Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics.

BACKGROUND: Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain. METHOD: We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors. RESULTS: The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted. COMPARISON WITH EXISTING METHODS: Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales. CONCLUSIONS: This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses.

Role of frontotemporal fiber tract integrity in task-switching performance of healthy controls and patients with temporal lobe epilepsy.

The objective of this study is to investigate the relationships among frontotemporal fiber tract compromise and task-switching performance in healthy controls and patients with temporal lobe epilepsy (TLE). We performed diffusion tensor imaging (DTI) on 30 controls and 32 patients with TLE (15 left TLE). Fractional anisotropy (FA) was calculated for four fiber tracts [uncinate fasciculus (UncF), arcuate fasciculus (ArcF), dorsal cingulum (CING), and inferior fronto-occipital fasciculus (IFOF)]. Participants completed the Trail Making Test-B (TMT-B) and Verbal Fluency Category Switching (VFCS) test. Multivariate analyses of variances (MANOVAs) were performed to investigate group differences in fiber FA and set-shifting performances. Canonical correlations were used to examine the overall patterns of structural-cognitive relationships and were followed by within-group bivariate correlations. We found a significant canonical correlation between fiber FA and task-switching performance. In controls, TMT-B correlated with left IFOF, whereas VFCS correlated with FA of left ArcF and left UncF. These correlations were not significant in patients with TLE. We report significant correlations between frontotemporal fiber tract integrity and set-shifting performance in healthy controls that appear to be absent or attenuated in patients with TLE. These findings suggest a breakdown of typical structure-function relationships in TLE that may reflect aberrant developmental or degenerative processes.

Abnormalities of cortical thickness in postictal psychosis.

Postictal psychosis (PIP), the occurrence of psychotic episodes following a seizure, is a common and serious comorbidity in patients with epilepsy. Yet, the anatomical correlates remain poorly defined. Here, we used quantitative MRI morphometry to identify structural abnormalities in the cortex of patients with PIP relative to patients with epilepsy without PIP and age- and gender-matched normal healthy controls. Comparison of patients with epilepsy and PIP with patients with epilepsy without PIP revealed increased cortical thickness in the right lateral prefrontal cortex, right anterior cingulate cortex, and right middle temporal gyrus. The PIP group was distinguished from the EC and NC groups by thicker cortex in the right rostral anterior cingulate cortex and thinner cortex in the right angular gyrus and the left middle temporal region. Findings indicate that PIP is associated with thickening of the right anterior cingulate cortex, which may serve as a marker for patients at risk for developing PIP.

Changes in fiber tract integrity and visual fields after anterior temporal lobectomy.

OBJECTIVE: To investigate postoperative changes in fiber tract integrity in patients with temporal lobe epilepsy (TLE) following anterior temporal lobectomy (ATL) and to determine whether postoperative changes are 1) stable vs progressive and 2) related to visual field defects. METHODS: Diffusion tensor imaging (DTI) was obtained in 7 patients with TLE before, 2 months after, and 1 year after ATL. Changes in fractional anisotropy (FA) were evaluated in a whole-brain voxel-wise analysis, as well within specific fiber tracts. Repeated-measures analysis of variance was performed to examine the time course of FA changes within ipsilateral and contralateral fiber tracts. Quantitative visual field analysis was performed to determine whether decreases in regional FA were related to the extent or location of visual field defects. RESULTS: Patients showed decreased FA 2 months post-ATL in ipsilateral fiber tracts transected during surgery (parahippocampal cingulum, uncinate fasciculus, inferior longitudinal fasciculus, and fornix), as well as in fiber tracts not directly transected (inferior fronto-occipital fasciculus and corpus callosum). Additional decreases in FA were not observed from 2 months to 1 year post-ATL. Visual field defects in most patients were characterized by incomplete quadrantanopsias. However, FA reductions in one patient extended into temporo-occipital cortex and the splenium of the corpus callosum and were associated with a complete hemianopia. CONCLUSIONS: Wallerian degeneration is apparent 2 months following unilateral ATLs in ipsilateral fibers directly and indirectly affected during surgery. These changes do not appear to progress over the course of a year, but may correlate with the nature and extent of postoperative visual field defects.

