Association Between Magnetoencephalography-Localized Epileptogenic Zone, Surgical Resection Volume, and Postsurgical Seizure Outcome.

PURPOSE: Surgical resection of magnetoencephalography (MEG) dipole clusters, reconstructed from interictal epileptiform discharges, is associated with favorable seizure outcomes. However, the relation of MEG cluster resection to the surgical resection volume is not known nor is it clear whether this association is direct and causal, or it may be mediated by the resection volume or other predictive factors. This study aims to clarify these open questions and assess the diagnostic accuracy of MEG in our center. METHODS: We performed a retrospective cohort study of 68 patients with drug-resistant epilepsy who underwent MEG followed by resective epilepsy surgery and had at least 12 months of postsurgical follow-up. RESULTS: Good seizure outcomes were associated with monofocal localization (χ2 = 6.94, P = 0.001; diagnostic odds ratio = 10.2) and complete resection of MEG clusters (χ2 = 22.1, P < 0.001; diagnostic odds ratio = 42.5). Resection volumes in patients with and without removal of MEG clusters were not significantly different (t = 0.18, P = 0.86; removed: M = 20,118 mm3, SD = 10,257; not removed: M = 19,566 mm3, SD = 10,703). Logistic regression showed that removal of MEG clusters predicts seizure-free outcome independent of the resection volume and other prognostic factors (P < 0.001). CONCLUSIONS: Complete resection of MEG clusters leads to favorable seizure outcomes without affecting the volume of surgical resection and independent of other prognostic factors. MEG can localize the epileptogenic zone with high accuracy. MEG interictal epileptiform discharges mapping should be used whenever feasible to improve postsurgical seizure outcomes.

Spatiotemporal profile of altered neural reactivity to food images in obesity: Reward system is altered automatically and predicts efficacy of weight loss intervention.

Introduction: Obesity presents a significant public health problem. Brain plays a central role in etiology and maintenance of obesity. Prior neuroimaging studies have found that individuals with obesity exhibit altered neural responses to images of food within the brain reward system and related brain networks. However, little is known about the dynamics of these neural responses or their relationship to later weight change. In particular, it is unknown if in obesity, the altered reward response to food images emerges early and automatically, or later, in the controlled stage of processing. It also remains unclear if the pretreatment reward system reactivity to food images is predictive of subsequent weight loss intervention outcome. Methods: In this study, we presented high-calorie and low-calorie food, and nonfood images to individuals with obesity, who were then prescribed lifestyle changes, and matched normal-weight controls, and examined neural reactivity using magnetoencephalography (MEG). We performed whole-brain analysis to explore and characterize large-scale dynamics of brain systems affected in obesity, and tested two specific hypotheses: (1) in obese individuals, the altered reward system reactivity to food images occurs early and automatically, and (2) pretreatment reward system reactivity predicts the outcome of lifestyle weight loss intervention, with reduced activity associated with successful weight loss. Results: We identified a distributed set of brain regions and their precise temporal dynamics that showed altered response patterns in obesity. Specifically, we found reduced neural reactivity to food images in brain networks of reward and cognitive control, and elevated reactivity in regions of attentional control and visual processing. The hypoactivity in reward system emerged early, in the automatic stage of processing (< 150 ms post-stimulus). Reduced reward and attention responsivity, and elevated neural cognitive control were predictive of weight loss after six months in treatment. Discussion: In summary, we have identified, for the first time with high temporal resolution, the large-scale dynamics of brain reactivity to food images in obese versus normal-weight individuals, and have confirmed both our hypotheses. These findings have important implications for our understanding of neurocognition and eating behavior in obesity, and can facilitate development of novel integrated treatment strategies, including tailored cognitive-behavioral and pharmacological therapies.

Automatic Detection of Epileptiform EEG Discharges based on the Semi-Classical Signal Analysis (SCSA) method.

In this paper we utilize a signal processing tool, which can help physicians and clinical researchers to automate the process of EEG epileptiform spike detection. The semi-classical signal analysis method (SCSA) is a data-driven signal decomposition method developed for pulse-shaped signal characterization. We present an algorithm framework to process and extract features from the patient's EEG recording by deriving the mathematical motivation behind SCSA and quantifying existing spike diagnosis criterion with it. The proposed method can help reduce the amount of data to manually analyse. We have tested our proposed algorithm framework with real data, which guarantees the method's statistical reliability and robustness.

Individual Magnetoencephalography Response Profiles to Short-Duration L-Dopa in Parkinson's Disease.

