Systems and methods for administering brain stimulation therapy

Abstract

The present disclosure provides systems and methods relating to brain stimulation therapy. In particular, the present disclosure provides systems and methods for identifying effective stimulation patterns for reducing one or more symptoms or a neurological or psychiatric disorder.

Description

DUKE-45293.601SYSTEMS AND METHODS FOR ADMINISTERING BRAIN STIMULATION THERAPYGOVERNMENT FUNDING10001] This invention was made with Government support under Federal Grant No. UH3NS103468 and UH3NS129898 awarded by National Institute of Neurological Disorders and Stroke. The Federal Government has certain rights to the invention.RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 685,802 filed August 22, 2024, which is incorporated herein by reference in its entirety for all purposes.FIELD

[0003] The present disclosure provides systems and methods relating to brain stimulation therapy. In particular, the present disclosure provides systems and methods for identifying effective stimulation patterns for reducing one or more symptoms or a neurological or psychiatric disorder.BACKGROUND

[0004] Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Deep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus (GP) is an effective surgical treatment for PD. Combined DBS of both STN and GP (dual target, DT DBS) may be more effective than DBS of either region alone. While DT DBS reduced both Unified Parkinson’s Disease Rating Scale (UPDRS) scores and levodopa equivalent daily dose, it remains unknown whether these benefits may be further improved with the optimization of stimulation parameters. The most widely reported biomarker for PD is the power of beta band (13 - 30 Hz) oscillations in the basal ganglia, which increase prominently in the pathological state, and there is a correlation between the reduction in beta power in the STN and the improvement in bradykinesia with treatment. A correlation has been reported betw een bradykinesia and STN beta powder at different amplitudes of 125 Hz DT DBS.

[0005] Stimulation amplitude and pulse width are determined based on the patient’s tolerance (i.e., side effects) and symptomatic relief. However, the frequency is typically set to 130 Hz, with few changes after the first clinical visit. Previous work demonstrated that betaDUKE-45293.601 oscillations in the STN can be enhanced or reduced by a pulse in the GPi aligned to a specific phase of the oscillation. Phase-alignment requires recording of the local field potential signal, as well as on-line determination of the instantaneous phase of oscillations which is not practical for implanted devices.SUMMARY

[0006] Embodiments of the present disclosure include a method of administering brain stimulation therapy to a subject. In accordance with these embodiments, the method includes delivering at least one first continuous stimulation pulse train to a first target region of the subj ect’s brain, and delivering at least one second continuous stimulation pulse train to a second target region of the subject's brain. In some embodiments, each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined inter-target delay.

[0007] In some embodiments, the delivery of the at least one first stimulation pulse to the first region of the subject’s brain synchronizes one or more types of brain oscillations. In some embodiments, the delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder. In some embodiments, the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and theta oscillations.

[0008] In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in the same anatomical brain region. In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions. In some embodiments, the first and / or the second target region of the subject’s brain is located in the subthalamic nucleus (STN). In some embodiments, the first and / or the second target region of the subject’s brain is located in the globus pallidus (GP). In some embodiments, the first target region of the subject’s brain is located in the STN, and wherein the second target region of the subject’s brain is located in the GP.

[0009] In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 2 Hz to about 125 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz toDUKE-45293.601 about 50 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 15 Hz.

[0010] In some embodiments, the predetermined inter-target delay is from about 1 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 10 ms.

[0011] In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz; and wherein the predetermined intertarget delay is from about 20 ms to about 50 ms.

[0012] In some embodiments, the predetermined inter-target delay is determined based on measuring at least one neurological biomarker associated with at least one symptom of a neurological or psychiatric disorder in the subject.

[0013] In some embodiments, the at least one neurological biomarker comprises alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and / or theta oscillations; and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the oscillations and treats the at least one symptom of the neurological or psychiatric disorder. In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.|0014] In some embodiments, the at least one neurological biomarker comprises beta oscillations, and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.

[0015] In some embodiments, the method does not comprise obtaining a neural recording of the subject’s brain.

[0016] Embodiments of the present disclosure also include a method for determining stimulation parameters for administering brain stimulation to a subject. In accordance with these embodiments, the method includes (i) delivering at least one first continuous stimulationDUKE-45293.601 pulse train to a first target region of the subject’s brain and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein the least one first and second continuous stimulation pulse trains are delivered at the same frequency; (ii) measuring amplitude of one or more types of brain oscillations in the subject’s brain during or after the delivery of the at least one second continuous stimulation pulse train; (iii) repeating steps (i) and (ii) while varying time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse train; and (iv) establishing an inter-target delay value by determining the time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse that produces the greatest suppression of the one or more types of brain oscillations.

[0017] In some embodiments, the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes the one or more ty pes of brain oscillations. In some embodiments, the delivery of the at least one second continuous stimulation pulse train after the inter-target delay suppresses or reduces the one or more types of brain oscillations and treats at least one symptom of a neurological or psychiatric disorder in the subject. In some embodiments, the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and / or theta oscillations. In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention- deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.

[0018] In some embodiments, the at least one type of brain oscillation comprises beta oscillations, and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subj ect.

[0019] In some embodiments, the method is repeated by delivering the least one first and second continuous stimulation pulse trains at at least one different frequency.

[0020] In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in the same anatomical brain region. In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions. In some embodiments, the first and / or the second target region of the subject’s brain is located in the subthalamic nucleusDUKE-45293.601(STN). In some embodiments, the first and / or the second target region of the subject's brain is located in the globus pallidus (GP).

[0021] Embodiments of the present disclosure also include a system for administering brain stimulation therapy to a subject to treat a neurological or psychiatric disorder. In accordance with these embodiments, the system includes at least one implantable electrode configured to deliver electrical stimulation to the subj ect’ s brain; and a pulse generator electronically coupled to the at last one implantable electrode, wherein the pulse generator is programmed to deliver at least one first continuous stimulation pulse train to a first target region of the subject’s brain and to deliver at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined inter-target delay.|0022] In some embodiments, the delivery' of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes one or more types of brain oscillations. In some embodiments, the delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder. In some embodiments, the one or more t pes of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and theta oscillations.

[0023] In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 2 Hz to about 125 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subj ect at a frequency ranging from about 10 Hz to about 15 Hz.

[0024] In some embodiments, the predetermined inter-target delay is from about about 1 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 50 ms.