Side matters: diffusion tensor imaging tractography in left and right temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Noninvasive imaging plays a pivotal role in lateralization of the seizure focus in presurgical patients with temporal lobe epilepsy (TLE). Our goal was to evaluate the utility of diffusion tensor imaging (DTI) tractography in TLE. MATERIALS AND METHODS: Twenty-one patients with TLE (11 right, 10 left TLE) and 21 controls were enrolled. A 1.5T MR imaging scanner was used to obtain 51 diffusion-gradient-direction images per subject. Eight pairs of white matter fiber tracts were traced, and fiber tract fractional anisotropy (FA) was calculated and compared with controls. Fiber tract FA asymmetry and discriminant function analysis were evaluated in all subjects and fiber tracts respectively. RESULTS: Compared with controls, patients with TLE demonstrated decreased FA in 5 ipsilateral fiber tracts. Patients with left TLE had 6 ipsilateral and 4 contralateral fiber tracts with decreased FA. Patients with right TLE had 4 ipsilateral but no contralateral tracts with decreased FA compared with controls. Right-sided FA asymmetry was demonstrated in patients with right TLE for 5 fiber tracts, and left-sided asymmetry, for patients with left TLE for 1 fiber tract. Discriminant function analysis correctly categorized patients into left-versus-right TLE in 90% of all cases (100% correct in all patients without hippocampal sclerosis) by using uncinate fasciculus and parahippocampal fiber tracts. CONCLUSIONS: We found widespread reductions in fiber tract FA in patients with TLE, which were most pronounced ipsilateral to the seizure focus. Patients with left TLE had greater, more diffuse changes, whereas patients with right TLE showed changes that were primarily ipsilateral. Disease was lateralized to a high degree independent of identifiable hippocampal pathology noted on conventional MR imaging.

Diffusion tensor imaging correlates of memory and language impairments in temporal lobe epilepsy.

OBJECTIVE: To investigate the relationship between white matter tract integrity and language and memory performances in patients with temporal lobe epilepsy (TLE). METHODS: Diffusion tensor imaging (DTI) was performed in 17 patients with TLE and 17 healthy controls. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated for six fiber tracts (uncinate fasciculus [UF], arcuate fasciculus [AF], fornix [FORX], parahippocampal cingulum [PHC], inferior fronto-occipital fasciculus [IFOF], and corticospinal tract [CST]). Neuropsychological measures of memory and language were obtained and correlations were performed to evaluate the relationship between DTI and neuropsychological measures. Hierarchical regression was performed to determine unique contributions of each fiber tract to cognitive performances after controlling for age and hippocampal volume (HV). RESULTS: Increases in MD of the left UF, PHC, and IFOF were associated with poorer verbal memory in TLE, as were bilateral increases in MD of the AF, and decreases in FA of the right AF. Increased MD of the AF and UF, and decreased FA of the AF, UF, and left IFOF were related to naming performances. No correlations were found between DTI measures and nonverbal memory or fluency in TLE. Regression analyses revealed that several fibers, including the AF, UF, and IFOF, independently predicted cognitive performances after controlling for HV. CONCLUSIONS: The results suggest that structural compromise to multiple fiber tracts is associated with memory and language impairments in patients with temporal lobe epilepsy. Furthermore, we provide initial evidence that diffusion tensor imaging tractography may provide clinically unique information for predicting neuropsychological status in patients with epilepsy.

Modelling the magnetic signature of neuronal tissue.

