsivity and valence, we showed an overall small, but significant(p<0.05), improvement in acceptance rates (~3% increase vs ~2% decrease) for Active vs Sham in the period from the last stimulation session through the last follow-up (ANOVA as above but with the Change in UG Response Rate from Baseline as the dependent variable). Significant reduction on the Inhibitory Control Task (ICT), which is used to assess impulsivity changes (14.4% vs 4.2%, Active vs Sham, p<0.05) in the period from the last stimulation session through the last follow-up (ANOVA as above but with the Change in Correct Responses from Baseline as the dependent variable).

[0224] EEG test results and recording of adverse events indicated no safety concerns with this treatment. Furthermore there no reports of any serious adverse events (SAEs) resulting from ESStim; No pathological EEG activity consistent with epileptiform discharges or persistent focal slowing; No significant decline in functional status caused by stimulation as defined by a significant worsening of functional status as compared with baseline (indexed by physical exam); No evidence of any new neurological signs and symptoms caused by stimulation as indexed by the neurological examination compared with baseline; No significant increase in opioid use caused by stimulation as defined by a significant increase in opioid use as compared with baseline.

[0225] We were also able to demonstrate that ESStim elicited a statistically significant renormalization of brain electrical activity following treatment for the Active compared to SHAM patients. We evaluated changes in resting EEG patterns associated with opiate addiction. Specifically, we investigated changes in power in alpha, beta, theta, delta, and gamma bands from baseline for Active vs SHAM. Active patients showed a statistically significant renormalization of brain electrical activity following treatment compared to SHAM relative to their baseline assessments. Most notably ESStim targeted to the left dorsolateral prefrontal cortex yielded behavioral and neurophysiological correlates. To this effect, electrodes at this location (F3, F4) showed a renormalization in power of the higher frequency components of approximately 2% in the alpha band (p=0.06), 5% in the beta band (p<0.05), 9% in the lower gamma band (p<0.05) between Active and SHAM relative to baseline following stimulation (i.e., a lowering of power), as measured at F3 with eyes closed, and approximately 3% in the alpha band (p<0.05), 4% in the beta band (p<0.05), 9% in the lower gamma band (p<0.05) between Active and SHAM relative to baseline following stimulation, as measured at F4 with eyes closed (all tested via student’s unpaired t-tests). In the lower frequency bands, we generally saw a nonsignificant increase in delta power (2%) and a ~4% decrease in theta power (p<0.05) in F4, and similar changes in F3. In summary, these findings reflect a significant renormalization of the typical elevated power seen in OUD patients in Active compared to SHAM relative to their baseline assessments. Additionally, neurophysiological changes correlate with our behavioral results. Finally, our results support that EEG-derived metrics might convey a potential marker for behavioral responses to ESStim for tuning stimulation dosage or identifying best-responders to stimulation.

[0226] The treatment effects can last from weeks to months past the duration of stimulation. See the incorporated priority applications for further details, examples, and results (e.g., RHEA 1 study in incorporated Provisional Patent Application No. 63 / 546,926 ).

[0227] EEG as Biomarker for Dosing Stimulation, Dosing Treatment Classifying Patients, and / or Predicting Outcomes:

[0228] OUD is diagnosed using qualitative criteria (i.e., clinical scales and questionnaires (e.g., DMSV criteria)), and toxicology screening with various degrees of testing accuracy (e.g., false positives or negatives, time span limitations). Biomarkers for OUD with diagnostic and prognostic value do not currently exist and represent an unmet need that has been recognized by NIDA and the FDA. Conventional OUD treatments (i.e., pharmacological and psychosocial interventions) are characterized by limited or diminishing efficacy, ceiling effects, and / or serious side effects. The availability of validated OUD biomarkers would be a key step in the development and approval of better treatments. Advances in neuroimaging techniques, and in particular recent evidence portrays electroencephalography (EEG) as a promising candidate to investigate the correlation between addiction and brain state. We have assessed OUD patients’ EEGs throughout ESStim therapy and identified distinct changes in patient’s EEGs that can serve as a biomarker for identifying / classifying OUD patients, and / or predicting their response to treatment, and / or identifying / classifying their response to therapy.

