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PET and fMRI studies suggest that auditory narrative comprehension is supported by a bilateral multilobar cortical network. The superior temporal resolution of magnetoencephalography (MEG) makes it an attractive tool to investigate the dynamics of how different neuroanatomic substrates engage during narrative comprehension. Using beta-band power changes as a marker of cortical engagement, we studied MEG responses during an auditory story comprehension task in 31 healthy adults. The protocol consisted of two runs, each interleaving 7 blocks of the story comprehension task with 15 blocks of an auditorily presented math task as a control for phonological processing, working memory, and attention processes. Sources at the cortical surface were estimated with a frequency-resolved beamformer. Beta-band power was estimated in the frequency range of 16-24 Hz over 1-sec epochs starting from 400 msec after stimulus onset until the end of a story or math problem presentation. These power estimates were compared to 1-second epochs of data before the stimulus block onset. The task-related cortical engagement was inferred from beta-band power decrements. Group-level source activations were statistically compared using non-parametric permutation testing. A story-math contrast of beta-band power changes showed greater bilateral cortical engagement within the fusiform gyrus, inferior and middle temporal gyri, parahippocampal gyrus, and left inferior frontal gyrus (IFG) during story comprehension. A math-story contrast of beta power decrements showed greater bilateral but left-lateralized engagement of the middle frontal gyrus and superior parietal lobule. The evolution of cortical engagement during five temporal windows across the presentation of stories showed significant involvement during the first interval of the narrative of bilateral opercular and insular regions as well as the ventral and lateral temporal cortex, extending more posteriorly on the left and medially on the right. Over time, there continued to be sustained right anterior ventral temporal engagement, with increasing involvement of the right anterior parahippocampal gyrus, STG, MTG, posterior superior temporal sulcus, inferior parietal lobule, frontal operculum, and insula, while left hemisphere engagement decreased. Our findings are consistent with prior imaging studies of narrative comprehension, but in addition, they demonstrate increasing right-lateralized engagement over the course of narratives, suggesting an important role for these right-hemispheric regions in semantic integration as well as social and pragmatic inference processing., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interests exist., (Copyright © 2022. Published by Elsevier Inc.)

