Contemporary functional neuroanatomy and pathophysiology of dystonia

Abstract

Dystonia is a disabling movement disorder characterized by abnormal postures or patterned and repetitive movements due to co-contraction of muscles in proximity to muscles desired for a certain movement. Important and well-established pathophysiological concepts are the impairment of sensorimotor integration, a loss of inhibitory control on several levels of the central nervous system and changes in synaptic plasticity. These mechanisms collectively contribute to an impairment of the gating function of the basal ganglia which results in an insufficient suppression of noisy activity and an excessive activation of cortical areas. In addition to this traditional view, a plethora of animal, genetic, imaging and electrophysiological studies highlight the role of the (1) cerebellum, (2) the cerebello-thalamic connection and (3) the functional interplay between basal ganglia and the cerebellum in the pathophysiology of dystonia. Another emerging topic is the better understanding of the microarchitecture of the striatum and its implications for dystonia. The striosomes are of particular interest as they likely control the dopamine release via inhibitory striato-nigral projections. Striosomal dysfunction has been implicated in hyperkinetic movement disorders including dystonia. This review will provide a comprehensive overview about the current understanding of the functional neuroanatomy and pathophysiology of dystonia and aims to move the traditional view of a 'basal ganglia disorder' to a network perspective with a dynamic interplay between cortex, basal ganglia, thalamus, brainstem and cerebellum.

Keywords: Basal ganglia; Cerebellum; Dystonia; Inhibition; Pathophysiology.

Fig. 1

Proposed functional alterations in X-linked dystonia parkinsonism over the disease course due to progressive striatal neurodegeneration. In the physiological state, neurons of the striosomes (S) send inhibitory GABAergic projections to dopamine-containing neurons of the SNc. The SNc innervates D1 and D2 receptor containing matrix (M) neurons and thus differentially modulates the balance between the direct and indirect pathway. Predominant degeneration of the striosomes results in a postulated SNc disinhibition in the early phase of XDP. Dopaminergic dysregulation shifts the balance between both pathways towards the direct pathway which results in impaired surround inhibition and facilitates dystonia. The degeneration of matrix neurons in later disease stages leads to MSA-like parkinsonism due to reduced postsynaptic dopamine receptor density. S striosomes, M matrix, SNc substantia nigra pars compacta, D1 dopamine D1 receptor, D2 dopamine D2 receptor, GABA gamma aminobutyric acid, MSA multiple system atrophy

Fig. 2

Schematic representation of brain structures involved in the pathogenesis of dystonia. Panel (a) shows the traditional view of distinct (striato-)pallido-thalamo-cortical and cerebello-thalamo-cortical pathways that convergently project to distinct thalamic nuclei and are only integrated at the neocortical level. Panel (b) shows the newly identified disynaptic anatomical connections (red arrows) linking the subthalamic nucleus with the cerebellar cortex via the pons and the dentate nucleus with the striatum via the thalamus. The contemporary model integrating the new connections (red arrows) is shown in panel (c). CC cerebellar cortex, CER cerebellum, CTX cortex, DN dentate nucleus, GPe globus pallidus externus, GPi globus pallidus internus, STN subthalamic nucleus, TH thalamus