Neuronal communication in the brain involves electrochemical currents, which produce magnetic fields. Stimulus-evoked brain responses lead to changes in these fields and can be studied using magneto- and electro-encephalography (MEG/EEG). In this paper we model the spatiotemporal distribution of the magnetic field of a physiologically idealized but anatomically realistic neuron to assess the possibility of using magnetic resonance imaging (MRI) for directly mapping the neuronal currents in the human brain. Our results show that the magnetic field several centimeters from the centre of the neuron is well approximated by a dipole source, but the field close to the neuron is not, a finding particularly important for understanding the possible contrast mechanism underlying the use of MRI to detect and locate these currents. We discuss the importance of the spatiotemporal characteristics of the magnetic field in cortical tissue for evaluating and optimizing an experiment based on this mechanism and establish an upper bound for the expected MRI signal change due to stimulus-induced cortical response. Our simulations show that the expected change of the signal magnitude is 1.6% and its phase shift is 1 degrees . An unexpected finding of this work is that the cortical orientation with respect to the external magnetic field has little effect on the predicted MRI contrast. This encouraging result shows that magnetic resonance contrast directly based on the neuronal currents present in the cortex is theoretically a feasible imaging technique. MRI contrast generation based on neuronal currents depends on the dendritic architecture and we obtained high-resolution optical images of cortical tissue to discuss the spatial structure of the magnetic field in grey matter.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients.

OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Top-down facilitation of visual recognition.

Cortical analysis related to visual object recognition is traditionally thought to propagate serially along a bottom-up hierarchy of ventral areas. Recent proposals gradually promote the role of top-down processing in recognition, but how such facilitation is triggered remains a puzzle. We tested a specific model, proposing that low spatial frequencies facilitate visual object recognition by initiating top-down processes projected from orbitofrontal to visual cortex. The present study combined magnetoencephalography, which has superior temporal resolution, functional magnetic resonance imaging, and a behavioral task that yields successful recognition with stimulus repetitions. Object recognition elicited differential activity that developed in the left orbitofrontal cortex 50 ms earlier than it did in recognition-related areas in the temporal cortex. This early orbitofrontal activity was directly modulated by the presence of low spatial frequencies in the image. Taken together, the dynamics we revealed provide strong support for the proposal of how top-down facilitation of object recognition is initiated, and our observations are used to derive predictions for future research.

3T phased array MRI improves the presurgical evaluation in focal epilepsies: a prospective study.

BACKGROUND: Although detection of concordant lesions on MRI significantly improves postsurgical outcomes in focal epilepsy (FE), many conventional MR studies remain negative. The authors evaluated the role of phased array surface coil studies performed at 3 Tesla (3T PA MRI). METHODS: Forty patients with medically intractable focal epilepsies were prospectively imaged with 3T PA-MRI including high matrix TSE T2, fluid attenuated inversion recovery, and magnetization prepared rapid gradient echo. All patients were considered candidates for epilepsy surgery. 3T PA-MRIs were reviewed by a neuroradiologist experienced in epilepsy imaging with access to clinical information. Findings were compared to reports of prior standard 1.5T MRI epilepsy studies performed at tertiary care centers. RESULTS: Experienced, unblinded review of 3T PA-MRI studies yielded additional diagnostic information in 48% (19/40) compared to routine clinical reads at 1.5T. In 37.5% (15/40), this additional information motivated a change in clinical management. In the subgroup of patients with prior 1.5T MRIs interpreted as normal, 3T PA-MRI resulted in the detection of a new lesion in 65% (15/23). In the subgroup of 15 patients with known lesions, 3T PA-MRI better defined the lesion in 33% (5/15). CONCLUSION: Phased array surface coil studies performed at 3 Tesla read by an experienced unblinded neuroradiologist can improve the presurgical evaluation of patients with focal epilepsy when compared to routine clinical 1.5T studies read at tertiary care centers.

How can intracranial recordings assist MEG source localization?

