Clinical Neurophysiology

The visual system is vital during critical activities such as driving. Studying how alcohol compromises the visual system physiologically is therefore important for safety reasons. The objective of the study was to investigate alcohol-related impairments in visual tasks performed under controlled breath alcohol concentrations (BAC) to determine dose-dependent effects. Alcohol's effects on smooth pursuit and saccadic eye movements at 0.06% and 0.10% BAC were examined whilst recording alcohol levels by real-time measurements using a high precision breath analyzer. Oculomotor performance was recorded from 25 subjects by electronystagmography comprising measurements of smooth pursuit gain, saccade velocity, saccade accuracy and two novel parameters further describing oculomotor performance. Alcohol deteriorated accuracy of smooth pursuit movements (p<0.001) and saccadic velocities (p<0.01) at 0.06% BAC. At 0.10% BAC, smooth pursuit gains (p<0.01), saccade accuracies and saccade latencies (p<0.01) were also affected. The ratio between saccade velocity and saccade amplitude decreased significantly under alcohol intoxication (p<0.01). Self-perceptions of drunkenness correlated well with changes in smooth pursuit accuracy, but poorly with other oculomotor measures. Several of the smooth pursuit and saccade functions were altered dose-dependently by alcohol and small changes in BAC substantially changed the effects observed. Additionally, alcohol altered the relationship between saccade velocity and saccade amplitude, diminishing the capacity for saccades to reach high peak velocities. The alcohol-induced oculomotor deficits, which were found already at 0.06% BAC by our more sensitive analysis methods, may have safety implications for tasks that rely on visual motor control and visual feedback.

To investigate the after-effects of 0.3 Hz repetitive transcranial magnetic stimulation (rTMS) on excitatory and inhibitory mechanisms at the primary motor cortex level, as tested by single-pulse TMS variables. In 9 healthy subjects, we studied a wide set of neurophysiological and behavioral variables from the first dorsal interosseous before (Baseline), immediately after (Post 1), and 90 min after (Post 2) the end of a 30 min long train of 0.3 Hz rTMS delivered at an intensity of 115% resting motor threshold (RMT). Variables under investigation were: maximal M wave, F wave, and peripheral silent period after ulnar nerve stimulation; RMT, amplitude and stimulus-response curve of the motor evoked potential (MEP), and cortical silent period (CSP) following TMS; finger-tapping speed. The CSP was consistently lengthened at both Post 1 and Post 2 compared with Baseline. The other variables did not change significantly. These findings suggest that suprathreshold 0.3 Hz rTMS produces a relatively long-lasting enhancement of the inhibitory mechanisms responsible for the CSP. These effects differ from those, previously reported, of 0.9-1 Hz rTMS, which reduces the excitability of the circuits underlying the MEP and does not affect the CSP. This provides rationale for sham-controlled trials aiming to assess the therapeutic potential of 0.3 Hz rTMS in epilepsy.

Spectral power of 40 all-night sleep EEGs (Cz-Pz bipolar lead) recorded in 20 healthy young subjects was calculated after normalization on 30-s consecutive epochs by means of an autocorrelation method based on a 15-order autoregressive model. The spectral parameters were calculated for the 7 main EEG bands: slow delta (0.7-2 Hz); fast delta (2-4 Hz); theta (4-8 Hz); alpha (8-12 Hz); sigma (12-16 Hz); beta1 (16-35 Hz); and beta 2 (>35 Hz). Strong negative correlations were found between power in the fast delta and either the alpha or the beta bands and between slow delta and theta bands, whereas the two delta bands showed little correlation with each other. The possibility that theses different relationships of slow and fast delta components with other frequency bands might reflect the neocortical or the thalamocortical origin of the delta waves is discussed.

