Probing modifications of cortical excitability during stroke recovery with navigated transcranial magnetic stimulation.

OBJECTIVE: To follow cortical excitability changes during recovery from stroke with navigated transcranial magnetic stimulation (nTMS), in particular, to characterize changes of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), to correlate them with recovery of upper extremity function, and to detect possible shifts of cortical hand representations. METHODS: Single and paired pulse nTMS were delivered to the hemisphere with infarction and to the hemisphere without infarction in 14 first-ever stroke patients at 1 (T1) and 3 months (T2) after stroke. Electromyographic responses to nTMS stimulation were recorded from the first dorsal interosseus muscles. nTMS was used to ensure an accurate coil repositioning in repeated measurements. Hand function recovery was clinically evaluated using the Action Research Arm Test (ARAT) and 9-hole peg test (9-HPT). RESULTS: SICI and ICF were modulated in both hemispheres during recovery. Inhibition in the hemisphere without infarction correlated significantly with the affected hand performance at T2; stronger disinhibition (poor inhibition) was associated with worse hand performance. Location of hand muscle representations was shifted in 3 well-recovered patients out of 14 patients at T2. CONCLUSIONS: In line with earlier studies, disinhibition in the hemisphere without infarction may be related to poor recovery of the affected hand. Usage of the affected hand during stroke recovery seems to influence these cortical excitability changes. nTMS is a valuable tool for tracking muscle cortical representation changes during brain reorganization.

Methodology for combined TMS and EEG.

The combination of transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) provides us the possibility to non-invasively probe the brain's excitability, time-resolved connectivity and instantaneous state. Early attempts to combine TMS and EEG suffered from the huge electromagnetic artifacts seen in EEG as a result of the electric field induced by the stimulus pulses. To deal with this problem, TMS-compatible EEG systems have been developed. However, even with amplifiers that are either immune to or recover quickly from the pulse, great challenges remain. Artifacts may arise from the movement of electrodes, from muscles activated by the pulse, from eye movements, from electrode polarization, or from brain responses evoked by the coil click. With careful precautions, many of these problems can be avoided. The remaining artifacts can be usually reduced by filtering, but control experiments are often needed to make sure that the measured signals actually originate in the brain. Several studies have shown the power of TMS-EEG by giving us valuable information about the excitability or connectivity of the brain.

Reproducibility of TMS-Evoked EEG responses.

Navigated transcranial magnetic stimulation combined with electroencephalography (nTMS-EEG), allows noninvasive studies of cortical excitability and connectivity in humans. We investigated the reproducibility of nTMS-EEG in seven healthy subjects by repeating left motor and prefrontal cortical stimulation with a 1-week interval. TMS was applied at three intensities: 90, 100, and 110% of subjects' motor threshold (MT). The TMS-compatible neuronavigation system guaranteed precise repositioning of the stimulation coil. The responses were recorded by a 60-channel whole head TMS-compatible EEG amplifier. A high overall reproducibility (r > 0.80) was evident in nTMS-EEG responses over both hemispheres for both motor and prefrontal cortical stimulation. The results suggest that nTMS-EEG is a reliable tool for studies investigating cortical excitability changes in the test-retest designs.

Electrophysiological correlates of short-latency afferent inhibition: a combined EEG and TMS study.

Cutaneous stimulation produces short-latency afferent inhibition (SAI) of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). Since the demonstration of SAI is primarily based on the attenuation of MEPs, its cortical origin is not yet fully understood. In the present study we combined TMS with concurrent electroencephalography (EEG) in order to obtain direct cortical correlates of SAI. TMS-evoked EEG responses and MEPs were analysed with and without preceding electrical stimulation of the index finger cutaneous afferents in ten healthy volunteers. We show that the attenuation of MEPs by cutaneous stimulation has its counterpart in the attenuation of the N100 EEG response. Moreover, the attenuation of the cortical N100 component correlated positively with the strength of SAI, indicating that the transient changes in cortical excitability can be reflected in the amplitude dynamics of MEPs. We hypothesize that the hyperpolarization of the pyramidal cells due to SAI lowers the capacity of TMS to induce the inhibitory current needed to elicit N100, thus leading to its attenuation. We suggest that the observed interaction of two inhibitory processes, SAI and N100, provides further evidence for the cortical origin of SAI.

The effect of methylphenidate on auditory information processing in healthy volunteers: a combined EEG/MEG study.

