Cortical excitability in DYT‐11 positive myoclonus dystonia

Myoclonus‐dystonia (M‐D) is an autosomal dominant movement disorder caused by mutations in the ε‐sarcoglycan gene (DYT11). We explore pathophysiological characteristics of M‐D with the hypothesis that they may be different from those of sporadic or genetic dystonia. We compared five carriers of the DYT11 gene mutation and 10 healthy controls. Using transcranial magnetic stimulation, we measured parameters assessing cortical membrane excitability (active motor threshold, aMT) and synaptic activity (short interval, sICI) and afferent (AI) intracortical inhibitions and their interaction. aMT was significantly higher in the DYT11 gene carriers than in normal subjects. The others parameters (sICI, AI and their interaction) were not different between the two groups. In DYT11 gene carriers cortical membrane excitability was impaired while parameters assessing cortical synaptic activity were normal. Opposite results have been obtained in focal sporadic and generalized DYT1 dystonias. © 2008 Movement Disorder Society     

A neurophysiological study of myoclonus in patients with DYT11 myoclonus‐dystonia syndrome

Mutations in the ?‐sarcoglycan (SGCE) gene have been associated with DYT11 myoclonus‐dystonia syndrome (MDS). The aim of this study was to characterize myoclonus in 9 patients with DYT11‐MDS presenting with predominant myoclonus and mild dystonia by means of neurophysiological techniques. Variously severe multifocal myoclonus occurred in all of the patients, and included short (mean 89.1 ± 13.3 milliseconds) electromyographic bursts without any electroencephalographic correlate, sometimes presenting a pseudo‐rhythmic course. Massive jerks could be evoked by sudden stimuli in 5 patients, showing a “startle‐like” muscle spreading and latencies consistent with a brainstem origin. Somatosensory evoked potentials and long‐loop reflexes were normal, as was silent period and long‐term intracortical inhibition evaluated by means of transcranial magnetic stimulation; however, short‐term intracortical inhibition revealed subtle impairment, and event‐related synchronization (ERS) in the beta band was delayed. Blink reflex recovery was strongly enhanced. Myoclonus in DYT11‐MDS seems to be generated at subcortical level, and possibly involves basal ganglia and brainstem circuitries. Cortical impairment may depend from subcortical dysfunction, but it can also have a role in influencing the myoclonic presentation. The wide distribution of the defective SCGE in DYT11‐MDS may justify the involvement of different brain areas. © 2008 Movement Disorder Society     

Pallidal and thalamic deep brain stimulation in myoclonus‐dystonia

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus‐dystonia (MD). We investigated short‐ and long‐term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi‐ and VIM‐DBS in MD. Ten MD‐patients (nine ε‐sarcoglycan‐mutation‐positive) were evaluated pre‐ and post‐surgically following continuous bilateral GPi‐ and VIM‐DBS at four time points: presurgical, 6, 12, and as a last follow‐up at a mean of 62.3 months postsurgically, and in OFF‐, GPi‐, VIM‐, and GPi‐VIM‐DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke‐Fahn‐Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL‐scores. MD‐symptoms significantly improved at 6 months post‐surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long‐term evaluation post‐surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long‐lasting stimulation‐related adverse events (AEs) were observed. Both GPi‐ and VIM‐DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation‐induced events of GPi‐DBS in comparison with VIM‐DBS, GPi‐DBS seems to be preferable. Combined GPi‐VIM‐DBS can be useful in cases of incapaciting myoclonus, refractory to GPi‐DBS alone. © 2010 Movement Disorder Society     

Abnormal low frequency drive in myoclonus‐dystonia patients correlates with presence of dystonia