Repetitive paired-pulse TMS (rPPS) given at an interstimulus interval (ISI) of 1.5 ms has been reported to induce a lasting motor evoked potential (MEP) facilitation. This after-effect was considered to be a cortical event because F-waves were not affected by the same rPPS. To confirm its cortical facilitation, we compared the after-effects of rPPS on MEPs to single pulse TMS over the motor cortex (motor cortical MEPs) with those to brainstem stimulation (brainstem MEPs). Subjects were 10 healthy volunteers. Suprathreshold paired-pulse TMS at an ISI of 1.5 ms was applied to the motor cortex for 30 min at a rate of 0.2 Hz. After intervention, we measured motor cortical MEPs for 30 min. We also studied brainstem MEPs in five subjects. Motor cortical MEPs were facilitated to about 190% of baseline (p<0.001) for 10 min post rPPS intervention and returned to the baseline at 10-15 min post intervention. Brainstem MEPs were not affected by the intervention. The facilitation of MEPs after rPPS at an interval of 1.5 ms occurs at the motor cortex. rPPS at an interval of 1.5 ms is an effective method for increasing motor cortical excitability.

Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites +20 and +10 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation.

High frequency oscillations (HFO) of 100-500Hz have been reported in epileptic human brain. However, the questions of how fast these oscillations can reach, and which frequency range is clinically important remain unanswered. We recorded interictal and ictal very high frequency oscillations (VHFO) of 1000-2500Hz by subdural electrodes using 10kHz sampling rate. We describe the characteristics of VHFO, and discuss their underlying mechanism and clinical significance. Five patients with neocortical epilepsy were studied. All patients underwent intracranial EEG monitoring with subdural electrodes. EEG recording with sampling rate of 10kHz was conducted. Histopathology revealed malformation of cortical development in all cases. In four of five patients, very high frequency activities of 1000-2500Hz were detected in highly localized cortical regions (one to four electrodes in individual patient). We named these activities "very high frequency oscillations (VHFO)". Interictally, VHFO appeared intermittently, and were interrupted by spikes. Sustained VHFO without spikes appeared around the start of seizures. Both interictal and ictal VHFO can be recorded by subdural electrodes. Compared to HFO previously reported, VHFO have much higher frequency, more restricted distribution, smaller amplitude, and different timing of onset. Recording of VHFO may be useful for identifying the epileptogenic zone.

To quantify the incidence of seizures and adverse events during standard electroencephalography (EEG). A retrospective random sample of 1000 of a total of 3391 reports of standard scalp EEG recordings during 2002 at Kings College Hospital were studied, and adverse events during standard EEG were recorded. Photic induced seizures and epileptiform activity were compared with the resting, hyperventilation and sleep EEG. Adverse events occurred in 131 records (13.1%), including seizures in 60 records (45 electro-clinical and 15 non-epileptic seizures). The overall incidence of electro-clinical seizures was not statistically different during the resting EEG (2.8%), sleep EEG (2%), hyperventilation EEG (2.1%) and during photic stimulation EEG (1.4%). There was a higher frequency of electro-clinical seizures during hyperventilation and sleep in those with a diagnosis of idiopathic generalised epilepsy (31.5%) and during photic stimulation in photosensitive patients (31%). The incidence of electro-clinical seizures was significantly less during activation procedures in focal epilepsies (2.6%). Activation techniques made a unique diagnostic contribution when routine resting EEG was normal or equivocal in 11% of cases. Adverse events occurred in 13.1% of records, and most were minor. Sixty of the adverse events were seizures. Those generated during the EEG were brief and safety precautions operated successfully. In those without a prior diagnosis, the chance of seizures is the same during both resting and activation EEG. In those patients with generalised epilepsy or photosensitivity, activation procedures have a higher rate of seizure induction. This study has implications for informed consent for EEG.

