Objective: To explore underlying circuit-level mechanisms in paroxysmal kinesigenic dyskinesia (PKD).

Background: While the cortico-striato-thalamo-cortical loop and cerebellum are implicated in PKD pathophysiology, the causal interactions among these nodes remain poorly understood. Moreover, involvement of emotional factors suggest potential limbic-motor interactions.

Method: Resting-state fMRI data were acquired from 77 PKD patients and 45 healthy controls. Patients were stratified into subgroups: remission R vs non-remission NR and emotion-sensitive ES vs emotion-insensitive non-ES. Four three-node dynamic causal modelings (DCMs) were constructed for each participant. Parametric empirical Bayes (PEB) was used for group-level effective connectivity (EC) analysis and between-group comparisons.

Results: PKD patients exhibited enhanced excitatory self-connection of the right putamen and strengthened inhibitory connection from the right putamen to the left cerebellum in putamen circuits. Additionally, in amygdala circuits, patients showed enhanced inhibitory influences from the right amygdala and right thalamus to the left cerebellum, along with reduced right cerebellar self-inhibition.

The NR group showed reduced left putamen self-excitation, enhanced left putamen to left thalamus excitation, and enhanced right thalamus to left cerebellum inhibition. The R group exhibited right thalamic self-excitation and enhanced left thalamus to right cerebellum inhibition.

The ES group showed reduced left amygdala to thalamus inhibition and weakened bidirectional cerebellum-thalamus connectivity. Correlation analysis in ES revealed pathological coupling among thalamic self-connection, thalamus-amygdala, and amygdala-cerebellum connections. In contrast, the non-ES group exhibited different change directions in the bilateral amygdala self-excitation.

Conclusion: This study identifies right putamen hyperexcitability and its aberrant inhibitory influence on the cerebellum as core pathophysiological features of PKD. Clinical remission involves both normalization of abnormalities. Emotion susceptibility in PKD is associated with disinhibition of amygdala-thalamic pathways and pathological coupling within limbic-motor circuits, while emotion-insensitive patients exhibit protective amygdala self-excitation regulation that buffers against affective influences. These findings provide a circuit-level framework for understanding PKD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/altered-motor-regulation-and-limbic-motor-circuits-in-paroxysmal-kinesigenic-dyskinesia/