Tisch, S.H.D.; (2007) Neuroplasticity following pallidal stimulation for dystonia. Doctoral thesis , University of London.

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Abstract

Dystonia is a disabling condition characterised by involuntary muscle spasms and abnormal postures. Its pathophysiology is incompletely understood but most lines of evidence point to an underlying defect of basal ganglia function leading to abnormal corticomotor output. Various abnormalities have been shown, including abnormal neuronal activity in basal ganglia output nuclei, defective neural inhibition at the spinal, brainstem, cortical level and sensorimotor misprocessing. More recently, increased neural plasticity has been found in dystonia patients in response to transcranial magnetic stimulation (TMS) protocols which induce motor cortex plasticity. Excessive plasticity might contribute to dystonia by promoting or reinforcing abnormal patterns of connectivity. The most significant advance in the treatment of generalised dystonia has been the development of globus pallidus internus (GPi) deep brain stimulation (DBS). Interestingly its beneficial effects are progressive over weeks to months rather than immediate. A plasticity effect has been implicated but physiological evidence has been lacking. Furthermore it is unknown what impact GPi DBS has on the underlying pathophysiology such as defective inhibition or excessive plasticity. The aim of the present work was to examine the impact of GPi DBS on underlying pathophysiological features such as disinhibition and abnormal motor cortical plasticity. In this thesis, studies in a consecutive series of dystonia patients, mainly those with primary generalised dystonia, who underwent bilateral GPi DBS, are presented. Patients were studied in a prospective, longitudinal manner with both clinical assessment of dystonia using a validated rating scale and electrophysiological studies including blink reflex excitability and forearm H-reflex reciprocal inhibition. In addition, once stable improvement had been achieved, the impact of GPi DBS on motor cortex plasticity was studied using TMS paired associative stimulation (PAS). The clinical study of these patients confirmed the therapeutic efficacy of GPi DBS and provided direct evidence of the superiority of the posteroventral globus pallidus as the optimal target. The longitudinal studies of blink and H-reflex, showed progressive normalisation of brainstem and spinal excitability, which correlated with the time-course of clinical improvement. These data provide the first evidence of reversal of underlying dystonia pathophysiology by GPi DBS and are compatible with progressive long-term neural reorganisation (plasticity) playing a role in the mechanism of action of GPi DBS. Furthermore, the result of TMS PAS experiments demonstrated that GPi DBS reduces the short-term plasticity of the motor cortex, the magnitude of this effect also correlated with therapeutic effect. This result is compatible with the concept that excessive plasticity promotes dystonia and reversal of these abnormalities may be another mechanism by which GPi DBS acts. In conclusion, work presented in this thesis provides the first electrophysiological correlates of clinical improvement in dystonia after GPi DBS, which collectively supports the notion that both long and short-term plasticity within the central nervous system are involved in the mechanism of GPi DBS action.

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