To study the effect of high-frequency (100 Hz) repetitive conditioning electrical stimulation (CES, 10 min) on human somatosensory evoked potentials (SEPs) to evaluate if short-term cortical plasticity could be induced. Painful electrical stimulations were applied to thumb (D1) and little finger (D5) fingertips, respectively. The 124-channel EEG was recorded from 10 healthy male volunteers. Peak stages around 34, 45, 212, 331 ms were analyzed with focal maximum amplitude (FA) and area magnitude (AM) of scalp field potential, topography, and equivalent current dipole source localisation, comparing before and after two-level CES (high- vs. low-level) applied to the He-Gu acupoint. After a high-level CES, the positive FA and AM of the current efflux showed a significant increase at the early phase 34 ms, and significantly decreased at 45 ms in D1 SEPs. The negative FA and AM of the current influx were significantly increased at late phase 350 ms of the D5 SEPs. Only 36 ms, the z-axis position of dipole was significantly changed from (x: -15.9 mm, y: 29.6 mm, z: 43.9 mm) to (x: -12.9 mm, y: 29.4mm, z: 51.5mm) for the D5 SEPs. The high-level CES significantly attenuated the subsequent cortical activation (45 ms peak for D1 stimulation). Both low- and high-level CES significantly enhanced the late activities (226, 350 ms) in D5 stimulation. This may be explained by pain sensation change at the level of subcortical cingulate cortex induced by the site-dependent post-effect of CES. This study showed cortical plasticity induced by conditioning somatosensory stimulation.

It has not been previously studied with a paired longitudinal design if visual excitability changes occur in the preattack period across the migraine cycle, or how excitability and habituation relate to migraine-attack severity, clinical photophobia and serotonin metabolism. Monocular 62' check reversals were applied in 33 adult migraine patients without aura (MwoA), 8 with aura (MA) and 31 controls. VEP was recorded in four blocks of 50 stimuli. P1 (P100) and N2 (N145) latency and N1P1 and P1N2 amplitude were measured. Serotonin was measured in plasma and platelets sampled before each session. Sessions were classified as preattack, attack, postattack or interictal. Migraine patients had significantly higher P1N2 amplitude before the attack compared to a paired interictal recording (n=13, p=0.03), but habituation difference was not found. MA patients had significantly higher P1N2 and N1P1 amplitude than controls and MwoA. P1 latency correlated positively with headache history duration. During attack, a positive correlation between P1N2 amplitude habituation and serotonin emerged in MA patients. Increased VEP P1N2 amplitude was observed within a few days before the attack. Visual cortex excitability seems to be generally increased in MA as compared to MwoA patients and controls. Increased excitability of the visual cortex seems to be detectable in the preattack state, supporting the concept of a cyclic CNS dysfunction in migraine.

Objective: The amplitude and latency of the P300 may be associated by variations in dopaminergic genes. The current study was conducted to determine whether functional variants of the catechol-O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) gene were associated with P300 amplitude and latency in an auditory oddball task. Methods: The P300 ERP was assessed by a two-tone auditory oddball paradigm in a large sample of 320 healthy volunteers. The Val108/158Met polymorphism (rs4680) of the COMT gene and the -1021C>T polymorphism (rs1611115) of the DBH gene were genotyped. P300 amplitude and latency were compared across genotype groups using analysis of variance. Results: There were no differences in demographic characteristics in subjects for genotypic subgroups. No genotype associations were observed for the P300 amplitude and latency on frontal, central and parietal electrode positions. Conclusions: COMT Val108/158Met and DBH -1021C>T polymorphisms do not show evidence of association with characteristics of the P300 ERP in an auditory oddball paradigm in healthy volunteers. Significance: We failed to find evidence for the association between dopaminergic enzymatic polymorphisms and the P300 ERP in healthy volunteers, in the largest study undertaken to date.

To provide pharmacological evidence that the after-effects of theta burst stimulation (TBS) involve plasticity like changes in cortical synaptic connections, using the N-methyl-D-aspartate receptor antagonist memantine. We performed a double blind, placebo-controlled study to evaluate the effect of memantine on the response of six healthy volunteers to TBS. We measured rest (RMT) and active (AMT) motor thresholds, and the amplitude of MEPs before and after continuous and intermittent TBS (cTBS/iTBS) after the administration of placebo or memantine. Memantine had no effect on RMT and AMT, while it blocked the suppressive effect of cTBS and the facilitatory effect of iTBS. The effects of iTBS and cTBS rely on NMDARs to produce after-effects in the motor cortex of conscious humans. The NMDA dependency of the after-effects of TBS adds to the understanding of the underlying mechanism of TBS, and suggests that these after-effects are likely to involve plasticity like changes at synaptic connections in motor cortex.

