A user's guide for the International Classification of Cognitive Disorders in Epilepsy.

To present the background, rationale, details pertaining to use and essential computational steps, synopsis of findings to date, and future directions for the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE)-an initiative of the ILAE Neuropsychology Task Force. Examined are: (a) the 6 steps leading to the derivation of a cognitive phenotype from neuropsychological test data with an accompanying case example, (b) concise review of all IC-CoDE research to date, (c) summary of identified correlates of IC-CoDE outcomes, and (d) future research and clinical directions for the initiative. The IC-CoDE is computationally uncomplicated with individual or group data and represents a novel approach leading to new insights in the neuropsychology of epilepsy, with applications to diverse datasets internationally informing the reliability and validity of the approach. The IC-CoDE represents a novel approach to the analysis and interpretation of neuropsychological data in epilepsy that offers to advance a global taxonomy of cognitive disorders in epilepsy facilitating international collaboration and big data science.

Multidisciplinary lifestyle interventions for neurological disorders during the Silent phase (MINDS) study: a multi-omics randomized controlled trial protocol.

INTRODUCTION: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. METHODS AND ANALYSIS: We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson's Disease, or Alzheimer's disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants' neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. PERSPECTIVES: The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. TRIAL REGISTRATION: The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Individual- and community-level social determinants of health are associated with cognition in older adults with focal epilepsy.

OBJECTIVE: Epilepsy is associated with significant health disparities, including access to specialized care and adverse outcomes that have been associated with several social determinants of health (SDOH). We sought to examine the relationship between individual- and community-level SDOH and cognitive outcomes in older adults with epilepsy. MATERIALS AND METHODS: We collected clinical, SDOH, and neuropsychological data in 57 older adults with epilepsy. Individual-level SDOH included patient factors (quality of education, income, insurance, marital status) and early-life environmental factors (parental education and occupation, childhood employment). Neighborhood deprivation was measured with the Area Deprivation Index (ADI). Stepwise regressions were conducted to examine the independent contribution of individual-level SDOH to cognitive performance, and Spearman rho correlations were conducted to examine the relationship between ADI and cognitive performance. The SDOH profiles of patients who met the criteria for cognitive impairment were examined. RESULTS: After controlling for clinical variables, patient factors (public health insurance, poorer quality of education) and early-life environmental factors (lower mother's education, lower father's and mother's occupational complexity, history of childhood employment) were significant predictors of lower performance on measures of global cognition, verbal learning and memory, processing speed, and executive function. Higher ADI values (greater disadvantage) were associated with lower scores on global cognitive measures, verbal learning and memory, and executive function. Patients who met criteria for cognitive impairment had, on average, a greater number of adverse SDOH, including lower household incomes and father's education, and higher ADI values compared to those who were cognitively intact. CONCLUSION: We provide new evidence of the role of individual- and community-level SDOH on cognitive outcomes in older adults with epilepsy. This emerging literature highlights the need to examine SDOH beyond epilepsy-related clinical factors. These data could inform the development of interventions focused on increasing access to epilepsy care, education, and resources and promoting brain and cognitive health within the most at-risk communities.

Validity of the MoCA as a cognitive screening tool in epilepsy: Are there implications for global care and research?

OBJECTIVE: This study evaluated the diagnostic performance of a widely available cognitive screener, the Montreal cognitive assessment (MoCA), to detect cognitive impairment in older patients (age ≥ 55) with epilepsy residing in the US, using the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) as the gold standard. METHODS: Fifty older adults with focal epilepsy completed the MoCA and neuropsychological measures of memory, language, executive function, and processing speed/attention. The IC-CoDE taxonomy divided participants into IC-CoDE Impaired and Intact groups. Sensitivity and specificity across several MoCA cutoffs were examined. Spearman correlations examined relationships between the MoCA total score and clinical and demographic variables and MoCA domain scores and individual neuropsychological tests. RESULTS: IC-CoDE impaired patients demonstrated significantly lower scores on the MoCA total, visuospatial/executive, naming, language, delayed recall, and orientation domain scores (Cohen's d range: 0.336-2.77). The recommended MoCA cutoff score < 26 had an overall accuracy of 72%, 88.2% sensitivity, and 63.6% specificity. A MoCA cutoff score < 24 yielded optimal sensitivity (70.6%) and specificity (78.8%), with overall accuracy of 76%. Higher MoCA total scores were associated with greater years of education (p = 0.016) and fewer antiseizure medications (p = 0.049). The MoCA memory domain was associated with several standardized measures of memory, MoCA language domain with category fluency, and MoCA abstraction domain with letter fluency. SIGNIFICANCE: This study provides initial validation of the MoCA as a useful screening tool for older adults with epilepsy that can be used to identify patients who may benefit from comprehensive neuropsychological testing. Further, we demonstrate that a lower cutoff (i.e., <24) better captures cognitive impairment in older adults with epilepsy than the generally recommended cutoff and provides evidence for construct overlap between MoCA domains and standard neuropsychological tests. Critically, similar efforts in other regions of the world are needed. PLAIN LANGUAGE SUMMARY: The Montreal cognitive assessment (MoCA) can be a helpful tool to screen for cognitive impairment in older adults with epilepsy. We recommend that adults 55 or older with epilepsy who score less than 24 on the MoCA are referred to a neuropsychologist for a comprehensive evaluation to assess any changes in cognitive abilities and mood.

