Selection of deep brain stimulation parameters for recovery of motor control and speech and multi-function electrode lead

Abstract

This disclosure provides a method for selecting parameters for stimulation of the thalamus using a deep brain stimulator to treat a motor disorder in a subject, such as paralysis of the upper limb and face muscles. Also provided are methods for treating motor disorder in a subject. Also provided is an implantable electrode lead for neuromodulation and recording, configured to provide targeted stimulation and / or recording to multiple anatomically distinct neural structures, specifically the thalamus, the motor cortex, and optionally, the corona radiata, using a single continuous elongate lead body.

Description

8123-111332-02SELECTION OF DEEP BRAIN STIMULATION PARAMETERS FOR RECOVERY OF MOTOR CONTROL AND SPEECH AND MULTI FUNCTION ELECTRODE LEADCROSS REFERENCE TO RELATED APPLICATIONS100011 This application claims priority to U.S. Provisional Application No. 63 / 682,936, filed August 14, 2024, and U.S. Provisional Application No. 63 / 829,127 file June 24, 2025, each of which is incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to the field of ameliorating symptoms of motor disorders by modulation of particular brain regions of the subject, as well as devices for use in such methods.BACKGROUND

[0003] People who suffer from a variety of disorders such as ischemic or hemorrhagic brain injury caused by stroke, traumatic brain injury, or neurodegenerative disorders such as ALS often experience motor paralysis and / or paresis in the limbs, as well as fine motor control and / or speech and swallowing deficits. These deficits lead to a loss of independence, difficulty in performing everyday tasks of daily living, and / or an inability or difficulty in communicating with the external world. Although physiotherapy and speech therapy are often used to help rehabilitate lost functions or prevent further degeneration of these symptoms, the majority of patients do not recover to a satisfactory level using these conventional treatment approaches. Further, intense physical therapy remains a routine intervention, but with limited efficacy.

[0004] Prior studies have shown the unexpected discovery that deep brain stimulation (DBS) of specific thalamic nuclei leads to improvements in voluntary movements affected by motor disorders in human subjects. However, identifying optimal stimulation parameters as well as specialized stimulation devices for treatment of motor disorders remains a complex and elusive process.SUMMARY100051 This disclosure provides a method for the selection of stimulation parameters for delivering deep brain stimulation to the thalamus to increase excitability of the motor cortex8123-111332-02 and consequently augment muscle activity. The method is useful, for example, to select deep brain stimulation parameters to treat a motor disorder in a subject, such as paralysis of the upper-limb and face muscles.

[0006] The disclosed method involves a multi-step process to select parameters for neurostimulation of the thalamus to treat a motor disorder in the subject. A first stimulus is applied to neurons of the thalamus, wherein the neurons comprise axons projecting to premotor or motor cortex, wherein the first stimulus is applied using a deep brain stimulator implanted in the subject or an external stimulator. A second stimulus is applied to the motor cortex of the subject to evoke motor evoked potentials (MEPs) in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject. The parameters of the first stimulus are varied and MEPs evoked concurrently with the first stimulus (using the varied parameters), as well as MEPs evoked asynchronously with the first stimulus, are recorded. Stimulation parameters for the first stimulus that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus are selected for neurostimulation of the thalamus to treat the motor disorder in the subject.

[0007] In some aspects, the first stimulus is applied to the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), or the ventralis intermediate nucleus (VIM) of the thalamus via the deep brain stimulator.

[0008] In some aspects, the deep brain stimulator is a multi-channel deep brain stimulator and varying parameters of the first stimulus comprises varying the pattern of channels used to apply the first stimulus. In some aspects, the first stimulus is an electrical stimulus and varying the parameters of the first stimulus comprises varying current, voltage amplitude, frequency, pulse width, and / or pulse pattern of the electrical stimulus.

[0009] In some examples, the subject has a motor disorder that results from ischemic brain injury, hemorrhagic brain injury, traumatic brain injury, brain injury caused by stroke, a neurodegenerative disorder, Parkinson’s disease, brain tumor(s), muscular dystrophy, myasthenia gravis, cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and / or transection of eloquent motor-related and / or speech-related gray or white matter.

[0010] In some examples, the motor disorder includes a motor impairment, such as, for example, a loss of muscle strength, a speech deficit, dysarthria, speech apraxia,8123-111332-02 discoordination of the oral / deglutition function, dysphagia, partial paralysis, paresis, loss of dexterity, reduced hand movement, reduced finger movement, uncontrallable muscle tone, essential tremor, and / or dystonia.

[0011] Further provided are methods for treating a motor disorder in a subject, comprising applying a therapeutically effective amount of stimulation to the neurons of the thalamus via the electrodes of the deep brain stimulator, wherein the stimulus is applied using the selected parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus.

[0012] Further provided herein is a novel implantable electrode lead for neuromodulation and recording with a deep brain stimulator, configured to provide targeted stimulation and / or recording to multiple anatomically distinct neural structures — specifically, the thalamus, the motor cortex, and optionally, the corona radiata — using a single continuous elongate lead body.

[0013] The multi-electrode lead comprises a lead body including a distal end and a proximal end defining a longitudinal axis of the lead body. A plurality of electrodes extends along the longitudinal axis of the lead body in a proximal to distal direction, each ending in an independently addressable electrical contact. A distal set of the independently addressable electrode contacts is positioned near the distal end of the lead body to contact the motor thalamus when the neural probe is implanted in the brain of a patient. A proximal set of the independently addressable electrode contacts is positioned near the proximal end of the lead body to contact the motor cortex when the neural probe is implanted in the brain of the patient. Optionally, a medial set of independently addressable electrode contacts is positioned in the middle of the lead body to contact the corona radiata between the motor thalamus and the motor cortex when the neural probe is implanted in the brain of the patient. The provided electrode lead allows for simultaneous stimulation and recording from both the motor cortex and motor thalamus, facilitating real-time adjustments and closed-loop control that surpasses the capabilities of current DBS and adaptive DBS systems. This integration aims to enhance motor function more effectively and efficiently, addressing the limitations observed in existing devices and methods.

[0014] The foregoing and other objects, features, and advantages of the examples will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.8123-111332-02BRIEF DESCRIPTION OF THE FIGURES

[0015] FIGs. 1A-1C: Selection of deep brain stimulation parameters in a human subject. (FIG. 1 A) Schema of the surgical strategy. (FIG. IB) Schema of the directional multichannel deep brain stimulator lead illustrating different contact / channels on the lead. (FIG. 1C) Boxplot of the AUC of a hand muscle MEPs when the hand Ml cortex was stimulated alone or paired with stimulation of different contacts of the deep brain stimulator lead at 50 Hz. Statistical significance one-tail bootstrapping with Bonferroni correction: p<0.001(***).

[0016] FIG. 2 is a graph illustrating a model of the effects of frequency-dependent deep brain stimulation (DBS) delivered to the VOP nucleus on excitatory neuron recruitment due to direct cortical stimulation (DCS). The network model qualitatively replicates experimentally-observed frequency dependence of DBS. The y-axis represents the percentage of the excitatory population recruited by a simulated DCS pulse meant to elicit MEPs. The recruitment of the excitatory neuronal population is a proxy measure of the evoked MEPs, as the percentage of the recruited excitatory population is directly (positively) correlated with the size of evoked MEPs. The x-axis represents the frequency of the applied DBS to the VOP. At low DBS frequencies (<10Hz), no facilitation of motor cortex stimulation was observed as the recruitment of the excitatory neuronal population of the motor cortex does not increase compared to no DBS (represented by the “0” VOP stimulation frequency in the plot). Middle DBS stimulation frequencies (25-130Hz) facilitate the motor cortex, represented by the increase in the recruitment of excitatory population. Finally, high- frequencies (>130Hz) show suppression of motor cortex represented through a decrease in the recruitment of the excitatory population.DETAILED DESCRIPTIONI. Introduction

[0017] Prior studies have shown the unexpected discovery that deep brain stimulation of specific areas in the thalamus leads to improvements in motor outputs of voluntary movements affected by motor disorders in human subjects (see, e.g., WO2023 / 220471, incorporated by reference herein). However, identifying optimal stimulation parameters and target thalamic nuclei for treatment of motor deficits is complex.

[0018] This disclosure describes a method for the selection of stimulation parameters for delivering deep brain stimulation to the thalamus to increase excitability of the motor cortex and consequently augment muscle activity. This method works both for upper-limb and face8123-111332-02 muscles. Individuals affected by different disorders, including stroke-induced ischemic or hemorrhagic brain injuries, traumatic brain injuries, or neurodegenerative conditions like ALS, frequently face motor paralysis in their limbs and in the face muscles and loss of speech. These impairments significantly impact their independence, making everyday activities and communication with others difficult. While physiotherapy and speech therapy are common treatments aimed at rehabilitating lost functions or slowing symptom progression, many patients do not achieve a level of recovery they find satisfactory.

