R. Gentner

Depression of Human Corticospinal Excitability Induced by Magnetic Theta-burst Stimulation: Evidence of Rapid Polarity-Reversing Metaplasticity

Metaplasticity refers to the activity-dependent modification of the ability of synapses to undergo subsequent potentiation or depression, and is thought to maintain homeostasis of cortical excitability. Continuous magnetic theta-burst stimulation (cTBS; 50 Hz-bursts of 3 subthreshold magnetic stimuli repeated at 5 Hz) is a novel repetitive magnetic stimulation protocol used to model changes of synaptic efficacy in human motor cortex. Here we examined the influence of prior activity on the effects induced by cTBS. Without prior voluntary motor activation, application of cTBS for a duration of 20 s (cTBS300) facilitated subsequently evoked motor potentials (MEP) recorded from APB muscle. In contrast, MEP-size was depressed, when cTBS300 was preceded by voluntary activity of sufficient duration. Remarkably, even without prior voluntary activation, depression of MEP-size was induced when cTBS was extended over 40 s. These findings provide in vivo evidence for extremely rapid metaplasticity reversing potentiation of corticospinal excitability to depression. Polarity-reversing metaplasticity adds considerable complexity to the brains response toward new experiences. Conditional dependence of cTBS-induced depression of corticospinal excitability on prior neuronal activation suggests that the TBS-model of synaptic plasticity may be closer to synaptic mechanisms than previously thought.

Modular Organization of Finger Movements by the Human Central Nervous System

The motor system may generate automated movements, such as walking, by combining modular spinal motor synergies. However, it remains unknown whether a modular neuronal architecture is sufficient to generate the unique flexibility of human finger movements, which rely on cortical structures. Here we show that finger movements evoked by transcranial magnetic stimulation (TMS) of the primary motor cortex reproduced distinctive features of the spatial representation of voluntary movements as identified in previous neuroimaging studies, consistent with naturalistic activation of neuronal elements. Principal component analysis revealed that the dimensionality of TMS-evoked movements was low. Principal components extracted from TMS-induced finger movements resembled those derived from end-postures of voluntary movements performed to grasp imagined objects, and a small subset of them was sufficient to reconstruct these movements with remarkable fidelity. The motor system may coordinate even the most dexterous movements by using a modular architecture involving cortical components.

Development and evaluation of a low-cost sensor glove for assessment of human finger movements in neurophysiological settings

Sensor gloves for measurements of finger movements are a promising tool for objective assessments of kinematic parameters and new rehabilitation strategies. Here, a novel low-cost sensor glove equipped with resistive bend sensors is described and evaluated. Resistive bend sensors were modified in order to optimize measurement accuracy (quantified as the stability of sensor signal after a fast and constant bending) and to increase sensor linearity, reducing calibration time from several minutes to only approximately 10s. Reliability analysis of the sensor glove in five subjects showed an intraclass correlation coefficient (ICC) of 0.93+/-0.05, a mean standard deviation of 1.59 degrees and an overall error of 4.96 degrees , comparable to previously evaluated sensor gloves. User acceptance and applicability, assessed by a user feedback questionnaire, was high. Thus, with minor modifications, resistive bend sensors are suitable for accurate assessments of human finger movements. The low material costs (<US

Theta-burst stimulation: Remote physiological and local behavioral after-effects

500) and easy manufacturing make this solution interesting for widespread use in research, clinical and rehabilitative settings.