MEG/EEG are the only non-invasive methods to instantaneously and directly measure the currents underlying cerebral information processing, but their ability to localize those currents is limited. Source localization from MEG is always uncertain, unless the signal is already known to be coming exclusively from a single focal source, or a few highly separated focal sources. Furthermore, since many cerebral currents produce little or no MEG signal, even accurate localization of the MEG sources may provide a very incomplete map of brain activation. Intracranial EEG (iEEG) can unambiguously localize sources, using steep voltage gradients, doubly-inverting gradients, traverses of the source structure from multiple directions, and/or spatial arrays of microelectrodes. These recordings show that except for a few milliseconds after the first cortical sensory response, multiple overlapping sources are active. For the commonly-studied cognitive potential components, N400 and P3b, iEEG demonstrates distributed sources in multiple lobes with similar time-courses. These data, as well as basic cortical neurophysiology from animal studies, do not support the common assumptions that the MEG generating sources are focal, and/or independent. Although focal hemodynamic activation is often described, this may be an artefact of the usual data analysis schemes. In summary, MEG source localization depends on prior assumptions of unknown accuracy, and MEG is insensitive to much cerebral activity. MEG publications should explicitly acknowledge these limitations. If possible, reference should be made to more certain knowledge, which in some cases includes iEEG.

Head position in the MEG helmet affects the sensitivity to anterior sources.

Current MEG instruments derive the whole-head coverage by utilizing a helmet-shaped opening at the bottom of the dewar. These helmets, however, are quite a bit larger than most people's heads so subjects commonly lean against the back wall of the helmet in order to maintain a steady position. In such cases the anterior brain sources may be too distant to be picked up by the sensors reliably. Potential "invisibility" of the frontal and anterior temporal sources may be particularly troublesome for the studies of cognition and language, as they are subserved significantly by these areas. We examined the sensitivity of the distributed anatomically-constrained MEG (aMEG) approach to the head position ("front" vs. "back") secured within a helmet with custom-tailored bite-bars during a lexical decision task. The anterior head position indeed resulted in much greater sensitivity to language-related activity in frontal and anterior temporal locations. These results emphasize the need to adjust the head position in the helmet in order to maximize the "visibility" of the sources in the anterior brain regions in cognitive and language tasks.

Cortical thickness in a case of congenital unilateral perisylvian syndrome.

In congenital perisylvian syndrome, there is polymicrogyric cortex distributed in variable extensions around the sylvian fissure. Unilateral cases usually present with congenital hemiparesis, while bilateral cases have pseudobulbar paralysis of the oropharingoglossal region. Both unilateral and bilateral cases have a high rate of epilepsy. Polymicrogyric cortex is characterized by too many small convolutions. Often there are no intervening sulci, and almost no white matter can be seen under them. On MRI they appear to have increased thickness. Bilateral and symmetric polimycrogiria can be hard to recognize on standard MRIs. Accurate and automated methods for measuring the thickness of cerebral cortex are available. They have mainly been used to study a variety of disorders with diminished cortical thickness. We studied a case of right perisylvian polymicrogyria, who presented in adult life with epilepsy and had a normal neurological exam. Fischl and Dale's automated cortical thickness analysis rendered a very clear picture of increased cortical thickness with values up to 9 mm in the affected areas (normal cortical thickness varies between 1 and 4.5 mm). The thickest areas were seen over grossly abnormal gyri on the reconstructed cerebral cortex. On MEG he presented a prominent and monotonous 9 Hz activity that was located within the limits of a thick gyrus. There was a significant difference of thickness between homologous hemispheric areas. To our surprise some areas of the left hemisphere also appeared to have increased thickness, raising the question of a bilateral asymmetric case.

Rapid distributed fronto-parieto-occipital processing stages during working memory in humans.

