Imaging studies in focal dystonias: a systems level approach to studying a systems level disorder

Abstract

Focal dystonias are dystonias that affect one part of the body, and are sometimes task-specific. Brain imaging and transcranial magnetic stimulation techniques have been valuable in defining the pathophysiology of dystonias in general, and are particularly amenable to studying focal dystonias. Over the past few years, several common themes have emerged in the imaging literature, and this review summarizes these findings and suggests some ways in which these distinct themes might all point to one common systems-level mechanism for dystonia. These themes include (1) the role of premotor regions in focal dystonia, (2) the role of the sensory system and sensorimotor integration in focal dystonia, (3) the role of decreased inhibition/increased excitation in focal dystonia, and (4) the role of brain imaging in evaluating and guiding treatment of focal dystonias. The data across these themes, together with the features of dystonia itself, are consistent with a hypothesis that all dystonias reflect excessive output of postural control/stabilization systems in the brain, and that the mechanisms for dystonia reflect amplification of an existing functional system, rather than recruitment of the wrong motor programs. Imaging is currently being used to test treatment effectiveness, and to visually guide treatment of dystonia, such as placement of deep brain stimulation electrodes. In the future, it is hoped that imaging may be used to individualize treatments across behavioral, pharmacologic, and surgical domains, thus optimizing both the speed and effectiveness of treatment for any given individual with focal dystonia.

Keywords: DBS.; DTI; Dystonia; MEG; PET; TMS; basal ganglia; botulinum toxin; cerebellum; fMRI; posture; premotor.

Fig. (1)

Conceptual model for dystonia and motor control driven by a combination of imaging data, motor circuitry cytoarchitecture, and clinical features of dystonia. This model builds on previous models and proposes three key new features that help to provide a more explicit mechanism for dystonia; these features are highlighted in gray shaded areas, A, B, and C, and are discussed in more detail in [15]. The model argues that dystonia is stereotyped because it reflects excessive amplification of a normal brain functional system. It also argues dystonia can be qualitatively heterogeneous because that functional system has several qualitatively different subcomponents. The proposed toggle system between activation of rest versus movement-related posture/stabilization programs would not only provide a highly efficient mechanism for coordinating across different postural subcomponents with a single neuron, but also offers a potential explanation why dystonia can be observed in both “low” and “high” dopamine states, such as in peak and end dose dystonias in Parkinson’s Disease [122]. The circuitry diagram here is shown in the “rest” or “tonic” dopamine state, and would be reversed during the “activated” or “phasic” state. Blue=movement-related circuitry; Orange=posture/stabilization-related circuitry. Solid lines indicate neuron is activated; dotted lines indicate neuron is inhibited. Plus and minus signs indicate whether a given neuron has an excitatory or inhibitory effect on its efferents (where multiple neuron types are present in a pathway, such as cerebellar output, no specific sign is indicated). GPi: internal globus pallidus; RN: red nucleus; PPN: pedunculopontine nucleus; Thal: thalamus.

Fig. (2)

Schematic diagram of how imaging can be a hypothesis-generating tool that gives us clues about systems neuroscience and potential etiology of abnormalities in dystonia.

Fig. (3)

Both premotor abnormalities and treatment-related effects have been observed across several forms of focal dystonia. (A) Reduced activity in SMA and dorsal premotor cortex during movement imagination in writer’s cramp patients relative to healthy controls [21]. (B) Reduced ipsilateral dorsal premotor and supplementary motor area (SMA) activation in cervical dystonia patients after (versus before) treatment with botulinum toxin (BTX) [23]. (C) Epidural premotor stimulation in cervical dystonia/upper limb dystonia patients led to normalization of elevated glucose metabolism in dorsal premotor and SMA regions [24]. (D) A transcranial magnetic stimulation (TMS) conditioning pulse over left dorsal premotor cortex led to premotor-motor inhibition at rest in focal hand dystonia patients, but not controls. This inhibition was absent during movement in patients, suggesting premotor cortex may play some role in abnormal primary motor cortex surround inhibition during movement in these patients [108]. The y-axis depicts premotor intracortical inhibition (the ratio between the conditioned and unconditioned motor evoked potential [MEP]), and the x-axis shows the conditions: rest, motor preparation (pre-electromyography [pre-EMG]), and movement (phasic).

Fig. (4)

Both functional and structural abnormalities have been shown in the cerebellum across several forms of focal dystonia. (A) Individuals with the DYT6 dystonia mutation exhibited reduced tractography through the major outflow pathway of the cerebellum relative to healthy controls, and there was a group-wise trend in which manifesting carriers exhibited greater reductions than those who did not manifest [52]. Colorized images of group differences are shown here for combined DYT1 and DYT6 data; the box and whisker plot is shown for DYT6 patients only. (B) Cervical dystonia patients exhibited reduced and increased probabilistic tractography from the left ansa lenticularis (AL) and right pallidum, respectively; the regions of difference intersect with the red nucleus (in purple), which is a major relay nucleus of the cerebellum [55]. (C) Both adductor (ADSD) and abductor (ABSD) forms of spasmodic dysphonia showed increased activation in the cerebellum during symptomatic syllable production, relative to controls [57].

Fig. (5)

Diffusion tensor imaging (DTI) tractography can be used for individualized placement of deep brain stimulation electrodes in white matter tracts. The figure shown here illustrates how this method was used for electrode placement in the dentato-rubro-thalamic tract in a therapy-refractory tremor patient (from [116]).