Clinical responses to dopamine replacement therapy for individuals with Parkinson's disease (PD) are often difficult to predict. We characterized changes in MDS-UPDRS motor factor scores resulting from a short-duration L-Dopa response (SDR), and investigated how the inter-subject clinical differences could be predicted from motor cortical magnetoencephalography (MEG). MDS-UPDRS motor factor scores and resting-state MEG recordings were collected during SDR from twenty individuals with a PD diagnosis. We used a novel subject-specific strategy based on linear support vector machines to quantify motor cortical oscillatory frequency profiles that best predicted medication state. Motor cortical profiles differed substantially across individuals and showed consistency across multiple data folds. There was a linear relationship between classification accuracy and SDR of lower limb bradykinesia, although this relationship did not persist after multiple comparison correction, suggesting that combinations of spectral power features alone are insufficient to predict clinical state. Factor score analysis of therapeutic response and novel subject-specific machine learning approaches based on subject-specific neuroimaging provide tools to predict outcomes of therapies for PD.

Focal Cortical Dysplasia and Generalized Epileptiform Discharges: Case Report and Literature Review.

BACKGROUND: Focal epilepsy can have a varied etiology, including malformations of cortical development (MCD), that can often be detected by Magnetic Resonance Imaging (MRI).Here we show a distinct characteristic of two forms of MCDs on MRI, with two tight dipole clusters in her MEG magnetoencephalography study, in a patient with electroencephalography (EEG) features of generalized epilepsy. CASE REPORT: This is a case presentation of a 20 years old female with epilepsy, found to have upon EMU admission two pathologies (FCD, heterotropia) over the right side near the collateral sulcus, and two tight clusters of dipoles over the right parietal and left temporo-parietal region, with generalized inter ictal discharges in her EEG. FCD is a common etiology of medically intractable seizures and usually in EEG it will show either: pseudo-periodic spikes or rhythmic spikes, poly-spike or repetitive electrographic seizures or a brief discharge of fast rhythmic activity, atypical presentation with generalized epileptiform discharges were rarely reported. CONCLUSION: The presence of MCD does not preclude a patient from having other types of epilepsy. Generalized epilepsy and focal related epilepsy have a distinct pathophysiology.

Using MEG to Understand the Progression of Light Sleep and the Emergence and Functional Roles of Spindles and K-Complexes.

We used tomographic analysis of MEG signals to characterize regional spectral changes in the brain at sleep onset and during light sleep. We identified two key processes that may causally link to loss of consciousness during the quiet or "core" periods of NREM1. First, active inhibition in the frontal lobe leads to delta and theta spectral power increases. Second, activation suppression leads to sharp drop of spectral power in alpha and higher frequencies in posterior parietal cortex. During NREM2 core periods, the changes identified in NREM1 become more widespread, but focal increases also emerge in alpha and low sigma band power in frontal midline cortical structures, suggesting reemergence of some monitoring of internal and external environment. Just before spindles and K-complexes (KCs), the hallmarks of NREM2, we identified focal spectral power changes in pre-frontal cortex, mid cingulate, and areas involved in environmental and internal monitoring, i.e., the rostral and sub-genual anterior cingulate. During both spindles and KCs, alpha and low sigma bands increases. Spindles emerge after further active inhibition (increase in delta power) of the frontal areas responsible for environmental monitoring, while in posterior parietal cortex, power increases in low and high sigma bands. KCs are correlated with increase in alpha power in the monitoring areas. These specific regional changes suggest strong and varied vigilance changes for KCs, but vigilance suppression and sharpening of cognitive processing for spindles. This is consistent with processes designed to ensure accurate and uncorrupted memory consolidation. The changes during KCs suggest a sentinel role: evaluation of the salience of provoking events to decide whether to increase processing and possibly wake up, or to actively inhibit further processing of intruding influences. The regional spectral patterns of NREM1, NREM2, and their dynamic changes just before spindles and KCs reveal an edge effect facilitating the emergence of spindles and KCs and defining the precise loci where they might emerge. In the time domain, the spindles are seen in widespread areas of the cortex just as reported from analysis of intracranial data, consistent with the emerging consensus of a differential topography that depends on the kind of memory stored.

MEG reveals a fast pathway from somatosensory cortex to occipital areas via posterior parietal cortex in a blind subject.