The pathophysiology of Myoclonus‐Dystonia (M‐D), an autosomal dominantly inherited movement disorder is largely unknown. In different forms of dystonia abnormal intermuscular coherence is present. The objective of this stufy was to investigate whether the myoclonic and dystonic features are the result of an abnormal common drive to the muscles in M‐D. Coherence analysis was performed in 20 DYT11 mutation carriers (MC) and 13 healthy controls during resting condition and during weak isometric contraction of the arm and neck. The EMG‐EMG coherence analysis showed significantly increased intermuscular 3 to 10 Hz coherence in 4 DYT11 MC with clinical pronounced (mobile and static) dystonia. This coherence was not present in DYT11 MC with mild (static) dystonia and/or predominating myoclonus. The EEG‐EMG analysis showed significant 15 to 30 Hz coherence during weak isometric contraction of the arm in five healthy controls, but in none of the DYT11 MC. The intermuscular coherence in the low frequency band in DYT11 MC with predominant dystonia is concordant with the previously described coherence in dystonia and suggests that the pathophysiology of M‐D shares common pathophysiological features with dystonia. The absence of 15 to 30 Hz EEG‐EMG coherence in DYT11 MC may reflect abnormal motor activation caused by an altered cortical drive because of the basal ganglia dysfunction. © 2007 Movement Disorder Society     

White matter abnormalities in gene‐positive myoclonus‐dystonia

Myoclonus‐dystonia is an autosomal dominantly inherited movement disorder clinically characterized by myoclonic jerks and dystonic movements of the upper body. Functional imaging and structural gray matter imaging studies in M‐D suggest defective sensorimotor integration and an association between putaminal volume and severity of dystonia, possibly because of neuronal plasticity. As we expect changes in the connections between the cortical and subcortical regions, we performed a combination of white matter voxel‐based morphometry (wVBM) and diffusion tensor imaging (DTI) to detect macro‐ and microstructural white matter changes, respectively, in DYT‐11 mutations carriers (M‐D). Sixteen clinically affected DYT‐11 mutation carriers and 18 control subjects were scanned with 3‐Tesla MRI to compare white matter volume, fractional anisotropy, and mean diffusivity between groups. In DYT11 mutation carriers, increased white matter volume and FA and decreased mean diffusivity werefound in the subthalamic area of the brain stem, including the red nucleus. Furthermore, decreased mean diffusivity was found in the subgyral cortical sensorimotor areas. The white matter changes found in the subthalamic area of the brain stem, connecting the cerebellum with the thalamus, are compatible with the hypothesis that abnormal function in M‐D involves a network that includes the cerebellum, brain stem, and basal ganglia. Whether these changes are causative or an effect of M‐D requires further study. © 2012 Movement Disorder Society     

Abnormalities of cortical excitability and cortical inhibition in cervical dystonia

Cortical excitability and cortico-cortical inhibition were examined in twenty-one patients suffering from idiopathic rotational cervical dystonia. Polymyography of cervical muscles, somatosensory evoked potential recordings, and paired transcranial magnetic stimulation were used to assess the dystonic disorder. The results were compared with those obtained in a group of sixteen healthy age-matched volunteers. Statistically significant differences between the patient group and the control group were found when the amplitude values of the mean P22/N30 component measured at F [3, 4] and C[3, 4]' electrode positions were compared. The mean amplitude of P22/N30 in both of these electrode positions contralaterally to the direction of head deviation was significantly higher in the patient group (p ≤ 0.05). The mean side-to-side P22/N30 amplitude ratio was calculated in both groups in the F[3, 4] and C[3, 4]' electrode positions: there was a significant difference between the two groups. The mean ratio (calculated contralaterally/ipsilaterally in the patient group and left/right side in the control group) was significantly higher in the patient group (p ≤ 0.05). There were statistically significant differences between the two groups when the mean values of MEP amplitudes following paired stimuli at short and medium interstimulus intervals (ISI)) were compared. The percentage of amplitude reduction registered at short ISI was significantly lower in the patient group when both 3 ms ISI and 5 ms ISI were considered, and when the hemisphere contralateral to the direction of head deviation was stimulated. There was also a difference (with the short ISI) when the hemisphere ipsilateral to the direction of head deviation was stimulated, but this difference was not significant (p < 0.5). Almost all of the amplitude changes following the paired stimulus at the longer ISI, i. e. 10, 15, and 20 ms were significantly different when the patient group was compared with control group: when the ipsilateral hemisphere was stimulated, the amplitude of conditioned responses was significantly higher following all three paired stimuli (with 10, 15, and 20 ms ISI) at the p ≤ 0.05 significance level; when the contralateral hemisphere was stimulated, they were significantly higher following the 10 and 20 ms ISI paired stimuli (significance level p ≤ 0.05). The interhemispheric difference in the patient group was significant only for the paired stimuli using 3 and 5 ms (short) ISI and 15 and 20 ms (medium) ISI. There was a significantly decreased inhibition at 3 and 5 ms ISI when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). Similarly, there was a significantly increased facilitation at 15 and 20 ms when the hemisphere contralateral to the direction of head deviation was stimulated, as compared with the hemisphere ipsilateral (p ≤ 0.05). The results indicate that a disorder of both cortical excitability and intracortical inhibition exists in patients with cervical dystonia, and that this disorder is lateralized, i. e. it is located within the hemisphere contralateral to the direction of head deviation. Received: 5 March 2002, Received in revised form: 1 August 2002, Accepted: 2 August 2002 Correspondence to Doc. MUDr Petr Kaňovsky, CSc.     