[0025] In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention- deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.DUKE-45293.601BRIEF DESCRIPTION OF THE DRAWINGS

[0026] FIGS. 1A-1D: Schematic of model and effect of DBS frequency on beta power in the computational model. A) Model topology, including the number of neurons per area of the brain modeled and interconnections. The color indicates antidromic activation due to DBS of the STN (yellow) and the GPi (blue). Bias currents (I) were applied to the STN. the GPi, the GPe, and the Th to set baseline firing rates. Abbreviations: (r / i) CTX Cortex, (id / d) Str Striatum, GP(e / i) Globus pallidus (extema / intema), STN Subthalamic nucleus. Th Thalamus. B-D) DT DBS (red) and STN DBS (blue) from 0 - 200 Hz. A - C) Power Spectral Density (PSD) for key points along the frequency tuning curve. D) Beta power (normalized to DBS off) over 0 - 200 Hz DT and STN DBS.

[0027] FIGS. 2A-2C: Effect of GPi DBS delivered at different phases of the ongoing beta oscillations in STN. A) Schematic of the controller. STN LFP was processed to extract the instantaneous phase of the beta oscillations. If the phase was within the epoch, the controller delivered a DBS pulse to the GPi and then deactivated for 20 ms. B) PSD plots for different conditions in target phases (colored lines), compared to DBS off PSD (black line). C) Normalized beta power across target phase epochs. Error bars show the range of results across ten trials with different random seeds in the model.

[0028] FIGS. 3A-3C: Effect of intemuclear pulse delay on beta power. A) Example GPi stimulation pulse (STN pulse delivered at time t = 0) across a range of intemuclear delays. B) PSDs at different delays compared to DBS off (black). C) Beta power across delays between the STN and GPi when stimulating at 22 Hz. 100 percent is baseline beta power. Error bars show the range of beta power across 10 trials.

[0029] FIG. 4: Model Validation. A) PSD comparisons of the healthy. Parkinsonian, and 130 Hz STN DBS applied to the Parkinsonian state in the STN, GPi and GPe (left to right). For the Parkinsonian state, there was an increase in power within the beta range compared to the healthy state, with a peak at 22 Hz in all three regions. This peak in the beta band was completely removed by 130 Hz STN DBS. B) PSTHs (bin size = 1 ms) of the average of 10 neurons across 100 simulations in the GPi and the GPe (left, right) after stimulation in the cortex. MFR for each region is shown as a red dotted line. Cortical stimulation consisted of one pulse (at t = 0), with a pulse width of 1 ms, in the Parkinsonian state, without DBS. For the GPi (i) there was a peak in activity after the cortical stimulation (0 - 50 ms), followed by a protracted inhibition of activity (50 - 125 ms). Post inhibition, activity peaked (125 - 150 ms) before resuming to normal behavior (~ 200 ms). For the GPe (ii), there was a short inhibitionDUKE-45293.601 in the activity (10 - 40 ms), followed by a period of excitation in which the GPe reached peak activity (~50 - 100 ms), before resuming baseline activity.

[0030] FIG. 5: Controller Accuracy. For the closed-loop stimulation, the phase of the LFP in the STN was plotted each time a DBS pulse was delivered. Histograms were made of the LFP phase of each pulse, each color in the legend representing the trials in which the controller boundaries started (left) and ended (right). For each stimulation setting, DBS pulses were delivered only within marked bounds, confirming the accuracy of the controller.

[0031] FIG. 6: Latency simulations. Beta power during DBS across intrahemispheric latencies for 16 Hz (top) and 28 Hz (bottom) DT DBS. The latency range was restricted to the length of the DBS frequency. From these results, it was observed that even if the DBS frequency does not exactly match the frequency of peak power of the beta oscillations (i.e. 22 Hz on the model), a residual beta power of 20.0 % (at 16 Hz DBS) and 22.0% (at 28 Hz DBS) can be observ ed by making changes in the latency. However, the latency that best-reduced beta power depended on DBS frequency. In both plots, beta power during the DBS off state was at 100% and signaled by a dotted line. Error bars represent the range of beta power at a given latency across 10 trials.

[0032] FIGS. 7A-7B: LFP power spectra at baseline (black), during 24 ms inter-target delay (blue), and 32 ms inter-target delay (red). Changes in power with DBS were consistent across the STN (A) and GPi (B). STN DBS with 24 ms inter-target delay reduced beta power, suggesting utility as a treatment for PD.

[0033] FIGS. 8A-8B: Parameterized inter-target delay. The inter-target delay between pairs of DBS pulses was swept from 2-44 ms with the DBS frequency held constant. Delays between 22 and 28 ms were best at reducing pathological beta oscillations in both the STN (A) and GPi (B).DETAILED DESCRIPTION

[0034] A validated computational model was used to quantify the effects of inter-target pulse timing, and more specifically, whether applying DBS at different phases of the beta oscillation in the STN would modulate the effectiveness of DBS. Variable timing of pulses to the beta phase affected beta power in humans and non-human primates. In the model described in this present disclosure, phase-based aDBS always reduced beta power compared to DBS off. However, the timing of the pulse relative to the beta oscillation modulated the extent of this reduction. Attempts were made to regulate the timing of the network by stimulating with beta frequency DBS in the STN (22 Hz) and subsequently suppressing the beta oscillations with theDUKE-45293.601GPi pulse by changing the delay between the two ipsilateral targets. The delay implemented by the Summit RC+S (1 / 4 of the frequency pulse, ~11 ms) produced nearly double the beta power from the DBS off state in the model. This prediction agreed with the increased beta power observed with beta frequency stimulation in the random frequency experiments. However, a 40 ms delay in the model resulted in an 88% reduction in beta power, and similar results were observed at other DBS frequencies. These results suggest that substantially lower DBS frequencies with a programmable (rather than fixed) STN to GP pulse delay could lead to effects similar to high-frequency DBS. Two other DBS frequencies mismatched from the endogenous beta oscillation frequency were also tested (i.e., 16 and 28 Hz, see FIG. 6). Similar modulation of beta power was observed for mismatched frequencies suggesting that it is unnecessary to match the frequency of the ongoing oscillation.

[0035] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.1. Definitions

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below7, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0037] The terms “comprise(s),’' “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0038] For the recitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1. 6.2, 6.3. 6.4, 6.5. 6.6, 6.7. 6.8, 6.9, and 7.0 are explicitly contemplated. Recitation of ranges of values herein are merely intended to serve as a shorthand method ofDUKE-45293.601 referring individually to each separate value falling within the range, unless otherwise- indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc., are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0039] “Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse), a non-human primate (e.g., a monkey, such as a cynomolgus or rhesus monkey, chimpanzee, etc.) and a human. In some embodiments, the subject may be a human or a non-human. In one embodiment, the subject is a human. The subj ect or patient may be undergoing various forms of treatment.

