Emerging concepts in the physiological basis of dystonia

Abstract

Work over the past 2 decades has led to substantial changes in our understanding of dystonia pathophysiology. Three general abnormalities appear to underlie the pathophysiological substrate. The first is a loss of inhibition. This makes sense considering that it may be responsible for the excess of movement and for the overflow phenomena seen in dystonia. A second abnormality is sensory dysfunction which is related to the mild sensory complaints in patients with focal dystonias and may be responsible for some of the motor dysfunction. Third, evidence from animal models of dystonia as well as from patients with primary dystonia has revealed significant alterations of synaptic plasticity characterized by a disruption of homeostatic plasticity, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. We speculate that during motor learning this abnormal plasticity may lead to an abnormal sensorimotor integration, leading to consolidation of abnormal motor engrams. If so, then removing this abnormal plasticity might have little immediate effect on dystonic movements because bad motor memories have already been ''learned'' and are difficult to erase. These considerations might explain the delayed clinical effects of deep brain stimulation (DBS) in patients with generalized dystonia. Current lines of research will be discussed from a network perspective. © 2013 Movement Disorder Society.

Keywords: dystonia; sensory-motor plasticity; basal ganglia; transcranial magnetic stimulation.

© 2013 Movement Disorder Society.

Figures

Fig. 1. Surround inhibition during motor imagery

Changes in mean motor evoked potential (MEP) size during motor imagery on the right side of healthy controls and on the affected side of patients. TMS was always given to the motor cortex contralateral to the imagined task. MEP size during motor imagery (MI) compared with rest condition recorded from different target muscles of the right upper limb after stimulation of the left hemisphere in controls (A) and patients with writer’s cramp (B). The bar chart illustrates the mean peak-to-peak amplitude (mV) of MEPs recorded at rest (open columns) and during MI (black columns). Each error bar equals standard error of the mean (SEM). MI elicited an attenuated and less focal increase in MEP amplitude in patients than in controls. FDI, first dorsal interosseus; APB, abductor pollicis brevis; ADM, abductor digiti minimi; ECR, extensor carpi radialis; BIC, biceps. *P

Fig.2. Paired associative stimulation

Effect of associative stimulation (PAS) on the size of motor evoked potentials (MEPs) of the right APB and FDI muscle in ten patients with writer’s cramp (right panel) and ten healthy controls (left panel). The bar chart illustrates the mean peak-to-peak amplitude (mV) of MEPs recorded at rest before (open columns) and after associative stimulation (shaded columns). Each error bar equals standard error of the mean (SEM). Representative examples of MEPs evoked in the right APB and FDI muscles are given for each group below each bar chart. Each trace represents an average of five consecutive MEPs. Associative stimulation led to an increase in MEPs size in patients and controls. However, the facilitatory effect was significantly stronger in patients. (from: Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, Scalfari A, Morgante F, Battaglia F, Romano M, Girlanda P. Abnormal associative plasticity of the human motor cortex in writer’s cramp. Brain. 2003 Dec;126(Pt 12):2586–96).

Fig.3. Homeostatic plasticity

Panel A illustrates the mean amplitude of MEPs after two types of conditioning in healthy controls. There was a “facilitatory” response to anodal TDCS pre-conditioning which was reversed by a subsequent period of 1 Hz rTMS. Conversely, “inhibitory” pre-conditioning with cathodal TDCS resulted in an opposite after effect of 1 Hz rTMS which led to an increase in corticospinal excitability. Panel B plots the changes in corticospinal excitability in writer’s cramp patients after the two types of conditioning. Patients showed an abnormal responsiveness to TDCS and rTMS. (i) Only anodal TDCS produced a normal facilitatory effect on corticospinal excitability, whereas “inhibitory” cathodal TDCS had no after effect on corticospinal excitability. (ii) Regardless of the type of pre-conditioning, rTMS had no consistent effect on corticospinal excitability. In particular, although anodal TDCS produced a “normal” facilitatory response, subsequent 1 Hz rTMS did not reverse the increase in excitability produced by anodal pre-conditioning. MEP amplitudes are given as a percentage of the MEP size at baseline. Each error bar equals standard error of the mean (SEM). (from: Quartarone A, Rizzo V, Bagnato S, Morgante F, Sant’Angelo A, Romano M, Crupi D, Girlanda P, Rothwell JC, Siebner HR. Homeostatic-like plasticity of the primary motor hand area is impaired in focal hand dystonia. Brain. 2005 Aug;128(Pt 8):1943–50)