Tics are the defining symptom of Tourette syndrome and other tic disorders (TDs); however, they form only a part of their overall symptoms. The recent surge of studies addressing the underlying pathophysiology of tics has revealed an intricate picture involving multiple brain areas and complex pathways. The myriad of pathophysiological findings stem, at least partially, from the multifaceted properties of tics and the disorders that express them. Distinct brain pathways mediate the expression of tics, whereas others are involved in the generation of the premonitory urge, associated comorbidities, and other changes in brain state. Expression of these symptoms is controlled by additional networks underlying voluntary suppression by the patient or those reflecting overall behavioral state. This review aims to simplify the complex picture of tic pathophysiology by dividing it into these key components based on converging data from human and animal model studies. Thus, involvement of the corticobasal ganglia pathway and its interaction with motor, sensory, limbic, and executive networks in each of the components as well as their control by different neuromodulators is described. This division enables a focused definition of the neuronal systems involved in each of these processes and allows a better understanding of the pathophysiology of TDs as a whole.

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Motor tics, the hallmark of Tourette syndrome (TS), are modulated by different behavioral and environmental factors. A major modulating factor is the sleepwake cycle in which tics are attenuated to a large extent during sleep. This study demonstrates a similar reduction in tic expression during sleep in an animal model of chronic tic disorders and investigates the underlying neural mechanism. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABA A antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a state-dependent dissociation between motor tic expression and their macro-level neural correlates (''LFP spikes'') during the sleep-wake cycle. Local field potential (LFP) spikes, which are highly correlated with tic expression during wakefulness, persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was time-locked to the LFP spikes during wakefulness, but this locking decreased significantly during sleep. These results suggest that whereas LFP spikes encode motor tic generation and feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in patients with TS during sleep and potentially during other behavioral states.

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AbstractMotor tics, the hallmark of Tourette syndrome, are modulated by different behavioral and environmental factors. A major modulating factor is the sleep-wake cycle in which tics are attenuated to a large extent during sleep. This study investigates the neural mechanisms underlying tic reduction during sleep in an animal model of chronic tic disorders. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABAA antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a dissociation between motor tic expression and their macro-level neural correlates (“LFP spikes”) during the sleep-wake cycle. LFP spikes persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was phase-locked to the LFP spikes during wakefulness but this locking decreased significantly during sleep. These results suggest that while LFP spikes, which are generated as a result of abnormal and focal disinhibition in the striatum, encode motor tic feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in TS patients during sleep and potentially during other behavioral states.Significance statementThe expression of motor tics, the defining symptom of Tourette syndrome, is modulated by environmental and behavioral factors. In this study, we explored the neurophysiological basis of the modulation mechanism via the sleep-wake cycle, using the rat model of chronic motor tic expression. Behaviorally, during sleep, tic frequency and intensity declined considerably. Physiologically, however, the macro-level neural correlates (termed “LFP spikes”) of tics persisted throughout the cycle, whereas the micro-level correlates were reduced during sleep. This dissociation between neuronal activity and its behavioral expression leads not only to a better understanding of tic modulation during sleep but may also suggest potential ways of affecting tic expression during natural behavior and when exposed to external modulating factors.

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