Amplified engagement of prefrontal cortex during control of voluntary action in Tourette syndrome

Abstract

Tourette syndrome is characterised by ‘unvoluntary’ tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus (IFG) is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. While tic suppression in Tourette Syndrome also engages the IFG, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during fMRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withheld responses to NoGo cues to, and decide whether to press or withhold to ‘Choose’ cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area (preSMA), IFG, insula, caudate nucleus, thalamus, and primary motor cortex. In Tourette syndrome, activity was elevated in the IFG, insula, and basal ganglia, most notably within the right IFG during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this IFG hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the preSMA to the caudate nucleus, globus pallidus, and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater IFG engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia.

Tourette syndrome research highlights from 2020

“…Rae and colleagues provide a high-quality study of action inhibition in TS comprising 23 adults with TS and 21 healthy controls using the same intentional inhibition task ( Rae et al . 2020 ).…”

“…Rae and colleagues provide a high-quality study of action inhibition in TS comprising 23 adults with TS and 21 healthy controls using the same intentional inhibition task (Rae et al 2020). Importantly, the authors chose a task that did not directly involve tics, so both groups could participate equally in inhibiting a movement.…”

Myoclonus and other jerky movement disorders

“…Of note, in this study self-paced voluntary actions (e.g., wrist extensions) in people with primary tic disorders were preceded, like in healthy control participants, by regular readiness potentials ( van der Salm et al, 2012 ). Indeed, the execution of voluntary actions, as well as reaction times in basic Go/NoGo paradigms in people with TS typically fall within the normal range of motor behavior ( Rae et al, 2020 , Thomalla et al, 2014 ). These results allow to draw several important conclusions often missed in the pathophysiological discussion of tics.…”

Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

“…Of relevance to the present discussion, several studies have shown that tic suppression and cognitive control of motor behaviour are underpinned by the activation of the prefrontal cortex (PFC). [130][131][132] Interestingly, the relationship between tic severity and waiting impulsivity is mediated by connectivity between the orbitofrontal cortex (a subregion of the PFC particularly susceptible to the adverse effects of stress) and the caudate nucleus. 107…”