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.
Children and adults with Tourette Syndrome (TS) frequently experience adverse outcomes including injuries, significant social complications, and high medical costs. The factors contributing to the emergence of tics may involve maladaptive sensory processing and inhibitory control of motor output, both of which depend on intact GABAergic function in sensorimotor cortex. To date, most studies focus primarily on the motor system in older teens and adults and thus fail to capture factors key to the emergence of severe symptoms. This has hindered the development of highly effective treatments. In this multi-PI proposal, the investigators bring complementary expertise to recruit a scientifically relevant, substantial population of children during a period where TS symptoms are developing in order to evaluate clinical symptoms, sensory discrimination and adaptation, motor cortex inhibitory physiology using Transcranial Magnetic Stimulation, and GABA in sensory motor cortex and supplementary motor areas using Magnetic Resonance Spectroscopy. The purpose of this study is to quantify GABAergic sensorimotor dysfunction in TS and correlate this with sensory function, motor physiology, and clinical symptoms in ways that will direct us to more effective childhood TS treatments that prevent adult complications.
| Mikkelsen, Mark; Saleh, Muhammad G; Near, Jamie et al. (2018) Frequency and phase correction for multiplexed edited MRS of GABA and glutathione. Magn Reson Med 80:21-28 |
