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.     

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     

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.     

Lack of inhibitory interaction between somatosensory afferent inputs and intracortical inhibitory interneurons in focal hand dystonia.

We looked for an impaired interaction in the primary motor cortex between intracortical inhibitory circuits and circuits fed by somatosensory inputs in patients with writer's cramp. Short-interval intracortical inhibition (sICI) to wrist extensor carpi radialis muscle (ECR) was conditioned by stimulation of antagonist muscle afferents and sICI to first dorsal interosseus (FDI) muscle by homotopic cutaneous afferents stimulation. sICI was assessed at rest and during a tonic contraction of the target muscle. Eighteen patients with writer's cramp (10 having a wrist dystonic posture in flexion during writing and 8 in extension) were compared to 14 control subjects. Peripheral inputs decreased sICI in control subjects. This decrease was lost in patients in both FDI and ECR, regardless of the wrist dystonic posture. By contrast, contraction-induced depression of sICI appeared dependant on the dystonic status of the muscle: depression of sICI to ECR was abolished in patients with wrist dystonic posture in flexion, but not in patients with dystonic posture in extension, sICI even giving way to motor-evoked potential facilitation. Loss of interaction between interneurons mediating sICI and peripheral inputs probably belongs to the initial abnormalities underlying dystonia. Lack of peripherally induced sICI modulation may oppose wrist and/or hand muscles synergies.     

Impaired intracortical inhibition in the primary somatosensory cortex in focal hand dystonia

Somesthetic temporal discrimination (STD) is impaired in focal hand dystonia (FHD). We explored the electrophysiological correlate of the STD deficit to assess whether this is due to dysfunction of temporal inhibition in the somatosensory inhibitory pathway or due to dysfunction in structures responsible for nonmodality‐specific timing integration. Eleven FHD patients and 11 healthy volunteers were studied. STD threshold was investigated as the time interval required for perceiving a pair of stimuli as two separate stimuli in time. We also examined the somatosensory‐evoked potential (SEP) in a paired‐pulse paradigm. We compared STD threshold and recovery function of SEP between the groups. STD thresholds were significantly greater in FHD than in healthy volunteers. The amount of P27 suppression in the 5 ms‐ISI condition was significantly less in FHD. It was also found that the STD threshold and P27 suppression were significantly correlated: the greater the STD threshold, the less the P27 suppression. Significantly less suppression of P27 with a lack of significant change in N20 indicates that the impairment of somatosensory information processing in the time domain is due to dysfunction within the primary somatosensory cortex, suggesting that that the STD deficit in FHD is more attributable to dysfunction in the somatosensory pathway. © 2007 Movement Disorder Society     

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.     

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.     

Impaired modulation of motor cortex excitability by homonymous and heteronymous muscle afferents in focal hand dystonia.

A decrease of heteronymous median nerve-evoked inhibition of corticospinal projections to forearm extensor muscles was reported in a group of 10 dystonic patients by Bertolasi and colleagues in 2003. Here we tested the excitability of corticomotoneuronal connections to both wrist extensor (ECR) and flexor (FCR) muscles after conditioning stimulation of median and also radial nerve at rest in a group of 25 patients with focal hand dystonia compared to 20 healthy subjects. We also investigated the effect of the wrist dystonic posture, either in flexion or in extension, on the afferent modulation of ECR and FCR motor evolved potentials (MEPs). The heteronymous (median-induced) but also homonymous (radial-induced) inhibitions (interstimuli intervals 13-21 ms) of ECR MEP size observed in healthy subjects were decreased in patients. In addition, homonymous (median-induced) facilitation of FCR MEP size was also decreased in patients while heteronymous inhibition (radial-induced) was not. Neither the involvement of the target muscle in the dystonic posture nor the origin of the afferent volley (from a dystonic muscle) influenced the degree of impairment of afferent modulation of the MEP. These findings support the view that a global abnormal somatosensory coupling in focal hand dystonia may contribute to an inadequate motor command to wrist muscles.     

Influence of repetitive hand movements on intracortical inhibition

Repetitive movements have been reported to induce task-specific changes of intracortical inhibition and facilitation, but the mechanism operating shortly after hand movement is unclear. Transcranial magnetic single and paired stimuli (2 ms) were applied to 15 healthy subjects at rest and 1 s after repetitive (every 6 s) active and passive hand extensions. Motor evoked potentials (MEPs) were recorded from hand extensors (agonists) and flexors (antagonists). A strong overall inhibitory effect was observed after applying paired stimuli. In agonists only, active movements produced significantly larger MEPs. Inhibition, however, did not differ between active or passive movements and rest. This suggests that MEP increases produced by active movements in agonists are not caused by disinhibition, but are rather due to excitation (facilitation). This finding may also have implications for future studies evaluating the preferential activation of target muscles in physiotherapy.     