Task-dependent intracortical inhibition is impaired in focal hand dystonia.

We tested whether task-dependent modulation of inhibition within the motor cortex is impaired in patients with dystonia. Paired-pulse transcranial magnetic stimulation (TMS) at an interstimulus interval of 2 msec was used to measure the effect of two different tasks on short ISI intracortical inhibition (SICI) in dystonic and normal subjects. In two experiments, SICI of the fourth dorsal interosseus (4DIO) and abductor pollicis brevis (APB) muscles were measured before and at the end of the training task. In the first experiment, subjects performed a nonselective task consisting of abducting the thumb, where the APB acted as agonist and the 4DIO as synergist. In the second experiment, the function of the 4DIO was changed as the subjects were asked to consciously inhibit this muscle while abducting the thumb (selective task). Therefore, while the APB was activated in both tasks, the 4DIO was activated in the nonselective task but was in the inhibitory surround in the selective task. We found that performance of the selective but not the nonselective task resulted in increased SICI in the 4DIO of normal but not in dystonic subjects. We conclude that task-dependent SICI is disturbed in patients with dystonia.     

Altered dorsal premotor–motor interhemispheric pathway activity in focal arm dystonia

Given the possible role of dorsal premotor cortex (PMd) in the pathophysiology of dystonia, we used transcranial magnetic stimulation (TMS) methods to study PMd and PMd–primary motor cortex (M1) interactions in patients with focal arm dystonia. Here, we tested the connectivity between left PMd and right M1 as well as the intracortical excitability of PMd in 11 right‐handed patients with focal arm/hand dystonia and nine age‐matched healthy controls. The results showed that excitability of the inhibitory connection between PMd and M1 was reduced in patients, but there was no significant difference to healthy subjects in the excitability of the facilitatory connection. A triple stimulation technique in which pairs of TMS pulses are given over PMd and their interaction measured in terms of the effect on the baseline PMd‐M1 connection failed to reveal the usual pattern of interaction between the pairs of PMd stimuli. Indeed, the results in patients were similar to those seen in a group of young healthy subjects after the excitability of PMd had been changed by pretreatment with high‐frequency rTMS. We suggest that reduced transcallosal inhibition from the PMd may be involved in the altered pattern of abnormal muscle contractions of agonists and antagonists (overflow). © 2007 Movement Disorder Society     

The effect of cutaneous input on intracortical inhibition in focal task‐specific dystonia

In normal subjects short interval intracortical inhibition (SICI) is topographically modulated by cutaneous input, which may be important for focusing muscle activation during tasks. In patients with writer's cramp, a task‐specific focal dystonia characterized by inappropriate and excessive muscle activation of the upper limb during certain motor tasks, intracortical inhibition is reduced at rest and lacks the normal topographically‐specific modulation during motor tasks. In the present study we investigated whether cutaneous input modulated SICI in a group of patients with writer's cramp and a control group of subjects. Electromyographic recordings were made from the right first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles. Brief electrical stimuli were applied to either digit II or digit V with ring electrodes. SICI was investigated using a paired transcranial magnetic stimulation paradigm employing interstimulus intervals of 1–15 ms. Cutaneous input from both digit II and digit V modulated motor evoked potentials and SICI in a topographically‐specific manner in control subjects. In contrast, cutaneous input failed to modulate motor evoked potentials or SICI in the focal hand dystonia patients. These results provide further evidence of abnormal sensorimotor integration in focal hand dystonia. © 2007 Movement Disorder Society     

Elevated threshold for intracortical inhibition in focal hand dystonia.

