Inhibition In Dystonia Research Articles

Globus pallidus internus activity increases during voluntary movement in children with dystonia

The rate model of basal ganglia function predicts that muscle activity in dystonia is due to disinhibition of thalamus resulting from decreased inhibitory input from pallidum. We seek to test this hypothesis in children with dyskinetic cerebral palsy undergoing evaluation for deep brain stimulation (DBS) to analyze movement-related activity in different brain regions. The results revealed prominent beta-band frequency peaks in the globus pallidus interna (GPi), ventral oralis anterior/posterior (VoaVop) subnuclei of the thalamus, and subthalamic nucleus (STN) during movement but not at rest. Connectivity analysis indicated stronger coupling between STN-VoaVop and STN-GPi compared to GPi-STN. These findings contradict the hypothesis of decreased thalamic inhibition in dystonia, suggesting that abnormal patterns of inhibition and disinhibition, rather than reduced GPi activity, contribute to the disorder. Additionally, the study implies that correcting abnormalities in GPi function may explain the effectiveness of DBS targeting the STN and GPi in treating dystonia.

Reappraising the role of motor surround inhibition in dystonia

BackgroundSurround inhibition (SI) in the motor system has been described to be decreased in patients with focal hand dystonia (FHD) but no evidence currently exists for patients with cervical dystonia (CD). ObjectiveTo characterise the SI profiles in three groups of participants: healthy volunteers, patients with FHD and patients with CD. To provide sample size calculations for future studies. MethodsSI was assessed using Transcranial Magnetic Stimulation (TMS) in 31 right-handed healthy participants, 11 patients with CD and 12 patients with FHD. In addition data of SI in patients with FHD were extracted from previously published and analysed for sample size calculations and assessment of SI variability. ResultsNo statistically significant difference in SI was found amongst the groups (healthy, FHD, CD). Analysis of combined current and previous data suggests that our study and all prior studies were underpowered. At least 26 participants in each group are required for a simple comparison of two groups. Analysis of published data indicated that SI is more variable in FHD patients compared to healthy controls. ConclusionsThe highly variable SI in patients with dystonia can confound statistical comparisons of mean differences. Larger studies are needed to assess SI in dystonia and to explore the origins of its variability.

P065 Abnormally low intracortical inhibition in dystonia with poor response to pallidal stimulation

Introduction Pallidal stimulation (GPi DBS) is an effective treatment of dystonic syndromes with a relatively high variability of clinical benefit. As patients with dystonia typically have a lower ability to suppress unwanted movements, we expected a decreased intracortical inhibition of motor cortex, which can be potentially reversed by GPi DBS. Objectives To distinguish between patients with dystonia according to the clinical outcome of GPi DBS using short-latency intracortical inhibition (SICI) of the motor cortex assessed by paired transcranial magnetic stimulation (TMS). Patients & methods We examined 22 patients (mean age 51 ± 17 years) with dystonia of various distribution and origin treated by GPi DBS in different time intervals from implantation. Paired TMS with subthreshold conditioning stimulus followed by a supratreshold testing stimulus 2.5 ms later were applied to the motor cortex to elicit SICI in GPi DBS ON and GPi DBS OFF condition two hours later. The clinical effect (CE) was expressed as a change in the dystonic score (Burke-Fahn-Marsden Dystonia rating Scale or Toronto Western Spasmodic Torticollis Scale) between actual GPi DBS ON condition and the preoperative state. Results The SICI was less effective in patients than in controls regardless of the ON and OFF conditions (p Download : Download high-res image (206KB) Download : Download full-size image ). Non-responders (n = 9; 50% CE, p Download : Download high-res image (225KB) Download : Download full-size image Fig. 2a) and in addition, the shortest MEP onset latency was observed in non-responders (p Conclusions Our results suggest that the best responders to GPi DBS treatment exhibited a similar level of SICI as in healthy controls. On the contrary, non-responders were unable to increase their reduced cortical inhibition and effectively suppressed dystonic symptoms. We speculate that decreased intracortical inhibition with abnormally fast transmission volley is underpinned by the poor complexity of the motor network. Supported by the grant IGA MZ CR NT12282-5/2011.

