Abnormal dorsal premotor-motor inhibition in writer's cramp.

The authors hypothesized that a deficient premotor-motor inhibitory network contributes to the unwanted involuntary movements in dystonia. The authors studied nine controls and nine patients with writer's cramp (WC). Dorsal premotor-motor cortical inhibition (dPMI) was tested by applying conditioning transcranial magnetic stimulation (TMS) to the dorsal premotor cortex and then a test pulse to the ipsilateral motor cortex at an interval of 6 ms. The authors used an H-reflex in flexor carpi radialis paired with TMS over the premotor cortex to assess for spinal cord excitability change. Finally, the authors interrupted a choice reaction time task with TMS over dorsal premotor cortex to assess performance in a nondystonic task. The results showed that WC patients exhibited dPMI at rest (88.5%, the ratio of conditioned to unconditioned test pulse), in contrast to controls, who did not show dPMI (109.6%) (P = 0.0198). This difference between patients and controls persisted during contraction (100% vs. 112%) and pen-holding (95.6% vs. 111%). The H-reflex in the arm was not modulated by the premotor cortex stimulation. The WC patients made more errors, and the error rate improved with TMS over the premotor cortex. These results suggest that abnormal premotor-motor interactions may play a role in the pathophysiology of focal dystonia. The dPMI was not modulated by task in either group, but was constantly greater in the patients. The significance of the increased inhibition is likely to be compensatory. It appears to be a robust finding and, in combination with other features, could be further explored as a biomarker.

Spatiotemporal dynamics of bimanual integration in human somatosensory cortex and their relevance to bimanual object manipulation.

Little is known about the spatiotemporal dynamics of cortical responses that integrate slightly asynchronous somatosensory inputs from both hands. This study aimed to clarify the timing and magnitude of interhemispheric interactions during early integration of bimanual somatosensory information in different somatosensory regions and their relevance for bimanual object manipulation and exploration. Using multi-fiber probabilistic diffusion tractography and MEG source analysis of conditioning-test (C-T) median nerve somatosensory evoked fields in healthy human subjects, we sought to extract measures of structural and effective callosal connectivity between different somatosensory cortical regions and correlated them with bimanual tactile task performance. Neuromagnetic responses were found in major somatosensory regions, i.e., primary somatosensory cortex SI, secondary somatosensory cortex SII, posterior parietal cortex, and premotor cortex. Contralateral to the test stimulus, SII activity was maximally suppressed by 51% at C-T intervals of 40 and 60 ms. This interhemispheric inhibition of the contralateral SII source activity correlated directly and topographically specifically with the fractional anisotropy of callosal fibers interconnecting SII. Thus, the putative pathway that mediated inhibitory interhemispheric interactions in SII was a transcallosal route from ipsilateral to contralateral SII. Moreover, interhemispheric inhibition of SII source activity correlated directly with bimanual tactile task performance. These findings were exclusive to SII. Our data suggest that early interhemispheric somatosensory integration primarily occurs in SII, is mediated by callosal fibers that interconnect homologous SII areas, and has behavioral importance for bimanual object manipulation and exploration.

State-dependent and timing-dependent bidirectional associative plasticity in the human SMA-M1 network.