[0040] ‘ ‘Treat,” “treating” or “treatment” are each used interchangeably herein to describe reversing, alleviating, or inhibiting the progress of a disease and / or injury, or one or more symptoms of such disease, to which such term applies. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a treatment to a subject that is not at the time of administration afflicted with the disease. “Preventing” also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease.

[0041] “Therapy” and / or “therapy regimen” generally refer to the clinical intervention made in response to a disease, disorder or physiological condition manifested by a patient or to which a patient may be susceptible. The aim of treatment includes the alleviation or prevention of symptoms, slowing or stopping the progression or worsening of a disease, disorder, or condition and / or the remission of the disease, disorder or condition.

[0042] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, neurobiology, microbiology, genetics, electrical stimulation, neural stimulation, neural modulation, and neural prosthesisDUKE-45293.601 described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular.2. Brain Stimulation Methods

[0043] The present disclosure provides systems and methods relating to brain stimulation therapy. In particular, the present disclosure provides systems and methods for identifying effective stimulation patterns for reducing one or more symptoms or a neurological or psychiatric disorder. In accordance with these embodiments, the present disclosure includes a method of administering brain stimulation therapy to a subject to treat a neurological or psychiatric disorder. In some embodiments, the method includes delivering at least one first continuous stimulation pulse train to a first target region of the subject’s brain, and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain. Continuous stimulation using pulse trains involves delivering a series of electrical pulses to modulate neural activity in a targeted area. This neuromodulation approach is used in various applications and is generally administered using specific pulse parameters, including but not limited to, frequency, amplitude, pulse width, and the like, which can be tailored to the desired therapeutic effect.

[0044] In some embodiments, each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined inter-target delay. As described further herein, an inter-target delay generally refers to the time betw een initiation of the first and second continuous stimulation pulse trains. Results of the present disclosure demonstrated that the delivery of a first stimulation pulse train to a region of a subject’ s brain synchronizes one or more types of brain oscillations (e.g., alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and finely tuned gamma oscillations). Therefore, in some embodiments, the delivery' of the at least one first stimulation pulse to the first region of the subject’s brain synchronizes one or more types of brain oscillations. Additionally, results of the present disclosure also demonstrated that the delivery of a second stimulation pulse train to a region of a subject’s brain suppresses or reduces one or more types of brain oscillations (e.g., alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and finely tuned gamma oscillations). Therefore, in some embodiments, the delivery' of the at least one second continuous stimulation pulse train suppresses or reducesDUKE-45293.601 one or more types of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder. In some embodiments, the one or more t pes of brain oscillations include, but are not limited to alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and finely tuned gamma oscillations.

[0045] As described further herein, each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined period of time referred to as the inter-target delay. The particular length of the inter-target delay can vary based on the symptoms and / or neurological or psychiatric disorder being treated, specific patient parameters, and / or specific system parameters. As described further below, the present disclosure also includes method for identifying a particular intertarget delay value to maximize a desired result (e.g., symptom relief). Once identified, the length of the inter-target delay with respect to administering brain stimulation therapy to a subj ect is considered to be predetermined. Therefore, in some embodiments, the predetermined inter-target delay is determined based on measuring at least one neurological biomarker associated with at least one symptom of a neurological or psychiatric disorder in the subject. In this manner, the inter-target delay can be determined or optimized for a particular subject in need of individualized neuromodulation therapy. Additionally, in contrast to other currently available methods, the methods of the present disclosure do not require obtaining a neural recording of the subject’s brain.

[0046] In accordance with these embodiments, a predetermined inter-target delay can be from about 1 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 100 ms. In some embodiments, the predetermined intertarget delay is from about 30 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 40 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 50 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 60 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 70 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 80 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from 90 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 90 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 80 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 70 ms. InDUKE-45293.601 some embodiments, the predetermined inter-target delay is from about 1 ms to about 60 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 30 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 20 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 10 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 30 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 30 ms. In some embodiments, the predetermined inter-target delay is from about 15 ms to about 35 ms. In other embodiments, the predetermined inter-target delay is from 0 ms to 15 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 12 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 10 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 8 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 6 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 4 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 2 ms.

[0047] In addition to determining the therapeutic value of an inter-target delay with respect to administering brain stimulation therapy to a subject, results of the present disclosure also demonstrated the therapeutic value of delivering continuous stimulation pulse trains at various frequencies separated by an inter-target delay. In accordance with these embodiments, and as described further herein, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to a subject at a frequency ranging from about 2 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 25 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 50 Hz to about 125 Hz. In some embodiments, atDUKE-45293.601 least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 75 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 100 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 100 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 10 Hz to about 75 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 25 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 30 Hz to about 90 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 40 Hz to about 80 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 40 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 15 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 15 Hz to about 35 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 15 Hz. In some embodiments, the at least oneDUKE-45293.601 first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency of about 10 Hz, 11 Hz. 12 Hz, 13 Hz, 14 Hz, or 15 Hz.

[0048] In some embodiments, at least one first continuous stimulation pulse train is delivered at a frequency that is substantially the same as the frequency at which the at least one second continuous stimulation pulse train is delivered. In other embodiments, at least one first continuous stimulation pulse train is delivered at a frequency that is different from the frequency at which the at least one second continuous stimulation pulse train is delivered. In some embodiments, the method is repeated by delivering the least one first and second continuous stimulation pulse trains at at least one different frequency.

[0049] The methods of administering brain stimulation therapy to a subject include delivering at least one first continuous stimulation pulse train to a first target region of the subj ect’s brain, and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain. In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in the same anatomical brain region. In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions. For the purposes of the present disclosure, anatomical brain regions are generally considered to be specific regions of a subject’s brain that have been characterized as having unique structure, connections, and / or functions. Therefore, with respect to the methods of the present disclosure, a first target brain region and a second target brain region can be in the same anatomical region (i.e., a specific region characterized as having unique structures, connections, and / or functions), or different anatomical regions (i.e., two different regions of a subject’s brain that have been characterized as having different structures, connections, and / or functions).

