Dataset Information

A Critical Investigation of Cerebellar Associative Learning in Isolated Dystonia.

ABSTRACT:

Background

Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered.

Objective

To systematically examine the influence of dystonia, dystonia subtype, and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex.

Methods

Original neurophysiological data from all published studies (until 2019) were shared and compared to an age- and sex-matched control group. Two raters blinded to participant identity rescored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block across raters was entered into a mixed repetitive measures model.

Results

Isolated dystonia (P = 0.517) and the subtypes of isolated dystonia (cervical dystonia, DYT-TOR1A, DYT-THAP1, and focal hand dystonia) had similar levels of eyeblink conditioning relative to controls. The presence of tremor did not significantly influence levels of eyeblink conditioning. A large range of eyeblink conditioning behavior was seen in both health and dystonia and sample size estimates are provided for future studies.

Conclusions

The similarity of eyeblink conditioning behavior in dystonia and controls is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

SUBMITTER: Sadnicka A

PROVIDER: S-EPMC9313805 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.