Document text
Principal Investigator: Jorge Alvaro Gonzalez-Martinez
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $618,013
Funding agency: National Institute of Neurological Disorders and Stroke
SUMMARY
Motivation: Stroke is one of the leading causes of permanent motor disability in the United States, affecting
approximately 795,000 people a year. Despite the large population size of affected individuals, intense physical
therapy remains the only significant intervention with limited impact on moderated to severe paresis. Therefore,
the development of novel and effective therapeutic approaches is necessary for these patients. Neurostimula-
tion, like deep brain stimulation (DBS), is a promising approach that could extend recovery beyond physical
therapy. A possible target for DBS to treat post-stroke motor deficits is the motor thalamus, which is a thalamic
relay with outgoing excitatory connectivity to sensory/motor cortices.
Project Goal: Here we propose to design a new DBS approach targeting the motor thalamus to improve motor
output following stroke. For this, we will perform a mechanistic-driven identification of the optimal target of
stimulation within the motor thalamus and optimization of the stimulation parameters in monkeys.
Hypothesis: we hypothesize that 1) stimulation of specific nuclei of the motor thalamus potentiates motor out-
put by increasing excitability of cortical motoneurons via thalamocortical synaptic excitatory projections; 2) a
restricted set of stimulation parameters enables potentiation of motor output that persists after stroke in anes-
thetized monkeys; and 3) in awake monkeys with chronic stroke improves motor performances.
Approach: We developed the first monkey model of stroke within the internal capsule (IC), a deep white matter
brain structure that hosts the cortico-spinal tract (CST) and that is often damaged after stroke. We will leverage
this model first in anesthetized monkeys to identify optimal stimulation targets and parameters. For this, we will
position a stimulating probe in IC and one in each nucleus of the motor thalamus. We will first establish the
optimal stimulation nucleus by elucidating mechanisms of action of stimulation and by identifying which nucleus
must be stimulated to maximize: 1) cortical evoked potentials (CEPs) in the motor cortex, and 2) motor evoked
potentials (MEPs) triggered by IC or motor cortex stimulation when paired with DBS. We will then compare
MEPs with continuous or burst DBS. We expect that the ventral laterolateral (VLL) nucleus will maximally po-
tentiates MEPs and CEPs when the CST are intact and after a stroke. Finally, we will test the effects of the
optimal stimulation target and parameters during behavioral upper-limb tasks in awake animals with chronic
stroke. We expect that also in this case VLL stimulation will improve strength and motor performances.
Preliminary data: We developed and piloted the necessary techniques: i) we have designed a robot-assisted
neurosurgery approach to lesion the IC without damaging the sensorimotor cortex; ii) we have piloted the ef-
fects of VLL stimulation in anesthetized animals; and iii) we have characterized a chronic model of IC stroke.
Perspective: These pre-clinical monkey data will provide critical evidence to support future human studies
involving implantation of FDA approved leads in the motor thalamus in people with lesions of the CST.
1
Terms: <Active Follow-up><Affect><Anesthesia><Anesthesia procedures><Animals><Anterolateral><Apoplexy><Area><Behavioral><Benign Essential Tremor><Brain><Brain Nervous System><Brain Vascular Accident><CNS plasticity><Cell Nucleus><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cervical><Chemosensitization><Chemosensitization/Potentiation><Chronic><Clinical><Clinical Trials><Corticospinal Tracts><Data><Data Analyses><Data Analysis><Deep Brain Stimulation><Development><Dyskinesia Syndromes><Electrocautery><Electrocoagulation><Electrodes><Electrophysiology><Electrophysiology (science)><Encephalon><Endocavitary Fulguration><Essential Tremor><Evoked Potentials><FDA approved><Fingers><Forearm><Frequencies><Fulguration><Future><Galvanocautery><Goals><Hand><Human><Impairment><Implant><Individual><Internal Capsule><Intervention><Intervention Strategies><Invaded><Lateral><Lead><Length><Lesion><Measures><Membrum superius><Modeling><Modern Man><Monkeys><Motivation><Motor><Motor Cell><Motor Cortex><Motor Evoked Potentials><Motor Neurons><Motor disability><Motor output><Movement Disorder Syndromes><Movement Disorders><Muscle><Muscle Paresis><Muscle Tissue><Muscle Weakness><Muscular Paresis><Muscular Weakness><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuronal Plasticity><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Nucleus><Palsy><Paralysed><Paresis><Patients><Pattern><Pb element><Performance><Persons><Physiatric Procedure><Physical Medicine Procedure><Physical Therapeutics><Physical therapy><Physiotherapy><Plegia><Population Sizes><Position><Positioning Attribute><Potentiation><Protocol><Protocols documentation><Recovery><Sensory><Severities><Source><Specificity><Stroke><Structure><Surgical Diathermy><Synapses><Synaptic><Techniques><Technology><Testing><Thalamic structure><Thalamus><Thermocoagulation><Training><Translations><United States><Upper Extremity><Upper Limb><Work><active followup><after stroke><awake><axon signaling><axon-glial signaling><axonal signaling><brain attack><central nervous system plasticity><cerebral vascular accident><cerebrovascular accident><chronic stroke><clinical relevance><clinically relevant><conditioning><data interpretation><design><designing><developmental><dexterity><disability><electrophysiological><experience><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><functional improvement><glia signaling><glial signaling><hands><heavy metal Pb><heavy metal lead><implantation><improve function><improved><improved functional outcomes><interventional strategy><motoneuron><motor deficit><motor impairment><motor recovery><motor symptom><movement impairment><movement limitation><muscular><nerve signaling><neural><neural control><neural plasticity><neural regulation><neural signaling><neuromodulation><neuromodulatory><neuronal><neuronal signaling><neuroplastic><neuroplasticity><neuroregulation><neurosurgery><neurotransmission><novel><paralysis><paralytic><paretic><paretic muscle><patient population><post stroke><poststroke><pre-clinical><preclinical><robot assistance><robot assisted><robotic assistance><sensory cortex><spasticity><spinal pathway><stroke model><stroke patient><stroked><strokes><substantia alba><synapse><thalamic><therapeutically effective><translation><white matter>