INTRODUCTION: The psychomotor stimulant methylphenidate (MPH) has been shown to improve attentional processes, reflected in behavioural measures such as vigilance, reaction time and visual attention tasks. The neural mechanisms of MPH action on sensory information processing, however, remain poorly understood. To the authors' knowledge, this present study is the first to investigate whether a single dose of MPH affects neural substrates of passive attention in healthy adults studied with simultaneous whole-head magnetoencephalography (MEG) and electroencephalography (EEG). METHODS: Monaural left-ear auditory stimuli were presented in an oddball paradigm with infrequent deviant tones differing in frequency and duration. Neuronal activity was recorded with simultaneous whole-head MEG and EEG in 13 healthy subjects (five females; aged 27 +/- 5 years) after oral administration of 40 mg MPH or placebo in a randomised, double-blind, cross-over design. We analysed both electric and magnetic N100, P200 and mismatch negativity (MMN) components. RESULTS: MPH increased arousal levels in visual analogue scales. MPH had no effect on the dipole strength of MMN or MMNm in either frequency or duration deviations. MPH did, however, reduce P200 amplitudes in EEG. CONCLUSIONS: The lack of effect of MPH on either MMN or MMNm suggests no association between catecholaminergic activities and MMN generation. However, our findings imply that MPH may change the neural bases of auditory information processing such as the early stimulus evaluation reflected in the P200 component. Dopamine and noradrenaline neurotransmitter systems could be responsible for the modulation of these processes. The exclusive effect of MPH on the P200 component could have a clinical application.

Effects of NMDA receptor antagonist memantine on mismatch negativity.

Mismatch negativity (MMN) and its magnetic counterpart (MMNm) have been shown to be altered in patients with various psychiatric and neurological disorders, e.g. Alzheimer's disease and schizophrenia, indicating deficits in involuntary attention. N-Methyl-D-aspartate (NMDA) receptor-mediated glutamate dysfunction is suggested to underlie these deficits. However, the role of NMDA receptors in involuntary attention is poorly understood. Memantine is an NMDA receptor antagonist that has been demonstrated to be effective in the treatment of patients with Alzheimer's disease. We aimed to investigate whether a single dose of memantine would affect MMN/MMNm in healthy subjects studied with simultaneous electroencephalography (EEG) and magnetoencephalography (MEG). Monaural left-ear auditory stimuli were presented in a passive oddball paradigm with infrequent deviant tones differing in frequency and duration. Neuronal activity was recorded in 13 healthy subjects after oral administration of 30mg of memantine or placebo in a randomized, double-blind, cross-over design. MMNm was analyzed using equivalent current dipoles. MMN was evaluated from frontocentral electrodes. Memantine lowered subjects' arousal level as measured by visual analog scales, and enhanced the amplitude of MMN in EEG. No differences in MMN latency were observed in MEG or EEG. Memantine did not affect the location, strength, amplitude or latency of MMNm, P1m, and N1m components. No changes in amplitude or latency were observed for P1 and N1 peaks. These results indicate that memantine affects involuntary attention without otherwise changing auditory processing of the stimuli. As memantine-induced changes in MMN were detected only in EEG, we suggest that the effect is mostly related to the frontal cortex.

Brain regions and their dynamics in prospective memory retrieval: a MEG study.

We measured brain activity using magnetoencephalography in five participants during ongoing tasks that included prospective memory, retrospective memory, and oddball trials. Sources were identified in the hippocampal formation and posterior parietal and frontal lobes. Posterior parietal cortex activation had an earlier onset in the prospective memory condition than retrospective memory or oddball conditions, a higher level of theta activity in the retrospective condition, and higher levels of upper alpha in the prospective and oddball conditions. Activation of the hippocampal formation had a longer duration in the retrospective memory and prospective memory conditions than the oddball condition, but prominent alpha and theta band activity was present in all three conditions. We interpret the early (87 ms) onset of activity in parietal cortex as evidence for an initial noticing of appropriate conditions for a PM response. Hippocampal activity may reflect a subsequent memory search for the intended action.

Averaged and single-trial brain responses in the assessment of human sound detection.

We investigated sound detection in humans with magnetoencephalography and behavioural measurements. Sounds with intensity increasing smoothly over 125-1000 ms elicited a transient response in auditory cortex with a peak latency in the 200-600 ms range. Importantly, peak latency accurately predicted behavioural reaction time and was unaffected by attentional engagement. Peak amplitude was augmented when the study participants attended to the stimuli and when stimulus duration was decreased. For investigating the cause of these amplitude variations in the averaged response we designed a wavelet-based method for analysing single-trial responses. We found that attention affects the amplitude of the single-trial responses whereas the intensity slope of the stimulus modifies their latency distribution. The transient response reported here holds promise for rapid, objective hearing assessment not requiring a behavioural task.

Validation of head movement correction and spatiotemporal signal space separation in magnetoencephalography.

OBJECTIVE: Our aim was to assess the effectiveness and reliability of spatiotemporal signal space separation (tSSS) and movement correction (MC) in magnetoencephalography (MEG) recordings disturbed by head movements and magnetized material on the head. METHODS: We recorded MEG from 20 healthy adults in stationary (reference) head position and during controlled head movements. Nearby magnetic interference sources were simulated by attaching magnetized particles on the subject's head. Auditory and somatosensory stimuli were presented. MC, tSSS and averaging were performed to obtain auditory (AEF) and somatosensory (SEF) evoked fields. Neuronal sources were modeled as equivalent current dipoles. MC was also validated by reconstructing signals generated by current dipoles in a phantom. RESULTS: After MC, the AEF and SEF responses recorded during intermittent head movements were similar in amplitude to the reference recordings and differed by 5-7mm in source location. The tSSS method removed artifacts due to the attached magnetized particles but did not affect the reference data. CONCLUSIONS: The methods are able to reliably recover MEG responses contaminated by movements and magnetic artifacts on the head. SIGNIFICANCE: The combination of tSSS and MC methods is especially useful in clinical measurements, where movements and magnetic disturbances are commonly present.

