Hartwig Roman Siebner

How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain

Transcranial direct current stimulation (tDCS) of the primary motor hand area (M1) can produce lasting polarity‐specific effects on corticospinal excitability and motor learning in humans. In 16u2003healthy volunteers, O positron emission tomography (PET) of regional cerebral blood flow (rCBF) at rest and during finger movements was used to map lasting changes in regional synaptic activity following 10u2003min of tDCS (±u20031u2003mA). Bipolar tDCS was given through electrodes placed over the left M1 and right frontopolar cortex. Eight subjects received anodal or cathodal tDCS of the left M1, respectively. When compared to sham tDCS, anodal and cathodal tDCS induced widespread increases and decreases in rCBF in cortical and subcortical areas. These changes in rCBF were of the same magnitude as task‐related rCBF changes during finger movements and remained stable throughout the 50‐min period of PET scanning. Relative increases in rCBF after real tDCS compared to sham tDCS were found in the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions irrespective of polarity. With the exception of some posterior and ventral areas, anodal tDCS increased rCBF in many cortical and subcortical regions compared to cathodal tDCS. Only the left dorsal premotor cortex demonstrated an increase in movement related activity after cathodal tDCS, however, modest compared with the relatively strong movement‐independent effects of tDCS. Otherwise, movement related activity was unaffected by tDCS. Our results indicate that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity. The extensive spatial and temporal effects of tDCS need to be taken into account when tDCS is used to modify brain function.

Age-related decrease in paired-pulse intracortical inhibition in the human primary motor cortex.

Using biphasic magnetic stimuli, paired-pulse transcranial magnetic stimulation (TMS) at short interstimulus intervals (ISIs) was employed to investigate age-related changes in the balance between intracortical inhibition and facilitation. In 26 right-handed healthy individuals, motor evoked potentials were recorded from the relaxed right first dorsal interosseus muscle after paired-pulse TMS of the left primary motor hand area. The magnitude of intracortical paired-pulse inhibition at ISIs of 1-5 ms was markedly reduced in elderly individuals, whereas no age effect was observed for intracortical paired-pulse facilitation at ISIs of 11-15 ms. This finding demonstrates that normal aging is associated with a relative decrease in the excitability of intracortical inhibitory circuits. In conclusion, paired-pulse TMS provides a non-invasive means of studying age-related functional changes in the motor cortex.

Lasting cortical activation after repetitive TMS of the motor cortex: A glucose metabolic study

Objective: Cerebral [18F]fluorodeoxy-d-glucose PET ([18F]FDG-PET) was used to visualize the lasting neuronal activation after repetitive transcranial magnetic stimulation (rTMS) over the left hand area of the primary motor cortex (M1HAND). Background: Applied over M1HAND, rTMS has been shown to produce a modulation of corticomotor excitability beyond the time of stimulation itself. Methods: Eight right-handed subjects underwent nonquantitative [18F]FDG-PET measurements during two experimental conditions: at rest and after focal subthreshold 5-Hz rTMS over the left M1HAND. In the post-rTMS condition, [18F]FDG was injected immediately after the administration of 1,800 magnetic pulses over the left M1HAND. Relative differences in normalized regional cerebral metabolic rate of glucose (normalized rCMRglc) between conditions were determined using a voxel-by-voxel Student’s t-test and volume-of-interest (VOI) analysis. Analysis was a priori restricted to the M1HAND, the supplementary motor area (SMA), and the primary auditory cortex of both hemispheres. Results: A 5-Hz rTMS of the left M1HAND caused a lasting relative increase in normalized rCMRglc within the M1HAND bilaterally and the SMA. The magnitude and the topographic pattern of persisting relative rCMRglc increases within these motor cortical areas demonstrated considerable interindividual variations. Conclusions: Subthreshold 5-Hz repetitive transcranial magnetic stimulation (rTMS) over the hand area of the primary motor cortex is associated with a persisting neuronal activation in a distinct set of motor cortical areas beyond the time of stimulation. The current findings demonstrate that [18F]FDG-PET can localize and quantify regional net changes in synaptic cortical activity after rTMS and thus might elucidate the mechanisms underlying rTMS-associated therapeutic effects.