[0019] In the disclosed method, one or more electrodes deliver electrical stimulation, or other forms of neurostimulation (e.g., transcranial magnetic stimulation) to the face or the hand cortical motor area to elicit MEPs in the muscles required for a desired function (e.g., muscles in the face, tongue, lips, and throat for speech or swallowing; forearm muscles for hand grasp; etc.). One or more electrodes (e.g., surface electromyography) records muscle activity from the selected muscles to obtain the MEPs. Simultaneously, one or more electrodes deliver electrical stimulation to the proprioceptive areas of the thalamus (e.g., ventral oralis anterior nucleus (VOA), ventro-oralis posterior (VOP) and the ventral intermediate nucleus (VIM)). The stimulating electrodes are placed to target the areas of the thalamus that project excitatory inputs to the premotor and motor cortices. The simultaneous stimulation of the face or the hand cortical motor area and the thalamus increases the amplitude of the MEPs.

[0020] The disclosed method detects the MEPs across the recorded muscles, and features of the MEP waveforms are measured (e.g., peak-to-peak amplitude, latency). These features are used to adjust the optimal thalamic stimulation parameters (e.g., current or voltage amplitude, frequency, pulse width, electrode pattern) for continuous or phasic deep brain stimulation to enhance movement for the desired function. This process may be iterative, involving the delivery of several stimuli and analysis of recorded MEPs to finetune the parameter selection.

[0021] By using recorded MEPs as the basis for selecting optimal thalamic stimulation parameters, the process of parameter selection for patients is more efficient on an individual basis and across the patient spectrum, with less dependence on trained experts, reducing time and costs.

[0022] Further, updates to stimulation parameters may be required if the patient experiences long-term therapeutic effects (e.g., increased muscle tone, changes in connectivity) of deep8123-111332-02 brain stimulation. The disclosed method also allows for more efficient updates to the deep brain stimulation parameters.Further provided herein is a novel implantable electrode lead for neuromodulation and recording with a deep brain stimulator, configured to provide targeted stimulation and / or recording to multiple anatomically distinct neural structures — specifically, the thalamus, the motor cortex, and optionally, the corona radiata — using a single continuous elongate lead body. The provided electrode lead allows for simultaneous stimulation and recording from both the motor cortex and motor thalamus, facilitating real-time adjustments and closed-loop control that surpasses the capabilities of current DBS and adaptive DBS systems. This integration aims to enhance motor function more effectively and efficiently, addressing the limitations observed in existing devices and methods.Electrode contacts are spaced down the lead to specifically target the motor thalamus and motor cortex, and optionally also the corona radiata. The lead is designed to go through a single trajectory and pass through motor cortex to corona radiata to motor thalamus. The design enables simultaneous electrical stimulation or recording from the motor cortex and the motor thalamus (and optionally the corona radiata), optimizing motor function through dynamic modulation of motor evoked potentials (MEPs) and closed-loop control. By addressing muscle activation and motor control impairments, the lead provides significant improvements in motor function for individuals with neurological disorders.IL Summary of Terms

[0023] Unless otherwise noted, technical terms are used according to conventional usage. As used herein, the term “comprises” means “includes.” Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. The scope of the claims should not be limited to those features exemplified. To facilitate review of the various examples, the following explanations of terms are provided:

[0024] About: As used herein, the term “about” refers to an approximation of a qualitative or quantitative measurement. Whether the measurement is qualitative or quantitative should be clear from its context. With regard to quantitative measurements, “about” refers to plus or minus 5% of a reference value. For example, “about” 100mA refers to 95mA to 105mA.8123-111332-02

[0025] Closed-loop: A stimulation mechanism wherein a sensor continuously records a feedback signal (for example, a signal correlated or causally linked to a motor deficit in a subject with a motor disorder), and a neurostimulator adjusts parameters of electrode control signals according to the feedback signal. Some examples herein utilize such a closed-loop stimulation mechanism. In specific examples, specific frequency bands, recorded from motor and / or pre-motor cortical areas, trigger application of electrical stimulus via one or more electrodes to thalamic neurons (for example, in the ventral thalamus) including axons projecting to premotor or motor cortex.

[0026] Corona Radiata: A fan-shaped mass of myelinated nerve fibers located in the cerebral hemispheres. It consists primarily of axons projecting between the cerebral cortex and deeper brain structures, converging toward the internal capsule. These fibers include both ascending sensory pathways and descending motor pathways, and they serve as a critical conduit for communication between the cortex and subcortical structures, including between the motor cortex and the motor thalamus.

[0027] Deep brain stimulation: Direct or indirect application of a stimulus to an area within the brain. In specific examples herein, selective deep brain stimulation of neurons in somatotopically and / or stereotactically defined thalamic nuclei is accomplished via electrical stimulation. According to alternative techniques, selective deep brain stimulation of neurons in somatotopically and / or stereotactically defined thalamic nuclei may be accomplished in other examples by optical stimulation via implanted optical fibers, magnetic stimulation, or pharmacological stimulation.

[0028] Deep Brain Stimulator (DBS): An implantable medical device configured to deliver controlled electrical stimulation to targeted neural structures within the brain for therapeutic modulation of neural activity. The DBS includes at least one implantable electrode lead having one or more electrically conductive contacts positioned to interface with predetermined intracranial target sites. The electrode lead is operatively coupled with a pulse generator configured to generate and deliver programmable stimulation waveforms to the contacts of the electrode lead. Typically, the electrode lead is coupled to the pulse generator via an electrically conductive extension cable disposed subcutaneously between the electrode lead(s) and the pulse generator to transmit electrical signals. The device typically also includes an external control or programming device configured to non-invasively adjust stimulation parameters including, but not limited to, contact selection, polarity, amplitude, pulse width, and frequency.8123-111332-02

[0029] Dysarthria: A speech motor deficit characterized, for example, by an inability of a subject to pronounce words clearly and correctly. Dysarthria can include, for example, the production of slowed and / or slurred speech. As used herein, the term “dysarthria” refers to a speech motor deficit distinct from aphasia. As used herein, “aphasia” refers to a cognitive impairment characterized by, for example, partial or complete loss of speech of a subject, and / or deficits in a subject’s understanding of written and spoken word.

[0030] Dysphasia: A motor deficit characterized, for example, by difficulty swallowing and weak neck muscles. Dysphasic subjects can require more time and effort to move food or liquid from the mouth to the stomach.

[0031] Electrode contact: An electrically conductive element disposed on an electrode lead and configured to interface with biological tissue for the delivery and / or reception of electrical signals. The electrode contact comprises a biocompatible conductive material exposed at the outer surface of the lead to permit electrical coupling with surrounding tissue, the remainder of the lead being insulated to prevent unintended current flow. Each electrode contact is operatively connected to at least one dedicated conductor extending within the lead body to a proximal connection interface, thereby enabling independent activation, polarity assignment, and adjustment of stimulation or sensing parameters via an associated pulse generator or external controller.

[0032] Directional electrode contacts are configured to deliver or receive electrical signals in a directionally selective manner relative to the longitudinal axis of the lead. A directional contact typical includes a circumferential portion of the electrode surface subdivided into one or more arcuate segments having an angular extent less than 360 degrees, each segment being individually addressable via a dedicated conductor. The configuration enables shaping of the electric field to preferentially stimulate or sense neural tissue in selected radial directions while reducing activation of adjacent non-target tissue.

[0033] Electrode lead: An elongate biocompatible medical component, typically flexible, configured for implantation within neural tissue and adapted to deliver and / or sense electrical signals. The electrode lead includes an elongate body having a proximal end and a distal end, the distal end configured for placement at a predetermined target site within the brain. The lead contains a plurality of electrically conductive contacts disposed along the lead, typically concentrated near the distal end, each contact being configured to interface with neural tissue to deliver stimulation and / or sense neural activity. A plurality of individually insulated8123-111332-02 conductors extends longitudinally through the elongate body from the proximal end to the contacts, with individual conductors coupled to individual contacts, making each contact individually addressable. The lead further contains an electrically insulating, biocompatible sheath surrounding the elongate body to electrically isolate adjacent conductors and contacts except at intended stimulation or sensing surfaces.

[0034] The proximal end of the electrode lead is configured to mechanically and electrically couple to an extension cable or pulse generator, thereby enabling selective activation of one or more contacts for targeted neuromodulation or recording.

[0035] Electrical stimulus: The passing of various types of current or voltage selectively through one or more electrodes to a target location in a subject (for example, specific areas of the ventral thalamus).

[0036] Implanting: Completely or partially placing a neural probe or device including a neural probe within a subject, for example, using surgical techniques. A device or probe is partially implanted when some of the device or probe reaches, or extends to the outside of, a subject. Implantable probes and devices may be implanted into neural tissue, such as the central nervous system, more particularly the brain, for treatment of different medical conditions and for various time periods. A neural probe or device can be implanted for varying durations, such as for a short-term duration (e.g., one or two weeks or less) or for long-term or chronic duration (e.g., one month, six months, one year, or more), as in a daily assistive device.

