Defective cerebellar control of cortical plasticity in writer’s cramp

Abstract

A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer's cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients' maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (-40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer's cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer's cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer's cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing.

Dissecting the Links Between Cerebellum and Dystonia

“…In the case of writer's cramp, the slower adaptation rates in Hoffland's study are in line with the findings of Hubsch et al [8] who compared the performance of 21 people with writer's cramp and 25 healthy controls in a reaching task that included a visuomotor conflict. They found that people with writer's cramp exhibited a complete loss of both inhibitory and excitatory cerebellar priming of cortical sensorimotor plasticity.…”

“…They found that people with writer's cramp exhibited a complete loss of both inhibitory and excitatory cerebellar priming of cortical sensorimotor plasticity. In a visuomotor task, people with writer's cramp were also less efficient than healthy subjects at washing out a previous adaptation strategy [8]. People with focal hand dystonia also showed abnormal associative learning in an eyeblink classical conditioning paradigm [24].…”

“…This localization of dystonia to the basal ganglia does not accommodate a growing body of clinical and experimental evidence of the involvement of other structures, and the concept of dystonia as a network disorder involving multiple brain regions has been proposed [2,3]. The role of the cerebellum in the pathophysiology of dystonia was first noted by Fletcher et al [4] and there is strong evidence of abnormal cerebellar function from pathological, neuroimaging, and neurophysiological studies [2,3,5], particularly in forms of primary dystonia [6][7][8].…”

Non-invasive cerebellar stimulation in dystonia

“…There is emerging evidence that motor learning is deficient in people with cervical dystonia using neurophysiological measures of learning [88,89]. People with FHD are slower to adapt to visuomotor perturbations than healthy adults [90]. The only working memory task tested to date to our knowledge is the mental rotation task, a visuospatial working memory task [78].…”

A single session of cerebellar theta burst stimulation does not alter writing performance in writer’s cramp

“…Although this role is not yet fully understood (Sadnicka et al, 2012), an elegant paper by Hubsch et al (2013) in Brain showed that in writer's cramp, a form of task-specific primary hand dystonia, the cerebellum has lost its ability to modulate sensorimotor plasticity of the motor cortex. As part of their study, they used the paired-associative stimulation protocol, a transcranial magnetic stimulation-based intervention to induce motor cortex plasticity, combined with either intermittent or continuous theta burst stimulation (TBS) over the cerebellum.…”