Plasticity of cortical inhibition in dystonia is impaired after motor learning and paired‐associative stimulation

Artificial induction of plasticity by paired associative stimulation (PAS) in healthy volunteers (HV) demonstrates Hebbian-like plasticity in selected inhibitory networks as well as excitatory networks. In a group of 17 patients with focal hand dystonia and a group of 19 HV, we evaluated how PAS and the learning of a simple motor task influence the circuits supporting long-interval intracortical inhibition (LICI, reflecting activity of GABA(B) interneurons) and long-latency afferent inhibition (LAI, reflecting activity of somatosensory inputs to the motor cortex). In HV, PAS and motor learning induced long-term potentiation (LTP)-like plasticity of excitatory networks and a lasting decrease of LAI and LICI in the motor representation of the targeted or trained muscle. The better the motor performance, the larger was the decrease of LAI. Although motor performance in the patient group was similar to that of the control group, LAI did not decrease during the motor learning as it did in the control group. In contrast, LICI was normally modulated. In patients the results after PAS did not match those obtained after motor learning: LAI was paradoxically increased and LICI did not exhibit any change. In the normal situation, decreased excitability in inhibitory circuits after induction of LTP-like plasticity may help to shape the cortical maps according to the new sensorimotor task. In patients, the abnormal or absent modulation of afferent and intracortical long-interval inhibition might indicate maladaptive plasticity that possibly contributes to the difficulty that they have to learn a new sensorimotor task.

Debunking the pathophysiological puzzle of dystonia – With special reference to botulinum toxin therapy

New neurophysiological insights into the natural behaviour of dystonia, obtained during the successful botulinum toxin A (BoNT) treatment of the disorder, have urged the inclusion of sensory (and particularly somatosensory) mechanisms into the pathophysiological background of dystonia. Muscle spindles play a pivotal role in the generation of dystonic movements. Abnormal behaviour in the muscle spindles that generates an irregular proprioceptive input via the group-IA afferents may result in abnormal cortical excitability and intracortical inhibition in dystonia. The aim of this article is to support our hypothesis that dystonic movement is at the end of an impaired function of somatosensory pathways and analysers, which, in turn, may be hinged on the abnormality of sensorimotor integration, that is, brain plasticity. BoNT treatment can potentially modulate this plasticity mechanism and is probably the seminal cause of the sustained effect of the subsequent BoNT-treatment sessions and the long-term alleviation of symptoms of dystonia.

On muscle spindles, dystonia and botulinum toxin

Dystonia may produce co-contractions and constant strain in numerous muscle fibers, including those of the muscle spindles. As proprioceptors, muscle spindles detect dynamic or static changes in muscle length and their afferent projections to the spinal cord play a central role in control of antagonistic muscles. Their parallel arrangement with extrafusal muscle fibers and association with the earlier recruited oxidative motor units allow them to conveniently sample the activity of all motor units and effectively modulate movement. At the same time, fusimotor muscle spindle innervation contracts the striated polar portions of the intrafusal muscle fibers and prevents their slackening during extrafusal muscle contractions. Botulinum toxin remains the most efficient therapy of dystonia. Its muscular mechanism of action is hinged on cholinergic blockade not only of extrafusal, but also of intrafusal muscle fibers. Besides being a targeted muscular therapy, the alteration of the corresponding sensory input following an effect of botulinum toxin on the intrafusal muscle fibers is pivotal in modulating loss of pre-synaptic inhibition in dystonia, including suppression of the tonic vibration reflex. Whether or not trans-synaptic botulinum toxin migration occurs, a modification of the central motor programming is bound to happen in dystonia, with botulinum toxin acting either as another 'sensory trick' or as a form of 'short-term plasticity'. Knowledge of the muscle spindle anatomy and function is key to unify our understanding of abnormal movements and of effects of botulinum toxin therapy. Thus, in dystonia, overactivity of muscles and increased spindle sensitivity are germane to botulinum toxin targets of action.

Reply: Plasticity and intracortical inhibition in dystonia--methodological reconsiderations