[0037] Motor impairment: The partial or total loss of function of a body part, for example, limbs, hands, fingers, neck, tongue, mouth, and face muscles. Particular motor impairments include loss of muscle strength, partial paralysis (paresis), loss of dexterity (such as hand finger movement), and uncontrollable muscle tone. As used herein, “motor impairment” includes dysphasia, dysarthria, and speech arrest. A subject can exhibit multiple motor impairments as co-morbidities of a motor disorder.

[0038] Motor cortex and pre-motor cortex: The term “motor cortex” refers to an area within the cerebral cortex of the brain that is involved in the planning, control, and execution of voluntary movements. The motor cortex is situated within the frontal lobe of the brain, next to the central sulcus. The motor cortex is the only motor control center above the spinal cord that can directly communicate with most of the other motor control structures, such as the thalamus. The term “pre-motor cortex” refers to an area located just anterior to the primary motor cortex, which is involved in planning and organizing movements and actions.8123-111332-02Neuronal activity in pre-motor cortex typically precedes activation of the primary motor cortex.

[0039] Motor threshold: The minimum thalamic stimulation intensity that can produce a motor output of a given amplitude from a muscle at rest (RMT) or during a muscle contraction (AMT).

[0040] Motor disorder: A disorder that comprises a loss of cortical muscle connection in the human subject. In examples herein, a motor disorder may be a speech disorder, a hand / arm motor disorder, or both (where both are independently referred to as a motor disorder). Motor disorders can result from a myriad of brain injuries; for example and without limitation, ischemic brain injury, hemorrhagic brain injury, traumatic brain injury, brain injury caused by stroke, brain injury caused by intraoperative stroke, a neurodegenerative disorder, Parkinson’ s disease, essential tremor, dystonia, brain tumor, muscular dystrophy, myasthenia gravis, cerebral palsy, multiple sclerosis, and amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, transection of eloquent motor and speech related gray or white matter, disorders causing dysarthria and / or dysphagia, and / or any other disorder resulting in discoordination of the oral / deglutition function.

[0041] Neural signal: An electrical signal originating in the nervous system of a subject. “Stimulating a neural signal” refers to application of an electrical current to the neural tissue of a subject in such a way as to cause neurons in the subject to produce an electrical signal (e.g., an action potential). An extracellular electrical signal can, however, originate in a cell, such as one or more neural cells. An extracellular electrical signal is contrasted with an intracellular electrical signal, which originates, and remains, in a cell. An extracellular electrical signal can comprise a collection of extracellular electrical signals generated by one or more cells.

[0042] Neurostimulator: A current or voltage-controlled electrical stimulation device. A neurostimulator controls the delivery of an electrical pulse, or pattern of electrical pulses, having defined parameters, for example and without limitation, pulse frequency, duration, amplitude, phase symmetry, duty cycle, pulse current, pulse width, and on-time and off-time. The controlled electrical pulse is delivered through one or more electrodes (for example, leadless electrode(s), or electrode(s) located at the end of a lead, a thin insulated wire) configured to apply the electrical stimulus to the brain of a subject. A neurostimulator may comprise at least one multiple contact lead. Neurostimulators may be utilized to apply a8123-111332-02 series of electrical pulse stimuli (e.g., charge balanced pulses) through at least one electrode; for example and without limitation, low-frequency pulse train patterns, frequency-sequenced pulse burst train patterns (e.g., wherein different sequences of modulated electrical stimuli are generated at different burst frequencies), and phasic train patterns (e.g., wherein the stimulus control parameters change over the course of feedback, from a distal source).

[0043] Perceptual threshold: The minimum thalamic stimulation intensity necessary for a conscious organism to be aware of a particular sensation.

[0044] Subject: Living multi-cellular vertebrate organisms, a category that includes human and non-human mammals, including non-human primates, rats, mice, guinea pigs, cats, dogs, cows, horses, and the like. Thus, the term “subject” includes both human and veterinary subjects.

[0045] Subthalamic area: A region of several grey matter nuclei and surrounding white matter structures located ventral to the thalamus, medial to the internal capsule and lateral to the hypothalamus. Subthalamic structures include the subthalamic nucleus, the zona incerta, the ansa lenticularis, and the Fields of Forel. The Field Hi of Forel (also known as the thalamic fascicle) is a horizontal white matter tract composed of the ansa lenticularis, lenticular fasciculus, and cerebellothalamic tracts between the suhthalamus and the thalamus. These fibers are projections to the ventral anterior and ventral lateral thalamus from the basal ganglia and the cerebellum.

[0046] Therapeutically effective amount: An amount sufficient to provide a beneficial, or therapeutic, effect to a subject or a given percentage of subjects. Therapeutically effective amounts of a treatment can be determined in many different ways, such as assaying for a reduction in a disease or condition (such as motor or sensory impairment to due epileptic seizure). Therapeutic treatments can be administered in a single application, or in several applications (e.g., chronically over an appropriate period of time). However, the effective amount can be dependent on the source applied, the subject being treated, the severity and type of the condition being treated, and the manner of administration.

[0047] Treating or treatment: With respect to disease or condition (e.g., motor or sensory impairment due to focal epilepsy), either term includes (1 ) preventing the disease or condition, e.g., causing the clinical symptoms of the disease or condition not to develop in a subject that may be exposed to or predisposed to the disease or condition but does not yet experience or display symptoms of the disease or condition, (2) inhibiting the disease or8123-111332-02 condition, e.g., arresting the development of the disease or condition or its clinical symptoms, or (3) relieving the disease or condition, e.g., causing regression of the disease or condition or its clinical symptoms.

[0048] Thalamus: A paired structure of gray matter located in the forebrain with nerve fibers projecting to multiple brain structure, including the hippocampus and cerebral cortex. The thalamus is divided into several sections, including the median, medial, anterior, and ventral thalamus, which contain different nuclei projecting to defined cortical regions.

[0049] Ventral thalamus: An area of the thalamus comprising the reticular nucleus, the zona incerta, and the ventral lateral geniculate nucleus. As used herein, “ventral thalamus” may refer to a set of particular thalamic nuclei including, for example and without limitation, ventral thalamic nuclei comprising primary thalamic relays for motor and sensory information from the body and head e.g., the ventralis oralis anterior (VOA), the ventralis oralis posterior nucleus (VOP), the ventralis intermediate nucleus (VIM), the ventralis caudal nucleus (VC), lateral areas of the VOP and / or VIM e.g., a lateral area of the VOP and / or VIM associated with arm movements), and medial areas of the VOP associated with face movements). Certain motor and sensory thalamic nuclei herein may be stereotactically defined by reference to one or more the following AC-PC-based stereotactic coordinates: lateral (from about 5 to about 16 mm lateral to the AC / PC line); anterior / posterior (from about 2 to about 10 mm anterior to PC); and dors al / ventral (from about +2 to about -6 mm from the AC / PC plane.III. Selection of Deep Brain Stimulation Parameters for Recovery of Motor Control and Speech

[0050] Provided herein are methods for selecting parameters for neurostimulation of the thalamus to treat a motor disorder in a subject, such as paralysis of the upper-limb and face muscles, which cause speech motor deficits.

[0051] The disclosed approach is effective for motor disorders involving both upper limb and facial muscles. Non-limiting examples include motor disorders resulting from at least one of ischemic brain injury, hemorrhagic brain injury, traumatic brain injury, brain injury caused by stroke, a neurodegenerative disorder, Parkinson’s disease, brain tumor, muscular dystrophy, myasthenia gravis, cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, or transection of eloquent motor-related and / or speech- related gray or white matter.8123-111332-02

[0052] The disclosed method involves a multi-step process to select parameters for neurostimulation of the thalamus to treat a motor disorder in a subject. A deep brain stimulator is implanted in the brain of the subject, contacting neurons of the thalamus, wherein the neurons comprise axons projecting to premotor or motor cortex. In some implementations, the deep brain stimulator is implanted to apply a stimulus to the VOP, the VOA, or the VIM of the thalamus. Additionally, a neurostimulator is implanted or positioned to stimulate MEPs in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject.

[0053] A first stimulus is applied to the neurons of the thalamus using the deep brain stimulator implanted in the subject. A second stimulus is applied to the motor cortex using the neurostimulator to evoke MEPs in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject. MEPs evoked concurrently and asynchronously with the stimulation of the neurons in the thalamus are recorded.

[0054] In some implementations, the concurrently evoked MEPs occur within 50 ms (such as within 20 ms or within 2-50 ms) of the first stimulus applied to neurons in the thalamus via the deep brain stimulator. In some implementations, the asynchronously evoked MEPs occur at least 100ms (such as at least 200 or at least 500 ms or longer) from any stimulation of the thalamus using the deep brain stimulator.

