WO2026036147A1 - Implantation of deep brain stimulation leads for recovery of motor control and speech - Google Patents

Abstract

This disclosure provides a method for optimizing surgical placement of stimulation leads within 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. Also provided are methods for treating motor disorders in a subject.

Description

8123-111331-02

IMPLANTATION OF DEEP BRAIN STIMULATION LEADS FOR RECOVERY OF MOTOR CONTROL AND SPEECH

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No. 63/681,314, filed August 9, 2024, which is incorporated by reference in its entirety.

FIELD

[0001] The present disclosure relates to the field of ameliorating symptoms of motor disorders by modulation of particular regions of the thalamus in a subject.

BACKGROUND

[0002] 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 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.

[0003] Prior studies have shown the unexpected discovery that deep brain stimulation of specific thalamic nuclei leads to improvements in voluntary movements affected by motor disorders in human subjects. However, identifying optimal placement of the electrode leads within the thalamus for treatment of motor disorders remains a complex and elusive process.

SUMMARY

[0004] This disclosure provides a method for optimizing surgical placement of stimulation leads within the thalamus to treat a motor disorder in a subject, such as paralysis of the upperlimb and face muscles, which cause speech motor deficits.

[0005] The disclosed method involves a multi-step process to select a target location in the thalamus for neurostimulation to treat a motor disorder in a subject. Microelectrode leads of a deep brain stimulator are implanted in the brain of the subject, contacting the ventral oralis 8123-111331-02 posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), and the ventralis intermediate nucleus (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 motor evoked potentials (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.

[0006] 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), and/or transection of eloquent motor-related and/or speech-related gray or white matter.

[0007] 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, discoordination of the oral/deglutition function, dysphagia, partial paralysis, paresis, loss of dexterity, reduced hand movement, reduced finger movement, uncontrollable muscle tone, essential tremor, and/or dystonia.

[0008] Further provided are methods for treating a motor disorder in a subject, comprising applying a therapeutically effective amount of stimulation (e.g., an electrical stimulus) to neurons at the selected target location in the thalamus of the subject with the motor disorder.

[0009] 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. 8123-111331-02

BRIEF DESCRIPTION OF THE FIGURES

[0010] FIG. 1: Intraoperative experimental setup. Subdural strips to apply direct cortical stimulation are placed over the face and hand representation of the primary motor cortex. Three microelectrodes are inserted through the VOP, VIM and VOA, allowing stimulation of the three nuclei. Additionally, such electrodes present recording microtips to monitor spiking activity with single nucleus specificity. Post-operative imaging allows precise localization of tested trajectories.

[0011] FIG. 2: Neuronal firing of VOA, VIM and VOP with upper-limb and facial movements. Example traces for EMG activity of the hand and face, with Multi Unit Activity of VOP, VIM and VOA during a facial movement and a hand movement. Pie charts show comprehensive results for 10 patients (20 thalamic mapping left and right).

[0012] FIGs. 3A-3D: Targeted DBS of the VOA, VIM and VOP. FIG. 3A: Example traces for EMG activity of the hand and face with DCS alone, and DCS paired with continuous stimulation of VOA, VOP and VIM. FIG. 3B: Boxplot showing the area under the curve for motor evoked potentials. FIG. 3C: Pie charts summarizing analysis on 8 patients tested on all three nuclei, showing which nucleus achieved highest muscle potentiation. FIG. 3D: Frequency-dependence effect on both hand and face motor output potentiation.

DETAILED DESCRIPTION

I. Introduction

[0013] 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 placement of the electrode leads within the thalamus for treatment of motor deficits is complex.

[0014] This disclosure provides a method for optimizing surgical placement of stimulation leads within the thalamus to treat motor deficits in a subject, such as paralysis of the upperlimb and face muscles, which cause speech and swallowing motor deficits and/or upper-limb motor deficits. The disclosed approach is effective for both upper-limb and facial muscles. Individuals suffering from various conditions, such as ischemic or hemorrhagic brain injuries resulting from strokes, traumatic brain injuries, or neurodegenerative diseases like ALS, often experience motor paralysis in both their limbs and facial muscles, along with speech and swallowing impairment. These difficulties greatly affect their independence and make daily 8123-111331-02 tasks and communication challenging. Although physiotherapy and speech therapy are frequently employed to help restore lost functions or decelerate the worsening of symptoms, many patients do not attain a level of recovery that they consider adequate.

