Functional and anatomical connectivity predict brain stimulation's mnemonic effects.

Closed-loop direct brain stimulation is a promising tool for modulating neural activity and behavior. However, it remains unclear how to optimally target stimulation to modulate brain activity in particular brain networks that underlie particular cognitive functions. Here, we test the hypothesis that stimulation's behavioral and physiological effects depend on the stimulation target's anatomical and functional network properties. We delivered closed-loop stimulation as 47 neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered the stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that LTC stimulation specifically improved memory when delivered to targets near white matter pathways. Memory improvement was largest for targets near white matter that also showed high functional connectivity to the brain's memory network. These targets also reduced low-frequency activity in this network, an established marker of successful memory encoding. These data reveal how anatomical and functional networks mediate stimulation's behavioral and physiological effects, provide further evidence that closed-loop LTC stimulation can improve episodic memory, and suggest a method for optimizing neuromodulation through improved stimulation targeting.

Accelerated long-term forgetting of recall and recognition memory in people with epilepsy.

PURPOSE: Persons with epilepsy (PWE) report memory deficits as one of the most distressing aspects of their disorder. Recently, a long-term memory deficit known as Accelerated Long-Term Forgetting (ALF) has been described in PWE. ALF is characterized by the initial retention of learned information, followed by an accelerated rate of memory decay. However, the rate of ALF varies widely across literature and it is unclear how it impacts different memory retrieval types. The current study aimed to capture the time course of ALF on both free recall and recognition memory using a movie-based task in PWE. METHODS: A sample of 30 PWE and 30 healthy comparison (HC) subjects watched a nature documentary and were tested on their recall and recognition of the film's content immediately after viewing and at delays of 24 hours, 48 hours, and 72 hours. Participants also rated the confidence they had in their recognition memory trial responses. RESULTS: For recall, PWE exhibit ALF at 72 hours (ß = -19.840, SE = 3.743, z(226) = -5.301, p < 0.001). For recognition, PWE had decreased performance compared to controls at the 24-hour (ß = -10.165, SE = 4.174, z(224) = -3.166, p = 0.004), 48-hour (ß = -8.113, SE = 3.701, z(224) = -2.195, p = 0.044), and 72-hour (ß = -10.794, SE = 3.017, z(224) = -3.295, p = 0.003) delays. The PWE group showed positive correlations (tau = 0.165, p < 0.001) between confidence ratings and accuracy, with higher confidence reflecting successful recognition. PWE were 49% less likely to answer either retrieval type correctly at 72 hours (OR 0.51, 95% CI [0.35, 0.74], p < 0.001). Left hemispheric seizure onset decreased the odds of successful retrieval by 88% (OR 0.12, 95% CI [0.01, 0.42], p = 0.019). CONCLUSIONS: These findings provide evidence of ALF in PWE, with a differential impact on recall and recognition memory. This further supports the call to include ALF assessments in standard memory evaluations in PWE. Additionally, identifying the neural correlates of ALF in the future will be important in developing targeted therapies to alleviate the burden of memory impairment for PWE.

Practical considerations in epilepsy neurostimulation.

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences.

Temporal lobe interictal spikes disrupt encoding and retrieval of verbal memory: A subregion analysis.

OBJECTIVE: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall. METHODS: Seventy-eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre-encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed-effects logistic regression. RESULTS: IS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63-.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27-.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66-.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62-.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08-.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07-.8, p < .05) reduced the probability of recalling a word. SIGNIFICANCE: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory.

A pilot study assessing the feasibility and acceptability of Project UPLIFT adapted for patients with psychogenic nonepileptic seizures.