[0055] In the disclosed method, the parameters of the first stimulus are varied, for example, in the case of an electrical stimulus, by variation of the current, voltage amplitude, frequency, pulse width, pulse pattern, and / or channel pattern (for a multi-channel deep brain stimulator) of the electrical stimulus. Stimulation parameters are selected that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus for neurostimulation of the thalamus to treat a motor disorder in a subject. Typically, during assessment of the different parameters for the first stimulus, the stimulation parameters for the second stimulus are held constant.

[0056] The primate (including humans and non-human primates) thalamus has a stereotactic and somatotopic organization that allows targeting of electrode leads to specific thalamic nuclei using a variety of suitable means, such as imaging and electrophysiological recordings. Specifically, deep brain stimulation is usually performed using stereotactic techniques. The stereotactic planning for motor thalamus targeting is based on stereotactic coordinates from the AC / PC plane and distance. The planning requires a pre-operative high-definition8123-111332-02 volumetric MRI, which can be fused with intraoperative CT images. Using indirect stereotactic planning, the motor thalamus is located approximately 10 mm lateral to the wall of the third ventricle, from 6 mm to 10 mm anterior to PC and at the AC / PC plane of the dors al / ventral orientation. In order to map the motor thalamus, at least three different trajectories are used with the microelectrodes oriented in a rostral to caudal arrangement: (1) the anterior trajectory targets the VOA nucleus (~10mm rostral to the posterior commissure - (PC); (2) the center trajectory targets the VOP nucleus (~8 mm rostral to PC); and (3) the posterior trajectory targets the VIM (~6 mm rostral to PC). The patients are then instructed to perform active and passive repetitive face, tongue and arm / hand movements while neural activity is recorded from the three microelectrodes along the three MER trajectories. The VIM is usually identified as the nucleus with an increasing firing rate during passive movements. The VOP is usually identified as the nucleus with an increasing firing rate during active arm movements and the VOA during active face movements.

[0057] Any suitable neurostimulator may be used to stimulate MEPs in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject. In some implementations, the MEPs are evoked by trans-cranial stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject. In some implementations, the MEPs are evoked by direct cortical stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject, for example, using an implanted electrocorticography (ECoG) strip or grid array of electrodes.

[0058] In some implementations, the direct cortical stimulation comprises electrical pulses having an amplitude of less than about 10 mA, pulse widths between about 60 ps and about 2 ms, and / or a pulse frequency between about 1 Hz and about 1000 Hz. In some implementations, the direct cortical stimulation comprises electrical pulses having an amplitude of about 10 mA, pulse widths of about 500 ps, and a pulse frequency of about 400 Hz. In some implementations, the direct cortical stimulation comprises a train of between 3 and 10 of the electrical pulses delivered every 1-5 seconds, such as a train of 5 of the electrical pulses delivered every 1-5 seconds.

[0059] In some implementations, the direct cortical stimulation comprises electrical pulses having an amplitude of less than about 10 mA, for example, less than 10 mA, less than 9 mA, less than 8 mA, less than 7 mA, less than 6 mA, less than 5 mA, less than 4 mA, less than 3 mA, less than 2 mA, or less than 1 mA.8123-111332-02

[0060] In particular examples, the direct cortical stimulation comprises electrical pulses with pulse widths between about 60 ps and about 2 ms; for example, between 100 ps and about 2 ms, between 200 ps and 2 ms, between 300 ps and 2 ms, between 400 ps and 2 ms, between 500 ps and 2 ms, between 600 ps and 2 ms, between 700 ps and 2 ms, between 800 ps and 2 ms, between 800 ps and 2 ms, between 900 ps and 2 ms, between 1 ms and 2 ms, between 1.5 ms and 2 ms, between 80 ps and 1.5 ms, between 100 ps and 1.5 ms, between 200 ps and 1.5 ms, between 300 ps and 1.5 ms, between 400 ps and 1.5 ms, between 500 ps and 1.5 ms, between 600 ps and 1 .5 ms, between 700 ps and 1 .5 ms, between 800 ps and 1 .5 ms, between 800 ps and 1.5 ms, between 900 ps and 1.5 ms, between 1 ms and 1.5 ms, between 1.5 ms and 2 ms, between 80 ps and 1 ms, between 100 ps and 1 ms, between 200 ps and 1 ms, between 300 ps and 1 ms, between 400 ps and 1 ms, between 500 ps and 1 ms, between 600 ps and 1 ms, between 700 ps and 1 ms, between 800 ps and 1 ms, between 800 ps and 1 ms, and between 900 ps and 1 ms.

[0061] In particular examples, the direct cortical stimulation includes a pulse frequency between about 1 Hz and about 1000 Hz; for example, between 50Hz and 1000Hz, between 100 Hz and 1000 Hz, between 100 Hz and 900 Hz, between 100 Hz and 800 Hz, between 100 Hz and 700 Hz, between 100 Hz and 600 Hz, between 100 Hz and 500 Hz, between 100 Hz and 400 Hz, between 100 Hz and 300 Hz, between 200 Hz and 500 Hz, between 300 Hz and 500 Hz and between 100 Hz and 200 Hz.

[0062] In some implementations, the first stimulus comprises an electrical stimulus having electrical pulses defined by parameters including, for example and without limitation, amplitude, pulse width, and pulse frequency. Such electrical pulses may include charge- balanced pulses. In these and further implementations, the electrical stimulus may be a continuous electrical stimulus, and / or a closed-loop electrical stimulus.

[0063] In some implementations, the first stimulus comprises an electrical stimulus having electrical pulses, and the pulse amplitude is varied. For example, to determine a pulse amplitude of the first stimulus that, when applied concurrently with the second stimulus, leads to an increase in MEP amplitude. In some such examples, the pulse amplitude of the first stimulus is varied from about 0.1 mA to about 20 mA, such as about 0. 1 mA to about 5 mA, about 0. 1 mA to about 10 mA, about 0. 1 mA to about 15 mA, about 1 mA to about 5 mA, about 1 mA to about 10 mA, about 1 mA to about 15 mA, or about 1 mA to about 20 mA. In particular examples, the first stimulus comprises an electrical stimulus having electrical pulses with an amplitude of less than about 15 mA; for example less than 10 mA,8123-111332-02 less than 10 mA, less than 9 mA, less than 8 mA, less than 7 mA, less than 6 mA, less than 5 mA, less than 4 mA, less than 3 mA, less than 2 mA, or less than 1 mA.

[0064] In some implementations, the first stimulus comprises an electrical stimulus having electrical pulses, and the pulse width is varied. For example, to determine a pulse width of the first stimulus that, when applied concurrently with the second stimulus, leads to an increase in MEP amplitude. In some such examples, the pulse width of the first stimulus is varied between about 60 ps and about 2 ms; for example, between 80 ps and 2 ms, between 100 ps and 2 ms, between 200 ps and 2 ms, between 300 ps and 2 ms, between 400 ps and 2 ms, between 500 ps and 2 ms, between 600 ps and 2 ms, between 700 ps and 2 ms, between 800 ps and 2 ms, between 800 ps and 2 ms, between 900 ps and 2 ms, between 1 ms and 2 ms, between 1.5 ms and 2 ms, between 80 ps and 1.5 ms, between 100 ps and 1.5 ms, between 200 ps and 1.5 ms, between 300 ps and 1.5 ms, between 400 ps and 1.5 ms, between 500 ps and 1.5 ms, between 600 ps and 1.5 ms, between 700 ps and 1.5 ms, between 800 ps and 1 .5 ms, between 800 ps and 1 .5 ms, between 900 p s and 1 .5 ms, between 1 ms and 1 .5 ms, between 1.5 ms and 2 ms, between 80 ps and 1 ms, between 100 ps and 1 ms, between 200 ps and 1 ms, between 300 ps and 1 ms, between 400 ps and 1 ms, between 500 ps and 1 ms, between 600 ps and 1 ms, between 700 ps and 1 ms, between 800 ps and 1 ms, between 800 ps and 1 ms, and between 900 ps and 1 ms.

[0065] In some implementations, the first stimulus comprises an electrical stimulus having electrical pulses, and the pulse frequency is varied. For example, to determine a pulse frequency of the first stimulus that, when applied concurrently with the second stimulus, leads to an increase in MEP amplitude. In particular examples, the first stimulus comprises an electrical stimulus having a pulse frequency between about 10 Hz and about 1000 Hz; for example, between 50Hz and 1000Hz, between 100 Hz and 1000 Hz, between 100 Hz and 900 Hz, between 100 Hz and 800 Hz, between 100 Hz and 700 Hz, between 100 Hz and 600 Hz, between 100 Hz and 500 Hz, between 100 Hz and 400 Hz, between 100 Hz and 300 Hz, between 100 Hz and 200 Hz, between 30 Hz and 130 Hz, between 100 Hz and 130 Hz. In some implementations, the pulse frequency is between 100Hz and 250Hz. In some implementations, the pulse frequency is between 30Hz and 130Hz. In some implementations, the pulse frequency is between 100Hz and 130Hz. In some implementations, the pulse frequency is between 50Hz and 130Hz. In some implementations, the pulse frequency is between 100Hz and 130Hz.8123-111332-02

[0066] In some implementations, the first stimulus comprises an electrical stimulus having electrical pulses varied between an amplitude of about 1 mA to about 10 mA, a pulse width of between about 60 ps and about 2 ms, and a pulse frequency between about 1 Hz and about 1000 Hz, such as between about 40 Hz and about 100 Hz, such as between about 50 Hz and about 80 Hz, for example, about 50 Hz or about 80 Hz.