Sir, We would like to thank Dr Rosenkrantz for her interest in our recent paper on physiological differences between patients with psychogenic and organic forms of limb dystonia. We are also very grateful for the opportunity to discuss in detail the connection between input–output relationships and effects of paired associative stimulation (PAS). It is a topic of some confusion among those who use transcranial magnetic stimulation and it is worthwhile exploring in detail possible connections between these two phenomena. In the usual PAS experimental design, a standard transcranial magnetic stimulus is used to evoke motor evoked potentials in the abductor pollicis brevis muscle. Application of the PAS25 protocol increases the amplitude of motor evoked potentials evoked by this standard pulse for the following 30 min or so. In contrast, the input–output curve uses a range of transcranial magnetic stimulation intensities to plot the relationship between intensity and size of evoked motor evoked potential. As Dr Rosenkranz points out, if the effect of PAS25 is equivalent to increasing the intensity of the transcranial magnetic stimulation pulse, then subjects who have a steeper input–output curve will achieve a greater increase in amplitude of motor evoked potential than those with a shallow input–output curve. However, first it is important to underline that proposing PAS25 to be the same as increasing the intensity of the transcranial magnetic stimulation pulse is not equivalent as saying that the effect is the ‘same’ as increasing transcranial magnetic stimulation intensity. Measurements of the strength-duration properties of transcranial magnetic stimulation indicate that it stimulates axons; turning up stimulation intensity increases response size because more axons are recruited at higher intensities. For PAS25 to have the ‘same’ effect we would have to propose that PAS25 increases the excitability of axonal membranes, so that more axons are stimulated by the standard …

Plasticity and intracortical inhibition in dystonia--methodological reconsiderations

Sir, I read with interest the article ‘Abnormal sensorimotor plasticity in organic but not psychogenic dystonia’ by Quartarone et al. published in Brain (2009; 132: 2871–7). Dystonia is a challenging condition for clinicians and neuroscientists alike. The presented symptoms are often bizarre and a diagnostic tool that reliably distinguishes between organic and psychogenic origin is highly desirable. In their manuscript, the authors describe that ‘plasticity’, which they refer to as long-term potentiation-like plasticity that can be induced by the paired-associative stimulation (PAS) protocol (Stefan et al. , 2000), is ‘abnormally high’ only in patients with organic dystonia, while short-interval intracortical inhibition, a parameter of GABA-ergic intracortical inhibition (Mueller-Dahlhaus et al. , 2008), is equally ‘abnormal’ in psychogenic and organic dystonia. They 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’. This conclusion is appealing since it not only offers a diagnostic tool for organic dystonia but also a simple solution to the intensively researched and still not well understood pathophysiology of this movement disorder. Transcranial magnetic stimulation is now an easily accessible and intensively used research tool in human basic and clinical neuroscience. With increasing insights into the mechanisms and effects of transcranial magnetic stimulation, even well established protocols such as short-interval intracortical inhibition or PAS are scrutinized again and further refined in order to make our research findings more reliable and valid. With this in mind, the findings and conclusions proposed in the current paper by Quartarone et al. (2009) require and might benefit from some methodological and conceptual re-considerations. There is no doubt that transcranial magnetic stimulation protocols, particularly PAS (Stefan et al. , 2000), have contributed significantly to our understanding of plasticity of the …

Reduced cerebral cortex inhibition in dystonia: Direct evidence in humans

A loss of inhibition in central motor circuits resulting in abnormal motor control is the hypothesised cause of dystonia. So far, changes in inhibitory function of cerebral cortex in dystonia, have been revealed only indirectly by recording muscle responses evoked by transcranial magnetic stimulation (TMS) of the brain. The aim of present study was to evaluate more directly cerebral cortex changes in dystonia. We had the almost unique opportunity to record directly motor cortex output after brain stimulation, in a dystonic patient who had epidural electrodes implanted in the upper cervical cord. We evaluated descending activity evoked by single and paired pulse TMS together with the inhibitory effects produced by afferent stimuli on TMS evoked activity, and compared the results with those obtained in thirteen subjects with no central nervous system abnormality who also had cervical spinal electrodes. The intrinsic inhibitory activity produced by paired TMS of the motor cortex, and the inhibitory effects produced by afferent inputs, were suppressed in the patient with dystonia. These findings provide a direct evidence of the abnormality in motor cortex inhibitory systems in dystonia. The abnormality in cortical inhibitory system might have a role in the pathophysiology of dystonia.

Interhemispheric inhibition is selectively impaired in mirror dystonia

Mirror movements are a common observation in patients with movement disorders and also in focal hand dystonia (FHD). Current findings of bilateral cortical and subcortical abnormalities even in patients with focal, unilateral symptoms may suggest that the contralateral primary motor cortex (M1) plays an important role in mirror dystonia (MD) and in the pathophysiology of FHD. Using transcranial magnetic stimulation (TMS) it has been demonstrated that the contralateral M1 can inhibit the output of the active M1. A reduction of the so-called inter-hemispheric inhibition (IHI) may contribute to the loss of inhibition in dystonia, and may also be relevant for the generation of MD.

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.