Neuroticism, a core personality trait characterized by a tendency towards experiencing negative affect, has been reported to be higher in people with temporal lobe epilepsy (TLE) compared with healthy individuals. Neuroticism is a known predictor of depression and anxiety, which also occur more frequently in people with TLE. The purpose of this study was to identify abnormalities in whole-brain resting-state functional connectivity in relation to neuroticism in people with TLE and to determine the degree of unique versus shared patterns of abnormal connectivity in relation to elevated symptoms of depression and anxiety. Ninety-three individuals with TLE (55 females) and 40 healthy controls (18 females) from the Epilepsy Connectome Project (ECP) completed measures of neuroticism, depression, and anxiety, which were all significantly higher in people with TLE compared with controls. Resting-state functional connectivity was compared between controls and groups with TLE with high and low neuroticism using analysis of variance (ANOVA) and t-test. In secondary analyses, the same analytics were performed using measures of depression and anxiety and the unique variance in resting-state connectivity associated with neuroticism independent of symptoms of depression and anxiety identified. Increased neuroticism was significantly associated with hyposynchrony between the right hippocampus and Brodmann area (BA) 9 (region of prefrontal cortex (PFC)) (p < 0.005), representing a unique relationship independent of symptoms of depression and anxiety. Hyposynchrony of connection between the right hippocampus and BA47 (anterior frontal operculum) was associated with high neuroticism and with higher depression and anxiety scores (p < 0.05), making it a shared abnormal connection for the three measures. In conclusion, increased neuroticism exhibits both unique and shared patterns of abnormal functional connectivity with depression and anxiety symptoms between regions of the mesial temporal and frontal lobe., Competing Interests: Declaration of competing interest Authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Behavioral and personality disorders in temporal lobe epilepsy (TLE) have been a topic of interest and controversy for decades, with less attention paid to alterations in normal personality structure and traits. In this investigation, core personality traits (the Big 5) and their neurobiological correlates in TLE were explored using the Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) and structural magnetic resonance imaging (MRI) through the Epilepsy Connectome Project (ECP). NEO-FFI scores from 67 individuals with TLE (34.6 ± 9.5 years; 67% women) were compared to 31 healthy controls (32.8 ± 8.9 years; 41% women) to assess differences in the Big 5 traits (agreeableness, openness, conscientiousness, neuroticism, and extraversion). Individuals with TLE showed significantly higher neuroticism, with no significant differences on the other traits. Neural correlates of neuroticism were then determined in participants with TLE including cortical and subcortical volumes. Distributed reductions in cortical gray matter volumes were associated with increased neuroticism. Subcortically, hippocampal and amygdala volumes were negatively associated with neuroticism. These results offer insight into alterations in the Big 5 personality traits in TLE and their brain-related correlates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study was undertaken to describe seizure phenotypes, natural progression, sleep-wake patterns, as well as periodicity of seizures in Kcna-1 null mutant mice. These mice were implanted with epidural electroencephalography (EEG) and electromyography (EMG) electrodes, and simultaneous video-EEG recordings were obtained while animals were individually housed under either diurnal (LD) condition or constant darkness (DD) over ten days of recording. The video-EEG data were analyzed to identify electrographic and behavioral phenotypes and natural progression and to examine the periodicity of seizures. Sleep-wake patterns were analyzed to understand the distribution and onset of seizures across the sleep-wake cycle. Four electrographically and behaviorally distinct seizure types were observed. Regardless of lighting condition that animals were housed in, Kcna-1 null mice initially expressed only a few of the most severe seizure types that progressively increased in frequency and decreased in seizure severity. In addition, a circadian periodicity was noted, with seizures peaking in the first 12h of the Zeitgeber time (ZT) cycle, regardless of lighting conditions. Interestingly, seizure onset differed between lighting conditions where more seizures arose out of sleep in LD conditions, whereas under DD conditions, the majority occurred out of the wakeful state. We suggest that this model be used to understand the circadian pattern of seizures as well as the pathophysiological implications of sleep and circadian disturbances in limbic epilepsies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal β-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid β-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The endogenous hormone melatonin has previously been shown to exert anticonvulsant effects in a variety of experimental models. Accordingly, we asked whether ramelteon, a synthetic and selective melatonin receptor agonist, might also possess anticonvulsant and/or antiepileptogenic properties., Methods: The effects of ramelteon (30 or 100 mg/kg intraperitoneally twice daily for 5 days) were evaluated in two animal models of epilepsy. In the rat rapid kindling model, baseline hippocampal afterdischarge properties, kindling progression, and hippocampal excitability in kindled animals were measured. Anti-ictogenic efficacy was assessed after acute administration in untreated kindled rats. In the spontaneously epileptic Kcna1-null mouse model, we determined seizure frequency and periodicity using continuous video/EEG monitoring over 72 hours. Further, circadian rest-activity rhythms in ramelteon-treated animals were studied with actigraphy., Results: In kindled animals, ramelteon reversed kindling-induced hippocampal excitability; however, it did not modify baseline afterdischarge properties, the progression and establishment of the kindled state in the rapid kindling model. However, in Kcna1-null mice, ramelteon (200 mg/kg/day) significantly attenuated seizure periodicity and frequency and improved circadian rest-activity rhythms compared with control animals., Conclusions: The selective melatonin receptor agonist ramelteon possesses anticonvulsant properties in a chronic epilepsy model. Our findings provide further support for melatonin receptors being potential novel targets for anticonvulsant drug development.

Nonconvulsive status epilepticus (NCSE) is a heterogeneous disorder with multiple subtypes. Although attempts have been made to define and classify this disorder, there is yet no universally accepted definition or classification that encompasses all subtypes or electroclinical scenarios. Developing such a classification scheme is becoming increasingly important, because NCSE is more common than previously thought, with a bimodal peak, in children and the elderly. Recent studies have also shown a high incidence of NCSE in the critically ill. Although strong epidemiological data are lacking, NCSE constitutes about 25-50% of all cases of status epilepticus. For the purposes of this review, we propose an etiological classification for NCSE including NCSE in metabolic disorders, NCSE in coma, NCSE in acute cerebral lesions, and NCSE in those with preexisting epilepsy with or without epileptic encephalopathy. NCSE is still underrecognized, yet potentially fatal if untreated. Diagnosis can be established using an electroencephalogram (EEG) in most cases, sometimes requiring continuous monitoring. However, in comatose patients, diagnosis can be difficult, and the EEG can show a variety of rhythmic or periodic patterns, some of which are of unclear significance. Although some subtypes of NCSE are easily treatable, such as absence status epilepticus, others do not respond well to treatment, and debate exists over how aggressively clinicians should treat NCSE. In particular, the appropriate treatment of NCSE in patients who are critically ill and/or comatose is not well established, and large-scale trials are needed. Overall, further work is needed to better define NCSE, to determine which EEG patterns represent NCSE, and to establish treatment paradigms for different subtypes of NCSE.

Status epilepticus and encephalopathy have been reported with use of cephalosporins in patients with renal failure. We here report the case of a 79-year-old patient with normal renal function who developed subtle mental status changes during cefepime therapy for urinary tract infection. Emergent electroencephalography revealed evidence of nonconvulsive status epilepticus (NCSE), which responded initially to lorazepam. Later, the patient's NCSE gradually resolved only after cefepime was discontinued, with mental status returning to baseline as the electroencephalography changes resolved. It should be recognized that cefepime therapy can cause NCSE even in the presence of normal renal function. Measurement of serum concentrations and changes in dosing guidelines can probably prevent NCSE during cefepime therapy.