[0067] In some aspects, prior to selection of stimulation parameters, a multi-step process to select a target location in the thalamus for neurostimulation to treat the motor disorder in the subject is used. In such aspects, microelectrode leads of a deep brain stimulator are implanted in the brain of the subject, contacting the VOP, the VOA, and the VIM of the thalamus. Typically, three separate leads are used to contact each of these three thalamic nuclei. Additionally, a neurostimulator is implanted or positioned to stimulate MEPs in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject. An electrical stimulus is applied to neurons in the VOP, the VOA, and the VIM, separately, via the implanted electrodes of the deep brain stimulator. MEPs evoked concurrently with the stimulation of the neurons in the VOP, the VOA, and the VIM are recorded. The particular thalamic nuclei (VOP, VOA, or VIM) that, when stimulated, leads to the greatest increase in amplitude of concurrently evoked MEPs is selected as the target location in the thalamus for neurostimulation to treat the motor disorder in the subject. The selected target location (e.g., the VOP, the VOA, or the VIM), can be stimulated with the implanted electrode (or a replacement electrode, for example, designed for long-term implantation or more detailed stimulation) to treat the motor disorder in the subject. After the target location is selected, stimulation parameters to be applied at the target location can be determined as described herein.

[0068] Also provided herein are methods for treating a subject (for example, a human subject) having a motor disorder. The methods comprise applying a therapeutically effective amount of stimulation to the neurons of the thalamus via the electrodes of the deep brain stimulator, wherein the stimulus is applied using the selected parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus. The treatment improves at least one motor output associated with the motor disorder.

[0069] Methods according to particular examples disclosed herein may be utilized to treat (z'.e., prevent, ameliorate, suppress, and / or alleviate) a subject’s motor disorder in an acute or a chronic phase of the motor disorder. In particular examples herein, a disclosed method is8123-111332-02 utilized to treat a subject with dysarthria or speech and oral apraxia. Particular examples of methods provided herein may be used to treat stroke subjects that suffer from arm and hand paresis, and / or lost or impaired speech deficits. In particular examples, methods provided herein are used to treat speech and vocalization impairments caused by motor control deficits, for example and without limitation, muscle weakness, dysarthria, dysphagia, apraxia of speech, and speech arrest. These motor control deficits affect about 50% of all acute stage stroke patients, and a third of chronic stage stroke patients.

[0070] In some examples herein, stimulation (e.g. continuous stimulation) of motor and sensory areas in the ventral thalamus leads to improvements in vocalization and dysarthria as well as reduced speech arrest. In particular examples, such stimulation results in faster activation of a subject’s facial muscles when performing speech therapy exercises than when no stimulation is applied. In particular examples, such stimulation results in increased amplitude of a subject’s arm movements, and / or grip strength, than when no stimulation is applied.

[0071] In particular examples, stimulation of the thalamus targets fibers connecting the thalamus to the pre-motor and motor cortices, thereby increasing the excitability of motor and pre-motor circuits to amplify voluntary motor output to peripheral circuits controlling muscles, for example, such that the stimulation facilitates the subject’s natural arm, facial, and / or tongue movements.

[0072] In some implementations, disclosed methods are effected by the use of an implanted neurostimulator that controls the stimulation (e.g., electrical stimulation via one or more implanted electrode(s)) according to predetermined parameters (such as the selected parameters discussed above), wherein application for the stimulus is determined by feedback in a closed-loop system. In particular implementations, methods disclosed herein can be used in combination with motor rehabilitation therapy to improve long-term recovery outcomes.

[0073] Deep brain stimulation is a neurosurgical procedure involving the implantation of one or more electrode(s) that deliver an electrical stimulus under the control of an externalized or implanted neurostimulator unit. Implantation of the electrode(s), and / or a neurostimulator in examples where the neurostimulator is not externalized, is typically performed by a clinical team including neurologists, neurosurgeons, neurophysiologists, and other specialists trained in the assessment, treatment, and care of neurological conditions. Typically, following selection of an appropriate subject and determination of the area of the subject’s brain to be8123-111332-02 stimulated, precise placement of at least one electrode in the area of the patient's thalamus or subthalamus is carried out in an operating room setting, typically utilizing brain imaging technology and stereotactic targeting made possible by the stereotypical organization of different areas of the thalamus or subthalamus. After administration of local anesthesia, the subject undergoing electrode implantation experiences little discomfort, and is generally kept awake during the implantation procedure to allow communication with the surgical team.

[0074] Some implementations herein employ an implant that includes one or more electrodes and / or neurostimulator implanted (e.g., fully or partially implanted) in the brain of a subject. Further implementations herein employ an implant that includes one or more magnets or optical fibers, and / or a neurostimulator implanted in the brain of a subject.

[0075] Numerous types and styles of neural implants (for example, implants including one or more electrodes for providing an electrical stimulus) are available and known to those in the art. Any neural implant for specific stimulation of a thalamic or subthalamic area in a subject may be utilized in specific implementations. In some implementations, more than one electrode is implanted, such as an array of electrodes. In additional implementations, a device is provided that can include one or more electrodes. Non-limiting examples include deep brain stimulators, EcoG grids, electrode arrays, microarrays e.g., Utah and Michigan microarrays), and microwire electrodes and arrays.

[0076] In some implementations, an implanted neurostimulator can be used for stimulating bio-electric (e.g., neural) signals to thalamic and subthalamic area in the subject. For example, an implanted neurostimulator may be implanted so as to specifically stimulate one or more area of a subject’s ventral thalamus for a period of at least 1 month; for example, at least 2, 6, 12, 18, 24, 30, 36, or more months, or longer.

[0077] In some implementations, circuitry is implanted connecting a neurostimulator to the one or more electrodes. In particular implementations, the circuits are fully implanted (typically in a subcutaneous pocket within a subject’s body), or are partially implanted in the subject. The operable linkage of the neurostimulator to the electrode(s) can be by way of one or more leads, although any operable linkage capable of transmitting a stimulation signal from the circuitry to the electrodes may be used in specific implementations.

[0078] In some implementations, electrodes used in accordance with the method are positioned in specific areas of the brain (such as the thalamus), so as to be capable of selective application of an electrical stimulus to the specific area, by any of the methods8123-111332-02 conventionally used for positioning of electrodes for deep brain stimulation. As is known in the art, the particular procedures used will vary according to the available equipment, training of personnel, and the circumstances of each case. Detailed examples of such procedures are described, for example, in Benabid et al., Movement Disorders 17 (Suppl. 3): S123-129 (2002), and in Schrader et al., Movement Disorders 17 (Suppl. 3): S167-174 (2002). In some examples, the procedures for placement and testing of electrodes are divided into several steps including mounting of a stereotactic ring on the patient’ s skull, and imaging by high resolution stereotactic commuted tomographic (CT) scanning of the head. The stereotactic CT scan is preferably preceded by high resolution, volumetric, and three tesla magnetic resonance imaging (MRI) in advance of placement of the stereotactic head ring. Planning of the surgical target sites within the brain and trajectories for approach to the selected targets can be achieved using the MRI images and computer software designed for stereotactic targeting, for example, Stereoplan™ Plus 2.3 (Stryker-Leibinger, Friedburg, Germany), and SNS™ 3.14 (Surgical Navigation Specialists, Mississauga, Canada).

[0079] Post-operative control of selective electrical stimulation of the thalamic and subthalamic areas by the implanted electrode is provided in some implementations by a neurostimulator that may be externalized or implanted; for example, subcutaneously (e.g., in the chest or belly of the subject). Following recovery from the implantation, surgery, and connection of electrode leads to the neurostimulator, the subject may be monitored and tested to establish parameters for the electrical stimulation based on the subject’s condition. In some implementations, electrical stimulation by the implanted electrode(s) is delivered to at least one specific area of the subject’s ventral thalamus while the subject is monitored for seizure activity. In some implementations, the parameters of the electrical stimulus controlled by the neurostimulator are adjusted according to changes in the patient activity due to the applied stimulus, for example, so as to reduce the frequency or severity of motor defect seizures with minimal side effects due to the applied electrical stimulus. In specific implementations, the operation of the device and / or the neurostimulator can be at least partially under the control of the subject once the subject is released from a clinical setting. For example, the subject can activate the neurostimulator in response to perceived need for enhanced motor activity. In these and further implementations, the subject is taught how to use the device and / or the neurostimulator.

