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.

Keywords: associative learning; cerebellum; dystonia; eyeblink conditioning.

FIG 1

Eyeblink conditioning in humans. Method (a) the unconditioned stimulus consists of electrical stimulation to the supraorbital nerve at 800 ms which causes a blink, the unconditioned response. The conditioning stimulus is an auditory tone that starts at 400 ms with a duration of 400 ms. With repeated pairings a conditioned blink response emerges prior to supraorbital nerve stimulation. (b) Rectified electromyographic traces from a single trial early with no conditioned response and a later trial when conditioning has developed. (c) Two assessors scored the number of conditioned responses in every trial whilst blinded to the participants' identity. Their post hoc concordance correlation coefficient was excellent across all blocks (values >0.7 are considered reasonable, see supplementary methods for detail). [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

(a) The range of conditioning across individuals is demonstrated in three dimensional plots for controls (n = 50) and dystonia (n = 51). Block numbers 1 to 6 are shown on the x‐axis, percent (%) conditioning on the vertical y‐axis, and participant number on the z‐axis. For each group the profile of responses is sorted according to the percent conditioning achieved by the final block. Percent conditioning for each block is marked by a filled circle and connected by a thin line of the same color. The groups were matched for age and sex. (b) For each plot, all participants (n = 101) are plotted in pale gray in the background to illustrate degree of variability. Each graph then shows the group mean and shaded standard error when grouped by presence of dystonia, age range, and sex (control = grey, dystonia = blue, ≤40 years = light green, 41–60 years = green, >60 years = dark green, female = orange, male = red). (c), (d) On the y‐axis of each plot the model counterfactual is plotted, reflecting the model's best estimate for conditioning behavior by block for each age (horizontal panels) and sex category (vertical panels). In (c) controls are plotted with a partially transparent grey line to aid visualization of overlapping lines. The key shows the marker size proportional to the number of patients in each group. [Color figure can be viewed at wileyonlinelibrary.com]