[0015] The placement of the stimulating electrodes should be strategically targeted towards the regions of the thalamus that send excitatory signals to the regions of the premotor and motor cortices associated with the motor disorder in the subject. However, this area of the thalamus is constituted of different nuclei (e.g., VOP, VOA, and the VIM) and the optimal nucleus for the potentiation of the motor output is often different for each patient. The disclosed method allows the selection of the optimal nucleus for the surgical implantation of stimulation leads.

[0016] In current clinical applications, the surgical implantation of the electrodes is driven by imaging and electrophysiological recordings of the thalamic neuronal activity. However, this information is not sufficient to select the optimal thalamic nucleus for the potentiation of face and arm/hand muscle activity. In the method provided herein, one or more electrodes provide electrical stimulation, or other types of neurostimulation such as transcranial magnetic stimulation, to the cortical motor areas of the face or hand. This stimulation induces motor evoked potentials (MEPs) in specific muscles associated with the motor disorder in the subject (such as muscles in the face, tongue, lips, and throat for speech or swallowing, or upper- and fore-arm muscles for arm movements and hand grasping). Additionally, one or more electrodes, such as surface electromyography sensors, are used to measure muscle activity in these targeted muscles to capture the MEPs. Electrical stimulation is then applied to the proprioceptive areas of the thalamus. This simultaneous activation of the cortical motor areas and the thalamus leads to an enhanced amplitude of the MEPs, which can be measured, for example, by peak-to-peak amplitude or area under the curve. The concurrent stimulation of the thalamus is tested for each thalamic nucleus of the proprioceptive areas of the thalamus. The optimal nucleus is the nucleus that results in larger peak-to-peak amplitude of the MEPs.

IL Summary of Terms

[0017] 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 8123-111331-02 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:

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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. 8123-111331-02

[0023] Electrical lead: A device or component of a device including one or more electrodes that can be placed in contact with neuronal tissue in a primate host and can pass electrical current from or to the neuronal tissue (e.g., to record and/or stimulate the neural signals). Electrical leads typically include conductive and non-conductive surfaces designed for contact with neuronal tissue when implanted in a subject, and include one or more electrodes that can be independently monitored from other conductive surfaces on or off the probe for recording and/or stimulating neural signals.

[0024] 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).

[0025] Electrode: An electric conductor through which an electric current can pass. An electrode can also be a collector and/or emitter of an electric current. In some implementations, an electrode is a solid and comprises a conducting metal as the conductive layer. Non-limiting examples of conducting metals include noble metals and alloys, such as stainless steel and tungsten. An array of electrodes refers to a device with at least two electrodes formed in any pattern. A multi-channel electrode includes multiple conductive surfaces that can independently activated to stimulate or record electrical current.

[0026] 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.

[0027] 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. 8123-111331-02

[0028] 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. Neuronal activity in pre-motor cortex typically precedes activation of the primary motor cortex.

[0029] 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).

[0030] 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), 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.

[0031] 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. 8123-111331-02

[0032] 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 a 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).

[0033] Perceptual threshold: The minimum thalamic stimulation intensity necessary for a conscious organism to be aware of a particular sensation.

[0034] 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.

[0035] 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 subthalamus and the thalamus. These fibers are projections to the ventral anterior and ventral lateral thalamus from the basal ganglia and the cerebellum.

[0036] 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 8123-111331-02 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.

[0037] 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 or 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.

[0038] 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.

[0039] 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. 8123-111331-02

III. Optimal Positioning of Thalamic Deep Brain Stimulation Leads For Treatment of Motor Disorders

[0040] Provided herein are methods for optimizing surgical placement of stimulation leads within 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.

[0041] 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), or transection of eloquent motor-related and/or speech-related gray or white matter.

[0042] The disclosed method involves a multi-step process to select a target location in the thalamus for neurostimulation to treat a motor disorder in a subject. Microelectrode leads of a deep brain stimulator are implanted in the brain of the subject. The leads contact the VOP, the VOA, and the VIM of the thalamus in the subject. 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, and 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.

[0043] In some implementations, the concurrently evoked MEPs occur within 50 ms (such as within 20 ms) of the electrical stimulus applied to neurons in the VOP, the VOA, or the VIM via the implanted electrodes of the deep brain stimulator.

[0044] The primate (including humans and non-human primates) thalamus has a stereotactic and somatotopic organization that allows targeting of electrode leads to the specific thalamic 8123-111331-02 nuclei using a variety of suitable means, such as imaging and electrophysiologically recordings. Specifically, DBS 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-definition volumetric MRI, which can be fused with intraoperative CT images. Using indirect stereotactic planning, the motor thalamus is located approximately 10mm lateral to the wall of the third ventricle, from 6 to 10mm anterior to PC and at the AC/PC plane of the dorsal/ventral orientation. In some implementations, 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.

