Christian Gerloff

Depression of motor cortex excitability by low‐frequency transcranial magnetic stimulation

We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.

Functional relevance of cross-modal plasticity in blind humans.

Functional imaging studies of people who were blind from an early age have revealed that their primary visual cortex can be activated by Braille reading and other tactile discrimination tasks. Other studies have also shown that visual cortical areas can be activated by somatosensory input in blind subjects but not those with sight. The significance of this cross-modal plasticity is unclear, however, as it is not known whether the visual cortex can process somatosensory information in a functionally relevant way. To address this issue, we used transcranial magnetic stimulation to disrupt the function of different cortical areas in people who were blind from an early age as they identified Braille or embossed Roman letters. Transient stimulation of the occipital (visual) cortex induced errors in both tasks and distorted the tactile perceptions of blind subjects. In contrast, occipital stimulation had no effect on tactile performance in normal-sighted subjects, whereas similar stimulation is known to disrupt their visual performance. We conclude that blindness from an early age can cause the visual cortex to be recruited to a role in somatosensory processing. We propose that this cross-modal plasticity may account in part for the superior tactile perceptual abilities of blind subjects.

Temporal and Spatial Dynamics of Cerebral Immune Cell Accumulation in Stroke

BACKGROUND AND PURPOSE Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. METHODS Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. RESULTS Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. CONCLUSIONS This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.

Brain Oscillatory Substrates of Visual Short-Term Memory Capacity

The amount of information that can be stored in visual short-term memory is strictly limited to about four items. Therefore, memory capacity relies not only on the successful retention of relevant information but also on efficient suppression of distracting information, visual attention, and executive functions. However, completely separable neural signatures for these memory capacity-limiting factors remain to be identified. Because of its functional diversity, oscillatory brain activity may offer a utile solution. In the present study, we show that capacity-determining mechanisms, namely retention of relevant information and suppression of distracting information, are based on neural substrates independent of each other: the successful maintenance of relevant material in short-term memory is associated with cross-frequency phase synchronization between theta (rhythmical neural activity around 5 Hz) and gamma (> 50 Hz) oscillations at posterior parietal recording sites. On the other hand, electroencephalographic alpha activity (around 10 Hz) predicts memory capacity based on efficient suppression of irrelevant information in short-term memory. Moreover, repetitive transcranial magnetic stimulation at alpha frequency can modulate short-term memory capacity by influencing the ability to suppress distracting information. Taken together, the current study provides evidence for a double dissociation of brain oscillatory correlates of visual short-term memory capacity.

Enhancing cognitive performance with repetitive transcranial magnetic stimulation at human individual alpha frequency.

We applied rapid‐rate repetitive transcranial magnetic stimulation (rTMS) at individual alpha frequency (IAF) to improve cognitive performance by influencing the dynamics of alpha desynchronization. Previous research indicates that a large upper alpha power in a reference interval preceding a task is related to both large suppression of upper alpha power during the task and good performance. Here, we tested the hypothesis that rTMS at individual upper alpha frequency (IAF + 1 Hz) can enhance alpha power in the reference interval, and can thus improve task performance. Repetitive TMS was delivered to the mesial frontal (Fz) and right parietal (P6) cortex, and as sham condition with 90°‐tilted coil (P6 position). The behavioural effect was assessed in a mental rotation task. Further control conditions were rTMS at a lower IAF (IAF − 3 Hz) and at 20 Hz. The results indicate that rTMS at IAF + 1 Hz can enhance task performance and, concomitantly, the extent of task‐related alpha desynchronization. This provides further evidence for the functional relevance of oscillatory neuronal activity in the alpha band for the implementation of cognitive performance.

The Role of Multiple Contralesional Motor Areas for Complex Hand Movements after Internal Capsular Lesion

Imaging techniques document enhanced activity in multiple motor areas of the damaged and contralesional (intact) hemisphere (CON-H) after stroke. In the subacute stage, increased activity within motor areas in the CON-H during simple movements of the affected hand has been shown to correlate with poorer motor outcome. For those patients in the chronic stage who recovered well, the functional relevance of an increased activation within the CON-H is unclear. Using trains of repetitive transcranial magnetic stimulation (TMS) during performance of complex finger movements, we tested the behavioral relevance of regional functional magnetic resonance imaging (fMRI) activation within the CON-H for sequential finger movement performance of the recovered hand in seven patients who had experienced a subcortical stroke. TMS was navigated over fMRI activation maxima within anatomically preselected regions of the CON-H, and effects were compared with those of healthy controls. Stimulation over the dorsal premotor cortex (dPMC), the primary motor cortex (M1), and the superior parietal lobe (SPL) resulted in significant interference with recovered performance in patients. Interference with the dPMC and M1 induced timing errors only, SPL stimulation caused both timing and accuracy deficits. The present results argue for a persistent beneficial role of the dPMC, M1, and SPL of the CON-H on some aspects of effectively recovered complex motor behavior after subcortical stroke.

Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract

1 The ability of the primary motor cortex (M1) to modulate motor responses in ipsilateral hand muscles seems to be important for normal motor control and potentially also for recovery after brain lesions. It is not clear which pathways mediate this ipsilateral modulation. Transcallosal connections have been proposed, but are known to be sparse between cortical hand motor representations in primates. The present study was performed to determine whether descending ipsilateral modulation of motor responses might also be mediated below the cortical level in humans. 2 A paired‐pulse protocol was used, in which motor‐evoked potentials (MEPs) were produced by cortical transcranial magnetic stimulation (cTMS) or by electrical stimulation of the pyramidal tract at the level of the pyramidal decussation (pdTES), in both preactivated and relaxed hand muscles. Paired stimuli were applied at various interstimulus intervals (ISIs) between 2 and 100 ms. The conditioning stimulus (CS) was always magnetic, and delivered to the M1 ipsilateral to the target hand, prior to the test stimulus (TS). The magnetic TS was delivered to the M1 contralateral to the target hand; the electrical TS was applied through electrodes placed over the mastoid process bilaterally. Further experiments included cortical electrical stimulation and H‐reflexes. The MEP amplitudes were averaged separately for each ISI and the control condition (no CS), and expressed as a percentage of the unconditioned response. 3 Conditioning stimulation of the ipsilateral M1 resulted in significant inhibition of magnetically evoked MEPs, and also of MEPs produced by pdTES. Inhibition occurred at ISIs between 6 and 50 ms, and was observed in preactivated and relaxed muscles. Higher CS intensities caused greater inhibition of both cTMS‐ and pdTES‐evoked MEPs. 4 While the conditioning effects on magnetically evoked muscle responses could be explained by a transcallosal mechanism, the effects on pdTES‐evoked MEPs cannot, because they are elicited subcortically and are therefore not susceptible to inhibitory mechanisms transmitted at the cortico‐cortical level. 5 In conclusion, the present results provide novel evidence that the inhibitory influence of the human M1 on ipsilateral hand muscles is to a significant extent mediated below the cortical level, and not only through cortico‐cortical transcallosal connections. They point to a concept of inhibitory interaction between the two primary motor cortices that is relayed at multiple levels along the neuroaxis, thus perhaps providing a structurally redundant system which may become important in case of lesions.

Reorganization in congenital hemiparesis acquired at different gestational ages

It is well established that the reorganizational potential of the developing human brain is superior to that of the adult brain, but whether age‐dependent differences exist already in the prenatal and perinatal period is not known. We have studied sensorimotor reorganization in 34 patients with congenital hemiparesis (age range, 5–27 years), using transcranial magnetic stimulation and functional magnetic resonance imaging during simple hand movements. Underlying pathologies were brain malformations (first and second trimester lesions; n = 10), periventricular brain lesions (early third trimester lesions; n = 12), and middle cerebral artery infarctions (late third trimester lesions; n = 12). Of this cohort, eight patients with malformations and all patients with periventricular lesions have been published previously. In all three groups of pathologies, transcranial magnetic stimulation identified patients in whom the paretic hand was controlled via ipsilateral corticospinal projections from the contralesional hemisphere (n = 16). In these patients, the motor dysfunction of the paretic hand correlated significantly with the timing period of the underlying brain lesion. This demonstrates that the efficacy of reorganization with ipsilateral corticospinal tracts indeed decreases during pregnancy. Ann Neurol 2004

Task-related coherence and task-related spectral power changes during sequential finger movements.

In order to investigate the activity of cortical regions in the control of complex movements, we studied task-related coherence (TRCoh) and task-related spectral power (TRPow) changes in 8 right-handed subjects during the execution of 4 different finger movement sequences of increasing complexity. All sequences were performed with the right hand and were paced by a metronome at 2 Hz. EEG power spectra and coherence values were computed within alpha (8-12 Hz) and beta (13-20 Hz) frequency bands for 29 scalp EEG positions during the execution of the sequences and were compared with values obtained during a rest (control) condition. Movement sequences were associated with TRPow decreases in the alpha and beta frequency bands over bilateral sensorimotor and parietal areas, with a preponderance over the contralateral hemisphere. Increases of TRCoh occurred over bilateral frontocentral regions. TRCoh decreases were present over the temporal and occipital areas. The spatial extent and the magnitude of TRPow decreases and TRCoh increases in both frequency bands were greater for sequential movements of higher complexity than for simpler ones. These results are consistent with previous findings of bilateral activation of sensorimotor areas during sequential finger movements. Moreover, the present results indicate an active intercommunication between bilateral and mesial central and prefrontal regions which becomes more intense with more complex sequential movements.

Dissociation of sustained attention from central executive functions: local activity and interregional connectivity in the theta range

Human brain oscillatory activity was analysed in the electroencephalographic theta frequency range (4–7 Hz) while subjects executed complex sequential finger movements with varying task difficulty and memory load. Local frontal‐midline theta activity was associated with the general level of cognitive demand, with the highest amplitudes in the most demanding condition. Using low‐resolution electromagnetic tomography analysis (LORETA), this theta activity was localized in the anterior cingulate gyrus including the cingulate motor area. These results suggest that local theta activity in the anterior cingulate gyrus represents correlates of an attentional system that allocate cognitive resources. In addition, interregional connectivity in the theta frequency range was modulated by memory‐related executive functions independently of task difficulty. Connectivity analyses revealed a more distributed long‐range network including frontal and parietal cortices during execution of novel compared with well‐trained finger movement sequences. Thus, these results are compatible with a model in which theta long‐range coupling indicates integration of sensory information into executive control components of complex motor behaviour.