The supplementary motor area (SMA-proper) plays a key role in the preparation and execution of voluntary movements. Anatomically, SMA-proper is densely reciprocally connected to primary motor cortex (M1), but neuronal coordination within the SMA-M1 network and its modification by external perturbation are not well understood. Here we modulated the SMA-M1 network using MR-navigated multicoil associative transcranial magnetic stimulation in healthy subjects. Changes in corticospinal excitability were assessed by recording motor evoked potential (MEP) amplitude bilaterally in a hand muscle. We found timing-dependent bidirectional Hebbian-like MEP changes during and for at least 30 min after paired associative SMA-M1 stimulation. MEP amplitude increased if SMA stimulation preceded M1 stimulation by 6 ms, but decreased if SMA stimulation lagged M1 stimulation by 15 ms. This associative plasticity in the SMA-M1 network was highly topographically specific because paired associative stimulation of pre-SMA and M1 did not result in any significant MEP change. Furthermore, associative plasticity in the SMA-M1 network was strongly state-dependent because it required priming by near-simultaneous M1 stimulation to occur. We conclude that timing-dependent bidirectional associative plasticity is demonstrated for the first time at the systems level of a human corticocortical neuronal network. The properties of this form of plasticity are fully compatible with spike-timing-dependent plasticity as defined at the cellular level. The necessity of priming may reflect the strong interhemispheric connectivity of the SMA-M1 network. Findings are relevant for better understanding reorganization and potentially therapeutic modification of neuronal coordination in the SMA-M1 network after cerebral lesions such as stroke.

Modulation of excitability in human primary somatosensory and motor cortex by paired associative stimulation targeting the primary somatosensory cortex.

Input from primary somatosensory cortex (S1) to primary motor cortex (M1) is important for high-level motor performance, motor skill learning and motor recovery after brain lesion. This study tested the effects of manipulating S1 excitability with paired associative transcranial stimulation (S1-PAS) on M1 excitability. Given the important role of S1 in sensorimotor integration, we hypothesized that changes in S1 excitability would be directly paralleled by changes in M1 excitability. We applied two established protocols (S1-PAS(LTP) and S1-PAS(LTD) ) to the left S1 to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like plasticity. S1 excitability was assessed by the early cortical components (N20-P25) of the median nerve somatosensory-evoked potential. M1 excitability was assessed by motor-evoked potential amplitude and short-interval intracortical inhibition. Effects of S1-PAS(LTP) were compared with those of a PAS(LTP) protocol targeting the left M1 (M1-PAS(LTP) ). S1-PAS(LTP) and S1-PAS(LTD) did not result in significant modifications of S1 or M1 excitability at the group level due to substantial interindividual variability. The individual S1-PAS-induced changes in S1 and M1 excitability showed no correlation. Furthermore, the individual changes in S1 and M1 excitability induced by S1-PAS(LTP) did not correlate with changes in M1 excitability induced by M1-PAS(LTP) . This demonstrates that the effects of S1-PAS in S1 are variable across individuals and, within a given individual, unrelated to those induced by S1-PAS or M1-PAS in M1. Potentially, this extends the opportunities of therapeutic PAS applications because M1-PAS 'non-responders' may well respond to S1-PAS.

Modulation of preparatory volitional motor cortical activity by paired associative transcranial magnetic stimulation.

Paired associative transcranial magnetic stimulation (PAS) has been shown to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like change in excitability of human primary motor cortex (M1), as probed by motor evoked potential (MEP) amplitude. In contrast, little is known about PAS effects on volitional motor cortical activity. In 10 healthy subjects, movement related cortical potentials (MRCP) were recorded to index volitional motor cortical activity during preparation of simple thumb abduction (prime mover: abductor pollicis brevis, APB) or wrist extension movements (prime mover: extensor carpi radialis, ECR). PAS(LTP) increased, PAS(LTD) decreased, and PAS(control) did not change MEP(APB), while MEP(ECR), not targeted by PAS, remained unchanged in all PAS conditions. PAS(LTP) decreased MRCP negativity during the late Bereitschaftspotential (-500 to 0 ms before movement onset), only in the APB task, and predominantly over central scalp electrodes contralateral to the thumb movements. This effect correlated negatively with the PAS(LTP) induced increase in MEP(APB). PAS(LTD) and PAS(control) did not affect MRCP amplitude. Findings indicate a specific interference of PAS with preparatory volitional motor cortical activity, suggestive of a net result caused by increased M1 excitability and disrupted effective connectivity between premotor areas and M1.

Long-latency afferent inhibition during phasic finger movement in focal hand dystonia.