BACKGROUND: People with psychogenic nonepileptic seizures (PNES) are at elevated risk of multiple psychiatric comorbidities. Current treatment gaps highlight the need for time-limited, distance-delivered interventions that can be cost-effectively delivered to patients with PNES. Project UPLIFT is a self-management program addressing mood problems in epilepsy that has not previously been adapted for PNES. The purpose of this study was to assess the feasibility and acceptability of UPLIFT for patients with PNES. METHODS: Project UPLIFT was minimally adapted by a multidisciplinary research group at Dartmouth-Hitchcock Medical Center. Participants were recruited into a nonrandomized pilot study and were assessed at baseline, after completing the intervention, and at 1-month follow-up. RESULTS: The intervention was adapted and delivered without additional modification. A total of eight participants enrolled in the trial, and six participated in the first session. All six participants who started UPLIFT completed the intervention, with a 98% attendance record across the eight sessions. At follow-up, 100% reported that UPLIFT provided useful tools for daily life. All participants continued using UPLIFT after completing the program, and 83% felt it helped with seizure management. Preliminary results provide proof-of-concept for future efficacy trials. CONCLUSION: This study provides initial support for the feasibility and acceptability of Project UPLIFT, minimally adapted for patients with PNES. As a time-limited program that can be distance-delivered to groups of patients, UPLIFT may be well-suited for the healthcare environment brought on by the COVID-19 pandemic.

Supervised machine learning to predict reduced depression severity in people with epilepsy through epilepsy self-management intervention.

OBJECTIVE: To develop a classifier that predicts reductions in depression severity in people with epilepsy after participation in an epilepsy self-management intervention. METHODS: Ninety-three people with epilepsy from three epilepsy self-management randomized controlled trials from the Managing Epilepsy Well (MWE) Network integrated research database met the inclusion criteria. Supervised machine learning algorithms were utilized to develop prediction models for changes in self-reported depression symptom severity. Features considered by the machine learning classifiers include age, gender, race, ethnicity, education, study type, baseline quality of life, and baseline depression symptom severity. The models were trained and evaluated on their ability to predict clinically meaningful improvement (i.e., a reduction of greater than three points on the nine-item Patient Health Questionnaire (PHQ-9)) between baseline and follow-up (<=12 weeks) depression scores. Models tested were a Multilayer Perceptron (ML), Random Forest (RF), Support Vector Machine (SVM), Logistic Regression with Stochastic Gradient Descent (SGD), K-nearest Neighbors (KNN), and Gradient Boosting (GB). A separate, outside dataset of 41 people with epilepsy was used in a validation exercise to examine the top-performing model's generalizability and performance with external data. RESULTS: All six classifiers performed better than our baseline mode classifier. Support Vector Machine had the best overall performance (average area under the curve [AUC] = 0.754, highest subpopulation AUC = 0.963). Our analysis of the SVM features revealed that higher baseline depression symptom severity, study type (i.e., intervention program goals), higher baseline quality of life, and race had the strongest influence on increasing the likelihood that a subject would experience a clinically meaningful improvement in depression scores. From the validation exercise, our top-performing SVM model performed similarly or better than the average SVM model with the outside dataset (average AUC = 0.887). SIGNIFICANCE: We trained an SVM classifier that offers novel insight into subject-specific features that are important for predicting a clinically meaningful improvement in subjective depression scores after enrollment in a self-management program. We provide evidence for machine learning to select subjects that may benefit most from a self-management program and indicate important factors that self-management programs should collect to develop improved digital tools.

Markers of Quality Care for Newly Diagnosed People With Epilepsy on Medicaid.

BACKGROUND: For newly diagnosed people with epilepsy (PWE), proper treatment is important to improve outcomes, yet limited data exist on markers of quality care. OBJECTIVE: Examine markers of quality care for newly diagnosed PWE. METHODS: Using Medicaid claims data (2010-2014) for 15 states we identified adults 18-64 years of age diagnosed with incident epilepsy in 2012 or 2013. We built 5 sequential logistic regression models to evaluate: (1) seeing a neurologist; (2) diagnostic evaluation; (3) antiepileptic medication adherence; (4) serum drug levels checked; and (5) being in the top quartile of number of negative health events (NHEs). We adjusted for demographics, comorbidities, county-level factors, and the outcomes from all prior models. RESULTS: Of 25,663 PWE, 37.3% saw a neurologist, with decreased odds for those of older age, those residing in counties with low-density of neurologists, and certain race/ethnicities; about 57% of PWE received at least 1 diagnostic test; and nearly 62% of PWE were adherent to their medication. The most common comorbidities were hypertension (37.1%) and psychoses (26.9%). PWE with comorbidities had higher odds of seeing a neurologist and to have NHEs. Substance use disorders were negatively associated with medication adherence and positively associated with high NHEs. CONCLUSIONS: There are notable differences in demographics among people with incident epilepsy who do or do not see a neurologist. Differences in NHEs persist, even after controlling for neurologist care and diagnostic evaluation. Continued attention to these disparities and comorbidities is needed in the evaluation of newly diagnosed PWE.

