Differentiating ictal/subclinical spikes and waves in childhood absence epilepsy by spectral and network analyses: A pilot study

ObjectiveChildhood absence epilepsy (CAE) is a disease with distinct seizure semiology and electroencephalographic (EEG) features. Differentiating ictal and subclinical generalized spikes and waves discharges (GSWDs) in the EEG is challenging, since they appear to be identical upon visual inspection. Here, spectral and functional connectivity (FC) analyses were applied to routine EEG data of CAE patients, to differentiate ictal and subclinical GSWDs.MethodsTwelve CAE patients with both ictal and subclinical GSWDs were retrospectively selected for this study. The selected EEG epochs were subjected to frequency analysis in the range of 1–30 Hz. Further, FC analysis based on the imaginary part of coherency was used to determine sensor level networks.ResultsDelta, alpha and beta band frequencies during ictal GSWDs showed significantly higher power compared to subclinical GSWDs. FC showed significant network differences for all frequency bands, demonstrating weaker connectivity between channels during ictal GSWDs.ConclusionUsing spectral and FC analyses significant differences between ictal and subclinical GSWDs in CAE patients were detected, suggesting that these features could be used for machine learning classification purposes to improve EEG monitoring.SignificanceIdentifying differences between ictal and subclinical GSWDs using routine EEG, may improve understanding of this syndrome and the management of patients with CAE.     

Spike‐associated networks and intracranial electrographic findings

Aims. Functional connectivity is providing new insights into the network nature of epilepsy with growing clinical applications. Our objective was to validate a novel magnetoencephalography‐based method to non‐invasively measure the epileptic network. Methods. We retrospectively identified pediatric and adult patients with refractory focal epilepsy who underwent pre‐surgical magnetoencephalography with subsequent intracranial electrographic monitoring. Magnetoencephalography tracings were visually reviewed, and interictal epileptiform discharges (“spikes”) were individually marked. We then evaluated differences in whole‐brain connectivity during brief epochs preceding the spikes and during the spikes using the Network‐Based Statistic to test differences at the network level. Results. In six patients with statistically‐significant network differences, we observed substantial overlap between the spike‐associated networks and electrographically active areas identified during intracranial monitoring (the spike‐associated network was 78% and 83% sensitive for intracranial electroencephalography‐defined regions in the irritative and seizure onset zones, respectively). Conclusion. These findings support the neurobiological validity of the spike‐associated network method. Assessment of spike‐associated networks has the potential to improve surgical planning in epilepsy surgery patients by identifying components of the epileptic network prior to implantation.     

Frequency‐specific changes in the default mode network in patients with cingulate gyrus epilepsy

To identify abnormal functional connectivity of the default mode network in cingulate gyrus epilepsy, which may yield new information about the default mode network and suggest a new cingulate gyrus epilepsy biomarker. Fifteen patients with cingulate gyrus epilepsy (mean age = 21 years) and 15 healthy controls (mean age = 24 years) were studied in the resting state using magnetoencephalography. Twelve brain areas of interest in the default mode network were extracted and investigated with multifrequency signals that included alpha (α, 8–13 Hz), beta (β, 14–30 Hz), and gamma (γ, 31–80 Hz) band oscillations. Patients with cingulate gyrus epilepsy had significantly greater connectivity in all three frequency bands (α, β, γ). A frequency‐specific elevation of functional connectivity was found in patients compared to controls. The greater functional connectivity in the γ band was significantly more prominent than that of the α and β bands. Patients with cingulate gyrus epilepsy and controls differed significantly in functional connectivity between the left angular gyrus and left posterior cingulate cortex in the α, β, and γ bands. The results of the node degree analysis were similar to those of the functional connectivity analysis. Our findings reveal for the first time that brain activity in the γ band may play a key role in the default mode network in cingulate gyrus epilepsy. Altered functional connectivity of the left angular gyrus and left posterior cingulate cortex may be a new biomarker for cingulate gyrus epilepsy.     

Prefrontal theta modulates sensorimotor gamma networks during the reorienting of attention

The ability to execute a motor plan involves spatiotemporally precise oscillatory activity in primary motor (M1) regions, in concert with recruitment of “higher order” attentional mechanisms for orienting toward current task goals. While current evidence implicates gamma oscillatory activity in M1 as central to the execution of a movement, far less is known about top‐down attentional modulation of this response. Herein, we utilized magnetoencephalography (MEG) during a Posner attention‐reorienting task to investigate top‐down modulation of M1 gamma responses by frontal attention networks in 63 healthy adult participants. MEG data were evaluated in the time–frequency domain and significant oscillatory responses were imaged using a beamformer. Robust increases in theta activity were found in bilateral inferior frontal gyri (IFG), with significantly stronger responses evident in trials that required attentional reorienting relative to those that did not. Additionally, strong gamma oscillations (60–80 Hz) were detected in M1 during movement execution, with similar responses elicited irrespective of attentional reorienting. Whole‐brain voxel‐wise correlations between validity difference scores (i.e., attention reorienting trials—nonreorienting trials) in frontal theta activity and movement‐locked gamma oscillations revealed a robust relationship in the contralateral sensorimotor cortex, supplementary motor area, and right cerebellum, suggesting modulation of these sensorimotor network gamma responses by attentional reorienting. Importantly, the validity difference effect in this distributed motor network was predictive of overall motor function measured outside the scanner and further, based on a mediation analysis this relationship was fully mediated by the reallocation response in the right IFG. These data are the first to characterize the top‐down modulation of movement‐related gamma responses during attentional reorienting and movement execution.     

