Towards a primate model of Gilles de la Tourette syndrome: Anatomo-behavioural correlation of disorders induced by striatal dysfunction (original) (raw)
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Brain and Development, 2003
Tourette's syndrome is characterized by simple, involuntary muscle contractions and/or more complex movements or stereotyped behaviors, including vocalizations. There are strong indications that the basal ganglia play an important role in the pathophysiology of Tourette's syndrome. The present account reviews the functional anatomy of the basal ganglia, with an emphasis on the prefrontal cortex-ventral striatopallidal system. Different parts of the basal ganglia and thalamocortical system, with a focus on the premotor and prefrontal cortices, are connected with each other via parallel, functionally segregated basal ganglia-thalamocortical systems. These parallel circuits, representing sensorimotor, cognitive and emotional-motivational behavioral processes, are connected with each other through specific pathways that serve to integrate these various functions. In the context of the discussion on the pathophysiological mechanisms that lead to the expression of tics, emphasis is placed on the pathways that lead from the ventral striatum via the dopaminergic substantia nigra to the dorsal striatum. The dorsal striatum is crucial for habit formation. A conclusion of this overview of the anatomical organization of the basal ganglia is that via dopaminergic pathways limbic-relation information can influence the expression of (fragments of) motor and behavioral repertoires. Whether such mechanisms indeed play a role in the expression of tics in Tourette's syndrome remains to be established.
PLoS computational biology, 2017
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 pathw...
The Neural Circuits That Generate Tics in Tourette's Syndrome
American Journal of Psychiatry, 2011
Objective-To study neural activity and connectivity within cortico-striato-thalamo-cortical circuits and to reveal circuit-based neural mechanisms that govern tic generation in Tourette syndrome. Method-We acquired fMRI data from 13 participants with Tourette syndrome and 21 controls during spontaneous or simulated tics. We used independent component analysis with hierarchical partner matching to isolate neural activity within functionally distinct regions of cortico-striatothalamo-cortical circuits. We used Granger causality to investigate causal interactions among these regions. Results-We found that the Tourette group exhibited stronger neural activity and interregional causality than controls throughout all portions of the motor pathway including sensorimotor cortex, putamen, pallidum, and substania nigra. Activity in these areas correlated positively with the severity of tic symptoms. Activity within the Tourette group was stronger during spontaneous tics than during voluntary tics in somatosensory and posterior parietal cortices, putamen, and amygdala/hippocampus complex, suggesting that activity in these regions may represent features of the premonitory urges that generate spontaneous tic behaviors. In contrast, activity was weaker in the Tourette group than in controls within portions of cortico-striato-thalamo-cortical circuits that exert top-down control over motor pathways (caudate and anterior cingulate cortex), and progressively less activity in these regions accompanied more severe tic symptoms, suggesting that faulty activity in these circuits may fail to control tic behaviors or the premonitory urges that generate them. Conclusions-Our findings taken together suggest that tics are caused by the combined effects of excessive activity in motor pathways and reduced activation in control portions of corticostriato-thalamo-cortical circuits.
Functional immaturity of cortico-basal ganglia networks in Gilles de la Tourette syndrome
Brain, 2012
Gilles de la Tourette syndrome is a clinically heterogeneous disorder with poor known pathophysiology. Recent neuropathological and structural neuroimaging data pointed to the dysfunction of cortico-basal ganglia networks. Nonetheless, it is not clear how these structural changes alter the functional activity of the brain and lead to heterogeneous clinical expressions of the syndrome. The objective of this study was to evaluate global integrative state and organization of functional connections of sensori-motor, associative and limbic cortico-basal ganglia networks, which are likely involved in tics and behavioural expressions of Gilles de la Tourette syndrome. We also tested the hypothesis that specific regions and networks contribute to different symptoms. Data were acquired on 59 adult patients and 27 gender-and age-matched controls using a 3T magnetic resonance imaging scanner. Cortico-basal ganglia networks were constructed from 91 regions of interest. Functional connectivity was quantified using global integration and graph theory measures. We found a stronger functional integration (more interactions among anatomical regions) and a global functional disorganization of cortico-basal ganglia networks in patients with Gilles de la Tourette syndrome compared with controls. All networks were characterized by a shorter path length, a higher number of and stronger functional connections among the regions and by a loss of pivotal regions of information transfer (hubs). The functional abnormalities correlated to tic severity in all corticobasal ganglia networks, namely in premotor, sensori-motor, parietal and cingulate cortices and medial thalamus. Tic complexity was correlated to functional abnormalities in sensori-motor and associative networks, namely in insula and putamen. Severity of obsessive-compulsive disorder was correlated with functional abnormalities in associative and limbic networks, namely in orbito-frontal and prefrontal dorsolateral cortices. The results suggest that the pattern of functional changes in cortico-basal ganglia networks in http://brain.oxfordjournals.org/ Downloaded from patients could reflect a defect in brain maturation. They also support the hypothesis that distinct regions of cortico-basal ganglia networks contribute to the clinical heterogeneity of this syndrome.