Cross-modal activity in visual cortex of blind subjects has been reported during performance of variety of non-visual tasks. A key unanswered question is through which pathways non-visual inputs are funneled to the visual cortex. Here we used tomographic analysis of single trial magnetoencephalography (MEG) data recorded from one congenitally blind and two sighted subjects after stimulation of the left and right median nerves at three intensities: below sensory threshold, above sensory threshold and above motor threshold; the last sufficient to produce thumb twitching. We identified reproducible brain responses in the primary somatosensory (S1) and motor (M1) cortices at around 20 ms post-stimulus, which were very similar in sighted and blind subjects. Time-frequency analysis revealed strong 45-70 Hz activity at latencies of 20-50 ms in S1 and M1, and posterior parietal cortex Brodmann areas (BA) 7 and 40, which compared to lower frequencies, were substantially more pronounced in the blind than the sighted subjects. Critically, at frequencies from α-band up to 100 Hz we found clear, strong, and widespread responses in the visual cortex of the blind subject, which increased with the intensity of the somatosensory stimuli. Time-delayed mutual information (MI) revealed that in blind subject the stimulus information is funneled from the early somatosensory to visual cortex through posterior parietal BA 7 and 40, projecting first to visual areas V5 and V3, and eventually V1. The flow of information through this pathway occurred in stages characterized by convergence of activations into specific cortical regions. In sighted subjects, no linked activity was found that led from the somatosensory to the visual cortex through any of the studied brain regions. These results provide the first evidence from MEG that in blind subjects, tactile information is routed from primary somatosensory to occipital cortex via the posterior parietal cortex.

Source space analysis of event-related dynamic reorganization of brain networks.

How the brain works is nowadays synonymous with how different parts of the brain work together and the derivation of mathematical descriptions for the functional connectivity patterns that can be objectively derived from data of different neuroimaging techniques. In most cases static networks are studied, often relying on resting state recordings. Here, we present a quantitative study of dynamic reconfiguration of connectivity for event-related experiments. Our motivation is the development of a methodology that can be used for personalized monitoring of brain activity. In line with this motivation, we use data with visual stimuli from a typical subject that participated in different experiments that were previously analyzed with traditional methods. The earlier studies identified well-defined changes in specific brain areas at specific latencies related to attention, properties of stimuli, and tasks demands. Using a recently introduced methodology, we track the event-related changes in network organization, at source space level, thus providing a more global and complete view of the stages of processing associated with the regional changes in activity. The results suggest the time evolving modularity as an additional brain code that is accessible with noninvasive means and hence available for personalized monitoring and clinical applications.

Spatiotemporal profiles of visual processing with and without primary visual cortex.

The spatiotemporal profiles of visual processing are normally distributed in two temporal phases, each lasting about 100 ms. Within each phase, cortical processing begins in V1 and traverses the visual cortical hierarchy. However, the causal role of V1 in starting each of these two phases is unknown. Here we used magnetoencephalography to study the spatiotemporal profiles of visual processing and the causal contribution of V1 in three neurologically intact participants and in a rare patient (GY) with unilateral destruction of V1, in whom residual visual functions mediated by the extra-geniculostriate pathways have been reported. In healthy subjects, visual processing in the first 200 ms post-stimulus onset proceeded in the two usual phases. Normally perceived stimuli in the left hemifield of GY elicited a spatiotemporal profile in the intact right hemisphere that closely matched that of healthy subjects. However, stimuli presented in the cortically blind hemifield produced no detectable response during the first phase of processing, indicating that the responses in extrastriate visual areas during this phase are determined by the feedforward progression of activity initiated in V1. The first responses occurred during the second processing phase, in the ipsilesional high-level visual areas. The activity then spread forward toward higher-level areas and backward toward lower-level areas. However, in contrast to responses in the intact hemisphere, the back-propagated activity in the early visual cortex did not exhibit the classic retinotopic organization and did not have well-defined response peaks.

Spatiotemporal dynamics of early spatial and category-specific attentional modulations.