Objective: Excessive daytime sleepiness (EDS) and sleep complaints are common among adults with epilepsy. We hypothesized that children with epilepsy have worse daytime sleepiness compared with controls., Methods: Children with and without epilepsy between ages 8 and 18 were recruited for the study. Parents and children were asked to fill out the Pediatric Sleep Questionnaire (PSQ) and Pediatric Daytime Sleepiness Scale (PDSS), respectively. The Mann-Whitney U test was used for group comparisons, with the Fischer exact or chi2 test for categorical variables. Regression analysis was used to identify predictors of EDS., Results: Twenty-six patients and matched controls were recruited for the study. Parents of children with epilepsy more often reported EDS (P < 0.001), symptoms of sleep-disordered breathing (P < 0.001), and parasomnias (P < 0.001) compared with controls. On the PDSS, children with epilepsy reported worse daytime sleepiness scores compared with controls (15.48 +/- 6.4 vs 11.88 +/- 5.25, P = 0.037). Based on conditional logistic regression modeling, symptoms of excessive daytime sleepiness [corrected] (OR = 15.3, 95% CI = 1.4-166.6) and parasomnias (OR = 12.4, 95% CI = 1.01-151.6) were significantly associated with having epilepsy when adjusted for duration of nightime sleep. Further, 10 children (38.5%) with epilepsy reported positive sleep-disordered breathing, whereas no one in the control group reported SDB (P < 0.001) [corrected] Epilepsy syndrome, anticonvulsants used, and presence or absence of seizure freedom, however, were not significant predictors of EDS among patients., Conclusions: Daytime sleepiness appears to be common in children with epilepsy, and may be due to underlying sleep disorders. Further confirmatory studies are needed using screening questionnaires and formal sleep studies to systematically study the prevalence of sleep complaints and role of sleep disorders in these patients.

We retrospectively studied the outcome of anterior temporal lobectomy (ATL) among a population of veterans and evaluated outcome related to comorbidities. Veterans who underwent ATL between 1990 and 2001 at the Veterans Administration Hospital in Madison, Wisconsin, were included. Data related to postoperative seizure outcome, quality of life outcome, and employment outcome were collected. Factors associated with favorable outcome and outcome related to comorbidities were evaluated. Twenty-seven patients were entered into the study. The mean age at onset of seizures was 25 years (+/-10.2). History of a non-substance abuse psychiatric diagnosis, and substance abuse was present in 26% (7/27) and 30% (9/27), respectively, prior to surgery. While 66.6% (18/27) had a good outcome (Engel's Class I), no difference in the frequency of good outcome was seen among the patients with a history of substance abuse, other psychiatric diagnosis (71%), or no psychiatric diagnosis (67%). There was a significant correlation between seizure outcome and quality of life score (r(s)=0.67, p<0.001) and postoperative employment gains (r(s)=0.48, p=0.01). Outcomes among veterans that underwent ATL can be satisfactory even in the context of the late mean age of epilepsy onset and the psychiatric diagnoses that were present in this sample.

Objective. Epilepsy in institutionalized severe developmentally disabled patients poses a therapeutic challenge. Frequently these patients have multiple seizure (sz) types that are often intractable. Both divalproex sodium (VPA) and lamotrigine (LTG) have demonstrated efficacy. We sought to examine the efficacy of this specific combination in a group of institutionalized, developmentally disabled patients with epilepsy.Methods. Medical and pharmacy records of all patients with developmental disabilities and intractable seizures were reviewed to identify those who had received VPA and LTG. This retrospective evaluation was structured with respect to time frame and outcome measure. Phase 1 consisted of baseline monotherapy with VPA. Phase 2 consisted of titration/dose escalation. Phase 3 was treatment observation period with the combination of both. Seizure frequency and adverse effect data were obtained from nursing or residential staff records. Primary outcome measures were change in seizure frequency between Phases 1 and 3. Additional measures were percentage of patients seizure-free and those with >75% reduction in seizures. A Wilcoxan signed rank test was used for statistical analysis.Results. Of 293 patients, 25 (12M/13F, 31.7+/-10.2 years) had VPA monotherapy following which LTG was added. Mean doses of VPA and LTG were 1474+/-728 and 165+/-111mg/day, respectively. Baseline seizure frequency ranged from 1 to 25 per month. Mean seizure frequency significantly decreased (6.5+/-vs2.0+/-4.0seizures/month, P<0.001). Sixty-four percent of these patients had >/=75% reduction in seizures 28% became seizure-free.Conclusions. The combination of VPA and LTG appears efficacious in this group of developmentally disabled patients with intractable seizures. Rash, which has been associated with this combination, was notably absent and this may reflect the slower titration schedule used.