Tourette’s Syndrome: Neurobiology

Author: Will Bowman

A diagram of brain regions.

Tourette’s Syndrome is a childhood onset disorder characterized by vocal and motor tics. Tics are described as sudden and involuntary movements that are rapid, recurrent, and nonrhythmic. Tics are reportedly generated by a new complex framework involving the cerebellum, cortex, and basal ganglia. Previous work had suggested that dopamine bursts in basal ganglia and cortex are sufficient for motor tic production, however this model does not compensate for observed dopaminergic bursts without co-production of a tic. The new framework allows for a prediction of tics due to dysfunction of the basal ganglia – cerebellular – thalamo – cortical circuits and their interaction with the primary motor cortex. It is proposed that tic production hinges on the selection of a basal ganglia – thalamo – cortical loop process, which can allow noise and inputs normally present to disinhibit the primary motor cortex. Therefore, if such a disinhibition coincides with a spurious activation of primary motor cortex the signal can be amplified by thalamo – cortical circuit and produce a motor tic. Sensitized neurons are more prone to this sort of behavior, and can be sensitized due to high extra-synaptic dopamine concentrations, and the disinhibitory action of the basal ganglia is currently described as a function of striatal dopamine release. This model predicts tic generation should increase with higher levels of dopamine, and therefore suggests tic treatment via attention to the dopaminergic systems (Caligiore, D, et al. 2017).

Further research has found immune system dysfunction is involved in Tourette’s Syndrome. Microglia are the neuroimmune cell and their activation in disease is associated with inflammation and neuronal damage. Mutations in microglial cells, expressing Hoxb8, are found to lead to pathologies such as excessive grooming in mice experiments used in Tourette’s Syndrome models. Around 40% of microglial cells express gene Hoxb8, and are therefore a subset of the total microglia, but Hoxb8 mutant mice only produce 15% of the total microglia in the brain of a normal mouse. Reduced microglial populations may play a role in the pathology. Excessive grooming is also associated with hyperexcitability of the thalamo-cortical circuits. Microglia in the basal ganglia and striatum were found to have dysfunction in patients with Tourette’s Syndrome, showing neurotoxic activation and increased inflammatory activation. In HDC knockout mice, the number of microglia expressing insulin growth factor 1 (Igf1) is reduced, but do not show inflammatory activation. Igf1 is necessary for neuronal survival. However, increased stress in the brain, by bacterial lipopolysaccharide, caused an increased expression of inflammatory response in HDC knockouts over wild-type, indicating a deficit in neuronal protection and over-reactivity to environmental challenges (Frick, L. et al. 2016).

Firing rate data on Globus pallidus internus neurons were investigated to explore a possible target for deep brain stimulation therapy in Tourette’s Syndrome. While similar firing patterns were found between healthy and Tourette’s patients, the distribution of the neurons with different firing modes was different. The Globus pallidus internus is subdivided into several functional territories, but differences in neural composition between anterior and posterior regions have never been described. The anterior and posterior regions are involved with the limbic and sensory-motor systems, respectively. However, due to these regions being associated with different basal ganglia – thalamo – cortical loops, there is evidence for the different electrophysiological profiles observed. Due to different clinical conditions under which the data was obtained however makes these differences uncomparable (Giorni, A. et al. 2017).

Studies involving fine motor task worked to better understand the relationship between Tourette’s, ability to lateralize fine motor tasks, and the transcallosal connectivity of motor cortical regions in the brain. The ability to lateralize fine motor control is typically associated with the transcallosal connectivity, however in Tourette’s patients this was not observed. A compensatory function was discovered in an over-recruitment of regions involved in self-regulation of motor controls. These regions, the contralateral premotor and prefrontal areas and ipsilateral inferior parietal lobule, are over-recruited in these tasks and such over-recruitment corresponded with tic severity in patients (Martino, D, et al. 2017).

Future research requires further understanding of the thalamo – cortical subsystems to better understand the mechanisms of tic production. The study of dopamine in subthalamic nucleus and in learning processes in the basal ganglia could better elucidate its role in Tourette’s Syndrome. Further exploration to the electrophysiological profile of the anterior and posterior Globus pallidus internus under comparable conditions may allow for understanding of relative firing rates between limbic and sensory-motor systems.

 

References:

 

Caligiore, Daniele, Francesco Mannella, Michael A. Arbib, and Gianluca Baldassarre. 2017. “Dysfunctions of the Basal Ganglia-Cerebellar-Thalamo-Cortical System Produce Motor Tics in Tourette Syndrome.” PLoS Computational Biology 13 (3): e1005395. https://doi.org/10.1371/journal.pcbi.1005395.

 

Frick, Luciana, and Christopher Pittenger. 2016. “Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS.” Journal of Immunology Research 2016: 8606057. https://doi.org/10.1155/2016/8606057.

 

Giorni, Andrea, François Windels, Peter G. Stratton, Raymond Cook, Paul Silberstein, Terrence Coyne, Peter A. Silburn, and Pankaj Sah. 2017. “Single-Unit Activity of the Anterior Globus Pallidus Internus in Tourette Patients and Posterior Globus Pallidus Internus in Dystonic Patients.” Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 128 (12): 2510–18. https://doi.org/10.1016/j.clinph.2017.10.003.

 

Martino, D., C. Delorme, E. Pelosin, A. Hartmann, Y. Worbe, and L. Avanzino. 2017. “Abnormal Lateralization of Fine Motor Actions in Tourette Syndrome Persists into Adulthood.” PloS One 12 (7): e0180812. https://doi.org/10.1371/journal.pone.0180812.

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