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.

Endogenous potentials generated in the human hippocampal formation and amygdala by infrequent events.

Infrequent, attended, auditory and visual stimuli evoke large potentials in the human limbic system in tasks that usually evoke endogenous potentials at the scalp. The limbic potentials reverse polarity over small distances and correlate with unit discharges recorded by the same electrodes, indicating that they are locally generated.

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.

Dynamic statistical parametric mapping: combining fMRI and MEG for high-resolution imaging of cortical activity.

Functional magnetic resonance imaging (fMRI) can provide maps of brain activation with millimeter spatial resolution but is limited in its temporal resolution to the order of seconds. Here, we describe a technique that combines structural and functional MRI with magnetoencephalography (MEG) to obtain spatiotemporal maps of human brain activity with millisecond temporal resolution. This new technique was used to obtain dynamic statistical parametric maps of cortical activity during semantic processing of visually presented words. An initial wave of activity was found to spread rapidly from occipital visual cortex to temporal, parietal, and frontal areas within 185 ms, with a high degree of temporal overlap between different areas. Repetition effects were observed in many of the same areas following this initial wave of activation, providing evidence for the involvement of feedback mechanisms in repetition priming.

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.

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.

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.

Role of inhibition in memory retrieval by hippocampal area CA3.

A network model with some general properties of hippocampal area CA3, and the results of its simulation on a massively parallel processor, are described. This network performs the tasks of recent declarative memory including recovery of complete traces from partial cues and recognition of familiarity. Immediate recurrent inhibition is essential for providing sensitivity to small cues while preventing spurious recall. Tonic inhibition seems to set the retrieval speed/accuracy trade-off. Delayed inhibition resets hippocampal activity. The behavior under excessive or deficient inhibition resembles that of amnesics with lesions in brainstem areas known to modulate hippocampal inhibition. The rate of recall and dynamics of inhibition by the model are similar to those inferred to occur in the human hippocampus from unit and evoked potential recordings. The model suggests a mechanism whereby the hippocampus can control its own plasticity. These simulations demonstrate that the retrieval mechanism in several hippocampal models is feasible and that the theta rhythm and the cognitive evoked potentials may be generated by synaptic events modulating network parameters.

Visual working memory in primary generalized epilepsy: an 18FDG-PET study.

It is generally believed that patients with primary generalized epilepsy have normal cognition and neuroimaging studies. We have previously shown that patients with juvenile myoclonic epilepsy (JME) have impaired visual working memory. In this study we examined relative regional changes in 18FDG uptake during a visual working memory paradigm in patients with JME. At rest, there were regional decreases in relative glucose uptake compared to controls. Unlike control subjects, increased activity in the dorsolateral prefrontal cortex was not found during the working memory task. Other regions with increased uptake in controls, such as premotor cortex and basal frontal cortex, also showed no increases, whereas medical temporal structures appeared to play a role in JME but not in control subjects' task performance. The data suggest that JME, a type of primary generalized epilepsy, may suffer from cortical disorganization that affects both the epileptogenic potential and frontal lobe cognitive functioning.

Primary or working memory in frontal lobe epilepsy: An 18FDG-PET study of dysfunctional zones.

INTRODUCTION: We previously demonstrated that patients with frontal lobe epilepsy show deficits on a visual working memory paradigm and that this paradigm produces increased 18FDG uptake in the dorsolateral prefrontal cortex (DPFC), premotor cortex, angular and supramarginal gyri, basal forebrain, and ventral frontal poles of normal subjects when compared with a control task. We hypothesized that subjects with frontal lobe epilepsy would have impaired frontal activation during this task. METHODS: One resting and two activated images were obtained with 18FDG-PET in 15 subjects and 14 controls. One was a delayed (DMS) and one an immediate (IMS) match to sample paradigm. Discriminant and factor analyses were used to analyze the data, supplemented by selected t tests. RESULTS: No differences in glucose uptake were found between the DMS and IMS in the epilepsy subjects, in distinct contrast to controls. A comparison between controls and epilepsy subjects showed differences both ipsilateral and contralateral to the epileptic focus in the frontal regions involved in the task, with small changes in nonfrontal, task-related regions as well. The task itself brought out or highly exaggerated differences seen at rest. There was weak evidence that other frontal and temporal regions were attempting to compensate for the DPFC deficit. CONCLUSION: A unilateral epileptic focus is capable of suppressing function along a large task-related circuit ipsilateral and contralateral to the focus. Peripheral cortical regions compensate poorly for the area of dysfunction.