[0080] In some examples, the parameters of the electrical stimulus controlled by the neurostimulator are adjusted according to changes in the one or more motor output(s) that are8123-111332-02 monitored while the subject performs the specific task, for example, so as to improve the motor outputs, thereby treating the subject’s motor disorder. In particular examples, the adjusted neurostimulator is part of a daily assistive device to treat the subject over an extended period of time. In specific examples, the operation of the device and / or the neurostimulator can be at least partially under the control of the subject once the subject is released from a clinical setting.

[0081] In some examples, the disclosed method benefits the chronic stroke patient population that suffers from arm and hand paresis and lost or impaired speech deficits. Specifically, speech and vocalization impairments caused by motor control deficits such as muscle weakness, dysarthria, dysphagia, apraxia of speech and speech arrest are treated. These deficits affect about 50% of all acute stage and a third of chronic stage stroke patients. This group includes patients with ALS, Multiple sclerosis, Parkinson’s, traumatic brain injury, brain tumors, muscular dystrophy, generalize myasthenia gravis, spinal muscular atrophy, and cerebral palsy.IV. Multi-Function Electrode Lead

[0082] Also provided herein is a novel implantable electrode lead for neuromodulation and recording, configured to provide targeted stimulation and / or recording to multiple anatomically distinct neural structures — specifically, the thalamus, the motor cortex, and optionally, the corona radiata — using a single continuous elongate lead body. The design enables simultaneous electrical stimulation or recording from the motor cortex and the motor thalamus, optimizing motor function through dynamic modulation of motor evoked potentials (MEPs) and closed-loop control. The electrode lead design offers substantial benefits for individuals suffering from motor paralysis due to stroke-induced ischemic or hemorrhagic brain injuries, traumatic brain injuries, or neurodegenerative conditions such as ALS. The enhanced stimulation capabilities aim to restore motor function, improve muscle activation, and facilitate better communication and independence.100831 The electrode lead is designed for insertion along a stereotactic path beginning at the cortical surface, passing through the motor cortex, intersecting the corona radiata region, and terminating at the thalamus. The single trajectory reduces surgical invasiveness compared to multiple-lead systems and allows for a single lead with contacts targeting multiple brain areas. The spacing between these sets of contacts is optimized to ensure effective targeting and interaction with the respective brain regions.8123-111332-02

[0084] The lead body is an elongate, flexible, biocompatible shaft extending along a longitudinal axis from a proximal end to a distal end. The distal end is configured for insertion into brain tissue and the proximal end is configured for connection to an electrically conductive extension cable that connects to a pulse generator or other system controller (or is directly connected to the pulse generator or other system controller). The lead body may have any shape suitable for implantation into brain tissue. Typically, the lead body has an annular shape with an outer diameter of between 1 and 2 mm. The length of the lead body is suitable for allowing contact with the target brain regions, such as the thalamus and the motor cortex. Any suitable material may be used to construct the lead body. Typically, the lead body is made of a biocompatible polymer such as polyurethane or silicone encapsulating individually insulated conductors.

[0085] The electrode lead contains multiple contact groups disposed along the lead body and positioned to contact target locations in the thalamus and the motor cortex when the lead is implanted in a patient.

[0086] The first contact group is located near the distal end of the electrode lead and is configured to stimulate and / or record neural signals at a target location in the thalamus. Any suitable number of contacts may be present, such as from 1 -20 contacts, for example, 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 contacts. The contacts can be ring contacts or directional contacts, or another suitable configuration. The contact surface may have any suitable size and shape, such as an axial length of from 0.5-2.0 mm with inter-contact spacing of from 0.5-2.0 mm.

[0087] The second contact group is located near the proximal end of the electrode lead and is configured to stimulate and / or record neural signals at a target location in the motor cortex. Any suitable number of contacts may be present, such as from 1-20 contacts, for example, 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 contacts. The contacts can be ring contacts or directional contacts, or another suitable configuration. The contact surface may have any suitable size and shape, such as an axial length of from 0.5-2.0 mm with inter-contact spacing of from 0.5- 2.0 mm.

[0088] Optionally, a third contact group is located between the first and second contact groups on the lead, positioned such that, upon implantation, the third contact group is adjacent to the corona radiata. Any suitable number of contacts may be present, such as from 1-20 contacts, for example, 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 contacts. The contacts can be ring contacts or directional contacts, or another suitable configuration. The contact surface8123-111332-02 may have any suitable size and shape, such as an axial length of from 0.5-2.0 mm with intercontact spacing of from 0.5-2.0 mm.

[0089] Each contact (whether a full ring or a segmented directional contact) in the first, middle, and second groups is connected to a dedicated insulated conductor extending along the lead body to the proximal end of the lead connector assembly. These wires are insulated individually so that current from one channel does not leak into another. Any suitable conductive material may be used for the conductors and insulation, such as MP35N alloy or similar high-fatigue-resistance metal for the conductors, with fluoropolymer insulation for durability and biocompatibility.

[0090] At the proximal end of the lead the conductors terminate in a connector block containing suitable contacts to couple the individual conductors of the lead with an electrically conductive extension cable that connects to a pulse generator or other appropriate apparatus (e.g., for recording electrical signals). This connector block mates with the extension cable via a suitable interface (such as a multi-pin interface) that allows continued electrical separation of the signal carried from the contacts along the conductors of the lead and through the extension cable to the pulse generator or other appropriate apparatus. Typically, the pulse generator is a multi-channel pulse generator capable of independent parameter control for each contact within the lead.

[0091] The provided electrode lead can be used in the method of selecting deep brain stimulation parameters provided in Section III, wherein the new lead is used as a single device to apply both the first stimulus (to the thalamus) and the second stimulus (to the motor cortex) of the method.

[0092] As discussed further herein, stimulation of the motor cortex induces MEPs in facial or upper limb muscles. By adjusting DBS parameters applied to the motor thalamus and the motor cortex in real-time, the provided lead allows for the identification of stimulation settings that maximize MEP amplitudes, thus optimizing therapeutic outcomes.

[0093] The provided electrode lead supports closed-loop control, where DBS parameters are dynamically adjusted based on real-time neural activity from the motor cortex. This adaptive approach ensures precise modulation of stimulation, enhancing muscle activation, range of motion, and overall motor function. By integrating real-time feedback from neural activity, the lead allows for personalized and responsive DBS programming. For closed-loop control, one or more contacts in the motor thalamus function as stimulating electrodes, and one or8123-111332-02 more contacts in the motor cortex function as sensing electrodes. The ability to simultaneously stimulate and record from distinct brain regions, combined with closed-loop control, provides a powerful tool for fine-tuning DBS parameters and achieving superior therapeutic outcomes.

[0094] The closed-loop system includes sensing circuitry that is integrated in the pulse generator or in an external processor, capable of detecting neural activity (e.g., local field potentials, evoked potentials, or multi-unit activity) from selected contacts of the lead. Additionally, the system includes a processing unit that is configured to analyze sensed neural signals in real-time to identify signal patterns indicative of motor state, tremor onset, abnormal oscillatory patterns, or other pathological activity. A rule set or adaptive model is used to adjust stimulation parameters based on detected neural events, for example to increase, decrease, or cease stimulation in the motor cortex in response to specific thalamic signal patterns, or modulate thalamic stimulation based on cortical activity.V. Additional Aspects

[0095] Aspect 1. A method for selecting parameters for neurostimulation of the thalamus to treat a motor disorder in a subject, comprising: applying a first stimulus to neurons of the thalamus, wherein the neurons comprise axons projecting to premotor or motor cortex, wherein the first stimulus is applied using a deep brain stimulator implanted in the subject; applying a second stimulus to the motor cortex of the subject to evoke motor evoked potentials (MEPs) in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject; recording MEPs evoked concurrently with the first stimulus and MEPs evoked asynchronously with the first stimulus; varying parameters of the first stimulus and selecting parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus for neurostimulation of the thalamus to treat the motor disorder in the subject.

[0096] Aspect 2. The method of Aspect 1, wherein the first stimulus is applied to the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), or the ventralis intermediate nucleus (VIM) of the thalamus via the deep brain stimulator.8123-111332-02

[0097] Aspect 3. The method of Aspect 1 or Aspect 2, wherein the method is performed without varying parameters of the second stimulus.

[0098] Aspect 4. The method of any one of the prior Aspects, wherein the concurrently evoked MEPs occur within 50 ms of application of the first stimulus.

[0099] Aspect 5. The method of any one of the prior Aspects, wherein the concurrently evoked MEPs occur within 2-50 ms of application of the first stimulus.

[0100] Aspect 6. The method of any one of the prior Aspects, wherein varying parameters of the first stimulus comprises varying a pattern of electrode contacts of the deep brain stimulator used to apply the first stimulus.

[0101] Aspect 7. The method of any one of the prior Aspects, wherein the first stimulus is an electrical stimulus and varying the parameters of the first stimulus comprises varying current, voltage amplitude, frequency, pulse width, and / or pulse pattern of the electrical stimulus.

