Faculty Bibliography

Brainstem nuclei dysfunction is implicated in sudden unexpected death in epilepsy. In animal models, deficient serotonergic activity is associated with seizure-induced respiratory arrest. In humans, glia are decreased in the ventrolateral medullary pre-Botzinger complex that modulate respiratory rhythm, as well as in the medial medullary raphe that modulate respiration and arousal. Finally, sudden unexpected death in epilepsy cases have decreased midbrain volume. To understand the potential role of brainstem nuclei in sudden unexpected death in epilepsy, we evaluated molecular signalling pathways using localized proteomics in microdissected midbrain dorsal raphe and medial medullary raphe serotonergic nuclei, as well as the ventrolateral medulla in brain tissue from epilepsy patients who died of sudden unexpected death in epilepsy and other causes in diverse epilepsy syndromes and non-epilepsy control cases (n = 15-16 cases per group/region). Compared with the dorsal raphe of non-epilepsy controls, we identified 89 proteins in non-sudden unexpected death in epilepsy and 219 proteins in sudden unexpected death in epilepsy that were differentially expressed. These proteins were associated with inhibition of EIF2 signalling (P-value of overlap = 1.29 × 10^-8, z = -2.00) in non-sudden unexpected death in epilepsy. In sudden unexpected death in epilepsy, there were 10 activated pathways (top pathway: gluconeogenesis I, P-value of overlap = 3.02 × 10^-6, z = 2.24) and 1 inhibited pathway (fatty acid beta-oxidation, P-value of overlap = 2.69 × 10^-4, z = -2.00). Comparing sudden unexpected death in epilepsy and non-sudden unexpected death in epilepsy, 10 proteins were differentially expressed, but there were no associated signalling pathways. In both medullary regions, few proteins showed significant differences in pairwise comparisons. We identified altered proteins in the raphe and ventrolateral medulla of epilepsy patients, including some differentially expressed in sudden unexpected death in epilepsy cases. Altered signalling pathways in the dorsal raphe of sudden unexpected death in epilepsy indicate a shift in cellular energy production and activation of G-protein signalling, inflammatory response, stress response and neuronal migration/outgrowth. Future studies should assess the brain proteome in relation to additional clinical variables (e.g. recent tonic-clonic seizures) and in more of the reciprocally connected cortical and subcortical regions to better understand the pathophysiology of epilepsy and sudden unexpected death in epilepsy.

Studies of epilepsy patients provide insight into the neuroscience of human memory. Patients with remote memory deficits may learn new information but have difficulty recalling events from years past. The processes underlying remote memory impairment are unclear and likely result from the interaction of multiple factors, including hippocampal dysfunction. The hippocampus likely has a continued role in remote semantic and episodic memory storage over time, and patients with mesial temporal lobe epilepsy (TLE) are at particular risk for deficits. Studies have focused on lateralization of remote memory, often with greater impairment in left TLE, which may relate to verbal task demands. Remote memory testing is restricted by methodological limitations. As a result, deficits have been difficult to measure. This review of remote memory focuses on evidence for its underlying neurobiology, theoretical implications for hippocampal function, and methodological difficulties that complicate testing in epilepsy patients.

Objective/UNASSIGNED:Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Although lots of effort has been made in identifying clinical risk factors for SUDEP in the literature, there are few validated methods to predict individual SUDEP risk. Prolonged postictal EEG suppression (PGES) is a potential SUDEP biomarker, but its occurrence is infrequent and requires epilepsy monitoring unit admission. We use machine learning methods to examine SUDEP risk using interictal EEG and ECG recordings from SUDEP cases and matched living epilepsy controls. Methods/UNASSIGNED:This multicenter, retrospective, cohort study examined interictal EEG and ECG recordings from 30 SUDEP cases and 58 age-matched living epilepsy patient controls. We trained machine learning models with interictal EEG and ECG features to predict the retrospective SUDEP risk for each patient. We assessed cross-validated classification accuracy and the area under the receiver operating characteristic (AUC) curve. Results/UNASSIGNED:The logistic regression (LR) classifier produced the overall best performance, outperforming the support vector machine (SVM), random forest (RF), and convolutional neural network (CNN). Among the 30 patients with SUDEP [14 females; mean age (SD), 31 (8.47) years] and 58 living epilepsy controls [26 females (43%); mean age (SD) 31 (8.5) years], the LR model achieved the median AUC of 0.77 [interquartile range (IQR), 0.73-0.80] in five-fold cross-validation using interictal alpha and low gamma power ratio of the EEG and heart rate variability (HRV) features extracted from the ECG. The LR model achieved the mean AUC of 0.79 in leave-one-center-out prediction. Conclusions/UNASSIGNED:Our results support that machine learning-driven models may quantify SUDEP risk for epilepsy patients, future refinements in our model may help predict individualized SUDEP risk and help clinicians correlate predictive scores with the clinical data. Low-cost and noninvasive interictal biomarkers of SUDEP risk may help clinicians to identify high-risk patients and initiate preventive strategies.