Endogenous potentials after anterior temporal lobectomy.

The scalp topography of endogenous potentials was studied in patients who had previously undergone unilateral anterior temporal lobectomy (ATL). These excisions include medial temporal lobe (MTL) structures that have been shown to generate large potentials during tasks that evoke P3 at the scalp. Following right or left ATL, patients showed no differences from unoperated control subjects in overall amplitude of P3 or any other potential measured. The topography of P3 was very similar in both ATL groups and the control subjects, with no differences in laterality. These results suggest that the MTL is not the major generator of the P3 recorded at the scalp in the tasks studied here.

Activity of human hippocampal formation and amygdala neurons during sleep.

Fine wire microelectrodes were implanted for diagnostic purposes in 17 patients suffering from psychomotor epilepsy. Single- and multiunit activity during waking and natural nocturnal slow wave sleep and REM sleep was recorded in the hippocampus (n = 42), hippocampal gyrus (n = 53), and amygdala (n = 32). The firing rates of hippocampal gyrus units usually decreased during slow wave sleep and then increased to levels equal to or above waking during REM. In contrast, the firing rates of hippocampal neurons generally increased during slow wave sleep and fell to very low levels during REM. The amygdala presented a more mixed pattern. Since the projection from the hippocampal gyrus to hippocampus is excitatory, their opposite patterns during sleep suggest that the tonic firing patterns of HC neurons may be mainly the result of subcortical afferents.

Divided attention-enhancing effects of AF102B and THA in aging monkeys.

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.

An 18FDG-PET study of cortical activation during a short-term visual memory task in humans.

Studies of subhuman primates and man have shown that the prefrontal cortex is important for spatial working memory. We have used 18fluorodeoxyglucose positron emission tomography (18FDG-PET) to study a non-spatial, abstract visual memory task of in man. Using a regions-of-interest approach with discriminant analysis of the relative regional cerebral metabolic rate of glucose consumption (rCMRGlc), we found that changes in dorsal prefrontal, premotor/motor frontal and posterior cingulate areas differentiated the primary memory task from the control task. Less robust increases in glucose uptake were observed in lateral parietal cortex, while some subcortical and limbic regions showed decreases. This is the first activation study with a non-spatial, visual task. These results complement previous studies in that they substantiate the role of the prefrontal cortex in the mediation of cross-temporal contingencies of behavior, and point to a role of the premotor region in this mediation as well.

Spatio-temporal stages in face and word processing. 2. Depth-recorded potentials in the human frontal and Rolandic cortices.

Evoked potentials (EPs) were recorded directly from 650 frontal and peri-Rolandic sites in 26 subjects during face and/or word recognition, as well as during control tasks (simple auditory and visual discrimination). Electrodes were implanted in order to localize epileptogenic foci resistant to medication, and thus direct their surgical removal. While awaiting spontaneous seizure onset, the patients gave informed consent to perform cognitive tasks during intracerebral EEG recording. The earliest potentials appeared to be related to sensory stimulation, were prominent in lateral prefrontal cortex, and occurred at peak latencies of about 150 and 190 ms. A small triphasic complex beginning slightly later (peak latencies about 200-285-350 ms) appeared to correspond to the scalp N2-P3a-slow wave, associated with non-specific orienting. Multiple components peaking from 280 to 900 ms, and apparently specific to words were occasionally recorded in the left inferior frontal g, pars triangularis (Broca's area). Components peaking at about 430 and 600 ms were recorded in all parts of the prefrontal cortex, but were largest (up to 180 microV) and frequently polarity-inverted in the ventro-lateral prefrontal cortex. These components appeared to represent the N4-P3b, which have been associated with contextual integration and cognitive closure. Finally, a late negativity (650-900 ms) was recorded in precentral and premotor cortices, probably corresponding to a peri-movement readiness potential. In summary, EP components related to early sensory processing were most prominent in lateral prefrontal, to orienting in medial limbic, to word-specific processing in Broca's area, to cognitive integration in ventro-lateral prefrontal, and to response organization in premotor cortices.(ABSTRACT TRUNCATED AT 250 WORDS)

Spatio-temporal stages in face and word processing. I. Depth-recorded potentials in the human occipital, temporal and parietal lobes [corrected].

