Increased cerebellar activation during sequence learning in DYT1 carriers: an equiperformance study

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Abstract
We have found that motor sequence learning and related brain activation is impaired in non-manifesting (nm) carriers of the DYT1 deletion for dystonia. In the present study we used a trial-and-error sequence-learning task in conjunction with an equiperformance study design to identify the neural substrates that support sequence learning in nmDYT1 mutation carriers. Six nmDYT1 mutation carriers and six control subjects were scanned with H215O PET during the performance of a trial-and-error guided, kinematically controlled motor sequence learning task and a matched motor execution task. Controls were matched for age and performance. PET data analysis was performed using statistical parametric mapping (SPM99). Although performing at matched levels, nmDYT1 mutation carriers overactivated the lateral cerebellum and the right inferotemporal cortex relative to age-matched controls (P < 0.001). In contrast, they showed relative activation deficits in the dorsolateral prefrontal cortex bilaterally, as well as in the left anterior cingulate and the dorsal premotor cortex (P < 0.001). Prominent compensatory involvement of the cerebellum during target learning is consistent with our prior sequence-learning experiments in nmDYT1 mutation carriers. Contrasting to mutation carriers, normals used bilateral cerebellar activation in conjunction with a prominent prefrontal bilateralization only when confronted with a much higher task difficulty. nmDYT1 mutation carriers lack recruitment of these prefrontal regions that depend on modulation within the cortico-striato-pallido-thalamocortical (CSPTC) loops. Instead, they compensate solely using cerebellar activation. This observation is in keeping with recent evidence of impaired structure/function relationships within CSPTC networks in dystonia perhaps occurring on a neurodevelopmental basis. The inability to recruit the appropriate set of neocortical areas because of altered fronto-striatal connectivity may have led to the shift to cerebellar processing.