[0102] Aspect 8. The method of Aspect 7, wherein the first stimulus comprises electrical pulses having an amplitude varied between about 0.1 mA to about 15 mA, pulse widths varied between about 60 ps and about 2 ms, and / or a pulse frequency varied between about 1 Hz and about 1000 Hz.

[0103] Aspect 9. The method of Aspect 7 or Aspect 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 40 Hz and about 100 Hz.

[0104] Aspect 10. The method of Aspect 7 or Aspect 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 30 Hz and about 130 Hz.

[0105] Aspect 11. The method of Aspect 7 or Aspect 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 100 Hz and about 130 Hz.

[0106] Aspect 12. The method of any one of Aspects 1-11, wherein the first stimulus is applied to the VOP.

[0107] Aspect 13. The method of any one of Aspects 1-11, wherein the first stimulus is applied to the VOA.8123-111332-02

[0108] Aspect 14. The method of any one of Aspects 1-11, wherein the first stimulus is applied to the VIM.

[0109] Aspect 15. The method of any one of the prior Aspects, wherein the second stimulus to evoke MEPs is applied using trans-cranial stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject.

[0110] Aspect 16. The method of any one of Aspects 1-14, wherein the second stimulus to evoke MEPs is applied by direct cortical stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject.

[0111] Aspect 17. The method of Aspect 16, wherein the direct cortical stimulation is applied using an implanted electrocorticography (ECoG) strip or grid array of electrodes.

[0112] Aspect 18. The method of Aspects 16, wherein the deep brain stimulator comprises a multi-electrode lead comprising: a lead body including a distal end and a proximal end defining a longitudinal axis of the lead body; and a plurality of electrodes extending along the longitudinal axis of the lead body in a proximal to distal direction, each ending in an independently addressable electrical contact; and wherein: a distal set of the independently addressable electrode contacts is positioned near the distal end of the lead body to contact the motor thalamus when the neural probe is implanted in the brain of a patient; a proximal set of the independently addressable electrode contacts is positioned near the proximal end of the lead body to contact the motor cortex when the neural probe is implanted in the brain of the patient; and wherein the first stimulus is applied using the distal set of independently addressable electrode contacts and the second stimulus to evoke MEPs by direct cortical stimulation is applied using the proximal set of independently addressable electrode contacts.

[0113] Aspect 19. The method of any one of Aspects 16-18, wherein the direct cortical stimulation comprises electrical pulses having an amplitude of less than about 15 mA, pulse widths between about 100 ps and about 2 ms, and / or a pulse frequency between about 1 Hz and about 1000 Hz.8123-111332-02

[0114] Aspect 20. The method of Aspect 19, wherein the direct cortical stimulation comprises electrical pulses having an amplitude of about 10 mA, pulse widths of about 500 ps, and a pulse frequency of about 400 Hz.

[0115] Aspect 21. The method of any one of Aspects 16-20, wherein the direct cortical stimulation comprises a train of between 3 and 10 of the electrical pulses delivered every 1 -5 seconds.

[0116] Aspect 22. The method of Aspect 21, wherein the direct cortical stimulation comprises a train of 5 of the electrical pulses delivered every 1-5 seconds.

[0117] Aspect 23. The method of any one of the prior Aspects, wherein the motor disorder of the subject comprises a motor impairment of the arms, fingers, or hands causing a loss of muscle strength, partial paralysis, paresis, loss of dexterity, reduced movement, uncontrollable muscle tone, or essential tremor.

[0118] Aspect 24. The method of any one of the prior Aspects, wherein the motor disorder of the subject is a speech disorder resulting in at least one speech motor impairment.

[0119] Aspect 25. The method of any one of the prior Aspects, wherein the motor disorder results from at least one of ischemic brain injury, hemorrhagic brain injury, traumatic brain injury, brain injury caused by stroke, a neurodegenerative disorder, Parkinson’s disease, brain tumor, muscular dystrophy, myasthenia gravis, cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and transection of eloquent motor-related and / or speech-related gray or white matter.

[0120] Aspect 26. The method of any one of the prior Aspects, wherein the motor disorder comprises a motor impairment causing a loss of muscle strength, a speech deficit, oral apraxia, dysarthria, partial paralysis, paresis, loss of dexterity, reduced hand movement, reduced finger movement, discoordination of the oral / deglutition function, dysphagia, uncontrollable muscle tone, essential tremor, and / or dystonia.

[0121] Aspect 27. The method of any one of the prior Aspects, further comprising treating the motor disorder in the subject by applying a therapeutically effective amount of stimulation to the neurons of the thalamus via the electrode contacts of the deep brain stimulator, wherein the stimulus is applied using the selected parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus.8123-111332-02

[0122] Aspect 28. A multi-electrode lead for use with a deep brain stimulator, the multielectrode lead comprising: a lead body including a distal end and a proximal end defining a longitudinal axis of the lead body; and a plurality of electrodes extending along the longitudinal axis of the lead body in a proximal to distal direction, each ending in an independently addressable electrical contact; and wherein: a distal set of the independently addressable electrode contacts is positioned near the distal end of the lead body to contact the motor thalamus when the neural probe is implanted in the brain of a patient; a proximal set of the independently addressable electrode contacts is positioned near the proximal end of the lead body to contact the motor cortex when the neural probe is implanted in the brain of the patient; and optionally a medial set of the independently addressable electrode contacts is positioned in the middle of the lead body to contact the corona radiata between the motor thalamus and the motor cortex when the neural probe is implanted in the brain of the patient.

[0123] Aspect 29. The multi-electrode lead of Aspect 28, wherein the distal set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

[0124] Aspect 30. The multi-electrode lead of Aspect 28 or Aspect 29, wherein the proximal set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

[0125] Aspect 31. The multi-electrode lead of any one of Aspects 28-30, wherein the medial set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

[0126] Aspect 32. The multi-electrode lead of any one of Aspects 28-31, wherein the distal set of the independently addressable electrode contacts is positioned to contact the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), or the ventralis intermediate nucleus (VIM) of the thalamus when the neural probe is implanted in the brain of the patient.8123-111332-02EXAMPLES

[0127] The following example is provided to illustrate particular features of certain aspects of the disclosure, but the scope of the claims should not be limited to those features exemplified.Example 1 Optimal parameters for thalamic deep brain stimulation for recovery of facial motor output

[0128] Deep brain stimulation of the motor thalamus has been shown to facilitate upper limb and face motor output by increasing the excitability of the motor cortex. However, identifying optimal stimulation parameters and target thalamic nuclei for treatment of motor deficits is complex and requires substantial assessment of patient motor outputs.

[0129] This example illustrates an improved method for the selection of stimulation parameters and thalamic nuclei for delivering deep brain stimulation to the thalamus to increase excitability of the motor cortex and consequently augment muscle activity. In the method, an EcoG array delivers electrical stimulation to the hand Ml cortical motor area to elicit MEPs of the hand. Surface electromyography is used to record facial muscle activity to identify MEPs. Simultaneously, a directional multi-channel deep brain stimulator lead implanted in the thalamus of the patient delivers electrical stimulation to the proprioceptive areas of the thalamus. The stimulating electrodes target the areas of the thalamus that project excitatory inputs to the premotor and motor cortices. The simultaneous stimulation of the hand or the hand cortical motor area and the thalamus increases the amplitude of the recorded MEPs. A variety of thalamic stimulation parameters are assessed, and used to adjust the optimal thalamic stimulation parameters (e.g., current or voltage amplitude, frequency, pulse width, electrode pattern) for continuous or phasic deep brain stimulation to enhance MEP amplitude and corresponding muscle function.

[0130] By using recorded MEPs as the basis for selecting optimal thalamic stimulation parameters, the process of parameter selection for patients is more efficient on an individual basis and across the patient spectrum, with less dependence on trained experts, reducing time and costs.

[0131] To show that MEP output can be used to optimize thalamic stimulation parameters to improve motor outcomes, a directional deep brain stimulator lead was implanted in the thalamus of a patient with a motor deficit (FIG. 1). Subdural electrocorticography (ECoG) electrodes were also placed over the Ml hand representation of this patient. Direct cortical8123-111332-02 stimulation (DCS) of the hand representation of primary motor cortex was applied through the ECoG strip (trains of 5 stimulation pulses (0.5 ms) at 400 Hz every two seconds) (FIG. 1). Concurrently, macrostimulation at 50 Hz was applied to the thalamus via different combinations of channels of the deep brain stimulator lead. The amplitude of MEPs evoked by DCS was measured with and without deep brain stimulation. Based on this assay, specific combinations of deep brain stimulator channels were identified that led to the greatest increase in MEP amplitude. This strategy was assessed in three human patients and it was demonstrated that MEP potentiation was stronger for two configurations: [-1 + 8] and [-1 +2,3,4] (FIG. 1C).Example 2 Frequency-Dependence of DBS Delivered to the VOP Nucleus to Enhance Excitatory Neuron Recruitment Due to Direct Cortical Stimulation of Motor Cortex

[0132] A computational network model of cortico-thalamic circuitry was constructed to evaluate the effects of deep brain stimulation (DBS) frequency delivered to the VOP nucleus on excitatory neuron recruitment due to direct cortical stimulation (DCS). The excitatory neuronal population within the motor cortex was represented with parameters calibrated to replicate experimentally observed MEPs.

