Tobias Bäumer

Magnetic stimulation of human premotor or motor cortex produces interhemispheric facilitation through distinct pathways

We explored interhemispheric facilitation (IHF) between (a) left and right primary motor cortex (M1) and (b) left dorsal premotor (dPM) and right M1 in 20 right‐handed healthy human subjects using a paired pulse transcranial magnetic stimulation (TMS) protocol. A conditioning TMS pulse (CP) applied to left M1 or dPM with an intensity of 80% and 60% active motor threshold (CP80%AMT and CP60%AMT, respectively) was followed by a test pulse (TP) over right M1 induced by anterior–posterior‐ or posterior–anterior‐ (TPAP, TPPA) directed currents in the brain at interstimulus intervals (ISIs) of 3–8 and 10 ms. EMG was recorded from left first dorsal interosseous muscle. In the main experimental condition IHF was evoked by CP80%AMT over left M1 and TPAP at ISIs of 6 and 8 ms. The same CP80%AMT produced IHF at an ISI of 8 ms when applied over left dPM but only with TPPA. In addition, when CP60%AMT was given to M1, IHF was present at an ISI of 6 ms (but not 8 ms) when followed by TPPA, indicating that IHF elicited over dPM was not caused by current spread of the conditioning pulse to M1. We conclude that IHF can be induced differentially by conditioning M1 and dPM using subthreshold CP. These facilitatory interactions depended on the intensity and ISI of the CP as well as the current flow direction of the TP. We suggest that not only do the CPs activate separate anatomical pathways but also that these pathways project to different populations of interneurons in the receiving M1. These may correspond to elements involved in the generation of I3 and I1 waves, respectively.

Repeated premotor rTMS leads to cumulative plastic changes of motor cortex excitability in humans

We explored the aftereffects of two premotor 1 Hz rTMS sessions on motor cortex excitability in healthy humans. In experiment 1, 11 healthy right-handed volunteers received 20-min submotor threshold 1 Hz rTMS trains over the left premotor cortex on 2 consecutive days. Left motor cortex excitability was determined at baseline, immediately after, 30, 60, 120 min, and 24 h after each rTMS session. We measured motor thresholds, amplitudes of motor-evoked potentials, silent periods, and paired-pulse excitability at interstimulus intervals (ISI) of 3-7, 10, and 15 ms. In experiment 2, 5 volunteers received two identical rTMS trains on Days 1 and 7. Measurements were carried out on Day 1 (first rTMS train), Day 2, and Day 7 (second rTMS train). In experiment 1 there was a selective increase of paired pulse facilitation at an ISI of 7 ms after rTMS lasting for less than 30 min on Day 1. This effect was also present after rTMS on Day 2. However, it persisted for at least 2 h. In experiment 2 the same extra facilitation was induced by rTMS on Days 1 and 7 but not on Day 2. It lasted for less than 30 min on both Day 1 and Day 7. We conclude that 1 Hz premotor rTMS leads to cumulative plastic changes of intrinsic motor cortex excitability when repeated within 24 h but not after 1 week, implying the formation of memory after the first rTMS train lasting more than a day but less than a week.

Structural Changes in the Somatosensory System Correlate with Tic Severity in Gilles de la Tourette Syndrome.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. Previous structural MRI studies have identified regional abnormalities in grey matter, especially in the basal ganglia. These findings are consistent with the assumption of alterations in cortico-striato-thalamo-cortical circuits and dopaminergic neurotransmission playing a major role in the pathophysiology of GTS. Additionally, recent imaging studies suggested an involvement of sensory-motor cortices in the pathophysiology of GTS. However, little is known about the role of white matter changes in GTS. In this study, we aimed to examine whether GTS is associated with abnormalities in white matter microstructure and whether these changes are correlated with tic severity. In a morphometric study based on diffusion tensor MRI of the whole brain, we compared brain tissue diffusion characteristics between 15 unmedicated adults with GTS without psychiatric co-morbidity and 15 healthy age- and sex-matched controls. We performed voxel-based morphometry (VBM) of regional fractional anisotropy (FA) values to identify regional differences in white matter microstructure between the groups. We also tested for a linear relationship between regional FA values and clinical scores of tic severity. Probabilistic fibre tracking was applied to characterize anatomical connectivity of those areas showing differences in regional FA. Compared with healthy controls, GTS patients showed bilateral FA increases in white matter underlying the post- and precentral gyrus, below the left supplementary motor area, and in the right ventro-postero-lateral part of the thalamus. The peak increase in FA was located below the left postcentral gyrus. Probabilistic tractography identified transcallosal and ipsilateral cerebello-thalamo-cortical pathways of the somatosensory system passing through this subcortical region. In patients, regional FA in this region showed an inverse linear relationship with tic severity. These findings demonstrate, for the first time, structural alterations in somatosensory pathways in GTS. Changes of water diffusion characteristics point towards reduced branching in somatosensory pathways in GTS patients. The negative correlation between higher regional FA values and fewer tics suggests that these alterations of white matter microstructure represent adaptive reorganization of somatosensory processing in GTS.