How does transcranial magnetic stimulation modify neuronal activity in the brain? - Implications for studies of cognition

Transcranial magnetic stimulation (TMS) uses a magnetic field to carry a short lasting electrical current pulse into the brain where it stimulates neurones, particularly in superficial regions of cerebral cortex. TMS can interfere with cognitive functions in two ways. A high intensity TMS pulse causes a synchronised high frequency burst of discharge in a relatively large population of neurones that is terminated by a long lasting GABAergic inhibition. The combination of artificial synchronisation of activity followed by depression effectively disrupts perceptual, motor and cognitive processes in the human brain. This transient neurodisruption has been termed a virtual lesion. Smaller intensities of stimulation produce less activity; in such cases, cognitive operations can probably continue but are disrupted because of the added noisy input from the TMS pulse. It is usually argued that if a TMS pulse affects performance, then the area stimulated must provide an essential contribution to behaviour being studied. However, there is one exception to this: the pulse could be applied to an area that is not involved in the task but which has projections to the critical site. Activation of outputs from the site of stimulation could potentially disrupt processing at the distant site, interfering with behaviour without having any involvement in the task. A final important feature of the response to TMS is context dependency, which indicates that the response depends on how excitable the cortex is at the time the stimulus is applied: if many neurones are close to firing threshold then the more of them are recruited by the pulse than at rest. Many studies have noted this context-dependent modulation. However, it is often assumed that the excitability of an area has a simple relationship to activity in that area. We argue that this is not necessarily the case. Awareness of the problem may help resolve some apparent anomalies in the literature.

Phonological decisions require both the left and right supramarginal gyri

Recent functional imaging studies demonstrated that both the left and right supramarginal gyri (SMG) are activated when healthy right-handed subjects make phonological word decisions. However, lesion studies typically report difficulties with phonological processing after left rather than right hemisphere damage. Here, we used a unique dual-site transcranial magnetic stimulation (TMS) approach to test whether the SMG in the right hemisphere contributes to modality-independent (i.e., auditory and visual) phonological decisions. To test task-specificity, we compared the effect of real or sham TMS during phonological, semantic, and perceptual decisions. To test laterality and anatomical specificity, we compared the effect of TMS over the left, right, or bilateral SMG and angular gyri. The accuracy and reaction times of phonological decisions were selectively disrupted relative to semantic and perceptual decisions when real TMS was applied over the left, right, or bilateral SMG. These effects were not observed for TMS over the angular gyri. A follow-up experiment indicated that the threshold-intensity for inducing a disruptive effect on phonological decisions was identical for unilateral TMS over the right or left SMG. Taken together, these findings provide converging evidence that the right SMG contributes to accurate and efficient phonological decisions in the healthy brain, with no evidence that the left and right SMG can compensate for one another during TMS. Our findings motivate detailed studies of phonological processing in patients with acute or long-term damage of the right SMG.

Shaping the excitability of human motor cortex with premotor rTMS

Recent studies have shown that low‐frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsal premotor cortex has a lasting influence on the excitability of specific neuronal subpopulations in the ipsilateral primary motor hand area (M1HAND). Here we asked how these premotor to motor interactions are shaped by the intensity and frequency of rTMS and the orientation of the stimulating coil. We confirmed that premotor rTMS at 1 Hz and an intensity of 90% active motor threshold (AMT) produced a lasting decrease in corticospinal excitability probed with single‐pulse TMS over the left M1HAND. Reducing the intensity to 80% AMT increased paired‐pulse excitability at an interstimulus interval (ISI) of 7 ms. Opposite effects occurred if rTMS was given at 5 Hz: at 90% AMT, corticospinal excitability increased; at 80% AMT, paired‐pulse excitability at ISI = 7 ms decreased. No effects were seen if rTMS was applied at the same intensities to prefrontal or primary motor cortices. These findings indicate that the intensity of premotor rTMS determines the net effect of conditioning on distinct populations of neurones in the ipsilateral M1HAND, but it is the frequency of rTMS that determines the direction of the induced change. By selecting the appropriate intensity and frequency, premotor rTMS allows to induce a predictable up‐ or down‐regulation of the excitability in distinct neuronal circuits of human M1HAND.

Continuous transcranial magnetic stimulation during positron emission tomography: a suitable tool for imaging regional excitability of the human cortex.

