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

PROJECT NARRATIVE Humans with stroke lesion invading the cortico-spinal tracts (CST) suffer from the most severe and permanent motor deficits, which include loss of finger dexterity and muscle weakness. Here, we aim at designing a new deep brain stimulation therapy to treat post-stroke muscle weakness and motor paresis by targeting the motor thalamus, i.e., a subcortical relay with outgoing excitatory connectivity to sensory/motor cortices. For this, we will demonstrate that motor thalamus stimulation increases the excitability of the motor cortex and that these excitatory inputs can potentiate motor output in intact animals and animals with chronic lesions of the CST both when anesthetized and during behaving motor tasks.