Features of intracranial interictal epileptiform discharges associated with memory encoding.

OBJECTIVE: Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding. METHODS: Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance. RESULTS: We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance. SIGNIFICANCE: Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity.

Factors correlated with intracranial interictal epileptiform discharges in refractory epilepsy.

OBJECTIVE: This study was undertaken to evaluate the influence that subject-specific factors have on intracranial interictal epileptiform discharge (IED) rates in persons with refractory epilepsy. METHODS: One hundred fifty subjects with intracranial electrodes performed multiple sessions of a free recall memory task; this standardized task controlled for subject attention levels. We utilized a dominance analysis to rank the importance of subject-specific factors based on their relative influence on IED rates. Linear mixed-effects models were employed to comprehensively examine factors with highly ranked importance. RESULTS: Antiseizure medication (ASM) status, time of testing, and seizure onset zone (SOZ) location were the highest-ranking factors in terms of their impact on IED rates. The average IED rate of electrodes in SOZs was 34% higher than the average IED rate of electrodes outside of SOZs (non-SOZ; p < .001). However, non-SOZ electrodes had similar IED rates regardless of the subject's SOZ location (p = .99). Subjects on older generation (p < .001) and combined generation (p < .001) ASM regimens had significantly lower IED rates relative to the group taking no ASMs; newer generation ASM regimens demonstrated a nonsignificant association with IED rates (p = .13). Of the ASMs included in this study, the following ASMs were associated with significant reductions in IED rates: levetiracetam (p < .001), carbamazepine (p < .001), lacosamide (p = .03), zonisamide (p = .01), lamotrigine (p = .03), phenytoin (p = .03), and topiramate (p = .01). We observed a nonsignificant association between time of testing and IED rates (morning-afternoon p = .15, morning-evening p = .85, afternoon-evening p = .26). SIGNIFICANCE: The current study ranks the relative influence that subject-specific factors have on IED rates and highlights the importance of considering certain factors, such as SOZ location and ASM status, when analyzing IEDs for clinical or research purposes.

40-Hz auditory stimulation for intracranial interictal activity: A pilot study.

OBJECTIVES: To study the effects of auditory stimuli on interictal epileptiform discharge (IED) rates evident with intracranial monitoring. MATERIALS AND METHODS: Eight subjects undergoing intracranial EEG monitoring for refractory epilepsy participated in this study. Auditory stimuli consisted of a 40-Hz tone, a 440-Hz tone modulated by a 40-Hz sinusoid, Mozart's Sonata for Two Pianos in D Major (K448), and K448 modulated by a 40-Hz sinusoid (modK448). Subjects were stratified into high- and low-IED rate groups defined by baseline IED rates. Subject-level analyses identified individual responses to auditory stimuli, discerned specific brain regions with significant reductions in IED rates, and examined the influence auditory stimuli had on whole-brain sigma power (12-16 Hz). RESULTS: All subjects in the high baseline IED group had a significant 35.25% average reduction in IEDs during the 40-Hz tone; subject-level reductions localized to mesial and lateral temporal regions. Exposure to Mozart K448 showed significant yet less homogeneous responses. A post hoc analysis demonstrated two of the four subjects with positive IED responses had increased whole-brain power at the sigma frequency band during 40-Hz stimulation. CONCLUSIONS: Our study is the first to evaluate the relationship between 40-Hz auditory stimulation and IED rates in refractory epilepsy. We reveal that 40-Hz auditory stimuli may be a noninvasive adjunctive intervention to reduce IED burden. Our pilot study supports the future examination of 40-Hz auditory stimuli in a larger population of subjects with high baseline IED rates.

A systematic literature review of recommendations for referral to specialty care for patients with epilepsy.