One-third of epilepsy patients suffer from medication-resistant seizures. While surgery to remove epileptogenic tissue helps some patients, 30-70% of patients continue to experience seizures following resection. Surgical outcomes may be improved with more accurate localization of epileptogenic tissue. We have previously developed novel thin-film, subdural electrode arrays with hundreds of microelectrodes over a 100-1000 mm² area to enable high-resolution mapping of neural activity. Here, we used these high-density arrays to study microscale properties of human epileptiform activity. We performed intraoperative micro-electrocorticographic recordings in nine patients with epilepsy. In addition, we recorded from four patients with movement disorders undergoing deep brain stimulator implantation as non-epileptic controls. A board-certified epileptologist identified microseizures, which resembled electrographic seizures normally observed with clinical macroelectrodes. Recordings in epileptic patients had a significantly higher microseizure rate (2.01 events/min) than recordings in non-epileptic subjects (0.01 events/min; permutation test, P = 0.0068). Using spatial averaging to simulate recordings from larger electrode contacts, we found that the number of detected microseizures decreased rapidly with increasing contact diameter and decreasing contact density. In cases in which microseizures were spatially distributed across multiple channels, the approximate onset region was identified. Our results suggest that micro-electrocorticographic electrode arrays with a high density of contacts and large coverage are essential for capturing microseizures in epilepsy patients and may be beneficial for localizing epileptogenic tissue to plan surgery or target brain stimulation.

Importance/UNASSIGNED:Non-communicable chronic diseases (NCDs) such as obesity, type 2 diabetes, heart disease, and cancer were rare among non-western populations with traditional diets and lifestyles. As populations transitioned toward industrialized diets and lifestyles, NCDs developed. Objective/UNASSIGNED:We performed a systematic literature review to examine the effects of diet and lifestyle transitions on NCDs. Evidence Review/UNASSIGNED:We identified 22 populations that underwent a nutrition transition, eleven of which had sufficient data. Of these, we chose four populations with diverse geographies, diets and lifestyles who underwent a dietary and lifestyle transition and explored the relationship between dietary changes and health outcomes. We excluded populations with features overlapping with selected populations or with complicating factors such as inadequate data, subgroups, and different study methodologies over different periods. The selected populations were Yemenite Jews, Tokelauans, Tanushimaru Japanese, and Maasai. We also review transition data from seven excluded populations (Pima, Navajo, Aboriginal Australians, South African Natal Indians and Zulu speakers, Inuit, and Hadza) to assess for bias. Findings/UNASSIGNED:The three groups that replaced saturated fats (SFA) from animal (Yemenite Jews, Maasai) or plants (Tokelau) with refined carbohydrates had negative health outcomes (e.g., increased obesity, diabetes, heart disease). Yemenites reduced SFA consumption by >40% post-transition but men's BMI increased 19% and diabetes increased ~40-fold. Tokelauans reduced fat, dramatically reduced SFA, and increased sugar intake: obesity and diabetes rose. The Tanushimaruans transitioned to more fats and less carbohydrates and used more anti-hypertensive medications; stroke and breast cancer declined while heart disease was stable. The Maasai transitioned to lower fat, SFA and higher carbohydrates and had increased BMI and diabetes. Similar patterns were observed in the seven other populations. Conclusion/UNASSIGNED:The nutrient category most strongly associated with negative health outcomes - especially obesity and diabetes - was sugar (increased 600-650% in Yemenite Jews and Tokelauans) and refined carbohydrates (among Maasai, total carbohydrates increased 39% in men and 362% in women), while increased calories was less strongly associated with these disorders. Across 11 populations, NCDs were associated with increased refined carbohydrates more than increased calories, reduced activity or other factors, but cannot be attributed to SFA or total fat consumption.

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10^-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10^-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10^-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

BACKGROUND AND OBJECTIVES:We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. METHODS:This international, multicenter, retrospective, nested case-control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. RESULTS:= 0.209). CONCLUSIONS:Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify individual SUDEP risk. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that in patients with epilepsy, some measures of HRV are associated with SUDEP.

The ability to process and respond to external input is critical for adaptive behavior. Why, then, do neural and behavioral responses vary across repeated presentations of the same sensory input? Ongoing fluctuations of neuronal excitability are currently hypothesized to underlie the trial-by-trial variability in sensory processing. To test this, we capitalized on intracranial electrophysiology in neurosurgical patients performing an auditory discrimination task with visual cues: specifically, we examined the interaction between prestimulus alpha oscillations, excitability, task performance, and decoded neural stimulus representations. We found that strong prestimulus oscillations in the alpha+ band (i.e., alpha and neighboring frequencies), rather than the aperiodic signal, correlated with a low excitability state, indexed by reduced broadband high-frequency activity. This state was related to slower reaction times and reduced neural stimulus encoding strength. We propose that the alpha+ rhythm modulates excitability, thereby resulting in variability in behavior and sensory representations despite identical input.