Interval timers and coupled oscillators both mediate the effect of temporally structured cueing.

When observers are presented with targets in the context of temporal structure, performance is modulated by that structure. Interval timing mechanisms and coupled oscillators are two popular classes of model that attempt to explain how temporal structure modulates attention and motor performance to bring about the behavioral costs and benefits of temporal structure. In this experiment, participants made speeded choice reactions to targets following a series of visual warning stimuli. The warning stimuli afforded prediction of target onset time. Brain activity related to temporally focused attention and motor preparation was measured using magnetoencephalography. Parietal, cerebellar, and somatomotor activity was found to be associated with response latency and the performance benefit of the cued relative to uncued targets. Parietal activity was consistent with an interval timing mechanism, while somatomotor activity was more consistent with a coupled oscillator mechanism. Cerebellar activity had features consistent with both mechanisms. To our knowledge, this is the first evidence that both processes occur simultaneously.

Parallel input makes the brain run faster.

In serial sensory processing, information flows from the thalamus via primary sensory cortices to higher-order association areas. However, association cortices also receive, albeit weak, direct thalamocortical sensory inputs of unknown function. For example, while information proceeds from primary (SI) to secondary (SII) somatosensory cortex in a serial fashion, both areas are known to receive direct thalamocortical sensory input. The present study examines the potential roles of such parallel input arrangements. The subjects were presented with median nerve somatosensory stimuli with the instruction to respond with the contralateral hand. The locations and time courses of the activated brain areas were first identified with magnetoencephalography (MEG). In a subsequent session, these brain areas were modulated with single-pulse transcranial magnetic stimulation (TMS) at 15-210 ms after the somatosensory stimulus while electroencephalography (EEG) was recorded. TMS pulses at 15-40 ms post-stimulus significantly speeded up reaction times and somatosensory-evoked responses, with largest facilitatory effects when the TMS pulse was given to contralateral SII at about 20 ms. To explain the results, we propose that the early somatosensory-evoked physiological SII activation exerts an SII-->SI influence that facilitates the reciprocal SI-->SII pathway - with TMS to SII we apparently amplified this mechanism. The results suggest that the human brain may utilize parallel inputs to facilitate long-distance cortico-cortical connections, resulting in accelerated processing and speeded reaction times. This arrangement could also allow very early top-down modulation of the bottom-up stream of sensory information.

MEG reveals different contributions of somatomotor cortex and cerebellum to simple reaction time after temporally structured cues.

Magnetoencephalography (MEG) was used to measure brain activity while participants performed a simple reaction to targets after either a random interval (uncued targets) or a series of isochronous warning stimuli with 200-ms intervals that acted as a countdown. Targets could arrive "on time" or "early" relative to the preceding warning stimuli. Cerebellar activity before any stimulus onset predicted uncued simple reaction time. Onset of activity in somatomotor cortex relative to the target predicted reaction time after two warning stimuli when the target arrived on time or early. After three warning stimuli, when the target arrived on time and was certain to occur, prestimulus cerebellar activity and somatomotor onset were significant predictors of reaction time. When the target arrived early after three warning stimuli, prestimulus cerebellar and cingulate activity were predictive. The cerebellar results may reflect a number of possible factors, including a role in timing, response readiness, prediction and attention.

Modulation of electroencephalographic responses to transcranial magnetic stimulation: evidence for changes in cortical excitability related to movement.

Transcranial magnetic stimulation (TMS) and multichannel electroencephalography (EEG) were used for the investigation of cortical excitability preceding voluntary movement in human subjects. The study showed the practical value of the combined TMS-EEG approach in differentiating between cortical and spinal-cord mechanisms, which is difficult with conventional electromyographic measures alone. TMS induced a pronounced negativity (N100) lasting for 150-200 ms, with the amplitude maximum in the stimulated hemisphere. When TMS was applied just before the onset of the visually triggered movement, N100 was markedly attenuated, although motor evoked potentials (MEPs) became larger. We suggest that the N100 component represents an inhibitory response following TMS. This interpretation is in agreement with intracellular recordings in animals, paired-pulse TMS studies and experiments showing increased premovement excitability on the basis of MEPs. N100 was not affected only by the subsequent movement, but also by the switching from rest to the motor-task condition, which caused a slight attenuation of the N100 component; no changes, however, were found in the amplitude of MEPs, suggesting that modified excitability did not affect the output of the corticospinal pyramidal cells. By contrast to MEPs, N100 was modulated also by the presentation of the visual stimulus alone, i.e. when no movement was required. This attenuation suggests that even in a rest condition visual stimuli have an access to the sensorimotor regions of the cortex, most probably through ascending arousal brain systems.