Target/standard discrimination difficulty was manipulated systematically to assess how this variable affects target and nontarget P300 scalp distributions for both auditory and visual stimuli. A 3-stimulus paradigm (target, standard, nontarget) was employed in which subjects (n = 16) responded only to an infrequently occurring target stimulus. The perceptual discrimination difficulty between the target and more frequently occurring standard stimuli was varied as Easy or Difficult in different conditions, while holding the nontarget stimulus properties constant. When target/standard discrimination was Easy, P300 amplitude was larger for the target than the nontarget across all electrode sites, and both demonstrated parietal maximums. In contrast, when target/standard discrimination was Difficult, target amplitude (P3b) was larger parietally and occurred later than nontarget components, whereas nontarget amplitude (P3a) was larger and earlier than the target P300 over the frontal electrode sites. Similar outcomes across task conditions were obtained for both auditory and visual stimuli. The findings suggest that target/standard discrimination difficulty, rather than stimulus novelty, determines P3a generation for both auditory and visual stimulus modalities.

The anatomical location of the motor area of the hand may be revealed using functional magnetic resonance imaging (fMRI). The motor cortex representation of the intrinsic hand muscles consists of a knob-like structure. This is omega- or epsilon-shaped in the axial plane and hook-shaped in the sagittal plane. As this knob lies on the surface of the brain, it can be stimulated non-invasively by transcranial magnetic stimulation (TMS). It was the aim of our study to identify the hand knob using fMRI and to reveal if the anatomical hand knob corresponds to the hand area of the motor cortex, as identified by TMS, by means of a frameless MRI-based neuronavigation system. Suprathreshold transcranial magnetic stimuli were applied over a grid on the left side of the scalp of 4 healthy volunteers. The motor evoked potentials (MEPs) were recorded from the contralateral small hand muscles, and the centers of gravity (CoG) of the MEPs were calculated. The exact anatomical localization of each point on the grid was determined using a frameless MRI-based neuronavigation system. In each subject, the hand area of the motor cortex was visualized using fMRI during sensorimotor activation achieved by clenching the right hand. In all 4 subjects, the activated precentral site in the fMRI and the CoG of the MEP of all investigated muscles lay within the predicted anatomical area, the so-called hand knob. This knob had the form of an omega in two subjects and an epsilon in the other two subjects. TMS is a reliable method for mapping the motor cortex. The CoG calculated from the motor output maps may be used as an accurate estimation of the location of the represented muscle in the motor cortex.

The present study was designed to investigate the attentional modulation of gamma band responses in a visual spatial attention task using a 128-channel-EEG-montage. Colored rectangles were presented on a screen. After 500 ms an arrow indicated whether subjects had to shift their attention to the left or right half of the screen to detect target stimuli. During the task, either the attended half of the screen rotated horizontally while the unattended part remained motionless, or vice versa. When subjects attended the rotating stimulus, we found significantly higher power in a specific gamma band from 35-51 Hz on parieto-occipital electrode sites contralateral to the stimulation side. In addition, after the onset of the arrow which indicated what side subjects should direct their attention to, the 35-51 Hz response shifted from a broad posterior distribution to an increase of power at parieto-occipital sites contralateral to the to-be-attended side. Furthermore, the rotating stimulus elicited higher gamma band power as compared to the standing stimulus at electrode locations, which may be related to the activity of underlying cortical structures specialized for motion processing. The present results replicate important parts of previous findings of enhanced gamma power when a moving stimulus was attended.