[0045] 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.

[0046] In some implementations, the direct cortical stimulation comprises electrical pulses having an amplitude of less than about 10 mA, pulse widths between about 100 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. 8123-111331-02

[0047] 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.

[0048] In particular examples, the direct cortical stimulation comprises electrical pulses with pulse widths between about 100 ps and about 2 ms; for example, between 200 LIS 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 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.

[0049] 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.

[0050] In some implementations, the electrical stimulus applied to neurons in the VOP, the VOA, and the VIM, includes 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.

[0051] In particular examples, the electrical stimulus applied to neurons in the VOP, the VOA, and the VIM includes electrical pulses with 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. 8123-111331-02

[0052] In particular examples, the electrical stimulus applied to neurons in the VOP, the VOA, and the VIM includes electrical pulses with pulse widths between about 80 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 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.

[0053] In particular examples, the electrical stimulus applied to neurons in the VOP, the VOA, and the VIM includes a pulse frequency between about 100 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, and between 100 Hz and 200 Hz. In some implementations, the pulse frequency is between 100Hz and 250Hz.

[0054] Accordingly, the electrical stimulus applied to neurons in the VOP, the VOA, and the VIM in particular implementations herein includes electrical pulses having an amplitude of less than about 10 mA, a pulse width of between about 100 ps and about 2 ms, and a pulse frequency between about 1 Hz and about 1000 Hz, such as between about 50 Hz and about 80 Hz, such as about 50 Hz or about 80 Hz.

[0055] Also provided herein are methods for treating a subject (for example, a human subject) having a motor disorder. The methods comprise (i) selecting a target location in the thalamus for neurostimulation to treat the motor disorder in a subject as discussed above, and (ii) applying a therapeutically effective amount of stimulation to the target location in the thalamus to treat the motor disorder in the subject. Any suitable stimulation parameters may be used to treat the patient, for example, stimulation parameters as described in WO2023/220471, incorporated by reference herein). 8123-111331-02

[0056] In some implementations, the method further comprises replacing the implanted electrode of the deep brain stimulator with a second electrode, for examples designed for long-term implantation and/or including multiple channels appropriately situations for stimulation of the target location in the thalamus.

[0057] Methods according to particular examples disclosed herein may be utilized to treat (i.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 is 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.

[0058] In some examples herein, stimulation (<?.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.

[0059] In some examples, a method for treating the subject having a motor disorder comprises applying a stimulus (e.g., an electrical stimulus) to neurons at the target location in the thalamus, wherein the neurons comprise axons projecting to premotor or motor cortex. The electrical stimulus can be applied with one or more electrodes controlled by a neurostimulator. The electrical stimulus improves at least one motor output associated with the motor disorder. In particular examples, measurements of the motor output are used to adjust the parameters of the electrical stimulus to provide an improvement thereof.

[0060] In particular examples, stimulation of the target location in 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 8123-111331-02 circuits controlling muscles, for example, such that the stimulation facilitates the subject’s natural arm, facial, and/or tongue movements.

[0061] In some implementations, disclosed methods are effected by the use of an implanted neurostimulator that controls the stimulation (<?. ., electrical stimulation via one or more implanted electrode(s)) according to predetermined parameters or parameters 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.

[0062] 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 be 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.

[0063] 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.

[0064] 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 8123-111331-02 microarrays), and microwire electrodes and arrays.

[0065] 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.

[0066] 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.

[0067] In some implementations, electrodes used in accordance with the invention are positioned in specific areas of the brain (such as the ventral thalamus), so as to be capable of selective application of an electrical stimulus to the specific area, by any of the methods 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).

[0068] 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 8123-111331-02 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 seizure activity due to the applied stimulus, for example, so as to reduce the frequency or severity of 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 sensation of an aura of the focal epilepsy. In these and further implementations, the subject is taught how to use the device and/or the neurostimulator.

[0069] 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 are 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. In these and further examples, the subject is taught how to use the device and/or the neurostimulator.