Transcranial direct current stimulation for the treatment of focal hand dystonia

The treatment of writer's cramp, a task‐specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause writer's cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative. In this randomized, double‐blind, sham‐controlled study, we investigated the efficacy of cathodal stimulation of the contralateral motor cortex in 3 sessions in 1 week. Assessment over a 2‐week period included clinical scales, subjective ratings, kinematic handwriting analysis, and neurophysiological evaluation. Twelve patients with unilateral dystonic writer's cramp were investigated; 6 received transcranial direct current and 6 sham stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained, leading to premature study termination. Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in writer's cramp. © 2011 Movement Disorder Society     

Intracortical excitability in the hand motor representation in hand dystonia and blepharospasm.

We sought to determine the activity of inhibiting and facilitating cortical circuits in areas surrounding a hand muscle motor representation in focal dystonia and in controls. In 15 patients with hand dystonia, 16 patients with blepharospasm, and age-matched controls, we applied suprathreshold transcranial magnetic stimuli with a figure-eight coil over the optimal representation of the relaxed abductor digiti minimi muscle of the dominant hand. Additional conditioning stimuli were given through a second figure-eight coil that was held either above the test coil or 2 cm or 4 cm apart in the anterior, posterior, lateral, or medial direction. We measured intracortical excitability in each of the nine positions of the conditioning coil. Intracortical inhibition was reduced in both patient groups at all conditioning coil positions. With both coils centered, the intracortical facilitation did not differ between patients and controls. After shifting the conditioning coil, the intracortical facilitation tended to be less diminished in patients than in controls, this difference between patients and controls was significant for the anterior, posterior, and medial 4-cm conditioning coil shift. Our results demonstrate decreased intracortical inhibition in the cortical hand muscle representation not only in patients with hand dystonia, but also in patients with blepharospasm. In addition, our findings in both patient groups show a trend toward a relatively increased intracortical facilitation in surrounding motor areas.     

Reliability of corticospinal excitability and intracortical inhibition in biceps femoris during different contraction modes

This study aimed to determine the test–retest reliability of a range of transcranial magnetic stimulation (TMS) outcomes in the biceps femoris during isometric, eccentric and concentric contractions. Corticospinal excitability (active motor threshold 120% [AMT120%] and area under recruitment curve [AURC]), short- and long-interval intracortical inhibition (SICI and LICI) and intracortical facilitation (ICF) were assessed from the biceps femoris in 10 participants (age 26.3 ± 6.0 years; height 180.2 ± 6.6 cm, body mass 77.2 ± 8.0 kg) in three sessions. Single- and paired-pulse stimuli were delivered under low-level muscle activity (5% ± 2% of maximal isometric root mean squared surface electromyography [rmsEMG]) during isometric, concentric and eccentric contractions. Participants were provided visual feedback on their levels of rmsEMG during all contractions. Single-pulse outcomes measured during isometric contractions (AURC, AMT110%, AMT120%, AMT130%, AMT150%, AMT170%) demonstrated fair to excellent reliability (ICC range, .51 to .92; CV%, 21% to 37%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .62 to .80; CV%, 19 to 42%). Single-pulse outcomes measured during concentric contractions demonstrated excellent reliability (ICC range, .75 to .96; CV%, 15% to 34%), whereas SICI, LICI and ICF demonstrated good to excellent reliability (ICC range, .65 to .76; CV%, 16% to 71%). Single-pulse outcomes during eccentric contractions demonstrated fair to excellent reliability (ICC range, .56 to .96; CV%, 16% to 41%), whereas SICI, LICI and ICF demonstrated good to excellent (ICC range, .67 to .86; CV%, 20% to 42%). This study found that both single- and paired-pulse TMS outcomes can be measured from the biceps femoris muscle across all contraction modes with fair to excellent reliability. However, coefficient of variation values were typically greater than the smallest worthwhile change which may make tracking physiological changes in these variables difficult without moderate to large effect sizes.     

Short-interval and long-interval intracortical inhibition of TMS-evoked EEG potentials

Background

Inhibition in the human motor cortex can be probed by means of paired-pulse transcranial magnetic stimulation (ppTMS) at interstimulus intervals of 2–3 ms (short-interval intracortical inhibition, SICI) or ～100?ms (long-interval intracortical inhibition, LICI). Conventionally, SICI and LICI are recorded as motor evoked potential (MEP) inhibition in the hand muscle. Pharmacological experiments indicate that they are mediated by GABAA and GABAB receptors, respectively.Objective/Hypothesis: SICI and LICI of TMS-evoked EEG potentials (TEPs) and their pharmacological properties have not been systematically studied. Here, we sought to examine SICI by ppTMS-evoked compared to single-pulse TMS-evoked TEPs, to investigate its pharmacological manipulation and to compare SICI with our previous results on LICI.