[0133] Cortical stimulation was applied via a simulated pulse meant to elicit MEPs. The recruitment of the excitatory neuronal population is a proxy measure of the evoked MEPs, as the percentage of the recruited excitatory population is directly (positively) correlated with the size of evoked MEPs. Thalamic stimulation was applied via simulated DBS to the VOP nucleus at frequencies ranging from 0 Hz (no stimulation) to 200 Hz.

[0134] The results are shown in FIG. 2. At low DBS stimulation frequencies (<10 Hz), recruitment of excitatory neurons remained near baseline levels (~25%), indicating negligible facilitation of motor cortex output. At intermediate DBS stimulation frequencies (25—130 Hz), recruitment increased significantly, peaking at approximately 65% recruitment, demonstrating facilitation of cortical excitation. Finally, higher DBS frequencies (>130Hz) show suppression of motor cortex excitation represented through a decrease in the recruitment of the excitatory population. The results illustrate frequency-dependence of deep brain stimulation delivered to the VOP nucleus on the resulting excitation and neuron recruitment at the motor cortex due to direct cortical stimulation.8123-111332-02

[0135] It will be apparent that the precise details of the methods described may be varied or modified without departing from the spirit of the described examples. We claim all such modifications and variations that fall within the scope and spirit of the claims below.

Claims

8123-111332-02It is claimed:

1. A method for selecting parameters for neurostimulation of the thalamus to treat a motor disorder in a subject, comprising: applying a first stimulus to neurons of the thalamus, wherein the neurons comprise axons projecting to premotor or motor cortex, wherein the first stimulus is applied using a deep brain stimulator implanted in the subject; applying a second stimulus to the motor cortex of the subject to evoke motor evoked potentials (MEPs) in one or more muscles of the face, neck, or upper limb affected by the motor disorder in the subject; recording MEPs evoked concurrently with the first stimulus and MEPs evoked asynchronously with the first stimulus; varying parameters of the first stimulus and selecting parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus for neurostimulation of the thalamus to treat the motor disorder in the subject.

2. The method of claim 1, wherein the first stimulus is applied to the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), or the ventralis intermediate nucleus (VIM) of the thalamus via the deep brain stimulator.

3. The method of claim 1 or claim 2, wherein the method is performed without varying parameters of the second stimulus.

4. The method of any one of the prior claims, wherein the concurrently evoked MEPs occur within 50 ms of application of the first stimulus.

5. The method of any one of the prior claims, wherein the concurrently evoked MEPs occur within 2-50 ms of application of the first stimulus.

6. The method of any one of the prior claims, wherein varying parameters of the first stimulus comprises varying a pattern of electrode contacts of the deep brain stimulator used to apply the first stimulus.8123-111332-027. The method of any one of the prior claims, wherein the first stimulus is an electrical stimulus and varying the parameters of the first stimulus comprises varying current, voltage amplitude, frequency, pulse width, and / or pulse pattern of the electrical stimulus.

8. The method of claim 7, wherein the first stimulus comprises electrical pulses having an amplitude varied between about 0.1 mA to about 15 mA, pulse widths varied between about 60 ps and about 2 ms, and / or a pulse frequency varied between about 1 Hz and about 1000 Hz.

9. The method of claim 7 or claim 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 40 Hz and about 100 Hz.

10. The method of claim 7 or claim 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 30 Hz and about 130 Hz.

11. The method of claim 7 or claim 8, wherein the first stimulus comprises electrical pulses having a pulse frequency varied between about 100 Hz and about 130 Hz.

12. The method of any one of claims 1-11, wherein the first stimulus is applied to the VOP.

13. The method of any one of claims 1-11, wherein the first stimulus is applied to the VOA.

14. The method of any one of claims 1-11, wherein the first stimulus is applied to the VIM.

15. The method of any one of the prior claims, wherein the second stimulus to evoke MEPs is applied using trans-cranial stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject.

16. The method of any one of claims 1-14, wherein the second stimulus to evoke MEPs is applied by direct cortical stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject.8123-111332-0217. The method of claim 16, wherein the direct cortical stimulation is applied using an implanted electrocorticography (ECoG) strip or grid array of electrodes.

18. The method of claims 16, wherein the deep brain stimulator comprises a multi-electrode lead comprising: a lead body including a distal end and a proximal end defining a longitudinal axis of the lead body; and a plurality of electrodes extending along the longitudinal axis of the lead body in a proximal to distal direction, each ending in an independently addressable electrical contact; and wherein: a distal set of the independently addressable electrode contacts is positioned near the distal end of the lead body to contact the motor thalamus when the neural probe is implanted in the brain of a patient; a proximal set of the independently addressable electrode contacts is positioned near the proximal end of the lead body to contact the motor cortex when the neural probe is implanted in the brain of the patient; and wherein the first stimulus is applied using the distal set of independently addressable electrode contacts and the second stimulus to evoke MEPs by direct cortical stimulation is applied using the proximal set of independently addressable electrode contacts.

19. The method of any one of claims 16-18, wherein the direct cortical stimulation comprises electrical pulses having an amplitude of less than about 15 mA, pulse widths between about 100 ps and about 2 ms, and / or a pulse frequency between about 1 Hz and about 1000 Hz.

20. The method of claim 19, wherein the direct cortical stimulation comprises electrical pulses having an amplitude of about 10 mA, pulse widths of about 500 ps, and a pulse frequency of about 400 Hz.

21. The method of any one of claims 16-20, wherein the direct cortical stimulation comprises a train of between 3 and 10 of the electrical pulses delivered every 1-5 seconds.

22. The method of claim 21 , wherein the direct cortical stimulation comprises a train of 5 of the electrical pulses delivered every 1-5 seconds.8123-111332-0223. The method of any one of the prior claims, wherein the motor disorder of the subject comprises a motor impairment of the arms, fingers, or hands causing a loss of muscle strength, partial paralysis, paresis, loss of dexterity, reduced movement, uncontrollable muscle tone, or essential tremor.

24. The method of any one of the prior claims, wherein the motor disorder of the subject is a speech disorder resulting in at least one speech motor impairment.

25. The method of any one of the prior claims, wherein the motor disorder results from at least one of ischemic brain injury, hemorrhagic brain injury, traumatic brain injury, brain injury caused by stroke, a neurodegenerative disorder, Parkinson’s disease, brain tumor, muscular dystrophy, myasthenia gravis, cerebral palsy, multiple sclerosis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, and transection of eloquent motor-related and / or speech-related gray or white matter.

26. The method of any one of the prior claims, wherein the motor disorder comprises a motor impairment causing a loss of muscle strength, a speech deficit, oral apraxia, dysarthria, partial paralysis, paresis, loss of dexterity, reduced hand movement, reduced finger movement, discoordination of the oral / deglutition function, dysphagia, uncontrollable muscle tone, essential tremor, and / or dystonia.

27. The method of any one of the prior claims, further comprising treating the motor disorder in the subject by applying a therapeutically effective amount of stimulation to the neurons of the thalamus via the electrode contacts of the deep brain stimulator, wherein the stimulus is applied using the selected parameters that lead to the greatest amplitude of MEPs evoked concurrently with the first stimulus compared to MEPs evoked asynchronously with the first stimulus.

28. A multi-electrode lead for use with a deep brain stimulator, the multi-electrode lead comprising: a lead body including a distal end and a proximal end defining a longitudinal axis of the lead body; and a plurality of electrodes extending along the longitudinal axis of the lead body in a proximal to distal direction, each ending in an independently addressable electrical contact;8123-111332-02 and wherein: a distal set of the independently addressable electrode contacts is positioned near the distal end of the lead body to contact the motor thalamus when the neural probe is implanted in the brain of a patient; a proximal set of the independently addressable electrode contacts is positioned near the proximal end of the lead body to contact the motor cortex when the neural probe is implanted in the brain of the patient; and optionally a medial set of the independently addressable electrode contacts is positioned in the middle of the lead body to contact the corona radiata between the motor thalamus and the motor cortex when the neural probe is implanted in the brain of the patient.

29. The multi-electrode lead of claim 28, wherein the distal set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

30. The multi-electrode lead of claim 28 or claim 29, wherein the proximal set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

31. The multi-electrode lead of any one of claims 28-30, wherein the medial set of the independently addressable electrode contacts comprises from 1-16 independently addressable electrode contacts.

32. The multi-electrode lead of any one of claim 28-31, wherein the distal set of the independently addressable electrode contacts is positioned to contact the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), or the ventralis intermediate nucleus (VIM) of the thalamus when the neural probe is implanted in the brain of the patient.

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