[This corrects the article DOI: 10.1371/journal.pcbi.1006234.].

Implanted neurostimulation devices are gaining traction as palliative treatment options for certain forms of drug-resistant epilepsy, but clinical utility of these devices is hindered by incomplete mechanistic understanding of their therapeutic effects. Approved devices for anterior thalamic nuclei deep brain stimulation (ANT DBS) are thought to work at a network level, but limited sensing capability precludes characterization of neurophysiological effects outside the thalamus. Here, we describe a patient with drug-resistant temporal lobe epilepsy who was implanted with a responsive neurostimulation device (RNS System), involving hippocampal and ipsilateral temporal neocortical leads, and subsequently received ANT DBS. Over 1.5 years, RNS System electrocorticography enabled multiscale characterization of neurophysiological effects of thalamic stimulation. In brain regions sampled by the RNS System, ANT DBS produced acute, phasic, frequency-dependent responses, including suppression of hippocampal low frequency local field potentials. ANT DBS modulated functional connectivity between hippocampus and neocortex. Finally, ANT DBS progressively suppressed hippocampal epileptiform activity in relation to the extent of hippocampal theta suppression, which informs stimulation parameter selection for ANT DBS. Taken together, this unique clinical scenario, involving hippocampal recordings of unprecedented chronicity alongside ANT DBS, sheds light on the therapeutic mechanism of thalamic stimulation and highlights capabilities needed in next-generation devices.

Objective

A fundamental question in epilepsy surgery is how to delineate the margins of cortex that must be resected to result in seizure freedom. Whether and which areas showing seizure activity early in ictus must be removed to avoid postoperative recurrence of seizures is an area of ongoing research. Seizure spread dynamics in the initial seconds of ictus are often correlated with postoperative outcome; there is neither a consensus definition of early spread nor a concise summary of the existing literature linking seizure spread to postsurgical seizure outcomes. The present study is intended to summarize the literature that links seizure spread to postoperative seizure outcome and to provide a framework for quantitative assessment of early seizure spread.

Methods

A systematic review was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A Medline search identified clinical studies reporting data on seizure spread measured by intracranial electrodes, having at least 10 subjects and reporting at least 1-year postoperative outcome in the English literature from 1990 to 2019. Studies were evaluated regarding support for a primary hypothesis: Areas of early seizure spread represent cortex with seizure-generating potential.

Results

The search yielded 4562 studies: 15 studies met inclusion criteria and 7 studies supported the primary hypothesis. The methods and metrics used to describe seizure spread were heterogenous. The timeframe of seizure spread associated with seizure outcome ranged from 1-14 seconds, with large, well-designed, retrospective studies pointing to 3-10 seconds as most likely to provide meaningful correlates of postoperative seizure freedom.

Significance

The complex correlation between electrophysiologic seizure spread and the potential for seizure generation needs further elucidation. Prospective cohort studies or trials are needed to evaluate epilepsy surgery targeting cortex involved in the first 3-10 seconds of ictus.

Brain anatomy and physiology support the human ability to navigate a complex space of perceptions and actions. To maneuver across an ever-changing landscape of mental states, the brain invokes cognitive control-a set of dynamic processes that engage and disengage different groups of brain regions to modulate attention, switch between tasks, and inhibit prepotent responses. Current theory posits that correlated and anticorrelated brain activity may signify cooperative and competitive interactions between brain areas that subserve adaptive behavior. In this study, we use a quantitative approach to identify distinct topological motifs of functional interactions and examine how their expression relates to cognitive control processes and behavior. In particular, we acquire fMRI BOLD signal in twenty-eight healthy subjects as they perform two cognitive control tasks-a Stroop interference task and a local-global perception switching task using Navon figures-each with low and high cognitive control demand conditions. Based on these data, we construct dynamic functional brain networks and use a parts-based, network decomposition technique called non-negative matrix factorization to identify putative cognitive control subgraphs whose temporal expression captures distributed network structures involved in different phases of cooperative and competitive control processes. Our results demonstrate that temporal expression of the subgraphs fluctuate alongside changes in cognitive demand and are associated with individual differences in task performance. These findings offer insight into how coordinated changes in the cooperative and competitive roles of cognitive systems map trajectories between cognitively demanding brain states.