Encoding of Motor Skill in the Corticomuscular System of Musicians

Theta-burst stimulation (TBS), a novel repetitive transcranial magnetic stimulation (TMS) protocol, is capable of suppressing the amplitude of contralateral motor-evoked potentials (MEP) for several minutes after the end of a conditioning train over the motor cortex. It remains unknown whether TBS leads to effects on motor cortical excitability when applied to contralateral brain sites distant but connected to motor cortex and whether TBS triggers measurable changes in force control. Subjects received bursts (50 Hz) of three subthreshold magnetic stimuli repeated at 5 Hz for 20 s (TBS-300) or 40 s (TBS-600) over the hand area of the left motor cortex (M1(LEFT)). With TBS-300, conditioning of right motor cortex (M1(RIGHT)), right dorsal premotor cortex (PMd(RIGHT)), and a mid-occipital (MO) region also were tested. Corticospinal excitability was probed by evoking MEPs in abductor pollicis brevis (APB) muscle by single suprathreshold stimuli over M1(LEFT) or M1(RIGHT) before and after TBS. Force level control was assessed in an isometric right thumb abduction task. With TBS-600, the time course of physiological and behavioral changes was monitored. TBS over either of the motor cortices reduced the amplitude of MEP in the contralateral APB and increased it in the ipsilateral APB. In contrast, conditioning TBS over PMd(RIGHT) or MO did not modify MEP size. Post-TBS right thumb force level control was impaired, with contralateral M1(LEFT) stimulation only, for a duration of at least 5 min. TBS may induce remote physiological effects and reveals local functional properties of the underlying brain region.

L-Type Voltage-Gated Ca2+ Channels: A Single Molecular Switch for Long-Term Potentiation/Long-Term Depression-Like Plasticity and Activity-Dependent Metaplasticity in Humans

How motor skills are stored in the nervous system represents a fundamental question in neuroscience. Although musical motor skills are associated with a variety of adaptations [1-3], it remains unclear how these changes are linked to the known superior motor performance of expert musicians. Here we establish a direct and specific relationship between the functional organization of the corticomuscular system and skilled musical performance. Principal component analysis was used to identify joint correlation patterns in finger movements evoked by transcranial magnetic stimulation over the primary motor cortex while subjects were at rest. Linear combinations of a selected subset of these patterns were used to reconstruct active instrumental playing or grasping movements. Reconstruction quality of instrumental playing was superior in skilled musicians compared to musically untrained subjects, displayed taxonomic specificity for the trained movement repertoire, and correlated with the cumulated long-term training exposure, but not with the recent past training history. In violinists, the reconstruction quality of grasping movements correlated negatively with the long-term training history of violin playing. Our results indicate that experience-dependent motor skills are specifically encoded in the functional organization of the primary motor cortex and its efferent system and are consistent with a model of skill coding by a modular neuronal architecture [4].

Plasticity in human motor cortex is in part genetically determined

The ability of synapses to undergo persistent activity-dependent potentiation or depression [long-term potentiation (LTP)/long-term depression (LTD)] may be profoundly altered by previous neuronal activity. Although natural neuronal activity can be experimentally manipulated in vivo, very little is known about the in vivo physiological mechanisms involved in regulating this metaplasticity in models of LTP/LTD. To examine whether Ca2+ signaling may influence metaplasticity in vivo in humans, we used continuous theta burst stimulation (cTBS) (Huang et al., 2005), a noninvasive novel repetitive magnetic stimulation protocol known to induce persistent alterations of corticospinal excitability whose polarity is changed by previous voluntary motor activity. When directed to the naive motor cortex, cTBS induced long-lasting potentiation of corticospinal excitability, but depression under the influence of nimodipine (NDP), an L-type voltage-gated Ca2+ channel (L-VGCC) antagonist. Both aftereffects were blocked by dextromethorphan, an NMDA receptor antagonist, supporting the notion that these bidirectional cTBS-induced alterations of corticospinal excitability map onto LTP and LTD as observed in animal studies. A short period of voluntary contraction and a small dose of NDP were each ineffective in blocking the cTBS-induced potentiation. However, when both interventions were combined, a depression was induced, and the magnitude of this depression increased with the dose of NDP. These findings suggest that Ca2+ dynamics determine the polarity of LTP/LTD-like changes in vivo. L-VGCCs may act as molecular switches mediating metaplasticity induced by endogenous neuronal activation.