Differences between control and focal hand dystonia (FHD) subject groups in short interval intracortical inhibition (SICI) as determined by paired transcranial magnetic stimulation (TMS) can be difficult to demonstrate, due to interindividual differences. The purpose of this study was to compare two TMS methods for assessing SICI in 8 control and 7 FHD subjects. Electromyographic (EMG) data were recorded from the first dorsal interosseous (FDI) muscle of the dominant hands of the control subjects and affected hands of the FHD subjects. The first method used a conventional approach of setting conditioning stimulus intensity to 80% of rest threshold (RTh) and test stimulus intensity to 120% RTh. Three interstimulus intervals (ISIs) were used: 2 msec, 3 msec, and the ISI between 2 and 3 msec that produced optimal SICI. The second method was novel in that test stimulus intensity was set to 150% active threshold (ATh), and conditioning stimulus intensity was varied between 50% and 100% ATh. The latter was determined at the threshold for SICI and expressed as a ratio of ATh. There was no difference between the subject groups in the degree of SICI produced using the first method, at the three ISIs studied. However, using the second method, the SICI threshold:ATh ratio was found to be significantly higher for FHD subjects. This finding suggests that determining the SICI threshold:ATh ratio may be a more sensitive measure of intracortical inhibitory function than more conventional methods.     

Continuous intrathecal baclofen infusions induced a marked increase of the transcranially evoked silent period in a patient with generalized dystonia

We observed a marked prolongation of the transcranially evoked silent period during continuous intrathecal administration of high doses of the gamma-aminobutyric acid (GABA)_B receptor agonist baclofen in a patient with generalized dystonia. Size of motor evoked potentials and central conduction time remained unchanged during intrathecal baclofen administration. The selective prolongation of the silent period during high-dose continuous intrathecal baclofen therapy supports the notion that GABA_B-ergic intracortical interneurons play a part in the generation of the transcranially evoked silent period. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1209–1212, 1998.     

Inherited myoclonus‐dystonia and epilepsy: Further evidence of an association?

Epilepsy and electroencephalogram (EEG) abnormalities have been considered exclusion criteria for the clinical diagnosis of myoclonus-dystonia (M-D). We report on the second M-D family in which several clinically affected epsilon-sarcoglycan gene (SGCE) mutation carriers have seizures in addition to myoclonus and dystonia, adding to the evidence that epilepsy and EEG abnormalities may form part of the phenotypic spectrum of the condition. A nonsense mutation in exon 3 (289C-->T) of SGCE resulting in the insertion of a premature stop codon (R97X) was detected in affected members of this family.     

Assessment of postexcitatory inhibition in patients with focal dystonia

The aim of our present study was to detect whether a generalized disturbance of intracortical inhibitory mechanisms as assessed by transcranial magnetic stimulation (TMS) can be observed in a movement disorder with localized clinical expression, that is, in focal cervical dystonia. We measured motor threshold intensity, central motor conduction time and the duration of postexcitatory inhibition evoked by single and paired stimuli TMS from a small hand muscle in 20 patients with idiopathic cervical dystonia, and 21 healthy volunteers. A significant difference could not be found in any of the neurophysiological parameters between patients and controls. These findings are unlike the observations made in Parkinson's disease and Huntington's disease, where significant changes of postexcitatory inhibition after TMS can be observed. This suggests a lack of widespread change in activity of underlying cortical inhibitory mechanisms, as seen in other diseases of the extrapyramidal system with more generalized clinical involvement.     