In the motor system, one specific movement is generated, and, simultaneously, other possible movements are suppressed; a process called surround inhibition. Focal hand dystonia (FHD) is a movement disorder characterized by a loss of surround inhibition. In order to explain the deficit in surround inhibition induced by volitional movement in FHD patients, we examined the inhibitory circuit activated by afferent stimulation at "long latency". We studied 14 patients (age 48.9+/-13.2 years, 3 females, 11 males) with idiopathic task-related FHD. To measure long-latency afferent inhibition (LAI), transcranial magnetic stimulation (TMS) was applied to the affected hemisphere for FHD patients and to the dominant hemisphere for 17 healthy volunteers. Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) and first dorsal interosseous (FDI) during rest and during voluntary phasic flexion of the second digit. Subjects were given electrical stimulation to either their fifth digit (homotopic to ADM, heterotopic to FDI) or their second digit (heterotopic to FDI, homotopic to ADM) at twice sensory perceptual threshold 180 ms prior to TMS application. Additionally, F-waves were recorded from ADM. At rest, we found a significant decrease in ADM MEP amplitudes with both homotopic and heterotopic stimulation compared to the corresponding non-stimulated trials. There was a trend toward less LAI in FHD patients. During movement, LAI was significantly decreased in both patients and controls. There was no significant group effect. The results for LAI in FDI were similar to those from ADM. F-wave area in ADM was greater during movement for both homo- and heterotopic stimulation. We found no difference in F-wave area between patients and healthy volunteers. Our results indicate that LAI is unlikely to be an underlying mechanism that contributes to the generation of normal surround inhibition in healthy volunteers or in the disruption of surround inhibition in FHD.

Differential effects of tactile high- and low-frequency stimulation on tactile discrimination in human subjects.

BACKGROUND: Long-term potentiation (LTP) and long-term depression (LTD) play important roles in mediating activity-dependent changes in synaptic transmission and are believed to be crucial mechanisms underlying learning and cortical plasticity. In human subjects, however, the lack of adequate input stimuli for the induction of LTP and LTD makes it difficult to study directly the impact of such protocols on behavior. RESULTS: Using tactile high- and low-frequency stimulation protocols in humans, we explored the potential of such protocols for the induction of perceptual changes. We delivered tactile high-frequency and low-frequency stimuli (t-HFS, t-LFS) to skin sites of approximately 50 mm2 on the tip of the index finger. As assessed by 2-point discrimination, we demonstrate that 20 minutes of t-HFS improved tactile discrimination, while t-LFS impaired performance. T-HFS-effects were stable for at least 24 hours whereas t-LFS-induced changes recovered faster. While t-HFS changes were spatially very specific with no changes on the neighboring fingers, impaired tactile performance after t-LFS was also observed on the right middle-finger. A central finding was that for both t-LFS and t-HFS perceptual changes were dependent on the size of the stimulated skin area. No changes were observed when the stimulated area was very small (< 1 mm2) indicating special requirements for spatial summation. CONCLUSION: Our results demonstrate differential effects of such protocols in a frequency specific manner that might be related to LTP- and LTD-like changes in human subjects.

Cholinergic gating of improvement of tactile acuity induced by peripheral tactile stimulation.

As shown in many animal experiments, cholinergic mechanisms participate in N-methyl-d-aspartate (NMDA) receptor-dependent neuroplasticity. Acetylcholine is thought to play a similar role in humans, where it modulates attention and learning. Here, we tested the cholinergic action on non-associative learning in the tactile domain. We studied the influence of scopolamine, a cholinergic antagonist, on changes in tactile acuity as induced by peripheral tactile coactivation. Coactivation is a non-associative tactile learning protocol and has been shown to improve tactile two-point discrimination of the stimulated finger in addition to selective changes of cortical processing. Under placebo conditions, tactile two-point discrimination was improved on the stimulated index finger. After application of scopolamine, tactile improvement was completely eliminated and tactile acuity was even impaired. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. The current results provide further evidence that in humans cholinergic mechanisms are also involved in non-associative learning induced by passive stimulation protocols.