LTP-like changes induced by paired associative stimulation of the primary somatosensory cortex in humans : source analysis and associated changes in behaviour

Neuronal plasticity refers to the ability of the brain to change in response to different experiences. Plasticity varies between people, but it is not known how much of this variability is due to differences in their genes. In humans, plasticity can be probed by a protocol termed paired associative stimulation and the changes in the motor system that are brought about by such stimulation are thought to be due to strengthening synapses which connect different neurons. We examined pairs of sisters which were either genetically identical (monozygotic) or different (dizygotic). We found that the variability within the monozygotic sister pairs was less than the variability within the dizygotic sister pairs. That plasticity in human motor cortex is in a substantial part genetically determined may be relevant for motor learning and neurorehabilitation, such as after stroke.

Rapid-onset central motor plasticity in multiple sclerosis.

Paired associative stimulation (PAS), which combines repetitive peripheral nerve stimulation with transcranial magnetic stimulation (TMS), may induce neuroplastic changes in somatosensory cortex (S1), possibly by long‐term potentiation‐like mechanisms. We used multichannel median nerve somatosensory evoked potential (MN‐SSEP) recordings and two‐point tactile discrimination testing to examine the location and behavioural significance of these changes. When TMS was applied to S1 near‐synchronously to an afferent signal containing mechanoreceptive information, MN‐SSEP changes (significant at 21–31 ms) could be explained by a change in a tangential source located in Brodmann area 3b, with their timing and polarity suggesting modification of upper cortical layers. PAS‐induced MN‐SSEP changes between 28 and 32 ms were linearly correlated with changes in tactile discrimination. Conversely, when the near‐synchronous afferent signal contained predominantly proprioceptive information, PAS‐induced MN‐SSEP changes (20–29 ms) were shifted medially, and tactile performance remained stable. With near‐synchronous mechanoreceptive stimulation subtle differences in the timing of the two interacting signals tended to influence the direction of tactile performance changes. PAS performed with TMS delivered asynchronously to the afferent pulse did not change MN‐SSEPs. Hebbian interaction of mechanoreceptive afferent signals with TMS‐evoked activity may modify synaptic efficacy in superficial cortical layers of Brodmann area 3b and is associated with timing‐dependent and qualitatively congruent behavioural changes.

Focal hand dystonia Lack of evidence for abnormality of motor representation at rest

Objective: To study rapid-onset central motor plasticity, and its relationship to motor impairment and CNS injury in patients with multiple sclerosis (MS). Methods: In this cross-sectional observational study, motor plasticity was examined neurophysiologically and behaviorally in 22 patients with moderately severe (median Expanded Disability Status Scale score 2.5 [0–6]) stable MS and matched healthy controls. First, plasticity was assessed using paired associative stimulation (PAS), a protocol modeling long-term synaptic potentiation in human cortex. PAS combines repetitive electric nerve stimulation with transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Second, motor learning was tested by a force production task. Motor impairment was assessed by functional tests. CNS injury was evaluated by obtaining normalized N-acetyl-aspartate (NAA/Cr) spectra using magnetic resonance spectroscopy and by the corticomuscular latency (CML) to the abductor pollicis brevis muscle as tested by TMS. Results: Patients with MS performed worse than controls in functional motor tests, CMLs were prolonged, and NAA/Cr was decreased. PAS-induced enhancement of corticospinal excitability and training-induced increments of motor performance were comparable between patients with MS and controls. Neither PAS-induced plasticity nor motor learning performance correlated with motor impairment or measures of CNS injury. Patients with high CNS injury and good motor performance did not differ significantly from those with high CNS injury and poor motor performance with respect to PAS-induced plasticity and motor learning success. Conclusions: Despite motor impairment and CNS injury in patients with multiple sclerosis (MS), rapid-onset motor plasticity is comparable to that in healthy subjects. Compensation of MS-related CNS injury is unlikely to be constrained by insufficient rapid-onset neuroplasticity.