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Tactile Adaptation in Tourette Syndrome: Probing GABA-Mediated Neuroplasticity

Principal Investigator:
Stewart
Mostofsky

Tourette Syndrome (TS) is a common developmental neuropsychiatric disorder that can have a substantial impact on quality of life. Despite being first described over a century ago, the neurobiology of TS remains poorly understood and therapeutic approaches are modestly effective at best. A deeper understanding of the pathophysiology of TS would be expected to lead to improved intervention and outcomes. The focus of such investigation thus far has nearly entirely been on examining dysfunction within motor systems. However, it is long-recognized that people with TS often report that a sensory “urge” (e.g., itchy throat) contributes the need to complete a tic (e.g., throat clearing), which provides relief, albeit temporary.

This, combined with more generalized difficulty ignoring faint, repetitive/consistent, tactile stimuli (e.g., shirt-tags), has led some to describe individuals with TS as having a “thin stimulus threshold” 1. The association of these “premonitory sensory urges” with tics is long recognized. Despite this, there has been limited examination of tactile sensory physiology in TS, and the neural underpinnings of premonitory urges, like TS itself, remain unclear. Fortunately, recent advances in behavioral and imaging methods provide an opportunity for detailed examination of tactile dysfunction in TS, and in doing so, a novel approach for identifying abnormalities in neuroplasticity that contribute to the occurrence of premonitory sensory urges and, more broadly, to the pathophysiology of TS.

It has been suggested that the premonitory urge to tic may represent failed adaptation to otherwise routine somatosensory experiences. This “adjustment of a sense to a specific perceptual stimulus within the brain,” is recognized as a form stimulus-dependent short-term neural plasticity 2, and is important in modulating the behavioral response to incoming sensory information.

In our laboratory, we have begun to quantify tactile adaptation using highly reliable methods with proven efficacy in children 3. Use of such methods has led to the discovery that adaptation to tactile stimulation is mediated by stimulus-dependent cortical GABAergic interneurons 4-7. Reduced GABAergic inhibition in TS has been a subject of increasing interest for over a decade, with evidence from a wide range of modalities implicating GABAergic dysfunction in TS. Such anomalies in GABAergic transmission may lead to abnormalities in neural plasticity and associated failed adaption, resulting in, at the sensory level, premonitory urges and, at the motor level, tics.

Preliminary data from our laboratory provide support for this construct, suggesting that children with TS show abnormalities in tactile adaptation consistent with GABAergic dysfunction. Building on these preliminary findings we propose to examine the following hypotheses: 1) children with TS will show impaired tactile adaptation in comparison to typically developing children (TDC), 2) for children with TS, impaired tactile adaptation will be correlated with increased tic and premonitory urge severity; 3) children with TS will show reduced GABA in primary sensorimotor cortex (SM1) and this will correlate with impaired tactile adaptation.

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