Dopaminergic influences on changes in human tactile acuity induced by tactile coactivation.

As shown in animal experiments, dopaminergic mechanisms participate in N-methyl-D-aspartate (NMDA) receptor-dependent neuroplasticity. Dopamine is thought to play a similar role in humans, where it influences learning and memory. Here, we tested the dopaminergic action on learning in the tactile domain. To induce tactile non-associative learning, we applied a tactile coactivation protocol, which is known to improve tactile two-point discrimination of the stimulated finger. We studied the influence of a single oral dose of levodopa (25, 50, 100, 250 or 350 mg) administered preceding the coactivation protocol on changes in tactile performance in different groups of subjects. In addition, 3 x 100 mg levodopa was administered over a time period of 3 h in another group. Under placebo conditions, tactile two-point discrimination was improved on the coactivated index finger. Similar improvement was found when 25, 50 and 250 mg levodopa was applied. On the contrary, tactile improvement was completely eliminated by 1 x 100 and 3 x 100 mg levodopa. No drug effects were found on the left index finger indicating that the drug had no effect on performance per se. In contrast to previous findings in the motor and speech domain, we found that the administration of levodopa exerts either no or even negative effects on non-associative learning in the human somatosensory system. Whenever levodopa is used in neurorehabilitative context, it has to be kept in mind that beneficial effects in the motor or speech domain cannot be easily generalized to other systems.

Relation of brain stimulation induced changes in MEP amplitude and BOLD signal.

BACKGROUND: Non-invasive human brain stimulation can induce long-term plasticity reflected by changes in putative markers of synaptic activation, such as the motor evoked potential (MEP) amplitude elicited by transcranial magnetic stimulation or the task-dependent blood oxygenation level-dependent (BOLD) signal measured by functional magnetic resonance imaging. OBJECTIVE: To study the relationship between brain stimulation induced changes in MEP amplitude and BOLD signal. METHODS: Paired associative stimulation of the hand area of the left primary somatosensory cortex (S1-PAS) was applied in 15 healthy subjects to induce excitability change in the adjacent primary motor cortex (M1) [Kriváneková et al. 2011, Eur J Neurosci 34:1292-1300]. Before and after S1-PAS, MEP amplitude in a right hand muscle, and the BOLD signal during a right hand motor or somatosensory activation task were measured. RESULTS: S1-PAS resulted in substantial individual MEP and BOLD signal changes, but these changes did not correlate in M1 or S1. CONCLUSIONS: Findings indicate that MEP amplitude and BOLD signal within the tested M1 reflect physiologically distinct aspects of synaptic excitability change. Therefore, it is suggested that MEP amplitude and BOLD signal are complementary rather than interchangeable markers of synaptic excitability.

The Bereitschaftspotential in essential tremor.

OBJECTIVE: Essential tremor (ET) is an involuntary postural oscillation. It is unclear to which extent motor cortical activity in preparation of volitional movement is abnormal in ET. We measured the Bereitschaftspotential (BP) to address this question. METHODS: Given the known influence of the cerebello-dentato-thalamo-cortical projection in the generation of the BP, patients were divided into two groups, defined by purely postural tremor (ET(PT)) or additional presence of intention tremor (ET(IT)) and compared to healthy controls. BP was recorded during self-paced rapid wrist extension movements. RESULTS: The late BP (500-0 ms before movement onset) was increased over the mid-frontal area in ET(PT), whereas it was reduced over the mid-parietal area in ET(IT) when compared to healthy controls. In addition, the late BP was reduced over a widespread centro-parietal area in ET(IT) compared to ET(PT). CONCLUSIONS: Findings suggest that presence vs. absence of cerebellar signs (intention tremor) in ET results in differential affection of volitional preparatory motor cortical activity. The BP increase in ET(PT) may indicate compensatory activity, whereas the widespread centro-parietal BP reduction in ET(IT) suggests dysfunction of the cerebello-dentato-thalamo-cortical projection. SIGNIFICANCE: Reduction of the late BP amplitude may serve as a surrogate marker for dysfunction of the cerebello-dentato-thalamo-cortical projection in ET.