In six healthy volunteers, H(2)(15)O positron emission tomography (PET) was employed to evaluate rate-dependent functional activation of the left primary sensorimotor hand area (SM1(HAND)) during subthreshold repetitive transcranial magnetic stimulation (rTMS). Using an eight-shaped coil, continuous trains of rTMS were delivered during nine 50-s H(2)(15)O PET scans. Nine different stimulation frequencies were used, ranging from 1 to 5 Hz. Stimulus intensity was set at 10% below active motor threshold. During three additional PET scans, an ineffective rTMS was applied via another eight-shaped coil, which was held 10 cm above the vertex. Statistical parametric mapping was employed to assess relative differences in normalized regional cerebral blood flow (rCBF) across conditions. Compared with ineffective rTMS, subthreshold rTMS increased normalized rCBF in the stimulated SM1(HAND). Moreover, the increase in rCBF in the left SM1(HAND) showed a linear positive relationship with the rate of rTMS, indicating a rate-dependent functional activation of the stimulated SM1(HAND). These data demonstrate that, by varying the variables of rTMS across scans, continuous rTMS during H(2)(15)O PET provides a noninvasive tool to study the regional excitability profile of a distinct cortical area.

Low-frequency rTMS over lateral premotor cortex induces lasting changes in regional activation and functional coupling of cortical motor areas

OBJECTIVEnTo study the effect of 0.9 Hz repetitive transcranial magnetic stimulation (rTMS) of the lateral premotor cortex on neuronal activity in cortical motor areas during simple motor tasks.nnnMETHODSnIn 8 subjects, electroencephalogram (EEG) and electromyogram (EMG) were simultaneously recorded during voluntary contractions of the thumb before and after a 15 min train of 0.9 Hz rTMS over the left lateral premotor cortex at stimulus intensity of 90% of active motor threshold. After-effects on cortical motor activity were assessed by measuring the task-related EEG power and inter-regional coherence changes, and the EEG-EMG coherence (EMGCoh).nnnRESULTSnLow-frequency rTMS over the premotor cortex gave rise to (i) a reduction of the task-related power decrease in the alpha and beta bands, (ii) a selective increase in the task-related coherence change among cortical motor areas in the upper alpha band, and (iii) a decrease in the cortico-muscular coherence. These effects lasted about 15 min after the end of rTMS intervention.nnnCONCLUSIONSnThe attenuated task-related power changes and decreased EMGCoh point to a lasting suppression of voluntary activation of cortical motor areas after rTMS. The present data provide an evidence for a transient reorganization of movement-related neuronal activity in the cortical motor areas after 0.9 Hz rTMS over the premotor cortex.nnnSIGNIFICANCEnLow-frequency rTMS changes the regional activation and functional coupling of cortical motor areas as demonstrated by EEG analysis.

Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of the human primary motor cortex (M1) provides a means of inducing lasting changes in cortical excitability and synaptic activity. Here we combined rTMS with positron emission tomography of regional cerebral blood flow (rCBF) to examine how an rTMS-induced change in intracortical excitability of inhibitory circuits affects regional synaptic activity. In a first set of experiments, we gave 150 biphasic pulses of 5 Hz rTMS at 90% of active motor threshold to left M1 and used single- and paired-pulse TMS to assess the conditioning effects of rTMS on motor cortical excitability at rest. rTMS conditioning led to a selective decrease in short-latency intracortical inhibition (SICI) without affecting short-latency intracortical facilitation or corticospinal excitability. The decrease in SICI lasted for approximately 8 min. In a second experiment, we used the same rTMS protocol and measured changes in regional synaptic activity (as indexed by rCBF) during and for up to 14 min after the end of rTMS. Subthreshold 5 Hz rTMS induced a region-specific increase in resting rCBF in the stimulated M1 lasting approximately 8 min. These results suggest that in the stimulated M1, temporary attenuation of SICI is paralleled by an increase in synaptic activity, consistent with reduced efficacy of intracortical GABA(A)-ergic synapses. The present findings demonstrate that short trains of low-intensity 5 Hz rTMS can be used to induce a transient change in function within a distinct cortical area. This opens up new possibilities for studying acute reorganization at the systems level in the intact human brain.

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.