Different attention types select and focus brain resources on relevant sensory information. However, key questions remain unresolved: when and where cortical visual processing is first modulated by different types of attention? How do such modulatory effects spread thereafter? Here, we address these issues for spatial and category-specific types of attention using magnetoencephalography (MEG). First we identified the dynamics of visual attention-independent sensory processing to serve as a baseline framework for the attentional modulations of interest. We found that visual information is processed through the entire hierarchy of visual areas in at least two phases, in the 40-130 ms and 130-230 ms periods respectively. Spatial attention modulations were identified from the beginning of the initial stimulus-evoked response in the primary visual cortex ~70 ms post-stimulus. Category-specific attention modulated face processing beginning from the first face-specific response in high-level object-related areas ~100 ms post-stimulus, substantially earlier than previously reported for face-directed attention. Thus both attention types modulated responses during the first processing phase, beginning at the earliest brain area capable of coding the attentional target. Thereafter attentional effects propagated through the visual cortex together with the stimulus-evoked activity. Category-specific attention did not affect the first-phase responses in low-level strongly retinotopic visual areas, while the second-phase responses were enhanced when the stimulus was the response target and reduced when it was a distractor. Responses during both phases in high-level object-related areas were enhanced by category-specific attention independent of their target/distractor status. Spatial attention effects were stronger in low-level areas, whereas category-specific attention effects were stronger in high-level object-related areas.

MEG's ability to localise accurately weak transient neural sources.

OBJECTIVE: To investigate the accurate localisation of weak, transient, neural sources under conditions of varying difficulty. METHODS: Multiple dipolar sources placed within a head-shaped phantom at superficial and deep locations were driven separately or simultaneously by a short-lasting current with varied amplitudes. Artificial MEG signals that were very similar to the human High Frequency Oscillations (HFO) were produced. MEG signals of HFO were also recorded from median nerve stimulation. Different inverse techniques were used to localise the phantom dipoles and the human HFO generators. RESULTS: The human HFO were measured around 200 and 600Hz by using only 120 trials. The 200Hz HFO were localised to BA3b. The superficial phantom's source was localised with an accuracy of 2-3mm by all inverse techniques (120 trials). The 'subcortical' source was localised with an error of approximately 5mm. Localisation of deeper 'thalamic' sources required more trials. CONCLUSION: MEG can detect and localise weak transient activations and the human HFO with an accuracy of a few mm at cortical and subcortical regions even when a small number of trials are used. SIGNIFICANCE: Localizing HFO to specific anatomical structures has high clinical utility, for example in epilepsy, where discrete HFO appears to be generated just before focal epileptic activity.

Attention modulates earliest responses in the primary auditory and visual cortices.

A fundamental question about the neural correlates of attention concerns the earliest sensory processing stage that it can affect. We addressed this issue by recording magnetoencephalography (MEG) signals while subjects performed detection tasks, which required employment of spatial or nonspatial attention, in auditory or visual modality. Using distributed source analysis of MEG signals, we found that, contrary to previous studies that used equivalent current dipole (ECD) analysis, spatial attention enhanced the initial feedforward response in the primary visual cortex (V1) at 55-90 ms. We also found attentional modulation of the putative primary auditory cortex (A1) activity at 30-50 ms. Furthermore, we reproduced our findings using ECD modeling guided by the results of distributed source analysis and suggest a reason why earlier studies using ECD analysis failed to identify the modulation of earliest V1 activity.

Precise mapping of early visual responses in space and time.

We used magnetoencephalography (MEG) to record brain activity while subjects passively viewed stimuli presented at eight different locations in the parafoveal and peripheral visual fields (VF). For each subject, the experiment was repeated on 3 different days. The generators of the early MEG signal components were localized using tomographic source analysis together with statistical parametric mapping. We identified activations throughout visual cortex in the first 100 ms of stimulus onset. The earliest stimulus-evoked responses were registered in V1. Then, activity with largely overlapping latencies spread rapidly to V2, V3 and throughout the whole visual system. Unambiguous and focal activations with precise onset, peak latencies, and peak amplitudes for each subject and day were identified in V1, in one ventral and three dorsal stream areas. Activations in all areas were consistent in location and timing across subjects and for each subject they were highly reproducible across 3 experimental days. Localization precision was typically within 2 mm in all areas. Retinotopic organizations of the identified areas were in good agreement with other neuroimaging and animal studies. The localization accuracy, as evidenced by computer simulations, was in line with our earlier fMRI/MEG study. On average, it was around 2 mm. Here we report, with very high reproducibility, the dynamics of early visual area activations and their dependence on the stimulated location of the VF. These results show for the first time in humans, significantly shorter onset latencies in V1 for peripheral than parafoveal VF stimulations.

Effects of attention and arousal on early responses in striate cortex.