[0050] In some embodiments, the first and / or the second target region of the subject’s brain is located in the subthalamic nucleus (STN). In some embodiments, the first target region of the subject’s brain is located in the STN, and the second target region of the subject’s brain is not located in the STN. In some embodiments, the first target region of the subject's brain is not located in the STN. and the second target region of the subject’s brain is located in the STN. In some embodiments, the first target region of the subject’s brain is located in the STN, and the second target region of the subject’s brain is located in the STN. In some embodiments, the first and / or the second target region of the subject's brain is located in the globus pallidus (GP) or the globus pallidus intemus (GPi). In some embodiments, the first target region of the subject’s brain is located in the GP / GPi, and the second target region of the subject’s brain isDUKE-45293.601 not located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is not located in the GP / GPi, and the second target region of the subject’s brain is located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is located in the GP / GPi, and the second target region of the subject’s brain is located in the GP / GPi. In some embodiments, the first target region of the subject's brain is located in the STN, and the second target region of the subject's brain is located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is located in the GP / GPi. and the second target region of the subject’s brain is located in the STN.

[0051] As described further herein, a particular inter-target delay can be determined based on measuring at least one neurological biomarker associated with at least one symptom of a neurological or psychiatric disorder in the subject. As would be understood by one of ordinary skill in the art, neuromodulation therapy often utilizes neurological biomarkers to optimize treatment parameters and to administer personalized therapy. Neurological biomarkers can include, but are not limited to, neurotransmitters, ionic concentrations, brain rhythms and oscillations, imaging data, electrophysiological data, and the like. In some embodiments, and as described further herein, at least one neurological biomarker can include alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and / or finely tuned gamma oscillations. In some embodiments, delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations and treats the at least one symptom of the neurological or psychiatric disorder. In some embodiments, the neurological or psychiatric disorder includes, but is not limited to, Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention- deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism. In some embodiments, and as described further herein, the at least one neurological biomarker comprises beta oscillations, and the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.

[0052] Embodiments of the present disclosure also include a method for determining stimulation parameters for administering brain stimulation -to a subject. In accordance with these embodiments, the method includes (i) delivering at least one first continuous stimulation pulse train to a first target region of the subject’s brain and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein the least one first and second continuous stimulation pulse trains are delivered at the same frequency; (ii) measuring amplitude of one or more types of brain oscillations in the subject’sDUKE-45293.601 brain after the delivery of the at least one second continuous stimulation pulse train; (iii) repeating steps (i) and (ii) while varying time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse train; and (iv) establishing an inter-target delay value by determining the time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse that produces the greatest suppression of the one or more types of brain oscillations.

[0053] In some embodiments, the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes the one or more types of brain oscillations. In some embodiments, the delivery of the at least one second continuous stimulation pulse train after the inter-target delay suppresses or reduces the one or more types of brain oscillations and treats at least one symptom of a neurological or psychiatric disorder in the subject. In some embodiments, the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and / or theta oscillations. In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention- deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism. In some embodiments, the at least one type of brain oscillation comprises beta oscillations, and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.

[0054] Embodiments of the present disclosure also include a method for determining stimulation parameters for administering brain stimulation to a subject (e g., establishing an inter-target delay value). In accordance with these embodiments, the method includes delivering at least one first continuous stimulation pulse train to a first target region of the subject’s brain and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein the least one first and second continuous stimulation pulse trains are delivered at the same frequency. In some embodiments, the method also includes measuring amplitude of one or more types of brain oscillations in the subject’s brain after the delivery of the at least one second continuous stimulation pulse train. In some embodiments, the method also includes repeating these steps while varying the time between the delivery' of the at least one first continuous stimulation pulse train and the deliver}' of the at least one second continuous stimulation pulse train. In some embodiments, the method also includes establishing an inter-target delay value by determining the time between the deliveryDUKE-45293.601 of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse that produces the greatest suppression of the one or more types of brain oscillations.

[0055] In some embodiments, the method is repeated by delivering the least one first and second continuous stimulation pulse trains at at least one different frequency. In accordance with these embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to a subject at a frequency ranging from about 2 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 25 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 50 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 75 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 100 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 100 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 75 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 25 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 30 Hz to about 90 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 40 Hz to about 80DUKE-45293.601Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 40 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 15 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 15 Hz to about 35 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 15 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency of about 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, or 15 Hz.

[0056] In some embodiments, the first target region of the subject's brain and the second target region of the subject’s brain are located in the same anatomical brain region. In some embodiments, the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions. For the purposes of the present disclosure, anatomical brain regions are generally considered to be specific regions of a subject’s brain that have been characterized as having unique structure, connections, and / or functions. In some embodiments, the first and / or the second target region of the subject’s brain is located in the subthalamic nucleus (STN). In some embodiments, the first target region of the subject’s brain is located in the STN, and the second target region of the subject’s brain is not located in the STN. In some embodiments, the first target region of the subject's brain is not located in the STN. and the second target region of the subject’s brain is located in the STN. In some embodiments, the first target region of the subject’s brain is located in the STN, and the second target region of the subject’s brain is located in the STN. In some embodiments, the first and / or the second target region of the subject's brain is located in the globus pallidus (GP) or the globus pallidus intemus (GPi). In some embodiments, the first target region of the subject’s brain is located in the GP / GPi, and the second target region of the subject’s brain isDUKE-45293.601 not located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is not located in the GP / GPi, and the second target region of the subject’s brain is located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is located in the GP / GPi, and the second target region of the subject’s brain is located in the GP / GPi. In some embodiments, the first target region of the subject's brain is located in the STN, and the second target region of the subject's brain is located in the GP / GPi. In some embodiments, the first target region of the subject’s brain is located in the GP / GPi. and the second target region of the subject’s brain is located in the STN.

[0057] In some embodiments, the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes the one or more types of brain oscillations. In some embodiments, the delivery’ of the at least one second continuous stimulation pulse train after the inter-target delay suppresses or reduces the one or more types of brain oscillations and treats at least one symptom of a neurological or psychiatric disorder in the subject. In some embodiments, the one or more types of brain oscillations include, but are not limited to alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and finely tuned gamma oscillations. In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism. In some embodiments, the at least one type of brain oscillation comprises beta oscillations, and the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.3. Brain Stimulation Systems|0058] Embodiments of the present disclosure also include a system for administering brain stimulation therapy to a subject to treat a neurological or psychiatric disorder. In accordance with these embodiments, the system includes at least one implantable electrode configured to deliver electrical stimulation to the subject’s brain, and a pulse generator electronically coupled to the at last one implantable electrode. In some embodiments, the pulse generator is programmed to deliver at least one first continuous stimulation pulse train to a first target region of the subject’s brain and to deliver at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulseDUKE-45293.601 train according to a predetermined inter-target delay. In some embodiments, the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia. Angelman syndrome, schizophrenia, bipolar disorder, and autism. 10059] As described further herein, each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined period of time referred to as the inter-target delay. The particular length of the inter-target delay can vary based on the symptoms and / or neurological or psychiatric disorder being treated, specific patient parameters, and / or specific system parameters. Once identified, the length of the inter-target delay with respect to administering brain stimulation therapy to a subject is considered to be predetermined. In accordance with these embodiments, a predetermined inter-target delay can be from about 1 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 30 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 40 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 50 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 60 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 70 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 80 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from 90 ms to about 100 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 90 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 80 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 70 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 60 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 30 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 20 ms. In some embodiments, the predetermined inter-target delay is from about 1 ms to about 10 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 20 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from about 30 ms to about 50 ms. In some embodiments, the predetermined inter-target delay is from aboutDUKE-45293.60120 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 40 ms. In some embodiments, the predetermined inter-target delay is from about 10 ms to about 30 ms. In some embodiments, the predetermined inter-target delay is from about 15 ms to about 35 ms. In other embodiments, the predetermined inter-target delay is from 0 ms to 15 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 12 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 10 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 8 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 6 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 4 ms. In some embodiments, the predetermined inter-target delay is from 0 ms to 2 ms.

