Cerebellum Involvement in Dystonia During Associative Motor Learning: Insights From a Data-Driven Spiking Network Model

Abstract

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Although dystonia is traditionally associated with basal ganglia dysfunction, recent evidence has been pointing to a role of the cerebellum, a brain area involved in motor control and learning. Cerebellar abnormalities have been correlated with dystonia but their potential causative role remains elusive. Here, we simulated the cerebellar input-output relationship with high-resolution computational modeling. We used a data-driven cerebellar Spiking Neural Network and simulated a cerebellum-driven associative learning task, Eye-Blink Classical Conditioning (EBCC), which is characteristically altered in relation to cerebellar lesions in several pathologies. In control simulations, input stimuli entrained characteristic network dynamics and induced synaptic plasticity along task repetitions, causing a progressive spike suppression in Purkinje cells with consequent facilitation of deep cerebellar nuclei cells. These neuronal processes caused a progressive acquisition of eyelid Conditioned Responses (CRs). Then, we modified structural or functional local neural features in the network reproducing alterations reported in dystonic mice. Either reduced olivocerebellar input or aberrant Purkinje cell burst-firing resulted in abnormal learning curves imitating the dysfunctional EBCC motor responses (in terms of CR amount and timing) of dystonic mice. These behavioral deficits might be due to altered temporal processing of sensorimotor information and uncoordinated control of muscle contractions. Conversely, an imbalance of excitatory and inhibitory synaptic densities on Purkinje cells did not reflect into significant EBCC deficit. The present work suggests that only certain types of alterations, including reduced olivocerebellar input and aberrant PC burst-firing, are compatible with the EBCC changes observed in dystonia, indicating that some cerebellar lesions can have a causative role in the pathogenesis of symptoms.

Infratentorial Morphometry and Deep Brain Stimulation Outcome in Cervical Dystonia

“…(60) Physiological cerebellar changes in focal dystonia have been debated to arise as part of the core pathology or as compensatory changes to basal ganglia dysfunction. (61,62) Purkinje cell loss, as observed in post-mortem patients with cervical dystonia,(12) is consistent with reduced cerebellar volumes identified in patients with poorer motor response to DBS. Purkinje cell loss has been proposed to result in diminished GABAergic olivo-cerebellar output to the thalamus,(63) resulting in greater impairment of motor networks, and in the current study, reduced efficacy of therapeutic targeting.…”

“…Damage to the cerebellopontine angle, referring to the space between the pons and cerebellum, has been shown to elicit cervical dystonia in a single case study,(59) indicating a pathophysiological role of brainstem-cerebellar coupling in symptom generation.Structural brain changes in focal dystonia are favoured within a compensatory framework in contrast to neurodegeneration. (60) Physiological cerebellar changes in focal dystonia have been debated to arise as part of the core pathology or as compensatory changes to basal ganglia dysfunction (61,62). Purkinje cell loss, as observed in post-mortem patients with cervical dystonia,(12) is consistent with reduced cerebellar volumes identified in patients with poorer motor response to DBS.…”

Iron accumulation and axonal damage of cerebellum in idiopathic cervical dystonia

“…The interactions between basal ganglia and cerebellum are complicated, and their roles in the pathophysiology of dystonia need to be confirmed by further studies. Computational modeling, including cerebellar and basal ganglia circuits, is considered a potential tool to investigate this exciting topic [62].…”

Cervical dystonia and no oculomotor apraxia as new manifestation of ataxia-telangiectasia-like disorder 1 – case report and review of the literature

“…In contrast to our patient, Although dystonia was present in some ATLD1 patients, it is not the main symptom of ATLD1. Dystonia is classically considered a basal ganglia disease, however now it is regarded as a network disorder with involvement of the cerebellum (32,33). Le Bar et al characterized familial phenotype associating dystonia and cerebellar atrophy (34).…”