Reduced intracortical facilitation in patients with cerebellar degeneration

Objectives - Transcranial magnetic stimulation (TMS) was used to study intracortical inhibitory and excitatory phenomena in patients with cerebellar ataxia. Methods - Motor evoked potentials (MEP) following single and paired TMS were recorded from the first dorsal interosseus muscle (FDI) in 15 patients with autosomal-dominant or idiopathic cerebellar ataxia and 15 age matched normal controls. Results- MEP amplitudes after paired TMS with short interstimulus intervals (1-4 ms) showing intracortical inhibition in the control group were not significantly different in the patient group. In contrast, with longer interstimulus intervals (8-20 ms) mean MEP amplitudes were significantly reduced in the patient group, indicating a decrease of intracortical facilitation. The mean postexcitatory inhibition after TMS was also significantly prolonged in the patient group. Conclusion -Our findings support the idea that the cerebellum physiologically exerts a facilitatory influence on the motor cortex which is decreased in patients with a cerebellar degeneration.     

Cutaneous afferent input does not modulate motor intracortical inhibition in ageing men

Afferent input has been shown to be a powerful modulator of cortical inhibition. Such modulation is likely to be important for the control of ongoing movement, but may also play a role in facilitating neuroplastic reorganisation. Human motor control and neuroplasticity both decline with ageing, whereas the efficacy of short‐interval intracortical inhibition (SICI) appears not to. We examined if ageing alters the efficacy of afferent modulation of SICI. Previously, electrical cutaneous stimulation of a finger has been shown to reduce SICI in the motor cortices of young adults. Paired‐pulse transcranial magnetic stimulation was used to assess SICI in the cortical representation of the first dorsal interosseous muscle. SICI was assessed separately under two conditions: with and without prior afferent input from electrical cutaneous stimulation of the index finger. Fifteen ‘young’ (20.1 ± 2.1 years) and 15 ‘old’ male humans (65.5 ± 3.9 years) were studied. SICI did not differ when young and old males were compared. However, when preceded by electrical cutaneous finger stimulation, SICI was reduced in young men but not old men. Reflex testing indicated preservation of the afferent volley to the cortex. These findings suggest that a contributing factor in the decline of motor function, and possibly neuroplasticity, with ageing is loss of SICI modulation, probably due to altered cortical sensorimotor integration of afferent input.     

Normal intracortical excitability in developmental stuttering.

Persistent developmental stuttering (PDS) shares clinical features with task-specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech-fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS.     

Inter-hemispheric inhibition is impaired in mirror dystonia

Surround inhibition, a neural mechanism relevant for skilled motor behavior, has been shown to be deficient in the affected primary motor cortex (M1) in patients with focal hand dystonia (FHD). Even in unilateral FHD, however, electrophysiological and neuroimaging studies have provided evidence for bilateral M1 abnormalities. Clinically, the presence of mirror dystonia, dystonic posturing when the opposite hand is moved, also suggests abnormal interhemispheric interaction. To assess whether a loss of inter-hemispheric inhibition (IHI) may contribute to the reduced surround inhibition, IHI towards the affected or dominant M1 was examined in 13 patients with FHD (seven patients with and six patients without mirror dystonia, all affected on the right hand) and 12 right-handed, age-matched healthy controls (CON group). IHI was tested at rest and during three different phases of a right index finger movement in a synergistic, as well as in a neighboring, relaxed muscle. There was a trend for a selective loss of IHI between the homologous surrounding muscles in the phase 50 ms before electromyogram onset in patients with FHD. Post hoc analysis revealed that this effect was due to a loss of IHI in the patients with FHD with mirror dystonia, while patients without mirror dystonia did not show any difference in IHI modulation compared with healthy controls. We conclude that mirror dystonia may be due to impaired IHI towards neighboring muscles before movement onset. However, IHI does not seem to play a major role in the general pathophysiology of FHD.     

Abnormal functional connectivity in focal hand dystonia: Mutual information analysis in EEG

The aim of the present study was to investigate functional connectivity in focal hand dystonia patients to understand the pathophysiology underlying their abnormality in movement. We recorded EEGs from 58 electrodes in 15 focal hand dystonia patients and 15 healthy volunteers during rest and a simple finger‐tapping task that did not induce any dystonic symptoms. We investigated mutual information, which provides a quantitative measure of linear and nonlinear coupling, in the alpha, beta, and gamma bands. Mean mutual information of all 58 channels and mean of the channels of interest representative of regional functional connectivity over sensorimotor areas (C3, CP3, C4, CP4, FCz, and Cz) were evaluated. For both groups, we found enhanced mutual information during the task compared with the rest condition, specifically in the beta and gamma bands for mean mutual information of all channels, and in all bands for mean mutual information of channels of interest. Comparing the focal hand dystonia patients with the healthy volunteers for both rest and task, there was reduced mutual information in the beta band for both mean mutual information of all channels and mean mutual information of channels of interest. Regarding the properties of the connectivity in the beta band, we found that the majority of the mutual information differences were from linear connectivity. The abnormal beta‐band functional connectivity in focal hand dystonia patients suggests deficient brain connectivity. © 2011 Movement Disorder Society