Cortical potentials were recorded from implanted electrodes during a difficult working memory task requiring rapid storage, modification and retrieval of multiple memoranda. Synchronous event-related potentials were generated in distributed occipital, parietal, Rolandic and prefrontal sites beginning approximately 130 ms after stimulus onset and continuing for >500 ms. Coherent phase-locked, event-related oscillations supported interaction between these dorsal stream structures throughout the task period. The Rolandic structures generated early as well as sustained potentials to sensory stimuli in the absence of movement. Activation peaks and phase lags between synaptic populations suggested that perceptual processing occurred exclusively in the visual association cortex from approximately 90 to 130 ms, with its results projected to fronto-parietal areas for interpretation from approximately 130 to 280 ms. The direction of interaction then appeared to reverse from approximately 300 to 400 ms, consistent with mental arithmetic being performed by fronto-parietal areas operating upon a visual scratch pad in the dorsolateral occipital cortex. A second reversal, from approximately 420 to 600 ms, may have represented an updating of memoranda stored in fronto-parietal sites. Lateralized perisylvian oscillations suggested an articulatory loop. Anterior cingulate activity was evoked by feedback signals indicating errors. These results indicate how a fronto-centro-parietal 'central executive' might interact with an occipital visual scratch pad, perisylvian articulatory loop and limbic monitor to implement the sequential stages of a complex mental operation.

Arousal-related P3a to novel auditory stimuli is abolished by a moderately low alcohol dose.

Concurrent measures of event-related potentials (ERPs) and skin conductance responses were obtained in an auditory oddball task consisting of rare target, rare non-signal unique novel and frequent standard tones. Twelve right-handed male social drinkers participated in all four cells of the balanced placebo design in which effects of beverage and instructions as to the beverage content (expectancy) were independently manipulated. The beverage contained either juice only, or vodka mixed with juice in the ratio that successfully disguised the taste of alcohol and raised average peak blood-alcohol level to 0.045% (45 mg/dl). ERPs were sensitive to adverse effects of mild inebriation, whereas behavioural measures were not affected. Alcohol ingestion reliably increased N2 amplitude and reduced the late positive complex (LPC). A large, fronto-central P3a (280 ms latency) was recorded to novel sounds in the placebo condition, but only on the trials that also evoked electrodermal-orienting responses. Both novel and target stimuli evoked a posterior P3b (340 ms), which was independent of orienting. Alcohol selectively attenuated the P3a to novel sounds on trials with autonomic arousal. This evidence confirms the previously suggested distinction between the subcomponents of the LPC: P3a may be a central index of orienting to novel, task-irrelevant but potentially significant stimuli and is an important component of the arousal system. P3b does not have a clear relationship with arousal and may embody voluntary cognitive processing of rare task-related stimuli. Overall, these results indicate that alcohol affects multiple brain systems concerned with arousal, attentional processes and cognitive-autonomic integration.

Timing and localization of movement-related spectral changes in the human peri-Rolandic cortex: intracranial recordings.

Event-related spectral power (ERSP) was measured from intracranial EEG and used to characterize the time-course and localization of the Rolandic mu rhythms in 12 patients during the delayed recognition of words or faces (DR) and the discrimination of simple lateralized visual targets (LVD). On each trial, the subject decided whether to make manual response (Go) or not (NoGo). ERSP increased on both Go and NoGo trials in peri-Rolandic regions of all subjects with a peak latency of approximately 330-ms poststimulus and duration of 260 ms during the DR task. The peak of this ERSP increase preceded movement by approximately 300 ms. All subjects produced a subsequent movement specific ERSP decrease of peri-Rolandic mu rhythms (starting approximately 90 ms before the average reaction time) with an peak latency of approximately 800 ms and duration of approximately 520 ms. The LVD task produced bilateral movement-selective readiness potentials and reproduced the movement-specific late ERSP decreases seen in the DR task (strongest from 7-24 Hz). Furthermore, the LVD task demonstrated that the late movement-related ERSP decrease is larger for the contralateral hand. However, the LVD task did not consistently reproduce the early ERSP increase seen in the DR task. Movement-related ERSP decreases were widespread, occurring in pre- and post-Rolandic as well as primary-motor, supplemental motor, and cingulate cortical regions. Other cortical areas including frontal, temporal, and occipital regions did not show movement-related ERSP changes. Peri-Rolandic ERSP decreases in mu rhythms correlate with the generation of a motor command. The early increases in mu may reflect a transient state of motor inhibition just prior to motor execution.