Hemispheric lateralization in top‐down attention during spatial relation processing: a Granger causal model approach

Magnetoencephalography was recorded during a matching‐to‐sample plus cueing paradigm, in which participants judged the occurrence of changes in either categorical (CAT) or coordinate (COO) spatial relations. Previously, parietal and frontal lobes were identified as key areas in processing spatial relations and it was shown that each hemisphere was differently involved and modulated by the scope of the attention window (e.g. a large and small cue). In this study, Granger analysis highlighted the patterns of causality among involved brain areas – the direction of information transfer ran from the frontal to the visual cortex in the right hemisphere, whereas it ran in the opposite direction in the left side. Thus, the right frontal area seems to exert top‐down influence, supporting the idea that, in this task, top‐down signals are selectively related to the right side. Additionally, for CAT change preceded by a small cue, the right frontal gyrus was not involved in the information transfer, indicating a selective specialization of the left hemisphere for this condition. The present findings strengthen the conclusion of the presence of a remarkable hemispheric specialization for spatial relation processing and illustrate the complex interactions between the lateralized parts of the neural network. Moreover, they illustrate how focusing attention over large or small regions of the visual field engages these lateralized networks differently, particularly in the frontal regions of each hemisphere, consistent with the theory that spatial relation judgements require a fronto‐parietal network in the left hemisphere for categorical relations and on the right hemisphere for coordinate spatial processing.     

Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV‐infected older adults

Combination antiretroviral therapy transformed human immunodefiency virus (HIV)‐infection from a terminal illness to a manageable condition, but these patients remain at a significantly elevated risk of developing cognitive impairments and the mechanisms are not understood. Some previous neuroimaging studies have found hyperactivation in frontoparietal networks of HIV‐infected patients, whereas others reported aberrations restricted to sensory cortices. In this study, we utilize high‐resolution structural and neurophysiological imaging to determine whether alterations in brain structure, function, or both contribute to HIV‐related cognitive impairments. HIV‐infected adults and individually matched controls completed 3‐Tesla structural magnetic resonance imaging (sMRI) and a mechanoreception task during magnetoencephalography (MEG). MEG data were examined using advanced beamforming methods, and sMRI data were analyzed using the latest voxel‐based morphometry methods with DARTEL. We found significantly reduced theta responses in the postcentral gyrus and increased alpha activity in the prefrontal cortices of HIV‐infected patients compared with controls. Patients also had reduced gray matter volume in the postcentral gyrus, parahippocampal gyrus, and other regions. Importantly, reduced gray matter volume in the left postcentral gyrus was spatially coincident with abnormal MEG responses in HIV‐infected patients. Finally, left prefrontal and postcentral gyrus activity was correlated with neuropsychological performance and, when used in conjunction, these two MEG findings had a sensitivity and specificity of over 87.5% for HIV‐associated cognitive impairment. This study is the first to demonstrate abnormally increased activity in association cortices with simultaneously decreased activity in sensory areas. These MEG findings had excellent sensitivity and specificity for HIV‐associated cognitive impairment, and may hold promise as a potential disease marker. Hum Brain Mapp 36:897–910, 2015. © 2014 Wiley Periodicals, Inc.     

Memory traces of long‐range coordinated oscillations in the sleeping human brain

Cognition involves coordinated activity across distributed neuronal networks. Neuronal activity during learning triggers cortical plasticity that allows for reorganization of the neuronal network and integration of new information. Animal studies have shown post‐learning reactivation of learning‐elicited neuronal network activity during subsequent sleep, supporting consolidation of the reorganization. However, no previous studies, to our knowledge, have demonstrated reactivation of specific learning‐elicited long‐range functional connectivity during sleep in humans. We here show reactivation of learning‐induced long‐range synchronization of magnetoencephalography power fluctuations in human sleep. Visuomotor learning elicited a specific profile of long‐range cortico‐cortical synchronization of slow (0.1 Hz) fluctuations in beta band (12–30 Hz) power. The parieto‐occipital part of this synchronization profile reappeared in delta band (1–3.5 Hz) power fluctuations during subsequent sleep, but not during the intervening wakefulness period. Individual differences in the reactivated synchronization predicted postsleep performance improvement. The presleep resting‐state synchronization profile was not reactivated during sleep. The findings demonstrate reactivation of long‐range coordination of neuronal activity in humans, more specifically of reactivation of coupling of infra‐slow fluctuations in oscillatory power. The spatiotemporal profile of delta power fluctuations during sleep may subserve memory consolidation by echoing coordinated activation elicited by prior learning. Hum Brain Mapp, 36:67–84, 2015. © 2014 Wiley Periodicals, Inc.     