An efficient procedure for the magnetoencephalographic determination of functional landmarks in the somatosensory cortex has been developed. Digits 2-5 are stimulated in randomized order using balloon diaphragms. The interval between two stimuli is 500 ms. Source locations in area 3b are derived by interpreting the field component with a mean latency of 48 ms in terms of an equivalent current dipole. The signal-to-noise ratio achieved in a given time for each of the 4 stimulation sites turned out to be only slightly smaller than the one obtained by stimulating a single site with an optimal interstimulus interval (about 1 s). Compared to a sequential investigation of the different sites, the proposed procedure allows the reduction of the overall measurement time by a factor of about 2.7.

Schizophrenia is associated with deficits in mismatch negativity (MMN) generation and in the ability to match two tones following brief delay. Both deficits reflect impaired early cortical processing of auditory information. However, the relationship between deficits in MMN generation and tone matching performance in schizophrenia has not been established. MMN and tone matching performance was evaluated in 12 schizophrenic subjects and 12 similar aged controls. A pitch separation known to produce non-ceiling performance in patients (5% Deltaf) was used. Narrow band filtering of MMN data was used to enhance signal-to-noise ratio. Schizophrenic subjects showed impairments in both MMN generation and tone matching performance. The two deficits were significantly correlated across subjects. In addition, decreased MMN amplitude and poorer tone matching performance correlated with increased severity of negative symptoms. These findings support the concept that similar neurophysiological mechanisms underlie MMN and tone matching deficits in schizophrenia. Further, they indicate that increased sensitivity to environmental change may be related to social withdrawal and other negative symptoms in schizophrenia.

Transcranial magnetic stimulation (TMS), a non-invasive means of electrically stimulating neurons in the human cerebral cortex, is able to modify neuronal activity locally and at distant sites when delivered in series or trains of pulses. Data from stimulation of the motor cortex suggest that the type of effect on the excitability of the cortical network depends on the frequency of stimulation. These data, as well as results from studies in rodents, have been generalized across brain areas and species to provide rationales for using repetitive TMS (rTMS) to treat various brain disorders, most notably depression. Research into clinical applications for TMS remains active and has the potential to provide useful data, but, to date, the results of blinded, sham-controlled trials do not provide clear evidence of beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. In this review, we discuss the clinical and scientific bases for using rTMS as treatment, and review the results of trials in psychiatric and neurological disorders to date.

Event-related brain potentials (ERPs) during a Go/NoGo task were investigated to elucidate the electrophysiological basis for executive and inhibitory control of responses. We studied Go/NoGo ERPs in 13 healthy subjects during a modified continuous performance test using high-density electroencephalogram (EEG) recording. We measured peak latency, amplitude, and topographic distribution of the components, and analyzed the neural sources using low-resolution electromagnetic tomography. There were no differences between the Go and NoGo conditions in the latency, amplitude, scalp topography, or the electrical source localization of the P1 and N1 components. The N2 component was seen only in the NoGo ERP, and its source was located in the right lateral orbitofrontal and cingulate cortex. The NoGo-P3 component had larger amplitude and longer latency, and was more anteriorly localized than Go-P3; Go-P3 was located mainly in the medial part of the parietal cortex, whereas the NoGo-P3 activity was observed in the left lateral orbitofrontal cortex. These results suggest that the lateral orbitofrontal and anterior cingulate areas play critical roles in the inhibitory control of behavior and that both hemispheres are involved in inhibitory cognitive function.

