Faculty Bibliography

The running-down phenomenon refers to 2 analogous but distinct entities that may be seen after epilepsy surgery. The first is clinical, and denotes a progressive diminution in seizures after epilepsy surgery in which the epileptogenic zone could not be completely removed (Modern Problems of Psychopharmacology 1970;4:306, Brain 1996:989). The second is electrographic, and refers to a progressive deactivation of a secondary seizure focus after removal of the primary epileptogenic zone. This progressive decrease in epileptiform activity may represent a reversal of secondary epileptogenesis, where a primary epileptogenic zone is postulated to activate epileptiform discharges at a second site and may become independent.³ The electrographic running-down phenomenon has been reported in only limited numbers of patients, using serial postoperative routine scalp electroencephalography (EEG) (Arch Neurol 1985;42:318). We present what is, to our knowledge, the most detailed demonstration of the electrographic running-down phenomenon in humans, made possible by chronic electrocorticography (ECoG). Our patient's left temporal seizure focus overlapped with language areas, limiting the resection to a portion of the epileptogenic zone, followed by implantation of a direct brain-responsive neurostimulator (RNS System, NeuroPace Inc.) to treat residual epileptogenic tissue. Despite the limited extent of the resection, the patient remains seizure-free more than 2 years after surgery, with the RNS System recording ECoG without delivering stimulation. We reviewed the chronic recordings with automated spike detection and inspection of electrographic episodes marked by the neurostimulator. These recordings demonstrate progressive diminution in spiking and rhythmic discharges, consistent with an electrographic running-down phenomenon.

For drug-resistant epilepsy, nonpharmacologic treatments should be considered early rather than late. Of the nondrug treatments, only resective surgery can be curative. Neurostimulation is palliative, i.e., not expected to achieve a seizure-free outcome. While resective surgery is the goal, other options are necessary because the majority of patients with drug-resistant epilepsy are not surgical candidates, and others have seizures that fail to improve with surgery or have only partial improvement but not seizure freedom. Neurostimulation modalities include vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS), each with its own advantages, disadvantages, and side effects. In most scenarios, determined by noninvasive evaluation, especially EEG and MRI, several strategies are reasonable. For focal epilepsies, the choices are between resective surgery, with or without intracranial EEG, and all three modalities of neurostimulation. In situations where resective surgery is likely to result in seizure freedom, such as mesiotemporal lobe epilepsy or lesional focal epilepsy, resection (standard, laser, or radiofrequency) is preferred. For difficult cases like extratemporal nonlesional epilepsies, neurostimulation offers a less invasive option than resective surgery. For generalized and multifocal epilepsies, VNS is an option, RNS is not, and DBS has only limited evidence. "This article is part of the Supplement issue Neurostimulation for Epilepsy."

Employing predictions based on environmental regularities is fundamental for adaptive behaviour. While it is widely accepted that predictions across different stimulus attributes (e.g., time and content) facilitate sensory processing, it is unknown whether predictions across these attributes rely on the same neural mechanism. Here, to elucidate the neural mechanisms of predictions, we combine invasive electrophysiological recordings (human electrocorticography in 4 females and 2 males) with computational modelling while manipulating predictions about content ('what') and time ('when'). We found that 'when' predictions increased evoked activity over motor and prefrontal regions both at early (∼180 ms) and late (430-450 ms) latencies. 'What' predictability, however, increased evoked activity only over prefrontal areas late in time (420-460 ms). Beyond these dissociable influences, we found that 'what' and 'when' predictability interactively modulated the amplitude of early (165 ms) evoked responses in the superior temporal gyrus. We modelled the observed neural responses using biophysically realistic neural mass models, to better understand whether 'what' and 'when' predictions tap into similar or different neurophysiological mechanisms. Our modelling results suggest that 'what' and 'when' predictability rely on complementary neural processes: 'what' predictions increased short-term plasticity in auditory areas, while 'when' predictability increased synaptic gain in motor areas. Thus, content and temporal predictions engage complementary neural mechanisms in different regions, suggesting domain-specific prediction signalling along the cortical hierarchy. Encoding predictions through different mechanisms may endow the brain with the flexibility to efficiently signal different sources of predictions, weight them by their reliability, and allow for their encoding without mutual interference.SIGNIFICANCE STATEMENTPredictions of different stimulus features facilitate sensory processing. However, it is unclear whether predictions of different attributes rely on similar or different neural mechanisms. By combining invasive electrophysiological recordings of cortical activity with experimental manipulations of participants' predictions about content and time of acoustic events, we found that the two types of predictions had dissociable influences on cortical activity, both in terms of the regions involved and the timing of the observed effects. Further, our biophysical modelling analysis suggests that predictability of content and time rely on complementary neural processes: short-term plasticity in auditory areas and synaptic gain in motor areas, respectively. This suggests that predictions of different features are encoded with complementary neural mechanisms in different brain regions.

