Tourette syndrome: brain neurophysiology, circuit dysfunction, and neuromodulation across invasive and noninvasive...

We review recent electrophysiological advances that have refined our understanding of tic generation in Tourette syndrome by characterizing dysfunction across cortico-striato-pallido-thalamo-cortical (CSPTC) circuits and their time-resolved dynamics. We integrate evidence across spatial scales - from single-unit activity to large-scale network coupling - and examine how these findings provide a mechanistic framework for interpreting both invasive and noninvasive neuromodulation approaches. Finally, we discuss how electrophysiological signatures of tics and premonitory urges may serve as candidate biomarkers to guide future, dynamically informed interventions.

At the microscale, intraoperative recordings indicate that GPi neurons in Tourette syndrome exhibit a burst-pause firing pattern with phasic modulation preceding tic onset, consistent with transient pallidal disinhibition. At the mesoscale, LFP recordings from centromedian nucleus and aGPi show increased low-frequency (3-12 Hz) power and pallido-thalamic coherence during tics, accompanied by reduced phase synchrony, suggesting dysrhythmic rather than coordinated network activity. At the macroscale, combined intracranial and scalp EEG recordings demonstrate that thalamo-frontal alpha-band connectivity progressively declines in the ~1.3 s preceding tic onset, propagating from sensorimotor to prefrontal regions. Importantly, these pretic dynamics are captured by measures of inter-regional coupling rather than local power, highlighting the relevance of distributed network interactions. These findings are beginning to inform neuromodulation strategies across modalities. Deep brain stimulation (DBS) targeting thalamic or pallidal regions provides clinically meaningful tic reduction, while connectomic analyses emphasize the role of distributed fibre pathways over single anatomical targets. In parallel, noninvasive approaches show mixed results: cortical stimulation techniques such as rTMS and tDCS have yielded inconsistent effects, whereas peripheral rhythmic stimulation, such as 10 Hz median nerve stimulation, has demonstrated efficacy in controlled trials, potentially through modulation of sensorimotor network dynamics.

Electrophysiological evidence across spatial scales supports a model of Tourette syndrome as a disorder of dynamic CSPTC circuit dysfunction. At the cellular level, GPi neurons exhibit a sparse but high-intensity bursting regime, with activity changes preceding tic onset. At the population level, low-frequency oscillations in pallido-thalamic networks track tic severity and distinguish tics from voluntary movements. At the network level, thalamo-frontal alpha-band coupling appears to exert a stabilizing influence, whose progressive reduction precedes tic expression. Together, these findings suggest that tic generation arises from temporally evolving disruptions in distributed network coordination rather than from static abnormalities within isolated regions. This framework provides a common basis for understanding both invasive and noninvasive neuromodulation and supports the development of electrophysiological biomarkers for adaptive, closed-loop therapeutic strategies.