[0070] Our method seeks to benefit the chronic stroke patient population that suffers from arm and hand paresis and lost or impaired speech deficits. Specifically, we are targeting the speech and vocalization impairments caused by motor control deficits like muscle weakness, dysarthria, dysphagia, apraxia of speech and speech arrest. These deficits affect about 50% of all acute stage and a third of chronic stage stroke patients. While our method was developed initially for the stroke patient population, this stimulation method could be extended to any population that suffers the above motor control deficits. This extended group could include ALS, Multiple sclerosis, Parkinson’s, traumatic brain injury, brain tumors, muscular dystrophy, generalized myasthenia gravis, and cerebral palsy. 8123-111331-02

IV. Additional Aspects of the Disclosure

[0071 ] Aspect 1. A method for selecting a target location in the thalamus for neurostimulation to treat a motor disorder in a subject, comprising: implanting electrodes of a deep brain stimulator in the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), and the ventralis intermediate nucleus (VIM) of the thalamus in the subject; applying an electrical stimulus to neurons in the VOP, the VOA, and the VIM, separately, via the implanted electrodes of the deep brain stimulator; stimulating 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 stimulation of the neurons in the VOP, the VOA, and the VIM; determining which of the VOP, the VOA, or the VIM, when stimulated, leads to the greatest increase in amplitude of concurrently evoked MEPs; selecting the VOP, the VOA, or the VIM, that, when stimulated, leads to the greatest increase in amplitude of concurrently evoked MEPs, as the target location in the thalamus for neurostimulation to treat the motor disorder in the subject.

[0072] Aspect 2. The method of Aspect 1, wherein the concurrently evoked MEPs occur within 50 ms of the electrical stimulus applied to neurons in the VOP, the VOA, or the VIM via the implanted electrodes of the deep brain stimulator.

[0073] Aspect 3. The method of Aspect 2, wherein the concurrently evoked MEPs occur within 2-50 ms of the electrical stimulus applied to neurons in the VOP, the VOA, or the VIM via the implanted electrodes of the deep brain stimulator.

[0074] Aspect 4. The method of any one of the prior Aspects, wherein the electrical stimulus applied to neurons of the VOP, the VOA, or the VIM 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.

[0075] Aspect 5. The method of Aspect 4, wherein the electrical stimulus comprises electrical pulses having a pulse frequency of between about 50 Hz and about 80 Hz.

[0076] Aspect 6. The method of Aspect 5, wherein the electrical stimulus comprises electrical pulses having a pulse frequency of about 50 Hz.

[0077] Aspect 7. The method of any one of the prior Aspects, wherein the MEPs are evoked 8123-111331-02 by trans-cranial stimulation of motor cortex controlling muscles of the face, neck, or upper limb affected by the motor disorder in the subject.

[0078] Aspect 8. The method of any one of the prior Aspects, wherein 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.

[0079] Aspect 9. The method of Aspect 8, wherein the direct cortical stimulation is applied using an implanted electrocorticography (ECoG) strip or grid array of electrodes.

[0080] Aspect 10. The method of Aspect 8 or Aspect 9, 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.

[0081] Aspect 11. The method of Aspect 10, 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.

[0082] Aspect 12. The method of Aspect 10 or Aspect 11, wherein the direct cortical stimulation comprises a train of between 3 and 10 of the electrical pulses delivered every 1-5 seconds.

[0083] Aspect 13. The method of Aspect 12, wherein the direct cortical stimulation comprises a train of 5 of the electrical pulses delivered every 1-5 seconds.

[0084] Aspect 14. 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.

[0085] Aspect 15. 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.

[0086] Aspect 16. 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), and transection of eloquent motor-related and/or speech- related gray or white matter. 8123-111331-02

[0087] Aspect 17. The method according to 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.

[0088] Aspect 18. The method of any one of the prior Aspects, further comprising applying a therapeutically effective amount of stimulation to the target location in the thalamus to treat the motor disorder in the subject.

EXAMPLES

[0089] The following examples are provided to illustrate particular features of certain examples, but the scope of the claims should not be limited to those features exemplified.

Example 1

Optimal Positioning of Thalamic Deep Brain Stimulation Leads for Recovery of Motor Control and Speech

[0090] DBS of the motor thalamus has been shown to facilitate upper limb and face motor output by increasing the excitability of the motor cortex. However, whether specific nuclei are optimal for upper limb or facial paresis remains unknown, thus limiting the efficacy of DBS.

[0091] In humans, the motor thalamus consists of multiple nuclei, including the ventral oralis anterior VOA, the VOP and the VIM. This example provides methodology to monitor brain electrophysiology and perform stimulation testing of three microelectrodes passing through the VOA, VOP, and VIM (FIG. 1).