To determine the reliability of computer measured non-rapid eye movement (NREM) and REM frequency bands in the 0.3-45 Hz range and to provide benchmark data for these measures in young normal (YN) and elderly normal (EN) subjects (Ss). Sleep EEG was recorded in 19 YN and 19 EN Ss on 4 non-consecutive baseline nights and simultaneously quantified as fast Fourier transform (FFT) power and 3 zero-cross period-amplitude (PA) measures: integrated amplitude, time in band and average wave amplitude. The shapes of both the FFT and PA spectra differed among Ss but were highly consistent within individuals. Inter-night reliability of the separate frequency bands was correspondingly high. Despite substantial age effects, the reliability of computer-measured sleep EEG in the elderly equaled that of the YN Ss. Within both the YN and EN groups, the shapes of the NREM and REM spectral curves differed significantly. The NREM and REM also differed significantly in the two age groups. Computer-measured sleep EEG is highly reliable across non-consecutive nights in both young and elderly normal Ss. The trait-like stability of these measures suggests they are genetically determined. This possibility is supported by twin study data that show strong heritability for FFT-measured waking EEG. The different shapes of NREM and REM spectra add further evidence that these are fundamentally different states of brain organization. The age differences in spectral shape, along with PA data for wave incidence, demonstrate that age effects on sleep EEG are not caused by changes in skull impedance or other non-cerebral factors.

A system for electrode placement is described. It is designed for studies on topography and source analysis of spontaneous and evoked EEG activity. The proposed system is based on the extended International 10-20 system which contains 74 electrodes, and extends this system up to 345 electrode locations. The positioning and nomenclature of the electrode system is described, and a subset of locations is proposed as especially useful for modern EEG/ERP systems, often having 128 channels available. Similar to the extension of the 10-20 system to the 10-10 system ("10% system"), proposed in 1985, the goal of this new extension to a 10-5 system is to further promote standardization in high-resolution EEG studies.

For many years people have speculated that electroencephalographic activity or other electrophysiological measures of brain function might provide a new non-muscular channel for sending messages and commands to the external world – a brain–computer interface (BCI). Over the past 15 years, productive BCI research programs have arisen. Encouraged by new understanding of brain function, by the advent of powerful low-cost computer equipment, and by growing recognition of the needs and potentials of people with disabilities, these programs concentrate on developing new augmentative communication and control technology for those with severe neuromuscular disorders, such as amyotrophic lateral sclerosis, brainstem stroke, and spinal cord injury. The immediate goal is to provide these users, who may be completely paralyzed, or ‘locked in’, with basic communication capabilities so that they can express their wishes to caregivers or even operate word processing programs or neuroprostheses. Present-day BCIs determine the intent of the user from a variety of different electrophysiological signals. These signals include slow cortical potentials, P300 potentials, and mu or beta rhythms recorded from the scalp, and cortical neuronal activity recorded by implanted electrodes. They are translated in real-time into commands that operate a computer display or other device. Successful operation requires that the user encode commands in these signals and that the BCI derive the commands from the signals. Thus, the user and the BCI system need to adapt to each other both initially and continually so as to ensure stable performance. Current BCIs have

This article reviews the event-related potential (ERP) literature in relation to attention-deficit/hyperactivity disorder (AD/HD). ERP studies exploring various aspects of brain functioning in AD/HD are reviewed, ranging from early preparatory processes to a focus on the auditory and visual attention systems, and the frontal inhibition system. Implications of these data for future research and development in AD/HD are considered. A complex range of ERP deficits has been associated with the disorder. Differences have been reported in preparatory responses, such as the contingent negative variation. In the auditory modality, AD/HD-related differences are apparent in all components from the auditory brain-stem response to the late slow wave. The most robust of these is the reduced posterior P3 in the auditory oddball task. There are fewer studies of the visual attention system, but similar differences are reported in a range of components. Results suggesting an inhibitory processing deficit have been reported, with recent studies of the frontal inhibitory system indicating problems of inhibitory regulation. The research to date has identified a substantial number of ERP correlates of AD/HD. Together with the robust AD/HD differences apparent in the EEG literature, these data offer potential to improve our understanding of the specific brain dysfunction(s) which result in the disorder. Increased focus on the temporal locus of the information processing deficit(s) underlying the observed range of ERP differences is recommended. Further work in this field may benefit from a broader conceptual approach, integrating EEG and ERP measures of brain function.