Humans employ attention to facilitate perception of relevant stimuli. Visual attention can bias the selection of a location in the visual field, a whole visual object or any visual feature of an object. Attention draws on both current behavioral goals and/or the saliency of physical attributes of a stimulus, and it influences activity of different brain regions at different latencies. Attentional effect in the striate and extrastriate cortices has been the subject of intense research interest in many recent studies. The consensus emerging from them places the first attentional effects in extrastriate areas, which in turn modulate activity of V1 at later latencies. In this view attention influences activity in striate cortex some 150 ms after stimulus onset. Here we use magnetoencephalography to compare brain responses to foveally presented identical stimuli under the conditions of passive viewing, when the stimuli are irrelevant to the subject and under an active GO/NOGO task, when the stimuli are cues instructing the subject to make or inhibit movement of his/her left or right index finger. The earliest striate activity was identified 40-45 ms after stimulus onset, and it was identical in passive and active conditions. Later striate response starting at about 70 ms and reaching a peak at about 100 ms showed a strong attentional modulation. Even before the striate cortex, activity of the right inferior parietal lobule was modulated by attention, suggesting this region as a candidate for mediating attentional signals to the striate cortex.

Real-time neural activity and connectivity in healthy individuals and schizophrenia patients.

Processing of facial information is distributed across several brain regions, as has been shown recently in many neuroimaging studies. Disturbances in accurate face processing have been repeatedly demonstrated in different stages of schizophrenia. Recently, electroencephalography (EEG) and tomographic analysis of average magnetoencephalographic (MEG) data were used to define the latencies of significant regional brain activations in healthy and schizophrenic subjects elicited during the recognition of facial expression of emotions. The current study re-examines these results using tomographic analysis of single trial MEG data. In addition to the areas identified by the analysis of the average MEG data, statistically significant activity is identified in several other areas, including a sustained increase in the right amygdala activity in response to emotional faces in schizophrenic subjects. The single trial analysis demonstrated that the reduced activations identified from the average MEG signal of schizophrenic subjects is due to high variability across single trials rather than reduced activity in each single trial. In control subjects, direct measures of linkage demonstrate distinct stages of processing of emotional faces within well-defined network of brain regions. Activity in each node of the network, confined to 30 to 40 ms latency windows, is linked to earlier and later activations of the other nodes of the network. In schizophrenic subjects, no such well-defined stages of processing were observed. Instead, the activations, although strong were poorly linked to each other, managing only isolated links between pairs of areas.

Brain activation sequences following electrical limb stimulation of normal and paraplegic subjects.

In current clinical practice the degree of paraplegia or quadriplegia is objectively determined with transcranial magnetic stimulation (TMS) and somatosensory-evoked potentials (SSEP). We measured the MEG signal following electrical stimulation of upper and lower limbs in two normal and three clinically complete paraplegic subjects. From the MEG signal we computed distributed estimates of brain activity and identified foci just behind the central sulcus consistent in location with primary somatosensory (SI) for arm and foot and secondary somatosensory (SII) areas. Activation curves were computed from regions of interest defined around these areas. Activation of the SI foot area was observed in normal and paraplegic subjects when the upper limb was stimulated. Surprisingly, for each paraplegic subject, stimulation below the lesion was followed by cortical activations. These activations were weak, only loosely time-locked to the stimulus and were seen intermittently behind the central sulcus and nearby cortical areas. Statistical analysis of tomographic solutions and activation curves showed consistent responses following foot stimulation in one paraplegic (PS1) and intermittently in another paraplegic subject. We repeated the same experiment for PS1 in a different laboratory and the results from the analysis of foot stimulation from both laboratories revealed statistically significant focal cortical response only in the contralateral SI foot area.

Timing and connectivity in the human somatosensory cortex from single trial mass electrical activity.

Parallel-distributed processing is ubiquitous in the brain but often ignored by experimental designs and methods of analysis, which presuppose sequential and stereotypical brain activations. We introduce here a methodology that can effectively deal with sequential and distributed activity. Regional brain activations elicited by electrical median nerve stimulation are identified in tomographic estimates extracted from single trial magnetoencephalographic signals. Habituation is identified in both primary somatosensory cortex (SI) and secondary somatosensory cortex (SII), often interrupted by resurgence of strong activations. Pattern analysis is used to identify single trials with homogeneous regional brain activations. Common activity patterns with well-defined connectivity are identified within each homogeneous group of single trials across the subjects studied. On the contralateral side one encounters distinct sets of single trials following identical stimuli. We observe in one set of trials sequential activation from SI to SII and insula with onset of SII at 60 msec, whereas in the other set simultaneous early co-activations of the same two areas.