Evoked potentials (EPs) were used to help identify the timing, location, and intensity of the information-processing stages applied to faces and words in humans. EP generators were localized using intracranial recordings in 33 patients with depth electrodes implanted in order to direct surgical treatment of drug-resistant epilepsy. While awaiting spontaneous seizure onset, the patients gave their fully informed consent to perform cognitive tasks. Depth recordings were obtained from 1198 sites in the occipital, temporal and parietal cortices, and in the limbic system (amygdala, hippocampal formation and posterior cingulate gyrus). Twenty-three patients received a declarative memory recognition task in which faces of previously unfamiliar young adults without verbalizable distinguishing features were exposed for 300 ms every 3 s; 25 patients received an analogous task using words. For component identification, some patients also received simple auditory (21 patients) or visual (12 patients) discrimination tasks. Eight successive EP stages preceding the behavioral response (at about 600 ms) could be distinguished by latency, and each of 14 anatomical structures was found to participate in 2-8 of these stages. The earliest response, an N75-P105, focal in the most medial and posterior of the leads implanted in the occipital lobe (lingual g), was probably generated in visual cortical areas 17 and 18. These components were not visible in response to words, presumably because words were presented foveally. A focal evoked alpha rhythm to both words and faces was also noted in the lingual g. This was followed by an N130-P180-N240 focal and polarity-inverting in the basal occipitotemporal cortex (fusiform g, probably areas 19 and 37). In most cases, the P180 was evoked only by faces, and not by words, letters or symbols. Although largest in the fusiform g this sequence of potentials (especially the N240) was also observed in the supramarginal g, posterior superior and middle temporal g, posterior cingulate g, and posterior hippocampal formation. The N130, but not later components of this complex, was observed in the anterior hippocampus and amygdala. Faces only also evoked longer-latency potentials up to 600 ms in the right fusiform g. Words only evoked a series of potentials beginning at 190 ms and extending to 600 ms in the fusiform g and near the angular g (especially left). Both words and faces evoked a N150-P200-PN260 in the lingual g, and posterior inferior and middle temporal g.(ABSTRACT TRUNCATED AT 400 WORDS)

Multiple microelectrode-recording system for human intracortical applications.

The human brain is dominated by the neocortex, a large folded surface, whose cellular and synaptic elements are arranged in layers. Since cortical structure is relatively constant across its surface, local information processing can be inferred from multiple laminar recordings of its electrical activity along a line perpendicular to its surface. Such recordings need to be spaced at least as close together as the cortical layers, and need to be wideband in order to sample both low frequency synaptic currents as well as high-frequency action potentials. Finally, any device used in the human brain must comply with strict safety standards. The current paper presents details of a system meeting these criteria, together with sample results obtained from epileptic subjects undergoing acute or chronic intracranial monitoring for definition of the epileptogenic region.

Localized brain metabolic response correlated with potentials evoked by words.

Evoked potentials (EPs) measure synaptic current flows that propagate from brain to scalp, Alternatively, positron emission tomography (PET) using fluoro-deoxyglucose (FDG) can measure the increased glucose metabolism supporting this synaptic activation. It is difficult to localize the brain activity-generating EPs from their scalp distribution, because activity originating in different regions tends to produce overlapping scalp topographies. In contrast, FDG-PET provides better spatial resolution for activity throughout the brain, but shows only the total metabolism integrated over a 30-min uptake period. We combined the temporal and psychological resolution of EPs with the spatial resolution of PET to help define when and where in the brain words are encoded for meaning.

Face-selective spectral changes in the human fusiform gyrus.

OBJECTIVE: To characterize ventral occipitotemporal and prefrontal EEG during cognitive processing. METHODS: Depth probes were implanted for seizure localization in 16 pharmaco-resistant epileptics. Probes penetrated from middle temporal through fusiform to lingual gyrus, and from inferior frontal to anterior cingulate gyrus. Event-related potentials (ERPs) and event-related spectral power (ERSP) were calculated during delayed recognition for faces or words. RESULTS: Face stimuli evoked a broadband fusiform ERSP increase from 5 to 45 Hz at 150-210 ms after stimulus onset. This ERSP increase was immediately followed by an ERSP decrease in the same region from 300 to 1000 ms. Both the early increased ERSP and the late decreased ERSP, were greater for faces than words. Simultaneous with the late temporal ERSP decrease, the prefrontal depth EEG displayed a low frequency (5-12 Hz) ERSP increase to face and word stimuli. CONCLUSION: Early temporal ERSP increases occur at a time when the fusiform gyrus is thought to contribute to face processing. This increase is also reflected in spectral analysis of the ERP, but the late temporal ERSP decrease and frontal ERSP increase are not. Thus, intracranial recordings in humans demonstrate event-related fluctuations in EEG spectral power with clear anatomical, temporal and cognitive specificity.