Homeostatic metaplasticity in the human somatosensory cortex.

Long-term potentiation (LTP) and long-term depression (LTD) are regulated by homeostatic control mechanisms to maintain synaptic strength in a physiological range. Although homeostatic metaplasticity has been demonstrated in the human motor cortex, little is known to which extent it operates in other cortical areas and how it links to behavior. Here we tested homeostatic interactions between two stimulation protocols -- paired associative stimulation (PAS) followed by peripheral high-frequency stimulation (pHFS) -- on excitability in the human somatosensory cortex and tactile spatial discrimination threshold. PAS employed repeated pairs of electrical stimulation of the right median nerve followed by focal transcranial magnetic stimulation of the left somatosensory cortex at an interstimulus interval of the individual N20 latency minus 15 msec or N20 minus 2.5 msec to induce LTD- or LTP-like plasticity, respectively [Wolters, A., Schmidt, A., Schramm, A., Zeller, D., Naumann, M., Kunesch, E., et al. Timing-dependent plasticity in human primary somatosensory cortex. Journal of Physiology, 565, 1039-1052, 2005]. pHFS always consisted of 20-Hz trains of electrical stimulation of the right median nerve. Excitability in the somatosensory cortex was assessed by median nerve somatosensory evoked cortical potential amplitudes. Tactile spatial discrimination was tested by the grating orientation task. PAS had no significant effect on excitability in the somatosensory cortex or on tactile discrimination. However, the direction of effects induced by subsequent pHFS varied with the preconditioning PAS protocol: After PAS(N20-15), excitability tended to increase and tactile spatial discrimination threshold decreased. After PAS(N20-2.5), excitability decreased and discrimination threshold tended to increase. These interactions demonstrate that homeostatic metaplasticity operates in the human somatosensory cortex, controlling both cortical excitability and somatosensory skill.

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.

Sustained increase of somatosensory cortex excitability by tactile coactivation studied by paired median nerve stimulation in humans correlates with perceptual gain.

Cortical excitability can be reliably assessed by means of paired-pulse stimulation techniques. Recent studies demonstrated particularly for motor and visual cortex that cortical excitability is systematically altered following the induction of learning processes or during the development of pathological symptoms. A recent tactile coactivation protocol developed by Godde and coworkers showed that improvement of tactile performance in humans can be achieved also without training through passive stimulation on a time scale of a few hours. Tactile coactivation evokes plastic changes in somatosensory cortical areas as measured by blood oxygenation level-dependent (BOLD) activation in fMRI or SEP-dipole localization, which correlated with the individual gain in performance. To demonstrate changes in excitability of somatosensory cortex after tactile coactivation, we combined assessment of tactile performance with recordings of paired-pulse SEPs after electrical median nerve stimulation of both the right coactivated and left control hand at ISIs of 30 and 100 ms before, 3 h after and 24 h after tactile coactivation. Amplitudes and latencies of the first and second cortical N20/P25 response components were calculated. For the coactivated hand, we found significantly lowered discrimination thresholds and significantly reduced paired-pulse ratios (second N20/P25 response/first N20/P25 response) at an ISI of 30 ms after tactile coactivation indicating enhanced cortical excitability. No changes in paired-pulse behaviour were observed for ISIs of 100 ms. Both psychophysical and cortical effects recovered to baseline 24 h after tactile coactivation. The individual increase of excitability correlated with the individual gain in discrimination performance. For the left control hand we found no effects of tactile coactivation on paired-pulse behaviour and discrimination threshold. Our results indicate that changes in cortical excitability are modified by tactile coactivation and were scaled with the degree of improvement of the individual perceptual learning. Conceivably, changes of cortical excitability seem to constitute an additional important marker and mechanism underlying plastic reorganization.