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Objective: Whether the basal ganglia are involved in the cortical synchronization during focal seizures is still an open question. In the present study, we proposed to synchronize cortico-striatal activities acutely inducing striatal disinhibition, performing GABA-antagonist injections within the putamen in primates. Method: Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of bicuculline (0.5–4 μL) were injected at a slow rate of 1 μL/min. Spontaneous behavioral changes were classified according to Racine’s scale modified for primates. These induced motor behaviors were correlated with electromyographic, electroencephalographic, and putaminal and pallidal local field potentials changes in activity. Results: acute striatal desinhibition induced focal motor seizures. Seizures were closely linked to cortical epileptic activity synchronized with a striatal paroxysmal activity. These changes in striatal activity preceded the cortical epileptic activity and the induced myoclonia, and both cortical and subcortical activities were coherently synchronized during generalized seizures. Interpretation: Our results strongly suggest the role of the sensorimotor striatum in the regulation and synchronization of cortical excitability. These dramatic changes in the activity of this “gating” pathway might influence seizure susceptibility by modulating the threshold for the initiation of focal motor seizures.

Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.

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Behavioral adaptation, a central feature of voluntary movement, is known to rely on top-down cognitive control. For example, the conflict-adaptation effect on tasks such as the Stroop task leads to better performance (e.g. shorter reaction time) for incongruent trials following an already incongruent one. The role of higher-order cortices in such between-trial adjustments is well documented, however, a specific involvement of the primary motor cortex (M1) has seldom been questioned. Here we studied changes in corticospinal excitability associated with the conflict-adaptation process. For this, we used single-pulse transcranial-magnetic stimulation (TMS) applied between two consecutive trials in an interference flanker task, while measuring motor-evoked potentials (MEPs) after agonistic and antagonistic voluntary movements. In agonist movement, MEP amplitude was modulated by recent movement history with an increase favoring movement repetition, but no significant change in MEP size was observed whether a previous trial was incongruent or congruent. Critically, for an antagonist movement, the relative size of MEPs following incongruent trials correlated positively with the strength of behavioral adaptation measured as the degree of RT shortening across subjects. This post-conflict increase in corticospinal excitability related to antagonist muscle recruitment could compensate for a potential deleterious bias due to recent movement history that favors the last executed action. Namely, it prepares the motor system to rapidly adapt to a changing and unpredictable context by equalizing the preparation for all possible motor responses.

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