Objective

Post-ictal EEG alterations have been identified in studies of intracranial recordings, but the clinical significance of post-ictal EEG activity is undetermined. The purpose of this study was to examine the relationship between peri-ictal EEG activity, surgical outcome, and extent of seizure propagation in a sample of pediatric epilepsy patients.

Methods

Intracranial EEG recordings were obtained from 19 patients (mean age = 11.4 years, range = 3-20 years) with 57 seizures used for analysis (mean = 3.0 seizures per patient). For each seizure, 3-min segments were extracted from adjacent pre-ictal and post-ictal epochs. To compare physiology of the epileptic network between epochs, we calculated the relative delta power (Δ) using discrete Fourier transformation and constructed functional networks based on broadband connectivity (conn). We investigated differences between the pre-ictal (Δ_pre, conn_pre) and post-ictal (Δ_post, conn_post) segments in focal-network (i.e., confined to seizure onset zone) versus distributed-network (i.e., diffuse ictal propagation) seizures.

Results

Distributed-network (DN) seizures exhibited increased post-ictal delta power and global EEG connectivity compared to focal-network (FN) seizures. Following DN seizures, patients with seizure-free outcomes exhibited a 14.7% mean increase in delta power and an 8.3% mean increase in global connectivity compared to pre-ictal baseline, which was dramatically less than values observed among seizure-persistent patients (29.6% and 47.1%, respectively).

Significance

Post-ictal differences between DN and FN seizures correlate with post-operative seizure persistence. We hypothesize that post-ictal deactivation of subcortical nuclei recruited during seizure propagation may account for this result while lending insights into mechanisms of post-operative seizure recurrence.

The neurological basis of affective behaviours in everyday life is not well understood. We obtained continuous intracranial electroencephalography recordings from the human mesolimbic network in 11 participants with epilepsy and hand-annotated spontaneous behaviours from 116 h of multiday video recordings. In individual participants, binary random forest models decoded affective behaviours from neutral behaviours with up to 93% accuracy. Both positive and negative affective behaviours were associated with increased high-frequency and decreased low-frequency activity across the mesolimbic network. The insula, amygdala, hippocampus and anterior cingulate cortex made stronger contributions to affective behaviours than the orbitofrontal cortex, but the insula and anterior cingulate cortex were most critical for differentiating behaviours with observable affect from those without. In a subset of participants (N = 3), multiclass decoders distinguished amongst the positive, negative and neutral behaviours. These results suggest that spectro-spatial features of brain activity in the mesolimbic network are associated with affective behaviours of everyday life.

When learning about dynamic and uncertain environments, people should update their beliefs most strongly when new evidence is most informative, such as when the environment undergoes a surprising change or existing beliefs are highly uncertain. Here we show that modulations of surprise and uncertainty are encoded in a particular, temporally dynamic pattern of whole-brain functional connectivity, and this encoding is enhanced in individuals that adapt their learning dynamics more appropriately in response to these factors. The key feature of this whole-brain pattern of functional connectivity is stronger connectivity, or functional integration, between the fronto-parietal and other functional systems. Our results provide new insights regarding the association between dynamic adjustments in learning and dynamic, large-scale changes in functional connectivity across the brain.

Objective

Current brain stimulation paradigms are largely empirical rather than theoretical. An opportunity exists to improve upon their modest effectiveness in closed-loop control strategies with the development of theoretically grounded, model-based designs.

Approach

Inspired by this need, here we couple experimental data and mathematical modeling with a control-theoretic strategy for seizure termination. We begin by exercising a dynamical systems approach to model seizures (n = 94) recorded using intracranial EEG (iEEG) from 21 patients with medication-resistant, localization-related epilepsy.

Main results

Although each patient's seizures displayed unique spatial and temporal patterns, their evolution can be parsimoniously characterized by the same model form. Idiosyncracies of the model can inform individualized intervention strategies, specifically in iEEG samples with well-localized seizure onset zones. Temporal fluctuations in the spatial profiles of the oscillatory modes show that seizure onset marks a transition into a regime in which the underlying system supports prolonged rhythmic and focal activity. Based on these observations, we propose a control-theoretic strategy that aims to stabilize ictal activity using static output feedback for linear time-invariant switching systems. Finally, we demonstrate in silico that our proposed strategy allows us to dampen the emerging focal oscillatory sources using only a small set of electrodes.

Significance

Our integrative study informs the development of modulation and control algorithms for neurostimulation that could improve the effectiveness of implantable, closed-loop anti-epileptic devices.