Low‐frequency median nerve stimulation, paired with suprathreshold transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis (APB) muscle induces a long‐lasting increase in the excitability of corticospinal output neurons, if median nerve stimulation is given 25 ms before TMS. Here we employed this protocol of stimulation to assess associative plasticity of the primary motor hand area in 10 patients with writer’s cramp and 10 age‐matched controls. Motor evoked potentials (MEPs) were recorded from right APB muscle and right first dorsal interosseus (FDI) muscle. Resting and active motor threshold, mean MEP amplitude at rest, short‐latency intracortical inhibition (SICI) at an interstimulus interval of 2 ms and the duration of the cortical silent period (CSP) were assessed immediately before and after associative stimulation. In both groups, associative stimulation led to an increase in resting MEP amplitudes which was more pronounced in the right APB muscle. Compared with healthy controls, stimulation‐induced facilitation of MEP amplitudes was stronger in patients with writer’s cramp. In addition, only patients showed a slight decrease of resting and active motor thresholds after conditioning stimulation. In both groups, associative stimulation induced a prolongation of CSP in the APB and FDI muscles, which was significant only in the APB muscle in healthy controls. Associative stimulation had no effects on SICI in patients and healthy controls. Taken together, in patients with writer’s cramp, the motor system exhibited an abnormal increase in corticospinal excitability and an attenuated reinforcement of intracortical inhibitory circuits that generate the CSP in response to associative stimulation. This altered pattern of sensorimotor plasticity may favour maladaptive plasticity during repetitive skilled hand movements and, thus, may be of relevance for the pathophysiology of writer’s cramp and other task‐specific dystonias.

Experimental models of Parkinson's disease have demonstrated abnormal synaptic plasticity in the corticostriatal system, possibly related to the development of levodopa-induced dyskinesias (LID). We tested the hypothesis that LID in Parkinson's disease is associated with aberrant plasticity in the human motor cortex (M1). We employed the paired associative stimulation (PAS) protocol, an experimental intervention involving transcranial magnetic stimulation (TMS) and median nerve stimulation capable of producing long-term potentiation (LTP) like changes in the sensorimotor system in humans. We studied the more affected side of 16 moderately affected patients with Parkinson's disease (9 dyskinetic, 7 non-dyskinetic) and the dominant side of 9 age-matched healthy controls. Motor-evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured at baseline before PAS and for up to 60 min (T0, T30 and T60) after PAS in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. PAS significantly increased MEP size in controls (+74.8% of baseline at T30) but not in patients off medication (T30: +0.07% of baseline in the non-dyskinetic, +27% in the dyskinetic group). Levodopa restored the potentiation of MEP amplitudes by PAS in the non-dyskinetic group (T30: +64.9% of baseline MEP) but not in the dyskinetic group (T30: −9.2% of baseline). PAS prolonged CSP duration in controls. There was a trend towards prolongation of CSP in the non-dyskinetic group off medications but not in the dyskinetic group. Levodopa did not restore CSP prolongation by PAS in the dyskinetic group. Our findings suggest that LTP-like plasticity is deficient in Parkinson's disease off medications and is restored by levodopa in non-dyskinetic but not in dyskinetic patients. Abnormal synaptic plasticity in the motor cortex may play a role in the development of LID.

Objective: To test whether abnormal sensorimotor plasticity in focal hand dystonia is a primary abnormality or is merely a consequence of the dystonic posture. Methods: This study used the paired associative stimulation (PAS) paradigm, an experimental intervention, capable of producing long term potentiation (LTP) like changes in the sensorimotor system in humans. PAS involves transcranial magnetic stimulation combined with median nerve stimulation. 10 patients with cranial and cervical dystonia, who showed no dystonic symptoms in the hand, and nine patients with hemifacial spasm (HFS), a non-dystonic condition, were compared with 10 healthy age matched controls. Motor evoked potential amplitudes and cortical silent period (CSP) duration were measured at baseline before PAS and for up to 60 min (T0, T30 and T60) after PAS in the abductor pollicis brevis and the first dorsal interosseus muscles. Results: Patients with dystonia showed a stronger increase in corticospinal excitability than healthy controls and patients with HFS. In addition, patients with dystonia showed a loss of topographical specificity of PAS induced effects, with a facilitation in both the median and ulnar innervated muscles. While PAS conditioning led to a prolonged CSP in healthy controls and patients with HFS, it had no effect on the duration of the CSP in patients with cranial and cervical dystonia. Conclusion: The data suggests that excessive motor cortex plasticity is not restricted to the circuits clinically affected by dystonia but generalises across the entire sensorimotor system, possibly representing an endophenotypic trait of the disease.

The excitability of inhibitory circuits in patients with writer's cramp is reduced at multiple levels within the sensorimotor system, including the primary motor hand area (M1). Although this may play a major role in the pathophysiology of writer's cramp, it is still unclear what factors may cause the imbalance between inhibition and excitation to arise. One possibility is that homeostatic mechanisms that keep cortical excitability within a normal physiological range are impaired. In eight patients with writer's cramp and eight healthy age-matched controls, we combined low-frequency repetitive transcranial magnetic stimulation (rTMS) with transcranial direct current stimulation (TDCS) to probe regional homeostatic plasticity of the left M1. Confirming our previous study (Siebner et al., J Neurosci 2004; 24: 3379–85), ‘facilitatory’ preconditioning of the M1 with anodal TDCS enhanced the inhibitory effect of subsequent 1 Hz rTMS on corticospinal excitability. Conversely, ‘inhibitory’ preconditioning with cathodal TDCS reversed the after effect of 1 Hz rTMS, producing an increase in corticospinal excitability. The results were quite different in patients with writer's cramp. Following preconditioning with TDCS, 1 Hz rTMS induced no consistent changes in corticospinal excitability, indicating a loss of the normal ‘homeostatic’ response pattern. In addition, the normal inhibitory effect of preconditioning with cathodal TDCS was absent. The present data suggest that homeostatic mechanisms that stabilize excitability levels within a useful dynamic range are impaired in patients with writer's cramp. We propose that a faulty homeostatic response to acute increases in corticospinal excitability favours maladaptive motor plasticity. The role of homeostatic-like plasticity in the pathophysiology of task-specific dystonias warrants further study.

Dystonia is characterized by two main pathophysiological abnormalities: ‘reduced’ excitability of inhibitory systems at many levels of the sensorimotor system, and ‘increased’ plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short-interval intracortical inhibition) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.