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

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.

Fig. 1

Activation responses during the trial-and-error-based sequence-learning task in nmDYT1 mutation carriers and controls (see text; Tables1 and 2).The surface rendering of the statistical map (SPM99 canonical template) reflects sequence-learning-related activation (TSEQ>CCW) specific to the six non-manifesting DYT1 mutation carriers (red) and specific to the six controls (green) as well as areas of overlapping activation (yellow). Sequence-learning activation responses in both groups were localized to the dorsolateral prefrontal cortex (DLPFC), dorsal premotor cortex (PMC) and to the medial and lateral parietal association cortices. Significant cerebellar activation responses were present in theDYT1group only.

Fig. 2

Brain regions in which learning-related activation responses during trial-and-error-based sequence-learning were reduced in nmDYT1 carriers relative to controls (Table 3, see text): SPM{t} maps (top panel) were superimposed on a single-subject MRI T1 template (x, y, z coordinates in MNI space indicate the position of the slice). Bar diagrams (bottom) illustrate adjusted regional cerebral blood flow (rCBF) during sequence learning (TSEQ) and during the motor reference task (CCW) in the respective cluster/VOI (mean ± SE) in the DYT1mutation carriers (dark gray) and controls (light gray). Decreased learning-related activation was present in the DLPFC (A) as well as in the left dPMC (B) with significant activation in controls, but not in carriers of the DYT1mutation. Additionally, nmDYT1s deactivated the anterior cingulate cortex (B), while controls activated this region. Significant contrasts of post hoc VOI comparisons are displayed (P-values of paired T-tests marked with asterisk). Brain activation during the baseline motor task was comparable across groups in all displayed regions (P > 0.2). (The colour stripe represents Tvalues thresholded at 3.5, P < 0.001.)

Fig. 3

Brain regions in which learning-related activation responses during trial-and-error-based sequence-learning were increased in DYT1 carriers relative to controls (Table 4; see text): SPM{t}maps (top panel) were superimposed on a single-subject MRI T1 template (x, y, z coordinates in MNI space indicate the position of the slice). Bar diagrams (bottom) illustrate adjusted regional cerebral blood flow (rCBF) during sequence learning (TSEQ) and during the motor reference task (CCW) in the respective cluster/VOI (mean ± SE) in the DYT1 mutation carriers (dark gray) and controls (light gray). Increased learning-related activation was present in the left cerebellar cortex and to a lesser degree in the right-sided homologue (A) as well as in the right inferotemporal cortex (B). Brain activation during the baseline motor task was comparable across groups in all displayed regions (P > 0.2). P-values refer to post hoc VOI testing using unpaired and paired (asterisk) T-tests. (The colour stripe for the left and right column represents T values thresholded at 3.5, P < 0.001, T values for the middle column were thresholded at 3.0, P < 0.005.)