[0060] In some embodiments, the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes one or more types of brain oscillations. In some embodiments, the delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder. In some embodiments, the one or more types of brain oscillations include, but are not limited to alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and finely tuned gamma oscillations.

[0061] Additionally, the pulse generator is programmed to deliver at least one first continuous stimulation pulse train to a first target region of the subject’s brain and to deliver at least one second continuous stimulation pulse train to a second target region of the subject’s brain at various frequencies. In accordance with these embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to a subject at a frequency ranging from about 2 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 25 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 50 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 75 Hz to about 125 Hz. In some embodiments, at least one firstDUKE-45293.601 continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 100 Hz to about 125 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 10 Hz to about 100 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 75 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subj ect at a frequency ranging from about 10 Hz to about 25 Hz. In some embodiments, at 1 east one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 30 Hz to about 90 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 40 Hz to about 80 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 40 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 15 Hz to about 50 Hz. In some embodiments, at least one first continuous stimulation pulse train and / or at least one second continuous stimulation pulse train can be delivered to the subject at a frequency ranging from about 15 Hz to about 35 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 15 Hz. In some embodiments, the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency of about 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, or 15 Hz.DUKE-45293.601

[0062] In accordance with the above embodiments, the systems described herein can be configured to administer any type of brain stimulation to a subject. In some embodiments, the system is configured to administer deep brain stimulation (DBS) to a subject. In some embodiments, the system is configured to administer epidural cortical stimulation to a subject. In some embodiments, the system is configured to administer epicortical cortical stimulation to a subject. In some embodiments, the system is configured to administer transcranial electrical stimulation to a subject. In some embodiments, the system is configured to administer transcranial magnetic stimulation to a subject. In some embodiments, the system is configured to administer any of the aforementioned types of brain stimulation to a subject as part of stimulation protocol that provides feedback control during stimulation (e.g., closed-loop stimulation).

[0063] In some embodiments, the systems of the present disclosure are configured to assess, measure, or quantify one or more neural biomarkers relating to a neurological disease or disorder. As would be understood by one of ordinary skill in the art, neurological biomarkers can include, but are not limited to. neurotransmitters, ionic concentrations, brain rhythms and oscillations, imaging data, electrophysiological data, and the like. In some embodiments, the neural biomarker includes oscillatory activity, which can be used together or independently as a neural biomarker for assessing symptoms relating to a neurological disease or disorder, and also for assessing treatment efficacy and / or efficiency. In some embodiments, at least one neurological biomarker can include alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, theta oscillations, high frequency oscillations, and / or finely tuned gamma oscillations. In some embodiments, delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations and treats the at least one symptom of the neurological or psychiatric disorder. In some embodiments, the neurological or psychiatric disorder includes, but is not limited to, Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attend on-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism. In some embodiments, the at least one neurological biomarker comprises beta oscillations, and the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subj ect.

[0064] In some embodiments, one or more stimulation parameters of the systems of the present disclosure can be adjusted based on information obtained from measuring at least one neural biomarker. In some embodiments, at least one neural biomarker includes oscillatoryDUKE-45293.601 activity, and information obtained from measuring the oscillatory' activity indicates a need to adjust one or more stimulation parameters to treat at least one symptom in the subject. In some embodiments, the one or more stimulation parameters comprise electrode placement, electrode contact selection, stimulation parameter selection, and / or closed-loop control. In some embodiments, the one or more stimulation parameters include stimulation pulse amplitude, stimulation pulse duration, stimulation pulse repetition rate, stimulation pulse shape, temporal patern of stimulation pulse train, and stimulation duty cycle. In some embodiments, the system allows for the adjustment of at least one parameter based on closed-loop control of one or more biomarkers. In some embodiments, the closed-loop control is a bang-bang controller, a PI controller or a PID controller. In other embodiments, the control is a neural network (e.g., a fully convoluted neural network).

[0065] Embodiments of the present disclosure also include a system comprising a device with a processor, and a plurality of electrodes in communication with the device. The plurality of electrodes is configured to be implanted in a brain of a subject. The processor is configured to acquire, via the plurality of electrodes, a plurality of electrical signals. In some embodiments, the plurality of electrodes that acquire a plurality of electrical signals is the same plurality of electrodes that provide electrical stimulation to the brain. The processor can be configured to determine whether a biomarker is present or absent in the plurality7of electrical signals, and / or to assess how a biomarker changes during the course of treatment (e.g., brain stimulation). The processor can also be configured to adjust at least one parameter based on the presence or absence of the biomarker, and / or the degree of chance in the biomarker.