OBJECTIVE: In epilepsy, patients who receive appropriate care receive treatment that differs substantially from those that do not. Given the need for a more detailed assessment of the role of specialty referral in the care of patients with epilepsy, this systematic literature review identified epilepsy care guidelines and recommendations that specifically address when and why people with epilepsy should be referred to specialty care. METHODS: This study identified recent (in the last 10 years) publications that made best-practice recommendations for referring people with epilepsy to a neurologist or epileptologist. We searched six databases in December 2018: MEDLINE (PubMed), Cochrane Library, ProQuest, Web of Science, CINAHL (Ebsco), Scopus (Elsevier). Search terms included "Epilepsy" OR "Seizures," "Guideline" OR "Practice Parameter," and "Referral." RESULTS: The 15 full-text articles identified included formal guidelines, summaries of these guidelines, or professional commentary that builds upon existing guidelines. Most of these publications came from the U.K and its National Institute for Health and Care Excellence. Overall, the included recommendations for referral varied considerably both for new-onset and refractory epilepsy. Although these recommendations were not consistent, it is reasonable to refer patients following the failure of 2 anti-seizure medication (ASM) trials. SIGNIFICANCE: Guidelines and informal recommendations are not consistent regarding best practices for specialty care referral for patients with epilepsy. These guidelines and recommendations should consider the context of care in real-world settings and suggest pragmatic approaches that optimize seizure control and functioning.

Self-rated executive dysfunction in adults with epilepsy and effects of a cognitive-behavioral intervention (HOBSCOTCH).

RATIONALE: Cognitive problems are common in adults with epilepsy and significantly affect their quality of life. HOBSCOTCH (HOme Based Self-management and COgnitive Training CHanges lives) was developed to teach problem-solving and compensatory memory strategies to these individuals. This study examined whether HOBSCOTCH is associated with improvement in specific aspects of subjective executive functions. METHODS: Fifty-one adults, age 18-65, with epilepsy and subjective cognitive concerns were randomized to receive HOBSCOTCH (n = 31) or a care-as-usual control sample (n = 20). Participants completed the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A), as well as the Patient Health Questionnaire-9 (PHQ-9) to assess depression. Rates of elevated (i.e., T ≥ 65, impaired) BRIEF-A scores at baseline, as well as pre-post score changes for the BRIEF-A clinical scales were evaluated. Significance was set at α = 0.05, one-tailed, given our directional hypothesis. RESULTS: At baseline, a considerable percentage of patients in the overall sample endorsed executive dysfunction on BRIEF-A scales: Inhibit = 28%, Shift = 51%, Emotional Control = 45%, Self-Monitor = 33%, Initiate = 35%, Working Memory = 88%, Plan/Organize = 45%, Task Monitor = 47%, Organization of Materials = 28%. Significant improvement was seen in mean T-scores for Inhibit, Shift, Initiate, and Working Memory in the treatment group, but only Working Memory improved in the control group. The control group endorsed worse task monitoring and organization of materials at baseline and follow-up. Change in depression was not observed for either group, and there was no association between changes in depression and BRIEF-A scores. CONCLUSIONS: A sizeable subset of adults with epilepsy reported experiencing executive dysfunction in their everyday lives, especially for working memory. HOBSCOTCH resulted in amelioration of subjective executive functioning independent of changes in mood.

The Managing Epilepsy Well (MEW) network database: Lessons learned in refining and implementing an integrated data tool in service of a national U.S. Research Collaborative.

Epilepsy self-management (ESM) is the summative set of behaviors that people with epilepsy use to cope with seizures and optimize health. This report describes the implementation and evolution of the Managing Epilepsy Well Network Database (MEW DB), an integrated data resource intended to advance knowledge on ESM. The MEW DB utilizes a three-tiered (Tier 1-3) system of data organization, with tiers of data generally increasing in ascending complexity or collection burden. A MEW DB Steering Committee (SC) establishes consensus on planned analyses using a standardized new analysis request template. The data management structure facilitates harmonization and integration of additional data, or to update the database as new data become available. The current MEW DB comprises 1,563 people with epilepsy. Mean age was 39.9 years, 64.9% women (N = 1006), 12.8% African American (N = 170), 22.2% Hispanic (N = 306). On average, individuals have lived with epilepsy since their early 20s and are prescribed between 1 and 2 antiepileptic drugs. The MEW DB spans multiple socio-ecological levels to provide a robust multi-tiered framework for studying ESM. A total of 41 common data elements have been identified through iterative consensus. This integrated database takes advantage of an extensive collective background of archival evidence in ESM and brings together engaged investigators to build a dataset that represents diverse types of individuals with epilepsy, targets health domains important to ESM, and facilitates analyses that would not be possible with sites operating independently. Overall, the MEW DB serves the greater mission of this research collaborative and has potential to advance ESM research.

