Congratulations to Grace Lowor, Julieth Gomez, Matthew Hook, Chris Butson, Kelly Foote, Michael S. Okun, and Aysegul Gunduz on the publication of “Understanding Network Interactions of Tic Generation in Tourette Syndrome,” which appears in the July/August issue of Brain Stimulation.
Abstract B38: Presented at the 2024 NYC Neuromodulation Conference
Synopsis
We hypothesize that tic generation is mediated through localized neuronal interactions across the thalamic-basal ganglia network. Electrophysiological recordings from the centromedian thalamus and the anterior globus pallidus internus showed that the two nuclei engage in low-frequency neuronal interactions known to be associated with tic electrophysiology, contributing to our understanding of the thalamic-basal ganglia circuitry in Tourette syndrome.
Background
Tourette syndrome (TS) is a neurological condition characterized by involuntary, repetitive movements and vocalizations called tics (Leckman, 2002). For patients with moderate to severe levels of motor and vocal tics, and other comorbidities who become resistant to standard medication and behavioral interventions (Cheung et al., 2007; Leckman, 2002), deep brain stimulation (DBS) has emerged as a potential treatment option (Baldermann et al., 2016; Smeets et al., 2016). We currently lack an ideal animal (TS) model, and standard functional imaging modalities generally reveal normal brain architecture (Frey & Gerry, 2006), hence understanding deep brain circuit interactions during tic generation will contribute to our understanding of TS and DBS therapy. This study aims to deepen this understanding of the neurophysiological basis of tic generation in two common deep brain targets for stimulation: the centromedian thalamus (CM) region and the anterior globus pallidus internus (aGPi), and their interaction.
Methods
Four consented patients with TS (four right-handed females; (mean±sd) 24±5.4 y/o) were each implanted with bilateral centromedian thalamus (CM) and anterior globus pallidus internus (aGPi) electrodes (n=16 leads) connected to two neurostimulators with aDBS capability under an FDA IDE. (Medtronic Percept PC). Preoperative MRI scans and post-operative CT scans were performed to localize the electrodes. Patients visited the clinic monthly for nine months, during which neural signals were recorded during periods of tics for 8-10 minutes and the absence of tics (baseline) for 2-3 minutes. For every neural recording, patients received no stimulation therapy. After each therapy visit, participants completed daily surveys at home to assess their tic and limbic symptoms in their daily living activities.
Results
Electrophysiological recordings from both CM and the aGPi revealed intra-hemispherical low- frequency (<20 Hz) power increase during tics. Pallido-thalamic coherency during tics was found in a pathological low-frequency band (1-10 Hz) distinguishable from baseline states in both hemispheres (p = 6.9e-05 (left hemisphere (L)); p = 2.14e-04 (right hemisphere (R))). During tics, the phase relationship between CM and aGPi in the aberrant pathological low-frequency band was significantly reduced compared to baseline with CM leading pallidal activity (p = 2.64e-03 (L); p = 5.96e-05 (R)). The internuclear phase difference in the left hemisphere was higher during tics than in the right hemisphere (p = 3.28e-05).
Discussion
We have shown neurophysiological evidence of thalamic-basal ganglia network interactions that lead to tic genesis in TS. Our results confirm previous electrophysiological recordings from the CM of 4 patients with TS that showed a low-frequency power (3–10 Hz) increase that was time- locked to tic onset (Cagle et al., 2020). This study has shown similar low-frequency neuronal activity (<20 Hz) in both the CM and aGPi and how the two brain regions interact to generate tics. In this study, we show that higher low-frequency network synchrony between the CM and aGPi leads to tic generation. During tics, both nuclei align in phase at low frequencies (1-10 Hz) for higher neuronal synchrony. Within the 10 Hz-low-frequency band, the pallido-thalamic phase relationship is greater in the left hemisphere; this laterality can be explained by the lateralization of tics which correlates to the handedness of patients also known as motor lateralization (Hemispheric Lateralisation, n.d.; Lateralization of Brain Function & Hemispheric Specialization, 2023). All patients in this study were right-handed and experienced their motor tics predominantly on the right side (Yazgan et al., 1995). Conclusively, the CM and the aGPi engage in neuronal interactions in low frequencies known to be associated with tic electrophysiology (Cagle et al., 2020). This could potentially address knowledge gaps in the field, revealing neurophysiological and connectivity evidence to identify pallido-thalamic network interactions of tic generation/suppression.