The cortical motor threshold reflects microstructural properties of cerebral white matter.

Transcranial magnetic stimulation (TMS) can be used to probe distinct aspects of excitability of the primary motor hand area (M1(Hand)). The motor threshold (MT) reflects the trans-synaptic excitability of corticospinal output neurons. The MT corresponds to the minimal intensity at which TMS evokes a contralateral motor response. Here, we employed diffusion-weighted imaging (DWI) to examine whether inter-individual differences in MT of the left and right M1(Hand), an index of cortical excitability, are associated with variations in fractional anisotropy (FA), an index of white matter microstructure. Resting and active MT showed an inverse linear relationship with regional FA values in large bihemispheric clusters, including the white matter underlying primary motor, premotor and posterior prefrontal cortices, as well as the genu of the internal capsule, cerebral peduncles and corpus callosum. The linear increase in FA with cortical excitability as indexed by the MT remained significant after controlling for differences in handedness or coil-cortex distance. The posterior limb of the internal capsule, where fast-conducting corticospinal fibres from M1(Hand) pass through, showed only a weak linear relationship between FA and MT. The FA measurements show that a high level of corticospinal excitability is associated with a higher fibre coherence in large parts of cerebral white matter. The higher FA values in the white matter beneath premotor and motor cortices may reflect a structural property of cortico-cortical connections that renders M1(Hand) more susceptible to TMS-induced trans-synaptic excitation of the corticospinal fibres and may account for the inverse linear relationship between MT and FA.

Investigating the human mirror neuron system by means of cortical synchronization during the imitation of biological movements

The human mirror neuron system (MNS) has recently been a major topic of research in cognitive neuroscience. As a very basic reflection of the MNS, human observers are faster at imitating a biological as compared with a non-biological movement. However, it is unclear which cortical areas and their interactions (synchronization) are responsible for this behavioural advantage. We investigated the time course of long-range synchronization within cortical networks during an imitation task in 10 healthy participants by means of whole-head magnetoencephalography (MEG). Extending previous work, we conclude that left ventrolateral premotor, bilateral temporal and parietal areas mediate the observed behavioural advantage of biological movements in close interaction with the basal ganglia and other motor areas (cerebellum, sensorimotor cortex). Besides left ventrolateral premotor cortex, we identified the right temporal pole and the posterior parietal cortex as important junctions for the integration of information from different sources in imitation tasks that are controlled for movement (biological vs. non-biological) and that involve a certain amount of spatial orienting of attention. Finally, we also found the basal ganglia to participate at an early stage in the processing of biological movement, possibly by selecting suitable motor programs that match the stimulus.

Laterality of interhemispheric inhibition depends on handedness

There is some evidence that handedness is related to lateralisation of excitability in the motor system. We investigated lateralisation of interhemispheric inhibition (IHI), motor thresholds and short interval intracortical inhibition (SICI) and facilitation (SICF) in relation to handedness in 12 right (RH) and 13 left handed (LH) subjects. Because there is some controversy as to the optimal localisation to produce IHI we also compared IHI induced by conditioning the dorsal premotor cortex (dPM) versus primary motor cortex (M1) in ten RH. IHI was stronger following conditioning the motor dominant as compared to the motor non-dominant hemisphere in RH and LH. Motor thresholds were higher when elicited over the right hemisphere than over the left in both RH and LH, while SICI and SICF showed no differences between hemispheres or dependency from handedness. We hypothesize that IHI is a function of handedness perhaps reflecting predominant usage of the dominant hand, while lateralisation of thresholds and intracortical excitability are determined by other factors.