[0092] Intraoperative experiments in n=10 human patients undergoing DBS implantation of the motor thalamus were performed. Through the procedure, patients were kept awake to monitor brain electrophysiology and perform stimulation testing of three microelectrode trajectories passing through the VOA, VOP, and VIM. Such trajectories were mapped with single unit activity to optimize target localization. Patients performed facial or upper limb movements while thalamic spiking activity from the microelectrodes and muscle activity through EMG needles was simultaneously recorded. It was observed that face and tongue movements correlated with increases in VOA single unit spiking activity, whereas arm 8123-111331-02 movements correlated with increases in VOP/VIM firing. Group level analysis of 20 thalamic mapping (from 10 patients) shows a novel hodological map of the motor thalamus along a rostral to caudal gradient, with face related regions located in more rostral nucleus (VOA) and hand/arm regions in caudal nuclei (VOP and/or VIM) (FIG. 2).

[0093] In the same intervention, it was proved that this thalamic organization results in a somatotopic facilitation of motor output from Ml. For this, subdural electrocorticography (ECoG) electrodes were placed over the Ml arm/hand representation as well as the Ml face representation (FIG. 3). Cortical stimulation was applied from the subdural strips and MEP amplitudes were compared without and with paired stimulation of the different nuclei.

Interestingly, it was found that the VOP was the best nucleus for both the hand and the face. Interestingly, this nucleus presents preferential projections towards Ml. The optimal DBS parameters for facial or upper limb deficits might rely on different mechanisms (such as frequency-dependent suppression). In fact, different behaviors to higher frequencies in the face and in the hand were observed, illustrating single-nucleus specificity to be highly relevant in the optimization of DBS.

[0094] It will be apparent that the precise details of the methods or compositions 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

8123-111331-02 It is claimed:

1. A method for selecting a target location in the thalamus for neurostimulation to treat a motor disorder in a subject, comprising: implanting electrodes of a deep brain stimulator in the ventral oralis posterior nucleus (VOP), the ventral oralis anterior nucleus (VOA), and the ventralis intermediate nucleus (VIM) of the thalamus in the subject; applying an electrical stimulus to neurons in the VOP, the VOA, and the VIM, separately, via the implanted electrodes of the deep brain stimulator; stimulating 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 stimulation of the neurons in the VOP, the VOA, and the VIM; determining which of the VOP, the VOA, or the VIM, when stimulated, leads to the greatest increase in amplitude of concurrently evoked MEPs; selecting the VOP, the VOA, or the VIM, that, when stimulated, leads to the greatest increase in amplitude of concurrently evoked MEPs, as the target location in the thalamus for neurostimulation to treat the motor disorder in the subject.

2. The method of claim 1 , wherein the concurrently evoked MEPs occur within 50 ms of the electrical stimulus applied to neurons in the VOP, the VOA, or the VIM via the implanted electrodes of the deep brain stimulator.

3. The method of claim 2, wherein the concurrently evoked MEPs occur within 2-50 ms of the electrical stimulus applied to neurons in the VOP, the VOA, or the VIM via the implanted electrodes of the deep brain stimulator.

4. The method of claim 1 , wherein the electrical stimulus applied to neurons of the VOP, the VOA, or the VIM comprises electrical pulses having an amplitude of less than about 15 mA, pulse widths between about 100 s and about 2 ms, and/or a pulse frequency between about 1 Hz and about 1000 Hz.

5. The method of claim 4, wherein the electrical stimulus comprises electrical pulses having a pulse frequency of between about 50 Hz and about 80 Hz. 8123-111331-02

6. The method of claim 5, wherein the electrical stimulus comprises electrical pulses having a pulse frequency of about 50 Hz.

7. The method of claim 1, wherein 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.

8. The method of claim 1 , wherein 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.

9. The method of claim 8, wherein the direct cortical stimulation is applied using an implanted electrocorticography (ECoG) strip or grid array of electrodes.

10. The method of claim 8, 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.

11. The method of claim 10, 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.

12. The method of claim 10, wherein the direct cortical stimulation comprises a train of between 3 and 10 of the electrical pulses delivered every 1-5 seconds.

13. The method of claim 12, wherein the direct cortical stimulation comprises a train of 5 of the electrical pulses delivered every 1-5 seconds.

14. The method of claim 1, 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. 8123-111331-02

15. The method of claim 1, wherein the motor disorder of the subject is a speech disorder resulting in at least one speech motor impairment.

16. The method of claim 1, 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), and transection of eloquent motor-related and/or speech-related gray or white matter.

17. The method of claim 1, 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.

18. The method of claim 1, further comprising applying a therapeutically effective amount of stimulation to the target location in the thalamus to treat the motor disorder in the subject.