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures.

OBJECTIVE: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System. METHODS: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up. RESULTS: One hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences. SIGNIFICANCE: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

Antiepileptic drug effects on subjective and objective cognition.

RATIONALE: Cognitive impairment is one of the most common complaints for persons with epilepsy (PWE). These impairments are not only associated with seizures, but are also regularly reported as adverse effects of antiepileptic drugs (AEDs). Previous studies have examined cognitive effects of both AED monotherapy and polytherapy, yet there is limited research on these differences with respect to both subjective and objective cognition. The current study uses data from previous research conducted by the Centers for Disease Control and Prevention (CDC)-sponsored Managing Epilepsy Well (MEW) Network collaborative. We used three distinct archival datasets from the following: (1) the HOBSCOTCH efficacy trial at Dartmouth-Hitchcock Medical Center (HOB-1), (2) the multisite replication trial (HOB-2), and (3) epilepsy self-management research conducted at the NYU School of Medicine. METHODS: This retrospective analysis combined baseline data from three datasets to determine how the number of AEDs and the type of AEDs were associated with subjective (patient-reported) and objective (examiner-assessed) cognition. Subjective cognition was captured using the cognitive subscale of the Quality of Life in Epilepsy Inventory (QOLIE-31) in all three datasets (n = 224), while objective cognition was measured using the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) in the HOB-1 dataset (n = 65) and the Brief Test of Adult Cognition by Telephone (BTACT) in the HOB-2 dataset (n = 91). Multivariable linear regression was utilized for our initial assessments, followed by propensity score matching to provide stronger control of covariates. Matching was based on significantly different covariates, such as education, depression, and history of prior epilepsy surgery. Nonparametric statistical tests were utilized to compare these matched subjects. RESULTS: Subjective cognitive impairment was significantly worse among individuals on polytherapy (2 + AEDs) compared with those on monotherapy (1 AED) (adjusted p  =  0.041). These findings were consistent with our propensity score matched comparison of monotherapy and polytherapy, which indicated that polytherapy was associated with worse overall subjective cognition (adjusted p = 0.01), in addition to impairments on the RBANS (Total score p = 0.05) and specific subdomains of the BTACT (Episodic Verbal Memory p < 0.01, Working Memory p < 0.01, Processing Speed p < 0.01). Interestingly, older generation AEDs were associated with better language performance than newer generation and combined generation AED therapy (RBANS Language p = 0.03). These language-specific findings remained significant after controlling for the effects of topiramate and zonisamide (p = 0.04). CONCLUSIONS: A greater number of AEDs is significantly and negatively associated with subjective and objective cognition in PWE, and is in line with previous research. Antiepileptic drug type did not, in itself, appear to be associated with subjective cognition. Our findings suggest that ineffective AEDs should be replaced, rather than introducing additional AEDs to a treatment regimen. Further, while subjective and objective cognition assessments were both sensitive at detecting differences based on AED status, the neuropsychological objective subdomains offer additional and specific insights into how cognition is impaired with AEDs.

Electrical Stimulation in Hippocampus and Entorhinal Cortex Impairs Spatial and Temporal Memory.

The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects' abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred.SIGNIFICANCE STATEMENT Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

Self-management for adults with epilepsy: Aggregate Managing Epilepsy Well Network findings on depressive symptoms.

OBJECTIVE: To assess depressive symptom outcomes in a pooled sample of epilepsy self-management randomized controlled trials (RCTs) from the Managing Epilepsy Well (MEW) Network integrated research database (MEW DB). METHODS: Five prospective RCTs involving 453 adults with epilepsy compared self-management intervention (n = 232) versus treatment as usual or wait-list control outcomes (n = 221). Depression was assessed with the nine-item Patient Health Questionnaire. Other variables included age, gender, race, ethnicity, education, income, marital status, seizure frequency, and quality of life. Follow-up assessments were collapsed into a visit 2 and a visit 3; these were conducted postbaseline. RESULTS: Mean age was 43.5 years (SD = 12.6), nearly two-thirds were women, and nearly one-third were African American. Baseline sample characteristics were mostly similar in the self-management intervention group versus controls. At follow-up, the self-management group had a significantly greater reduction in depression compared to controls at visit 2 (P < .0001) and visit 3 (P = .0002). Quality of life also significantly improved in the self-management group at visit 2 (P = .001) and visit 3 (P = .005). SIGNIFICANCE: Aggregate MEW DB analysis of five RCTs found depressive symptom severity and quality of life significantly improved in individuals randomized to self-management intervention versus controls. Evidence-based epilepsy self-management programs should be made more broadly available in neurology practices.

Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex.

Direct electrical stimulation of the human brain can elicit sensory and motor perceptions as well as recall of memories. Stimulating higher order association areas of the lateral temporal cortex in particular was reported to activate visual and auditory memory representations of past experiences (Penfield and Perot, 1963). We hypothesized that this effect could be used to modulate memory processing. Recent attempts at memory enhancement in the human brain have been focused on the hippocampus and other mesial temporal lobe structures, with a few reports of memory improvement in small studies of individual brain regions. Here, we investigated the effect of stimulation in four brain regions known to support declarative memory: hippocampus, parahippocampal neocortex, prefrontal cortex and temporal cortex. Intracranial electrode recordings with stimulation were used to assess verbal memory performance in a group of 22 patients (nine males). We show enhanced performance with electrical stimulation in the lateral temporal cortex (paired t-test, P = 0.0067), but not in the other brain regions tested. This selective enhancement was observed both on the group level, and for two of the four individual subjects stimulated in the temporal cortex. This study shows that electrical stimulation in specific brain areas can enhance verbal memory performance in humans.awx373media15704855796001.

Balance and reaction time do not rapidly improve off antiseizure drugs.

OBJECTIVE: People with epilepsy (PWE) exercise less than the general population and describe a lower level of fitness. Exercise improves comorbidities associated with epilepsy and may help seizure control. We aimed to record balance and reaction time in patients undergoing antiseizure drug (ASD) taper in the epilepsy monitoring unit (EMU) to determine if there is a reversible, dose-dependent effect of these medications. METHODS: We tested 21 patients and 21 controls using a Wii Balance Board (WBB) and online reaction time test. The patients were recruited during an EMU stay and were tested before and after medication taper. Drug levels were also checked. Sway from center of pressure (COP) and speed of sway were tested with eyes open on two legs, eyes closed on two legs, and eyes open on one leg. Reaction time was tested. RESULTS: Compared with controls, patients on ASDs had more sway from COP (with eyes open on two legs: p = 0.0022 in the anterior-posterior axis and p = 0.022 in the medial-lateral axis using linear regression) and worse reaction time (p < 0.001 using linear regression, adjusted for age and gender). There was no difference in reaction time or sway from COP between trials 1 and 2, before and after stopping ASDs (p = 0.2 using a paired t test for reaction time and p = 0.08 using a paired t test for speed of sway with eyes closed). There was no relationship between time since last seizure or duration of seizures and balance or reaction time. DISCUSSION: Balance and reaction time in patients on ASD is impaired compared with controls. There is no immediate improvement in these measures following ASD withdrawal. This difference may result from vestibular or cerebellar effects. More research is needed to determine the individual effects of particular medications on balance and reaction time.

Neurostimulation for Memory Enhancement in Epilepsy.

PURPOSE OF REVIEW: Memory is one of the top concerns of epilepsy patients, but there are no known treatments to directly alleviate the memory deficits associated with epilepsy. Neurostimulation may provide new therapeutic tools to enhance memory in epilepsy patients. Here, we critically review recent investigations of memory enhancement using transcranial electrical stimulation (tES), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), chronic intracranial stimulation, and acute intracranial stimulation. RECENT FINDINGS: Existing literature suggests that transcranial direct current stimulation (tDCS) produces a small enhancement in memory in neuropsychological patients, but transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) have not been found to have an effect on memory. Most studies of transcranial magnetic stimulation (TMS) have found that TMS has no positive effect on memory. Vagus nerve stimulation can acutely enhance memory, while chronic therapy does not appear to alter memory performance. We found that there is the most evidence for significant memory enhancement using intracranial stimulation techniques, especially chronic stimulation of the fornix and task-responsive stimulation of the lateral temporal lobe. Presently, there are no existing therapeutic options for directly treating epilepy-related memory deficits. While neurostimulation technologies for memory enhancement are largely still in the experimental phase, neurostimulation appears promising as a future technique for treating epilepsy-related memory deficits.