Sadnicka, A; (2016) The role of the cerebellum in the pathophysiology of dystonia. Doctoral thesis , UCL (University College London).

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Abstract

Research over the last decade has refined our understanding of the neuroanatomical substrates of dystonia. In addition to basal ganglia dysfunction a much wider sensorimotor network has been implicated and within this network the cerebellum is heralded as a core node. Much of the literature linking the cerebellum to dystonia consists of cases in which lesions of the cerebellum are linked to abnormal posture or indirect experimental associations (reviewed in chapter 1). Better defining the functional role of the cerebellum in the pathophysiology of dystonia could provide a scientific rational for future therapeutic advances, adding further weight to an early neurosurgical literature which advocates targeting the cerebellum and its outflow tracts. Within this thesis I applied experimental techniques from which direct inferences about cerebellar function could be made, trying to better define how the cerebellum is functionally involved in the pathogenesis of isolated dystonia. Methodology can be divided into major themes (i) two studies exploring cerebellar modulation of dystonic neurophysiological hallmarks; impaired motor surround inhibition (chapter 2) and excessive plasticity (chapter 3) (ii) evaluation of eye-blink conditioning a form of cerebellar associative learning (chapter 4, chapter 8) (iii) exploring whether millisecond timing, a cerebellar encoded process, is at the root of abnormal temporal discrimination thresholds (chapter 5) and finally (iv) testing adaptation a kinematic cerebellar paradigm in cervical dystonia (chapter 6) and DYT1 dystonia (chapter 7). Overall, my application of the ‘purest’ cerebellar paradigms did not provide a robust functional correlate to implicate specific cerebellar functions as a driver of dystonic pathophysiology. I present good evidence that fundamental computations such as adaptation and associative learning are intact in various groups of isolated dystonia. Thus isolated dystonia does not seem to selectively impair cerebellar functions (as currently defined). It is only with future research that we will be able to determine whether dystonia corrupts function(s) inherent to the dystonic network which includes the cerebellum or whether the cerebellar abnormalities observed experimentally are compensatory in nature.

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