[0229] Recent evidence demonstrates the correlation between addiction and brain state. Specifically, studies have provided evidence that chronic opiate abuse affects various brain areas, including prefrontal cortex, temporal insula and thalamus, nucleus accumbens, amygdala, and sensorimotor cortices. These represent areas that can be targeted either with stimulation for treatment and / or as markers one can identify to classify, predict, and / or identify best treatments for a patient. Structural changes such as volume changes (e.g., loss at left nucleus accumbens and increase at right amygdala), altered network activation (executive, reward, habit, salience, self-directed, memory), and default mode / resting state connectivity changes have been observed. These changes can be investigated with neuroimaging methods and non-invasive brain stimulation assessments.

[0230] Among neuroimaging techniques, Electroencephalography (EEG) has several advantages that makes it a promising tool to develop a biomarker. EEG recordings of brain electrical activity are performed via electrodes placed on the scalp. They are low-cost, portable, and non-invasive, which makes them ideal for monitoring and tracking subjects over multiple sessions. Also, they have high temporal resolution (order of ms), and their use is established in clinical practice. The recent development of high-density EEG and advances in computational techniques have enabled analyses that were not possible with older systems, for example generation of topographical scalp maps that allow monitoring of different areas of the brain simultaneously, subregional and hemispheric analyses, and source reconstruction. Surprisingly, EEG studies on OUD are scarce and have been mainly performed with older systems with just a few channels. Most studies investigated changes in frequency bands (delta, theta, alpha, beta, and / or gamma), evaluated at individual electrodes. None have evaluated impact of stimulation, and in particular ESStim. Event- related potentials (ERPs) have also been used to examine key processes involved in drug addiction from various perspectives and have especially focused on neurocognitive consequences of OUD via P300 measurements of attention to different stimuli. While these studies have shown that EEG can potentially be used to detect changes in brain activity induced by substance use disorder and / or OUD, they also have a number of limitations, which have hampered their actual exploitation for development of OUD biomarkers. Besides a limited number of channels, the non-specific nature of these metrics (often reflecting superposition of various underlying processes) and nonstandardized, sub-optimal signal processing pipelines have arguably contributed to low signal-to- noise ratio, reproducibility, specificity and sensitivity in these studies. In effect, these past devices use single channel EEG and insufficient analysis methods that preclude biomarker identification. The potential of high-density EEG in developing OUD biomarkers is still largely underexplored. Overall, EEG studies have either technological limitations and / or do not account for potential clinical differences in the OUD patient cohort so as to potentially establish clinically relevant OUD biomarkers.