Our visual environment constantly changes, yet we experience the world as a stable, unified whole. How is this stability achieved? It has been proposed that the brain preserves an implicit perceptual memory in sensory cortices [1] which stabilizes perception towards previously experienced states [2,3]. The role of higher-order areas, especially prefrontal cortex (PFC), in perceptual memory is less explored. Because PFC exhibits long neural time constants, invariance properties, and large receptive fields which may stabilize perception against time-varying inputs, it seems particularly suited to implement perceptual memory [4]. Support for this idea comes from a neuroimaging study reporting that dorsomedial PFC (dmPFC) correlates with perceptual memory [5]. But dmPFC also participates in decision making [6], so its contribution to perceptual memory could arise on a post-perceptual, decisional level [7]. To determine which role, if any, PFC plays in perceptual memory, we obtained direct intracranial recordings in six epilepsy patients while they performed sequential orientation judgements on ambiguous stimuli known to elicit perceptual memory [8]. We found that dmPFC activity in the high gamma frequency band (HGB, 70-150 Hz) correlates with perceptual memory. This effect is anatomically specific to dmPFC and functionally specific for memories of preceding percepts. Further, dmPFC appears to play a causal role, as a patient with a lesion in this area showed impaired perceptual memory. Thus, dmPFC integrates current sensory information with prior percepts, stabilizing visual experience against the perpetual variability of our surroundings.

OBJECTIVE:We sought to determine whether the presence or surgical removal of certain nodes in a connectivity network constructed from intracranial electroencephalography recordings determines postoperative seizure freedom in surgical epilepsy patients. METHODS:We analyzed connectivity networks constructed from peri-ictal intracranial electroencephalography of surgical epilepsy patients before a tailored resection. Thirty-six patients and 123 seizures were analyzed. Their Engel class postsurgical seizure outcome was determined at least one year after surgery. Betweenness centrality, a measure of a node's importance as a hub in the network, was used to compare nodes. RESULTS:The presence of larger quantities of high-betweenness nodes in interictal and postictal networks was associated with failure to achieve seizure freedom from the surgery (p < 0.001), as was resection of high-betweenness nodes in three successive frequency groups in mid-seizure networks (p < 0.001). CONCLUSIONS:Betweenness centrality is a biomarker for postsurgical seizure outcomes. The presence of high-betweenness nodes in interictal and postictal networks can predict patient outcome independent of resection. Additionally, since their resection is associated with worse seizure outcomes, the mid-seizure network high-betweenness centrality nodes may represent hubs in self-regulatory networks that inhibit or help terminate seizures. SIGNIFICANCE/CONCLUSIONS:This is the first study to identify network nodes that are possibly protective in epilepsy.

Mnemonic decision-making has long been hypothesized to rely on hippocampal dynamics that bias memory processing toward the formation of new memories or the retrieval of old ones. Successful memory encoding may be best optimized by pattern separation, whereby two highly similar experiences can be represented by underlying neural populations in an orthogonal manner. By contrast, successful memory retrieval is thought to be supported by a recovery of the same neural pattern laid down during encoding. Here we examined how hippocampal pattern completion and separation emerge over time during memory decisions. We measured electrocorticography activity in the human hippocampus and posterior occipitotemporal cortex (OTC) while participants performed continuous recognition of items that were new, repeated (old), or highly similar to a prior item (similar). During retrieval decisions of old items, both regions exhibited significant reinstatement of multivariate high-frequency activity (HFA) associated with encoding. Further, the extent of reinstatement of encoding patterns during retrieval was correlated with the strength (HFA power) of hippocampal encoding. Evidence for encoding pattern reinstatement was also seen in OTC on trials requiring fine-grained discrimination of similar items. By contrast, hippocampal activity showed evidence for pattern separation during these trials. Together, these results underscore the critical role of the hippocampus in supporting both reinstatement of overlapping information and separation of similar events.

OBJECTIVE Somatic variants are a recognized cause of epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants may underlie a wider range of focal epilepsy, including non-lesional focal epilepsy (NLFE). Through genetic analysis of brain tissue, we evaluated the role of somatic variation in focal epilepsy with and without MCD. METHODS We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD. RESULTS We observed somatic variants in five cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in resected brain, and absent from leukocytes, in 3/18 individuals (17%) with NLFE, one female and two males, with variant allele frequencies (VAFs) in brain-derived DNA of 2-14%. Pathologic evaluation revealed focal cortical dysplasia type Ia (FCD1a) in two of the three NLFE cases. In the MCD cohort, nonsynonymous variants in SCL35A2 were detected in the brains of two males with intractable epilepsy, developmental delay, and MRI suggesting FCD, with VAFs of 19-53%; FCD1a was not observed in either brain tissue specimen. INTERPRETATION We report somatic variants in SLC35A2 as an explanation for a substantial fraction of NLFE, a largely unexplained condition, as well as focal MCD, previously shown to result from somatic mutation but until now only in PI3K-AKT-mTOR pathway genes. Collectively, our findings suggest a larger role than previously recognized for glycosylation defects in the intractable epilepsies.

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10-16Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but about half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ∼25-50ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25-50Hz) and high (70-170Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.SIGNIFICANCE STATEMENTBursts of ∼14Hz oscillations, lasting about a second, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.