Idiopathic focal epilepsies: the “lost tribe”

The term idiopathic focal epilepsies of childhood (IFE) is not formally recognised by the ILAE in its 2010 revision (Berg et al., 2010 ), nor are its members and boundaries precisely delineated. The IFEs are amongst the most commonly encountered epilepsy syndromes affecting children. They are fascinating disorders that hold many “treats” for both clinicians and researchers. For example, the IFEs pose many of the most interesting questions central to epileptology: how are functional brain networks involved in the manifestation of epilepsy? What are the shared mechanisms of comorbidity between epilepsy and neurodevelopmental disorders? How do focal EEG discharges impact cognitive functioning? What explains the age‐related expression of these syndromes? Why are EEG discharges and seizures so tightly locked to slow‐wave sleep? In the last few decades, the clinical symptomatology and the respective courses of many IFEs have been described, although they are still not widely appreciated beyond the specialist community. Most neurologists would recognise the core syndromes of IFE to comprise: benign epilepsy of childhood with centro‐temporal spikes or Rolandic epilepsy (BECTS/RE); Panayiotopoulos syndrome; and the idiopathic occipital epilepsies (Gastaut and photosensitive types). The Landau‐Kleffner syndrome and the related (idiopathic) epilepsy with continuous spikes and waves in sleep (CSWS or ESES) are also often included, both as a consequence of the shared morphology of the interictal discharges and their potential evolution from core syndromes, for example, CSWS from BECTS. Atypical benign focal epilepsy of childhood also has shared electro‐clinical features warranting inclusion. In addition, a number of less well‐defined syndromes of IFE have been proposed, including benign childhood seizures with affective symptoms, benign childhood epilepsy with parietal spikes, benign childhood seizures with frontal or midline spikes, and benign focal seizures of adolescence. The term “benign” is often used in connection with the IFEs and is increasingly being challenged. Certainly most of these disorders are not associated with the devastating cognitive and behavioural problems seen with early childhood epileptic encephalopathies, such as West or Dravet syndromes. However, it is clear that specific, and sometimes persistent, neuropsychological deficits in attention, language and literacy accompany many of the IFEs that, when multiplied by the large numbers affected, make up a significant public health problem. Understanding the nature, distribution, evolution, risk and management of these is an important area of current research. A corollary to such questions regarding comorbidities is the role of focal interictal spikes and their enduring impact on cognitive functioning. What explains the paradox that epilepsies characterised by abundant interictal epileptiform abnormalities are often associated with very few clinical seizures? This is an exciting area in both clinical and experimental arenas and will eventually have important implications for clinical management of the whole child, taking into account not just seizures, but also adaptive functioning and quality of life. For several decades, we have accepted an evidence‐free approach to using or not using antiepileptic drugs in IFEs. There is huge international variation and only a handful of studies examining neurocognitive outcomes. Clearly, this is a situation ready for an overhaul in practice. Fundamental to understanding treatment is knowledge of aetiology. In recent years, there have been several significant discoveries in IFEs from studies of copy number variation, exome sequencing, and linkage that prompt reconsideration of the “unknown cause” classification and strongly suggest a genetic aetiology. The IFE are strongly age‐related, both with regards to age of seizure onset and remission. Does this time window solely relate to a similar age‐related gene expression, or are there epigenetic factors involved that might also explain low observed twin concordance? The genetic (and epigenetic) models for different IFEs, their comorbidities, and their similarities to other neurodevelopmental disorders deserve investigation in the coming years. In so doing, we will probably learn much about normal brain functioning. This is because these disorders, perhaps more than any other human brain disease, are disorders of functional brain systems (even though these functional networks may not yet be fully defined). In June 2012, an international group of clinical and basic science researchers met in London under the auspices of the Waterloo Foundation to discuss and debate these issues in relation to IFEs. This Waterloo Foundation Symposium on the Idiopathic Focal Epilepsies: Phenotype to Genotype witnessed presentations that explored the clinical phenomenology, phenotypes and endophenotypes, and genetic approaches to investigation of these disorders. In parallel, the impact of these epilepsies on children and their families was reviewed. The papers in this supplement are based upon these presentations. They represent an updated state‐of‐the‐art thinking on the topics explored. The symposium led to the formation of international working groups under the umbrella of “Luke's Idiopathic Focal Epilepsy Project” to investigate various aspects of the idiopathic focal epilepsies including: semiology and classification, genetics, cognition, sleep, high‐frequency oscillations, and parental resources (see www.childhood-epilepsy.org ). The next sponsored international workshop, in June 2014, was on randomised controlled trials in IFEs and overnight learning outcome measures.