[0231] As described above, we have been investigating the use of a novel non-invasive brain stimulation technology, ESStim, targeted to the left dorsolateral pre-frontal cortex (DLPFC) for the treatment of OUD. As part of the Phase I work, we conducted a multi -center, double-blinded, placebo-controlled, randomized study where we enrolled and assessed 26 OUD patients. Phase II studies are currently ongoing. During the Phase I studies, we showed that, compared to SHAM, ESStim significantly improved patient cravings and impulsivity from baseline in OUD patients, as measured by data taken from computerized tests implementing an Opioid Cue-Exposure Task for Craving Assessment, an Ultimatum Game, and an Inhibitory Control Task. Urine toxicology results also demonstrated reduced drug use in the Active vs SHAM groups. Additionally, EEG reflected a significant renormalization of the typical elevated power seen in OUD patients in Active compared to SHAM relative to their baseline assessments (e.g., see Figure 8). In these studies, EEG-based metrics were based on changes in power in alpha (, beta (, theta (, delta (, and gamma (bands from baseline taken from rest EEG. Frontal electrodes (F3, F4) showed a renormalization in power of the higher frequency components of approximately 2% in the alpha band (p=0.06), 5% in the beta band (p<0.05), 9% in the lower gamma band (p<0.05) between Active and SHAM relative to baseline following stimulation (i.e., a lowering of power), as measured at F3 with eyes closed, and approximately 3% in the alpha band (p<0.05), 4% in the beta band (p<0.05), 9% in the lower gamma band (p<0.05) between Active and SHAM relative to baseline following stimulation, as measured at F4 with eyes closed (all tested via student’s unpaired t-tests). In the lower frequency bands, we generally saw a nonsignificant increase in delta power (2%) and a ~4% decrease in theta power (p<0.05) in F4, and similar changes in F3. Furthermore, these patients also demonstrated a significant reduction in opioid craving and reduced drug use. EEG signals are able to track changes associated to treatment (and / or be used as a marker to identify best responders to therapy). We can use EEG biomarker(s) and the methods we outline for identifying candidate biomarkers of OUD for diagnosis, disease monitoring, and / or prediction of OUD treatment response.

[0232] EEG-based biomarkers for OUD can be used diagnostic, monitoring, and / or prognostic purposes. While our past experiments were focused on EEG at rest (eyes open and / or eyes closed), and used in conjunction with a Craving / Cue Exposure test during which subjects are exposed to visual drug-cues EEG can be gathered in numerous ways and performing numerous tasks, such as EEG at rest (eyes open), EEG at rest (eyes closed), EEG during a Cue Exposure test with visual cues, EEG during a Cue Exposure test with auditory cues, EEG during a Cue Exposure test with olfactory cues, EEG during a Cognitive Task, EEG during a Working Memory Task, EEG during a Visual Task, EEG during an Auditory Task, EEG during a Motor Task, EEG during Sleep, EEG during REM Sleep, EEG during NREM Sleep, EEG during a Nap, EEG during Meditation, EEG during Biofeedback Training, EEG during Neurofeedback Training, EEG during a Stress Test, EEG during Emotional Stimuli Exposure, EEG during Pain Induction, EEG during a Reaction Time Task, EEG during a Learning Task, EEG during a Problem-Solving Task, EEG during a Decision-Making Task, EEG during a Language Task, EEG during Reading, EEG during Listening to Music, EEG during Watching a Video, EEG during a Startle Response Test, EEG during a Go / No-Go Task, EEG during a Stroop Task, EEG during a Stop-Signal Task, EEG during a Gambling Task, EEG during a Delayed Match-to- Sample Task, EEG during an Oddball Paradigm, EEG during a Continuous Performance Task, EEG during a Sustained Attention Task, EEG during a Flanker Task, EEG during a Task Switching Paradigm, EEG during an Emotion Regulation Task, EEG during a Dual Task, EEG during a Visuospatial Task, EEG during a Handedness Task, EEG during an Eye Movement Task, EEG during a Speech Production Task, EEG during a Math Calculation Task, EEG during a Taste Test, EEG during an Olfactory Discrimination Task, EEG during a Tactile Stimulation Task, and / or EEG during Hypnosis. EEG is a versatile technique used to record electrical activity of the brain under various conditions and stimuli. The different ways to record EEG listed above cover a broad range of scenarios, including resting states, cognitive tasks, sensory exposures, emotional stimuli, and different sleep stages, all of which allow for a biomarker for OUD for diagnosis, disease monitoring, and / or prediction of OUD treatment response. EEG can also be recorded during everyday conditions and states that may or may not involve specific tasks or tests, such as for example EEG during spontaneous conversation, EEG during free movement, EEG during quiet wakefulness, EEG during deep relaxation, EEG during passive listening, EEG during exercise, EEG during fasting, EEG during meal consumption, EEG during caffeine consumption, EEG during dehydration, EEG during hydration, EEG during standing, EEG during sitting, EEG during lying down, EEG during postural changes, EEG during physical fatigue, EEG during mental fatigue, EEG during sensory deprivation, EEG during temperature changes, EEG during acclimatization, EEG during hyperventilation, EEG during controlled breathing, EEG during deep breathing, EEG during eye tracking, EEG during spontaneous blinking, EEG during eye closure, EEG during eye opening, EEG during yawning, EEG during sneezing, EEG during swallowing, EEG during speaking, EEG during humming, EEG during whistling, EEG during laughter, EEG during crying, EEG during light exposure, EEG during electric stimulation, EEG during magnetic stimulation, EEG during ultrasound stimulation, EEG during ESStim, EEG during acupuncture, EEG during chiropractic adjustment, EEG during physical therapy, and / or EEG during drug use and / or through the time course of a drugs impact on the person.