[0066] In some embodiments, an electrode(s) used in the systems of the present disclosure can be one or more electrodes configured as part of the distal end of a lead or be one or more electrodes configured as part of a leadless system to apply electrical pulses to the targeted tissue region. Electrical pulses can be supplied by a pulse generator coupled to the electrode / lead. In one embodiment, the pulse generator can be implanted in a suitable location remote from the electrode / lead (e.g., in the shoulder region); however, that the pulse generator could be placed in other regions of the body or externally to the body. When implanted, at least a portion of the case or housing of the pulse generator can serve as a reference or return electrode. Alternatively, the lead can include a reference or return electrode (comprising a multipolar (such as bipolar) arrangement), or a separate reference or return electrode can be implanted or atached elsewhere on the body (comprising a monopolar arrangement).|0067] In some embodiments, the pulse generator used in the systems of the present disclosure are electrically coupled to a plurality of electrodes, and the pulse generator includesDUKE-45293.601 a power source. In some embodiments, the pulse generator is implantable. The pulse generator can include stimulation generation circuitry’, which can include an on-board, programmable microprocessor, which has access to and / or carries embedded code. The code expresses preprogrammed rules or algorithms under which desired electrical stimulation is generated, having desirable electrical stimulation parameters that may also be calculated by the microprocessor, and distributed to the electrode(s) on the lead. According to these programmed rules, the pulse generator directs the stimulation through the lead to the electrode(s). which serves to selectively stimulate the targeted tissue region. The code may be programmed, altered or selected by a clinician to achieve the particular physiologic response desired.4. Materials and Methods

[0068] Computational Model and Experiment Design. The previously reported biophysical computational model of the rodent cortico-basal ganglia-thalamic closed-loop was adapted. The original model featured 10 biophysical neurons in each of the following regions: the cortex (CTX), the striatum, STN, globus pallidus externa (GPe), GPi, and thalamus (Th). The model was modified to include GP DBS and DT DBS. The model was then adapted to human physiology and validated its response to phase-targeted DBS (Tables 2-4).

[0069] Table 2: Synaptic delay modifications between rodent and primate models.

[0070] Table 3: Changes to the bias current between the rodent and primate models.

[0071] Table 4: Comparison of model-based mean firing rates with experimental firing rates obtained from the literature.

[0072] To analyze the frequency response, the DBS frequency was varied from 0 - 200 Hz in steps of 5 Hz in independent simulations. The beta power was calculated, and the medianDUKE-45293.601 beta power across 10 trials per frequency was plotted in a frequency tuning curve. The same process was utilized for the analysis of ST and DT DBS.

[0073] To test the response of the model to phasic stimulation, a controller was designed based on Escobar Sanabria et al. (FIG. 2A). The controller assessed the phase of the LFP in the STN once every 1.3 ms. To calculate the phase, a 6 Hz wide second-order non-causal Butterworth filter centered around the peak frequency of the beta oscillation was first applied to the STN LFP signal. The instantaneous phase of the oscillations was calculated with a Hilbert transform and the MATLAB function angle() through the last 10 ms. However, the phases from the last 0.5 ms w ere excluded to account for the settling time of the filter. The controller was tested at multiple phases for the application of DBS — each condition consisted of a range of 7i / 12 between - n and n. If the phase of the oscillation calculated fell within the range, a stimulation pulse (300 nA with a pulse width of 0.3 ms) was applied to the GPi (with antidromic activation). The controller was then disabled for the following 20 ms allowing a maximum DBS frequency of 50 Hz. Ten iterations of 10 s simulations were performed with each condition.

[0074] The DBS artifact was removed by blanking during the time of stimulation (0. 1 ms before to 2 ms after), calculated beta power using the pwelchQ function, and then integrated over the peak beta band (19 - 25 Hz) using the trapz() function. For display, beta power was normalized by dividing by the beta power at baseline (PD condition, without DBS).

[0075] To conduct inter-target delay experiments. eDBS was applied and the inter-target pulse delay was varied as a new parameter. The delay was introduced as the duration (in ms) from the rising edge of the STN pulse to the rising edge of the GPi pulse. Across iterations, delays were swept from 0 to 46 ms with 2 ms windows. The DBS artifact was removed by blanking during the time of stimulation (0. 1 ms before to 2 ms after), calculated beta power using the pwelch() function, and then integrated over the beta band (13 - 30 Hz) using the trapz() function. For display, beta power was normalized by dividing by the beta power at baseline (PD condition, without DBS).

[0076] Adaptation of the Original Model to the Human Basal Ganglia. Randomization was applied to the initial conditions of the different cell types, conductance, and the stimulated subset of neurons across ten trials per experimental condition. Beta power was calculated from the LFP using p welch)) and integrated over the beta band using trapz(). After incorporating GP DBS into the model, it was found that without antidromic activation of the STN, GPi DBS had little effect on the beta power. Further, modeling studies using realistic axonal pathways have shown DBS to antidromically activate regions through afferent axons projecting to theDUKE-45293.601 stimulated nucleus. Therefore, antidromic activation was added within regions connected to the stimulated region (e.g. GPe and CTX in the case of STN DBS, STN and GPe for GPi DBS). Antidromic activation latency was the same as the synaptic delay between the regions. Because complete activation of all ten neurons must override endogenous network activity, DBS and antidromic activation were only applied to 60% of the neurons, chosen at random.

[0077] The model was adapted to the human basal ganglia. To do so, the synaptic delays were modified for key regions (Table 2) and the antidromic activation. To achieve mean firing rates found in primates, the current bias was altered in the GPi, GPe, and Th. A bias current was added and injected directly into the STN. The magnitude of the bias currents was determined empirically with a parameter sweep and was evaluated by minimizing the difference in mean firing rate observed in literature across the STN and GPi / e (Table S3 and S4). The LFP of the STN, GPi, and GPe were calculated by summing the transmembrane potentials of all cells in a region at each time point.

[0078] To produce average firing rates observed in the literature, a parameter sweep of the bias currents of the STN, GPi, GPe, and Th w as conducted. The best parameters were identified by summation of the difference between the mean firing rates (MFR) values found in the literature and the MFRs from the model in the STN, GPi, and GPe (Table 4). The final mismatch from the target w as 3.10 action potentials per second.

[0079] Model Validation. With the bias currents in place, the PSD for the healthy state, the PD state without DBS, and the PD state with 130 Hz DBS were examined (FIG. 4A). An increase in oscillatory activity was observed in the beta band, with peak activity at 22 Hz in the PD state compared to the healthy condition. When DBS was applied, the oscillatory activity was reduced. 130Hz DBS reduced the oscillations in the beta band within the model, as observed in humans with PD.

[0080] The response of the globus pallidus neurons to cortical stimulation was analyzed, a supra-threshold stimulus pulse was applied to each cortical neuron in the PD state. The peristimulus time histograms (PSTH) of the GPi and the GPe were quantified. The analysis for the PSTH started at 50 ms prior to the cortical stimulus and ended 350 ms after. The final plot was averaged over 100 trials of 10 neurons with a bin width of 1 ms. The model results (FIG. 4B) were compared to those previously observed in humans with PD. A similar response was observed from the model as observed in Nishibayashi et al, 2011, (their Figure 1A2, A4 and A6). In the GPi, a peak activity period was followed by a protracted period of inhibition and another peak in activity (FIG. 4Bi). In the GPe, a short period of inhibition was observed, followed by a peak in activity, before resuming regular behavior (FIG. 4Bii).DUKE-45293.601

[0081] Adaptive DBS. For the aDBS experiments, experiments were conducted to assess if the controller was activated within the correct window. For each controller setting, DBS was delivered only if the phase was within the boundaries determined and not anytime else (FIG. 5). To calculate the difference in total electrical energy (TEED) delivered during the aDBS experiments, it was determined that DBS amplitude, DBS pulse width, and contact impedance would not change compared to eDBS. The maximum average pulse rate was therefore determined for the simulation that most reduced beta power (i.e. JC / 6 to n / 4); the equivalent DBS frequency was 27.60 Hz. The calculated TEED was 21.23%. Thus, using aDBS reduced TEED by 78.77% compared to the standard 130 Hz GP DBS.