Phenotypic spectrum and sex effects in eleven myoclonus‐dystonia families with ε‐sarcoglycan mutations

Myoclonus‐dystonia (M‐D) due to SGCE mutations is characterized by early onset myoclonic jerks, often associated with dystonia. Penetrance is influenced by parental sex, but other sex effects have not been established. In 42 affected individuals from 11 families with identified mutations, we found that sex was highly associated with age at onset regardless of mutation type; the median age onset for girls was 5 years versus 8 years for boys (P < 0.0097). We found no association between mutation type and phenotype. © 2007 Movement Disorder Society     

Impaired heteronymous somatosensory motor cortical inhibition in dystonia.

A typical pathophysiological abnormality in dystonia is cocontraction of antagonist muscles, with impaired reciprocal inhibitory mechanisms in the spinal cord. Recent experimental data have shown that inhibitory interactions between antagonist muscles have also a parallel control at the level of the sensorimotor cortex. The aim of this work was to study heteronymous effects of a median nerve stimulus on the corticospinal projections to forearm muscles in dystonia. We used the technique of antagonist cortical inhibition, which assesses the conditioning effect of median nerve afferent input on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in ipsilateral forearm extensor muscles at rest. Nine healthy subjects and 10 patients with torsion dystonia participated in the study. MEPs and somatosensory evoked potentials were normal in patients. In healthy subjects, median nerve stimulation at 15- to 18-msec intervals inhibited the test MEPs in forearm extensors. In dystonic patients, median nerve stimulation delivered at the same conditioning-test intervals elicited significantly less inhibition of the test MEP. On the whole, these data suggest an impaired sensory-motor integration in dystonia and, more specifically, the decreased antagonistic cortical inhibition could suggest that functional interactions between antagonist muscles are primarily impaired at the cortical level.     

Botulinum toxin injections reduce associative plasticity in patients with primary dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long‐term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation‐evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short‐interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Task-dependent modulation of silent period duration in focal hand dystonia.

Focal hand dystonia (FHD) is a movement disorder that is also associated with impaired sensory function and sensorimotor integration. The aim of this study was to assess the modulation of inhibitory function in the motor cortex during the performance of four motor tasks (isometric pinch grip, writing, texture discrimination, and a phasic control task) in 8 FHD and 8 control subjects. The affected hands of the FHD subjects and the dominant hands of the control subjects were tested. Inhibitory function was assessed using transcranial magnetic stimulation to evoke a silent period in the ongoing electromyographic activity of the target muscle (first dorsal interosseous). There was no difference between FHD subjects and control subjects in silent period duration, which was significantly longer during the phasic texture discrimination and phasic control task than during the isometric pinch or writing. This finding suggests that the phasic nature of the task may increase cortical inhibitory function, rather than the sensory discrimination task itself. The accuracy of texture discrimination was significantly lower in FHD subjects than in control subjects. Sensory discrimination tasks do not appear to directly modulate the inhibitory processes responsible for the duration of the silent period.     

Changes in short afferent inhibition during phasic movement in focal dystonia

Impaired surround inhibition could account for the abnormal motor control seen in patients with focal hand dystonia, but the neural mechanisms underlying surround inhibition in the motor system are not known. We sought to determine whether an abnormality of the influence of sensory input at short latency could contribute to the deficit of surround inhibition in patients with focal hand dystonia (FHD). To measure digital short afferent inhibition (dSAI), subjects received electrical stimulation at the digit followed after 23 ms by transcranial magnetic stimulation (TMS). Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) during rest and during voluntary phasic flexion of the second digit. F-waves were also recorded. We studied 13 FHD patients and 17 healthy volunteers. FHD patients had increased homotopic dSAI in ADM during flexion of the second digit, suggesting that this process acts to diminish overflow during movement; this might be a compensatory mechanism. No group differences were observed in first dorsal interosseous. Further, no differences were seen in the F-waves between groups, suggesting that the changes in dSAI are mediated at the cortical level rather than at the spinal cord. Understanding the role of these inhibitory circuits in dystonia may lead to development of therapeutic agents aimed at restoring inhibition.