[0233] Data sets can be analyzed with statistical methods with the objective of predicting / classifying patients’ clinical status. For example, analysis techniques include EEG source analysis, EEG connectivity analysis, EEG spectral analysis, EEG time-frequency analysis, EEG coherence analysis, EEG phase locking value (PLV) analysis, EEG independent component analysis (ICA), EEG event-related potentials (ERPs), EEG microstate analysis, EEG power spectral density (PSD) analysis, EEG functional connectivity, EEG effective connectivity, EEG graph theory analysis, EEG network analysis, EEG source localization, EEG dipole modeling, EEG phase-amplitude coupling (PAC) analysis, EEG cross-frequency coupling (CFC) analysis, EEG artifact rejection, EEG sleep spindle analysis, EEG alpha wave analysis, EEG beta wave analysis, EEG delta wave analysis, EEG theta wave analysis, EEG gamma wave analysis, EEG slow wave analysis, EEG fast wave analysis, EEG background rhythm analysis, EEG reactivity analysis, EEG transient analysis, EEG seizure detection, EEG spike detection, EEG polyspike analysis, EEG sharp wave analysis, EEG slow wave activity, EEG asymmetry analysis, EEG coherence mapping, EEG phase synchronization, EEG desynchronization, EEG burst suppression analysis, EEG topographic mapping, EEG dipole source analysis, EEG magnetic source imaging (MSI), EEG beamforming, EEG source imaging, EEG phase resetting, EEG entropy analysis, EEG complexity analysis, EEG fractal analysis, EEG linear analysis, EEG non-linear analysis, EEG phase difference analysis, EEG inter-channel phase analysis, EEG amplitude analysis, EEG latency analysis, EEG coherence spectra, EEG cross-spectral analysis, EEG correlation analysis, EEG neural synchrony, EEG evoked potentials, EEG induced potentials, EEG slow cortical potentials, EEG fast Fourier transform (FFT) analysis, EEG wavelet transform, EEG time-domain analysis, EEG frequency-domain analysis, EEG phase space reconstruction, EEG nonlinear dynamics, EEG Lyapunov exponent analysis, EEG Hurst exponent analysis, EEG detrended fluctuation analysis, EEG recurrence quantification analysis, EEG wavelet coherence, EEG Hilbert transform, EEG independent vector analysis (IVA), EEG canonical correlation analysis (CCA), EEG multiscale entropy, EEG sample entropy, EEG approximate entropy, EEG permutation entropy, EEG bispectral analysis, EEG quadratic phase coupling, EEG cross-bispectrum analysis, EEG higher- order spectra, EEG power-law scaling, EEG multifractal analysis, EEG spectral entropy, EEG mutual information analysis, EEG directed transfer function (DTF), EEG partial directed coherence (PDC), EEG Granger causality, EEG phase slope index (PSI), EEG linear regression analysis, EEG Bayesian analysis, EEG state-space modeling, EEG Kalman filtering, EEG tensor decomposition, EEG principal component analysis (PCA), EEG spatial filtering, EEG common spatial pattern (CSP) analysis, and / or EEG independent component selection. For example, EEG source analysis identifies the origin of electrical activity in the brain, helping to localize brain functions or pathologies. It can be coupled with stimulation to identify sources affected by stimulation and / or targets for stimulation. EEG connectivity analysis examines the interactions between different brain regions, providing insights into brain network dynamics. It can be coupled with stimulation to identify potential dynamics impacted by stimulation and / or targets for stimulation and / or potential optimal time for delivery of stimulation. EEG spectral analysis analyzes the frequency components of EEG signals to understand brain wave patterns. Spectral Analysis can, for example, identify specific wave patterns associated with a patient's state, such as those...