Interhemispheric effects of high and low frequency rTMS in healthy humans

OBJECTIVE We investigated whether repetitive transcranial magnetic stimulation (rTMS) applied to the right motor cortex modified the excitability of the unstimulated left motor cortex. METHODS Interhemispheric effects of 0.5 and 5 Hz subthreshold rTMS over the right motor cortex were examined by single pulse and paired pulse TMS and by transcranial electrical stimulation (TES) applied to the unstimulated left motor cortex. The effects of (a) 1800 pulses real and sham rTMS with 5 Hz, (b) 180 pulses real and sham rTMS with 0.5 Hz and (c) 1800 pulses real rTMS with 0.5 Hz were studied. RESULTS Following 5 Hz right motor rTMS motor evoked potential (MEP) amplitudes induced by single pulse TMS over the left motor cortex increased significantly. Intracortical inhibition (ICI) and facilitation (ICF) and MEP amplitudes evoked by TES were unchanged. Sham stimulation had no influence on motor cortex excitability. After 180 pulses right motor cortex rTMS with 0.5 Hz a significant decrease of left motor ICF, but no change in single pulse MEP amplitudes was found. A similar trend was observed with 1800 pulses rTMS with 0.5 Hz. CONCLUSIONS High frequency right motor rTMS can increase left motor cortex excitability whereas low frequency right motor rTMS can decrease it. These effects outlast the rTMS by several minutes. The underlying mechanisms mediating interhemispheric excitability changes are likely to be frequency dependent.

Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest – A bifocal TMS study

OBJECTIVE In macaques, intracortical electrical stimulation of ventral premotor cortex (PMv) can modulate ipsilateral primary motor cortex (M1) excitability at short interstimulus intervals (ISIs). METHODS Adopting the same conditioning-test approach, we used bifocal transcranial magnetic stimulation (TMS) to examine intrahemispheric connectivity between left PMv and M1 in humans. A conditioning stimulus (CS) was applied to PMv at intensities of 80% and 90% of active motor threshold (AMT) and 90% and 110% of resting motor threshold (RMT). A supra-threshold test stimulus (TS) was given 2, 4, 6, 8 and 10 ms after the CS and the amplitude of the motor evoked potential (MEP) was measured to probe corticospinal excitability. RESULTS The CS facilitated corticospinal excitability in ipsilateral M1 when PMv was stimulated with 80% AMT 4 or 6 ms before the TS. At the same ISIs, the CS suppressed corticospinal excitability when the stimulus intensity was increased to 90% RMT. Conditioning effects were site-specific because conditioning the dorsal premotor cortex (PMd) at three different sites produced different effects. Using neuronavigated TMS the PMv site where applied CS produced changes in ipsilateral M1 excitability was located at the border between ventral Brodmann area (BA) 6 and BA 44, the human homologue of monkeys PMv (area F5). CONCLUSION We infer that the corticospinal motor output from M1 to contralateral hand muscles can be facilitated or inhibited by a CS over ipsilateral PMv. SIGNIFICANCE The fact that conditioning effects following PMd stimulation differ from those after PMv stimulation supports the concept that inputs from premotor cortices to M1 are functionally segregated.

Abnormal plasticity of the sensorimotor cortex to slow repetitive transcranial magnetic stimulation in patients with writer's cramp

Previous studies demonstrated functional abnormalities in the somatosensory system, including a distorted functional organization of the somatosensory cortex (S1) in patients with writers cramp. We tested the hypothesis that these functional alterations render S1 of these patients more susceptible to the “inhibitory” effects of subthreshold 1 Hz repetitive transcranial magnetic stimulation (rTMS) given to S1. Seven patients with writers cramp and eight healthy subjects were studied. Patients also received rTMS to the motor cortex hand area (M1). As an outcome measure, short‐latency afferent inhibition (SAI) was tested. SAI was studied in the relaxed first dorsal interosseous muscle using conditioning electrical stimulation of the index finger and TMS pulses over the contralateral M1. Baseline SAI did not differ between groups. S1 but not M1 rTMS reduced SAI in patients. rTMS had no effects on SAI in healthy subjects. Because SAI is mediated predominantly at a cortical level in the sensorimotor cortex, we conclude that there is an abnormal responsiveness of this area to 1 Hz rTMS in writers cramp, which may represent a trait toward maladaptive plasticity in the sensorimotor system in these patients.

Impaired induction of long‐term potentiation‐like plasticity in patients with high‐functioning autism and Asperger syndrome

Aim  We aimed to investigate the induction of long‐term potentiation (LTP)‐like plasticity by paired associative stimulation (PAS) in patients with high‐functioning autism and Asperger syndrome (HFA/AS).