Behavioral and Movement Disorders Induced by Local Inhibitory Dysfunction in Primate Striatum
Cerebral Cortex, 2009
The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.
Proceedings of the National Academy of Sciences, 2015
Gilles de la Tourette syndrome (TS) is characterized by tics, which are transiently worsened by stress, acute administration of dopaminergic drugs, and by subtle deficits in motor coordination and sensorimotor gating. It represents the most severe end of a spectrum of tic disorders that, in aggregate, affect ∼ 5% of the population. Available treatments are frequently inadequate, and the pathophysiology is poorly understood. Postmortem studies have revealed a reduction in specific striatal interneurons, including the large cholinergic interneurons, in severe disease. We tested the hypothesis that this deficit is sufficient to produce aspects of the phenomenology of TS, using a strategy for targeted, specific cell ablation in mice. We achieved ∼ 50% ablation of the cholinergic interneurons of the striatum, recapitulating the deficit observed in patients postmortem, without any effect on GABAergic markers or on parvalbumin-expressing fast-spiking interneurons. Interneuron ablation in the dorsolateral striatum (DLS), corresponding roughly to the human putamen, led to tic-like stereotypies after either acute stress or d-amphetamine challenge; ablation in the dorsomedial striatum, in contrast, did not. DLS interneuron ablation also led to a deficit in coordination on the rotorod, but not to any abnormalities in prepulse inhibition, a measure of sensorimotor gating. These results support the causal sufficiency of cholinergic interneuron deficits in the DLS to produce some, but not all, of the characteristic symptoms of TS.
Brain, 2009
Gilles de la Tourette syndrome is a neuropsychiatric disorder in which cortical disinhibition has been proposed as a pathophysiological mechanism involved in the generation of tics. Tics are typically reduced during task performance and concentration. How this task-dependent reduction of motor symptoms is represented in the brain is not yet understood. The aim of the current research was to study motorcortical excitability at rest and during the preparation of a simple motor task. Transcranial magnetic stimulation was used to examine corticospinal excitability, short-interval intracortical inhibition and intracortical facilitation in a group of 11 patients with Gilles de la Tourette syndrome and age-matched healthy controls. Parameters of cortical excitability were evaluated at rest and at six points in time during the preparation of a simple finger movement. Patients with Gilles de la Tourette syndrome displayed significantly reduced short-interval intracortical inhibition at rest, while no differences were apparent for unconditioned motor evoked potential or intracortical facilitation. During the premovement phase, significant differences between groups were seen for single pulse motor evoked potential amplitudes and short-interval intracortical inhibition. Short-interval intracortical inhibition was reduced in the early phase of movement preparation (similar to rest) followed by a transition towards more inhibition. Subsequently modulation of short-interval intracortical inhibition was comparable to controls, while corticospinal recruitment was reduced in later phases of movement preparation. The present data support the hypothesis of motorcortical disinhibition in Gilles de la Tourette syndrome at rest. During performance of a motor task, patients start from an abnormally disinhibited level of short-interval intracortical inhibition early during movement preparation with subsequent modulation of inhibitory activity similar to healthy controls. We hypothesize that while at rest, abnormal subcortical inputs from aberrant striato-thalamic afferents target the motor cortex, during motor performance, motor cortical excitability most likely underlies top-down control from higher motor areas and prefrontal cortex, which override these abnormal subcortical inputs to guarantee adequate behavioural performance.
Brain, 2009
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Previous structural MRI studies have identified regional abnormalities in grey matter, especially in the basal ganglia. These findings are consistent with the assumption of alterations in cortico-striato-thalamo-cortical circuits and dopaminergic neurotransmission playing a major role in the pathophysiology of GTS. Additionally, recent imaging studies suggested an involvement of sensory-motor cortices in the pathophysiology of GTS. However, little is known about the role of white matter changes in GTS. In this study, we aimed to examine whether GTS is associated with abnormalities in white matter microstructure and whether these changes are correlated with tic severity. In a morphometric study based on diffusion tensor MRI of the whole brain, we compared brain tissue diffusion characteristics between 15 unmedicated adults with GTS without psychiatric co-morbidity and 15 healthy age-and sex-matched controls. We performed voxel-based morphometry (VBM) of regional fractional anisotropy (FA) values to identify regional differences in white matter microstructure between the groups. We also tested for a linear relationship between regional FA values and clinical scores of tic severity. Probabilistic fibre tracking was applied to characterize anatomical connectivity of those areas showing differences in regional FA. Compared with healthy controls, GTS patients showed bilateral FA increases in white matter underlying the post-and precentral gyrus, below the left supplementary motor area, and in the right ventro-postero-lateral part of the thalamus. The peak increase in FA was located below the left postcentral gyrus. Probabilistic tractography identified transcallosal and ipsilateral cerebellothalamo-cortical pathways of the somatosensory system passing through this subcortical region. In patients, regional FA in this region showed an inverse linear relationship with tic severity. These findings demonstrate, for the first time, structural alterations in somatosensory pathways in GTS. Changes of water diffusion characteristics point towards reduced branching in somatosensory pathways in GTS patients. The negative correlation between higher regional FA values and fewer tics