Claims

WHAT IS CLAIMED IS:

1. An apparatus for treating neurological disease comprising: an electrical source capable of generating an electric field across a region of tissue; and a means for altering the impedance of said tissue relative to said electric field, whereby the alteration of the impedance of said tissue relative to said electric field generates an altered current in said tissue; and the means for altering impedance in tissue is an ultrasonic source with a Mechanical Index of less than 1.9 and a Thermal Index of less than 1.5.

2. The apparatus of claim 1, wherein said electrical source is applied non-invasively.

3. The apparatus of claim 1, wherein said means for altering impedance is applied non- invasively.

4. The apparatus of claim 1, wherein said electrical source is a time varying inductive magnetic field generated from an external source.

5. The apparatus of claim 1, wherein said electrical source is at least one electrode.

6. The apparatus of claim 1, wherein said electric field and said means for altering impedance can be applied to neural tissue to assist in the treatment of ailments selected from Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Alzheimer’s Disease, Dystonia, Tics, Spinal Cord Injury, Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol Craving, Nicotine Craving, Stuttering, Tinnitus, Spasticity, Parkinson’s Disease, Parkinsonianism, Obsessions, Depression, Schizophrenia, Bipolar Disorder, Acute Mania, Catonia, Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome, Phantom Limb Pain, Epilepsy, Stroke, Auditory Hallucinations, Movement Disorders, Neurodegenerative Disorders, Pain Disorders, Metabolic Disorders, Addictive Disorders, Psychiatric Disorders, Traumatic Nerve Injury, and / or Sensory Disorders.

7. The apparatus of claim 1, wherein said electric field and said means for altering impedance stimulate a structure or multiple structures within the brain or nervous system selected from dorsal lateral prefrontal cortex, any component of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem, thalamus, inferior colliculus, superior colliculus, periaqueductal gray, primary motor cortex, supplementary motor cortex, occipital lobe, Brodmann areas 1-52, primary sensory cortex,primary visual cortex, primary auditory cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal lobe, parietal lobe, sub-cortical structures, peripheral nerves and spinal cord.

8. An apparatus for stimulating neural activity in biological tissue comprising: a DC electrical source capable of generating an electric field across a region of tissue; and a means for altering the impedance of said tissue relative to said electric field, whereby the alteration of the impedance of said tissue relative to said electric field generates a displacement current in said tissue and / or the alteration of conductivity in said tissue alters an ohmic current in the tissue; and the means for altering impedance in tissue is an ultrasonic source with a Mechanical Index of less than 1 and a Thermal Index of less than 1.5.

9. An apparatus for generating currents in biological tissue comprising: an electrical source capable of generating an electric field across a region of tissue; and an ultrasound device which generates a mechanical field focused on a sub-region of tissue, whereby the combined effects of said electric field and said mechanical field generate an altered current with a newly generated displacement current within said region of tissue; and said ultrasonic device operates with a Mechanical Index of less than 1.9 and a Thermal Index of less than 1.5.

10. The apparatus of claim 5, wherein said electrical source is shaped to at least partially enclose said ultrasonic source.

11. The apparatus of claim 1, wherein said ultrasonic source is a pulsed signal.

12. The apparatus of claim 9, wherein said ultrasonic device produces a pulsed signal.

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