Abstract
Motor tics are a cardinal feature of Tourette syndrome and are traditionally associated with an excess of striatal dopamine in the basal ganglia. Recent evidence increasingly supports a more articulated view where cerebellum and cortex, working closely in concert with basal ganglia, are also involved in tic production. Building on such evidence, this article proposes a computational model of the basal ganglia-cerebellar-thalamo-cortical system to study how motor tics are generated in Tourette syndrome. In particular, the model: (i) reproduces the main results of recent experiments about the involvement of the basal ganglia-cerebellar-thalamo-cortical system in tic generation; (ii) suggests an explanation of the system-level mechanisms underlying motor tic production: in this respect, the model predicts that the interplay between dopaminergic signal and cortical activity contributes to triggering the tic event and that the recently discovered basal ganglia-cerebellar anatomical pathway may support the involvement of the cerebellum in tic production; (iii) furnishes predictions on the amount of tics generated when striatal dopamine increases and when the cortex is externally stimulated. These predictions could be important in identifying new brain target areas for future therapies. Finally, the model represents the first computational attempt to study the role of the recently discovered basal ganglia-cerebellar anatomical links. Studying this non-cortex-mediated basal ganglia-cerebellar interaction could radically change our perspective about how these areas interact with each other and with the cortex. Overall, the model also shows the utility of casting Tourette syndrome within a system-level perspective rather than viewing it as related to the dysfunction of a single brain area.
Highlights
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the presence of sudden and repetitive involuntary movements or vocalizations, generally termed as “tics”, having differing degrees of intensity and frequency, and unpredictable duration [1, 2]
The system-level architecture of the model is formed by four main components: the basal ganglia component (BG) reproduces the key anatomical and functional features of Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics the basal ganglia building on the computational models proposed in [21, 70,71,72]; the cerebellum component (Cer) captures some critical anatomical and functional aspects of the cerebellum pivoting on the models proposed in [68, 73, 74]; the motor thalamus and the primary motor cortex components, which do not focus on anatomical features, only reproduce functional aspects related to the activity of distinct neural populations
Dysfunctions of the basal ganglia-cerebellar-thalamo-cortical system produce motor tics areas of the system formed by BG, M1, and Cer; (ii) understand the system-level mechanisms underlying such phenomena; (iii) produce predictions on tic-related abnormal activities in regions not investigated in the experiment with real subjects (e.g., STN and Thalamus component (Th)), on how the tic generation changes with an increase of striatal dopamine, and on how it changes with a modulation of the activity of M1
Summary
Tourette syndrome (TS) is a neuropsychiatric disorder characterized by the presence of sudden and repetitive involuntary movements or vocalizations, generally termed as “tics”, having differing degrees of intensity and frequency, and unpredictable duration [1, 2]. Tics in TS are associated with basal ganglia abnormalities and in particular with a dysfunction of the striatal GABAergic networks leading to an excess of striatal dopamine [13,14,15,16]. This excess might cause an abnormal functioning of the basal ganglia-thalamo-cortical circuit leading to the production of tics [17]. In non-pathological conditions, the inhibition of specific GABAergic output nuclei of the basal ganglia leads to release the activity within the target thalamus areas forming loops with primary motor cortex, allowing the focused disinhibition of specific motor patterns. An alteration in striatal dopamine release as in TS may induce the production of tics as a consequence of a focal excitatory abnormality in the striatum that causes an undesired disinhibition of thalamo-cortical circuits [15, 17] whose effect is the production of tics
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