GABAergic Sensorimotor Dysfunction in Tourette Syndrome

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 DESCRIPTION (provided by applicant): Tourette Syndrome (TS) is a common, childhood-onset neurological disorder characterized by involuntary and compulsively-performed patterned movements called "tics," often preceded by sensory "premonitory urges." Severe cases suffer substantial morbidity, despite the use of antipsychotics and even deep brain stimulation. The neurobiology of TS likely involves both atypical motor and sensory development; however, the majority of investigations to date have focused on the pathophysiology and treatment implications of dysfunction in motor system circuits only. Innovative methods are now available to probe the relationship between sensory function and motor control in children, investigations critical for developing better treatments for severe TS. In prior NIH funded research, Drs. Mostofsky and Gilbert, have employed careful clinical phenotyping, transcranial magnetic stimulation (TMS), and magnetic resonance spectroscopy (MRS) in evaluating pathophysiology of neurobehavioral disorders in children. This study builds on prior work as well as new data quantifying sensorimotor adaptation in TS. The over-arching hypothesis of this proposal is that GABAergic dysfunction in sensorimotor cortex results in a combination of abnormal sensory adaptation and impaired inhibitory motor function that underlie the emergence of symptoms of premonitory urges and tics in TS. The primary aim of this study is to quantify the relationship between sensory adaptation, inhibitory motor physiology, and urge and tic severity in children with TS and to compare these metrics with GABA levels in sensorimotor cortex and supplementary motor area. The investigators in this multi-PI study bring a unique combination of complementary scientific and clinical expertise, established scientific collaborations using innovative methods, and solid preliminary data to support this novel study of the pathophysiology of TS. To this end we propose the following aims: Aim 1: To evaluate and compare tactile sensitivity and adaptation in children with Tourette Syndrome (TS) and typically developing children (TDC) and determine whether impaired tactile adaptation is associated with premonitory urge severity and tic severity. Aim 2: To measure and compare inhibition in bilateral motor cortex (M1) using TMS in children with TS and TDC and determine whether reduced M1 inhibition is associated with tic severity. Aim 3: To measure and compare GABA levels in bilateral sensorimotor cortex (S1/M1) and supplementary motor area (SMA) in children with TS and TDC and determine whether S1/M1 GABA correlates with tactile adaptation, M1 inhibition, and premonitory urge and tic severity in TS. This innovative investigation of tactile, motor, and GABAergic dysfunction during emergence of tics in childhood will provide information vital for identifying treatments that reduce symptoms and prevent adverse outcomes in TS.