[0082] Intrahemispheric Delay Results. By varying the delay of pulses between the STN and GPi, a large decrease in beta power was observed when DBS was matched to the frequency of the ongoing oscillation. However, it was unclear whether it was necessary to match the frequency of the endogenous beta oscillation. Therefore, latency sweep simulations were repeated with DBS frequencies mismatched to the frequency of the beta oscillation, both 16 Hz and 28 Hz DBS. The period of the DBS limited the range of latencies tested. Intrahemispheric latency could both potentiate or reduce the beta band oscillation with DBS mismatched to the endogenous beta oscillation (FIG. 7). Indeed for 16 Hz the overall shape of the change with increasing latency matched that resulting from 22 Hz DBS. However, during 22 Hz DBS the reduction in beta power was greater (i.e. 87.9%) compared to either 16 Hz or 28 Hz DBS (a reduction of 80.0% and 78.0%. respectively).5. Examples

[0083] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and appreciable, and may be made using suitable equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are merely intended only to illustrate some aspects and embodiments of the disclosure, and should not be viewed as limiting to the scope of the disclosure. The disclosures of all journal references, U.S. patents, and publications referred to herein are hereby incorporated by reference in their entireties.

[0084] The present disclosure has multiple aspects, illustrated by the following non-limiting examples. It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure.DUKE-45293.601 which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.Example 1

[0085] Computational model predicts effective low frequency DBS. A biophysically based computational model of the human motor cortico-basal ganglia-thalamo-cortical loop (FIG. 1A) was used to quantify the effects of DBS frequency and inter-target delay beyond what is possible with currently implanted devices. After validating the model (FIG. 4), frequency tuning curves were generated for both DT and STN DBS (FIGS. 1B-1D). Generally, beta power decreased with increasing DBS frequency for both DT and STN DBS, and beta power reached minima at 105 Hz (DT DBS) and 110 Hz (STN DBS). Beyond these minima, increasing the frequency led to slight increases in beta power. DT DBS produced a greater reduction in beta power than STN DBS, but the difference between DT and STN DBS was slight.

[0086] Next, the effects of delivering pulses to the GPi at different phases of the STN beta oscillation were quantified. A controller was built to simulate adaptive DBS (aDBS) based on work by Sanabria et al. While a decrease in beta power was observed at all different settings of the controller, there were stark differences in beta power depending on the oscillation phase when stimulation was delivered (FIG. 2). Pulses delivered to the GPi during STN beta oscillation phases between -3TI / 4 and -7n / 12 reduced beta power to about 70% of baseline power (or a reduction of ~1.5 dB). However, when the controller applied pulses between 71 / 6 and 7i / 3, beta power was reduced to less than 20% of the baseline beta power (80% or -7.0 dB reduction) while maintaining a lower total electrical energy delivered (TEED) compared to 130 Hz ST DBS (FIG. 5).

[0087] Next, the effects of varying the delay between the DBS pulses delivered to the STN and the pulses delivered to the GPi during open-loop DT DBS were quantified. The DBS frequency was set to that of the peak beta power (22 Hz) and the inter-target delay was changed from 0 to 46 ms in increments of 2 ms (FIG. 3 A). The frequency of DBS was chosen to match the peak of the beta power to entrain most easily the endogenous beta oscillation by excitatory pulses delivered in the STN. The beta power was increased or decreased by DBS depending on the delay between STN and GPi pulses. DBS with inter-target delays greater than 30 ms decreased beta power and reached a minimum at 40 ms (12.1% of baseline, FIGS. 3Bi, 3C). When the delay was set between 8 ms and 30 ms, beta power increased compared to baseline, with a maximum of 164% of baseline power (12 ms, FIGS. 3Bii, 3C). The dependence of beta power on delay - decreasing with short delays (i.e. 0 - 6 ms), increasing with longer delaysDUKE-45293.601(i.e., 8 - 30 ms), and decreasing again with very long delays (> 30 ms) - was replicated across DBS frequencies in the beta range (i.e., 16 Hz and 28 Hz, FIG. 6). However, when the delay was nearly a complete period long (i.e., the GP pulse slightly led the STN pulse), beta power increased. The reduction in beta power was not as large as during high-frequency DT DBS or 130 Hz ST DBS (12.1% vs 1.02% and 1.39% residual beta power respectively), but the DBS frequency was reduced from 125 Hz to 22 Hz thereby reducing the TEED by 82.4% compared to 125 Hz DT DBS and by 66. 1% when compared to 130 Hz STN DBS.Example 2

[0088] STN - STN Low Frequency DBS Results. In the following experiment, two pluses were delivered to the STN with a preset delay every ~50 ms (continuous ~20 Hz DBS). The value of the inter-target delay was swept from 2 - 44 ms. The power of the beta band was calculated from LFPs in the STN and the GPi. Ten trials at each inter-target delay were averaged and normalized by the power in the beta band in the absence of DBS. Example spectra are provided in FIG. 7, which shows LFP power spectra at baseline (i.e., no DBS, black), during 24 ms inter-target delay (blue), and 32 ms inter-target delay (red). Changes in power with DBS were consistent across the STN (FIG. 7A) and GPi (FIG. 7B). STN DBS with 24 ms intertarget delay reduced beta power, demonstrating utility' as a treatment for PD. Additionally, inter-target delay between pairs of DBS pulses was swept from 2-44 ms with the DBS frequency held constant (FIG. 8). Delays between 22 and 28 ms were most effective at reducing pathological beta oscillations in both the STN (FIG. 8A) and GPi (FIG. 8B), again demonstrating utility as a treatment for PD.

Claims

DUKE-45293.601CLAIMSWhat is claimed is:

1. A method of administering brain stimulation therapy to a subject, the method comprising: delivering at least one first continuous stimulation pulse train to a first target region of the subject’s brain; and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain; wherein each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined intertarget delay.