Early discrimination of coherent versus incoherent motion by multiunit and synaptic activity in human putative MT+.

A laminar probe was chronically implanted in human putative MT+. The area was specifically responsive to globally coherent visual motion, a crucial aspect of the perception of movement through space. The probe contained 23 microcontacts spaced every 175 microm in a linear array roughly perpendicular to the cortical surface. Current-source density (CSD) and multiunit activity (MUA) were recorded while viewing initially stationary random dot patterns that either moved incoherently or dilated from the central fixation. Onset of visual motion evoked large MUA/CSD activity, with coherent motion evoking earlier and faster-rising MUA/CSD activity than incoherent, in both superficial and deep pyramidal layers. The selective response, peaking at approximately 115 ms, was especially large in deep pyramids, providing evidence that information necessary for visual flow calculations is projected from MT+ at an early latency to distant structures. The early onset of differential MUA/CSD implies that the selectivity of this area does not depend on recurrent inhibition or other intrinsic circuitry to detect coherent motion. The initially greater increase of MUA to coherent stimuli was followed by a greater decrease beginning at approximately 133 ms, apparently because of recurrent inhibition. This resulted in the total MUA being greater to incoherent than coherent stimuli, whereas total rectified CSD was overall greater to coherent than to incoherent stimuli. However, MUA distinguished stationary from moving stimuli more strongly than did CSD. Thus, while estimates of total cell firing (MUA), and of total synaptic activity (CSD) generally correspond to previously reported BOLD results, they may differ in important details.

Spatiotemporal maps of brain activity underlying word generation and their modification during repetition priming.

Spatiotemporal maps of brain activity based on magnetoencephalography were used to observe sequential stages in language processing and their modification during repetition priming. Subjects performed word-stem completion and produced either novel or repeated (primed) words across trials. Activation passes from primary visual cortex (activated at approximately 100 msec after word presentation), to left anteroventral occipital ( approximately 180 msec), to cortex in and near Wernicke's ( approximately 210 msec) and then Broca's ( approximately 370 msec) areas. In addition, a posteroventral temporal area is activated simultaneously with posterosuperior temporal cortex. This area shows an early ( approximately 200-245 msec) increase in activation to repeated word stems. In contrast, prefrontal and anterior temporal regions showed activity reductions to repeated word stems late ( approximately 365-500 msec) in processing. These results tend to support classical models of language and suggest that an effect of direct item repetition is to allow word-form processing to increase its contribution to task performance while concurrently allowing reductions in time-consuming frontal temporal processing.

Spatiotemporal mapping of brain activity by integration of multiple imaging modalities.

Functional magnetic resonance imaging (fMRI) and positron emission tomography measure local changes in brain hemodynamics induced by cognitive or perceptual tasks. These measures have a uniformly high spatial resolution of millimeters or less, but poor temporal resolution (about 1s). Conversely, electroencephalography (EEG) and magnetoencephalography (MEG) measure instantaneously the current flows induced by synaptic activity, but the accurate localization of these current flows based on EEG and MEG data alone remains an unsolved problem. Recently, techniques have been developed that, in the context of brain anatomy visualized with structural MRI, use both hemodynamic and electromagnetic measures to arrive at estimates of brain activation with high spatial and temporal resolution. These methods range from simple juxtaposition to simultaneous integrated techniques. Their application has already led to advances in our understanding of the neural bases of perception, attention, memory and language. Further advances in multi-modality integration will require an improved understanding of the coupling between the physiological phenomena underlying the different signal modalities.