Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Catherine Delnooz (Donders Series 141)

7 January, 2014

Promotor: Prof.dr. B.R. Bloem, copromotor: dr. B.P.C. van de Warrenburg

Unravelling primary focal dystonia. A treatment update and new pathophysiological insights

The first two chapters provide a concise overview of medical and allied health treatment strategies in dystonia, with a focus on primary dystonia. Because dystonia’ s pathophysiology remains incompletely understood, its treatment is only symptomatic. The current keystones of medical symptomatic treatment include chemodenervation with botulinum toxin injections, drug treatment, and surgical treatment such as deep brain stimulation. Besides the treatment of dystonia, it is crucial to consider and treat the common non-motor complications (e.g. mood disorders and pain) as well as the secondary orthopaedic and neurological complications. Some potentially interesting allied health interventions include: physical therapy in addition to botulinum toxin injections in cervical dystonia; sensorimotor training and transcutaneous electrical nerve stimulation in writer’s cramp; and speech therapy added to botulinum toxin injections in laryngeal dystonia.

The third chapter focuses on the alterations in neural activity related to task-specificity, i.e. the planning of writing, in patients with simple writer’s cramp, using motor imagery and fMRI as tools. This study showed that simple writer’s cramp is characterized by abnormally increased activity in the dorsal premotor cortex when imagined actions are specifically related to writing, even when having the mere intention to write.

In the fourth chapter we investigated the functional connectivity underlying the abovementioned planning defect as found in writer’s cramp patients. Focusing our analysis on the premotor-parietal network, we found that writer’s cramp patients have reduced functional connectivity between the left dorsal premotor cortex and left area 5L and 7PC, which are involved in somatosensory guidance of (hand) movements.

In the fifth chapter we investigated functional connectivity in cervical dystonia patients in comparison to healthy subjects; and after Botulinum toxin treatment. We evaluated a range of resting state networks with resting state fMRI as a tool. Also, we evaluated functional connectivity within cervical dystonia patients after botulinum toxin treatment, which they had already been receiving for several years. Cervical dystonia patients demonstrated reduced connectivity within the primary visual network and sensorimotor network, involving areas relevant for motor planning and spatial cognition. Four to five weeks after botulinum toxin treatment, there was partial restoration of this dystonia-related connectivity. In contrast, we found increased connectivity in cervical dystonia patients between the executive control network and areas related to motor planning.

In the sixth chapter we further explored functional connectivity changes in cervical dystonia, and focused specifically on cortico-striatal connections. We demonstrated that cervical dystonia patients exhibited decreased connectivity between the mid-dorsal putamen and a fronto-parietal network assumed to be crucial for motor planning, while the anterior putamen had increased connectivity with motor planning areas within the sensorimotor network. Furthermore, botulinum toxin treatment increased connectivity between the midventral striatum and the executive control network.

In the last chapter we studied grey matter morphology in cervical dystonia patients in comparison to healthy subjects, and related to botulinum toxin treatment. We observed that cervical dystonia patients have reduced grey matter volume in the left inferior frontal gyrus, corresponding to the lateral premotor cortex and ventrolateral prefrontal cortex. Four to five weeks after botulinum toxin injections treatment, grey matter volume increased in the right lateral premotor cortex.

The leading results are derived from several advanced neuroimaging techniques demonstrating altered task-related activity, altered functional connectivity, and altered grey matter morphology in motor planning-related brain areas. These combined observations demonstrate that the observed alterations within motor planning-related networks reflect a primary (functional) error of focal dystonia, suggesting that faulty motor planning is crucial for the development of primary focal dystonia.