Neuroimaging studies have suggested an evolution of the brain activation pattern in the course of motor recovery after stroke. Initially poor motor performance is correlated with an recruitment of the uninjured hemisphere that continuously vanished until a nearly normal (contralateral) activation pattern is achieved and motor performance is good. Here we were interested in the early brain activation pattern in patients who showed a good and rapid recovery after stroke. Ten patients with first-ever ischemic stroke affecting motor areas had to perform self-paced simple or more complex movements with the affected or the unaffected hand during functional magnetic resonance imaging (fMRI). The location and number of activated voxels above threshold were determined. To study possible changes in the cortical motor output map the amplitude of the motor evoked potentials (MEP) and the extent of the excitable area were determined using transcranial magnetic stimulation (TMS). The pattern of activation observed with movements of the affected and the unaffected hand was similar. In the simple motor task significant (P<0.05) increases were found in the primary motor cortex ipsilateral to the movement, the supplementary motor area and the cerebellar hemisphere contralateral to the movement during performance with the affected hand compared to movements with the unaffected hand. When comparing simple with more complex movements performed with either the affected or the unaffected hand, a further tendency to increased activation in motor areas was observed. The amplitude of MEPs obtained from the affected hemisphere was smaller and the extent of cortical output maps was decreased compared to the unaffected hemisphere; but none of the patients showed MEPs at the affected hand when the ipsilateral unaffected motor cortex was stimulated. Despite a rapid and nearly complete motor recovery the brain activation pattern was associated with increased activity in (bilateral) motor areas as revealed with fMRI. TMS revealed impaired motor output properties, but failed to demonstrate ipsilateral motor pathways. Successful recovery in our patients may therefore rely on the increased bilateral activation of existing motor networks spared by the injury.

High-frequency deep brain stimulation (DBS) of the thalamus or basal ganglia represents an effective clinical technique for the treatment of several medically refractory movement disorders. However, understanding of the mechanisms responsible for the therapeutic action of DBS remains elusive. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS. Four general hypotheses have been developed to explain the mechanism(s) of DBS: depolarization blockade, synaptic inhibition, synaptic depression, and stimulation-induced modulation of pathological network activity. Using the results from functional imaging, neurochemistry, neural recording, and neural modeling experiments we address the general hypotheses and attempt to reconcile what have been considered conflicting results from these different research modalities. Our analysis suggests stimulation-induced modulation of pathological network activity represents the most likely mechanism of DBS; however, several open questions remain to explicitly link the effects of DBS with therapeutic outcomes.

Integration of sensory information by cortical network binding appears to be crucially involved in target detection. Studies in schizophrenia using functional and diffusion tensor neuroimaging, event-related potentials and EEG coherence indicate an impairment of cortical network coupling in this disorder. Previous electrophysiological investigations in animals and humans suggested that gamma activity (oscillations at around 40 Hz) is essential for cortical network binding. Studies in medicated schizophrenia provide evidence for a reduced gamma activity in the context of auditory stimulus processing. This is the first investigation of oscillatory activations in the gamma-band in an auditory oddball paradigm in unmedicated schizophrenic patients. EEG gamma-band responses (GBRs) of 15 drug-free schizophrenic patients and 15 age- and gender-matched healthy controls were compared. A wavelet transform based on Morlet wavelets was employed for the calculation of oscillatory GBRs. In response to standard stimuli, early evoked GBRs (20-100 ms), which are supposed to reflect auditory cortex activation, did not show significant group differences. However, schizophrenic patients showed reduced evoked GBRs in a late latency range (220-350 ms), particularly after target stimuli. This deficit occurred over right frontal scalp regions. Furthermore, significant correlations were observed between oscillatory GBRs and clinical parameters in schizophrenic patients. The results are consistent with a relative preserved stimulus processing in the auditory cortex as reflected by the early GBR. The reduced late GBR is compatible with an abnormal interaction within a frontal lobe network, as was postulated by previous neuroimaging studies. The present study provides evidence for disturbed processing within frontal cortical regions in unmedicated schizophrenic patients as indicated by reduced evoked EEG GBRs.