2. The method of claim 1, wherein the delivery of the at least one first stimulation pulse to the first region of the subject's brain synchronizes one or more types of brain oscillations.

3. The method of claim 1 or claim 2, wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more ty pes of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder.

4. The method of claim 2 or claim 3, wherein the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and theta oscillations.

5. The method of any one of claims 1 to 4, wherein the first target region of the subject’s brain and the second target region of the subject’s brain are located in the same anatomical brain region.

6. The method of any one of claims 1 to 4, wherein the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions.

7. The method of any one of claims 1 to 6, wherein the first and / or the second target region of the subject’s brain is located in the subthalamic nucleus (STN).DUKE-45293.6018. The method of any one of claims 1 to 7, wherein the first and / or the second target region of the subject’s brain is located in the globus palhdus (GP).

9. The method of claim 7 or claim 8, wherein the first target region of the subject’s brain is located in the STN, and wherein the second target region of the subject’s brain is located in the GP.

10. The method of any one of claims 1 to 9, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 2 Hz to about 125 Hz.

11. The method of any one of claims 1 to 10, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 50 Hz.

12. The method of any one of claims 1 to 11, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz.

13. The method of any one of claims 1 to 12, wherein the predetermined inter-target delay is from about 1 ms to about 100 ms.

14. The method of any one of claims 1 to 12, wherein the predetermined inter-target delay is from about 20 ms to about 50 ms.

15. The method of any one of claims 1 to 13, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 10 Hz to about 30 Hz; and wherein the predetermined inter-target delay is from about 20 ms to about 50 ms.

16. The method of any one of claims 1 to 15, wherein the predetermined inter-target delay is determined based on measuring at least one neurological biomarker associated with at least one symptom of a neurological or psychiatric disorder in the subject.DUKE-45293.60117. The method of claim 16, wherein the at least one neurological biomarker comprises alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and / or theta oscillations; and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the oscillations and treats the at least one symptom of the neurological or psychiatric disorder.

18. The method of any one of claims 1 to 17, wherein the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.

19. The method of any one of claims 1 to 18, wherein the at least one neurological biomarker comprises beta oscillations, and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.

20. The method of any one of claims 1 to 19, wherein the method does not comprise obtaining a neural recording of the subject’s brain.

21. A method for determining stimulation parameters for administering brain stimulation to a subject, the method comprising:(i) delivering at least one first continuous stimulation pulse train to a first target region of the subject’s brain and delivering at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein the least one first and second continuous stimulation pulse trains are delivered at the same frequency;(ii) measuring amplitude of one or more ty pes of brain oscillations in the subject’s brain after the delivery of the at least one second continuous stimulation pulse train;(iii) repeating steps (i) and (ii) while varying time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the at least one second continuous stimulation pulse train; and(iv) establishing an inter-target delay value by determining the time between the delivery of the at least one first continuous stimulation pulse train and the delivery of the atDUKE-45293.601 least one second continuous stimulation pulse that produces the greatest suppression of the one or more types of brain oscillations.

22. The method of claim 21, wherein the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes the one or more types of brain oscillations.

23. The method of claim 21 or claim 22, wherein the delivery of the at least one second continuous stimulation pulse train after the inter-target delay suppresses or reduces the one or more types of brain oscillations and treats at least one symptom of a neurological or psychiatric disorder in the subject.

24. The method of any one of claims 21 to 23, wherein the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and / or theta oscillations.

25. The method of any one of claims 21 to 24, wherein the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.

26. The method of any one of claims 21 to 25, wherein the at least one type of brain oscillation comprises beta oscillations, and wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces the beta oscillations and treats at least one symptom of Parkinson’s Disease (PD) in the subject.

27. The method of any one of claims 21 to 26, wherein the method does not comprise obtaining a neural recording of the subject’s brain.

28. The method of any one of claims 21 to 27, wherein the method is repeated by delivering the least one first and second continuous stimulation pulse trains at at least one different frequency.DUKE-45293.60129. The method of any one of claims 21 to 28, wherein the first target region of the subject’s brain and the second target region of the subject’s brain are located in the same anatomical brain region.

30. The method of any one of claims 21 to 28, wherein the first target region of the subject’s brain and the second target region of the subject’s brain are located in different anatomical brain regions.

31. The method of any one of claims 21 to 30, wherein the first and / or the second target region of the subject’s brain is located in the subthalamic nucleus (STN).

32. The method of any one of claims 21 to 30, wherein the first and / or the second target region of the subject’s brain is located in the globus pallidus (GP).

33. A system for administering brain stimulation therapy to a subject to treat a neurological or psychiatric disorder, the system comprising: at least one implantable electrode configured to deliver electrical stimulation to the subject’s brain; and a pulse generator electronically coupled to the at last one implantable electrode, wherein the pulse generator is programmed to deliver at least one first continuous stimulation pulse train to a first target region of the subject’s brain and to deliver at least one second continuous stimulation pulse train to a second target region of the subject’s brain, wherein each pulse in the second continuous stimulation pulse train is delivered after each pulse in the first continuous stimulation pulse train according to a predetermined inter-target delay.

34. The system of claim 33, wherein the delivery of the at least one first continuous stimulation pulse train to the first target region of the subject’s brain synchronizes one or more types of brain oscillations.

35. The system of claim 33 or claim 34, wherein the delivery of the at least one second continuous stimulation pulse train suppresses or reduces one or more types of brain oscillations, thereby treating at least one symptom of the neurological or psychiatric disorder.DUKE-45293.60136. The system of any one of claims 33 to 35, wherein the one or more types of brain oscillations are selected from alpha oscillations, beta oscillations, delta oscillations, gamma oscillations, and theta oscillations.

37. The system of any one of claims 33 to 36, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 2 Hz to about 125 Hz.

38. The system of any one of claims 33 to 36, wherein the at least one first continuous stimulation pulse train and / or wherein the at least one second continuous stimulation pulse train is delivered to the subject at a frequency ranging from about 20 Hz to about 30 Hz.

39. The system of any one of claims 33 to 38, wherein the predetermined inter-target delay is from about 1 ms to about 100 ms.

40. The system of any one of claims 33 to 38, wherein the predetermined inter-target delay is from about 20 ms to about 50 ms.

41. The system of any one of claims 33 to 40, wherein the neurological or psychiatric disorder is selected from Parkinson’s Disease (PD), essential tremor (ET), Alzheimer’s Disease (AD), Attention-deficit / hyperactivity disorder (ADHD), depression, anxiety, epilepsy, dystonia, Angelman syndrome, schizophrenia, bipolar disorder, and autism.

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