Cross-cultural application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE): Cognitive phenotypes in people with temporal lobe epilepsy in India.

OBJECTIVE: Efforts to understand the global variability in cognitive profiles in patients with epilepsy have been stymied by the lack of a standardized diagnostic system. This study examined the cross-cultural applicability of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) in a cohort of patients with temporal lobe epilepsy (TLE) in India that was diverse in language, education, and cultural background. METHODS: A cohort of 548 adults with TLE from Mumbai completed a presurgical comprehensive neuropsychological evaluation. The IC-CoDE taxonomy was applied to derive cognitive phenotypes in the sample. Analyses of variance were conducted to examine differences in demographic and clinical characteristics across the phenotypes, and chi-squared tests were used to determine whether the phenotype distribution differed between the Mumbai sample and published data from a multicenter US sample. RESULTS: Using the IC-CoDE criteria, 47% of our cohort showed an intact cognitive profile, 31% a single-domain impairment, 16% a bidomain impairment, and 6% a generalized impairment profile. The distribution of cognitive phenotypes was similar between the Indian and US cohorts for the intact and bidomain phenotypes, but differed for the single and generalized domains. There was a larger proportion of patients with single-domain impairment in the Indian cohort and a larger proportion with generalized impairment in the US cohort. Among patients with single-domain impairment, a greater proportion exhibited memory impairment in the Indian cohort, whereas a greater proportion showed language impairment in the US sample, likely reflecting differences in language administration procedures and sample characteristics including a higher rate of mesial temporal sclerosis in the Indian sample. SIGNIFICANCE: Our results demonstrate the applicability of IC-CoDE in a group of culturally and linguistically diverse patients from India. This approach enhances our understanding of cognitive variability across cultures and enables harmonized and inclusive research into the neuropsychological aspects of epilepsy.

Automated detection of cognitive impairment in clinical practice.

OBJECTIVE: Cognitive impairment is now recognized as an impending public health crisis. About one-third of adults are concerned about their cognition, and the prevalence of objective cognitive impairment is much higher among those with neurological disorders. Existing screening tools are narrowly focused on detecting dementia in older adults and must be clinician-administered and scored, making them impractical for many neurology practices. This study examined the utility of a brief, self-administered, computerized cognitive screening tool, the Brief Assessment of Cognitive Health (BACH), in identifying cognitive impairment in adults. METHODS: 912 adults (ages 18-84) completed BACH and a neuropsychological battery. Multivariable models were developed to provide a BACH index score reflecting the probability of cognitive impairment for individual patients. Predictive accuracy was compared to that of the Montreal Cognitive Assessment (MoCA) in a subset of 160 older adults from a Memory Disorders clinic. RESULTS: The final multivariable model showed good accuracy in identifying cognitively impaired individuals (c = 0·77). Compared to MoCA, BACH had superior predictive accuracy in identifying older patients with cognitive impairment (c = 0·79 vs. 0·67) as well as differentiating those with MCI or dementia from those without cognitive impairment (c = 0·86 vs. c = 0·67). CONCLUSIONS: Results suggest that cognitive impairment can be identified in adults using a brief, self-administered, automated cognitive screening tool, and BACH provides several advantages over existing screeners: self-administered; automatic scoring; immediate results in health record; easily interpretable score; utility in wide range of patients; and flags for treatable factors that may contribute to cognitive complaints (i.e., depression, sleep problems, and stress).

Utility of automated memory measures in identifying cognitive impairment in adults with epilepsy.

OBJECTIVE: Cognitive impairment is prevalent in epilepsy and often presents at the time of initial diagnosis. This study sought to validate brief, self-administered, iPad-based recognition memory tasks in a sample of patients with epilepsy and to examine their screening utility in identifying patients with cognitive impairment. METHODS: The Words and Faces tests were administered to 145 adult patients with epilepsy along with a neuropsychological battery. Correlation analyses examined the convergent and divergent validity of the Words and Faces tests, and a series of logistic regression analyses examined discriminative ability in identifying patients with and without cognitive impairments on neuropsychological measures. Patient performance was compared to that of a healthy control group (n = 223), and the relationship between the Words and Faces test performance and disease-related variables (i.e., antiepileptic medication burden, seizure lateralization/localization) was examined. RESULTS: The Words and Faces tests were positively correlated with traditional paper-and-pencil neuropsychological measures of episodic memory, with generally moderate to large effect sizes (r > .40), while correlations between the Words and Faces tests and non-memory measures were generally small in magnitude (r < .30). Patients with epilepsy had significantly lower scores on Words and Faces tests compared to healthy controls, and performance was associated with antiepileptic medication burden and seizure localization. The Words and Faces tests demonstrated good predictive accuracy in identifying any cognitive impairment (concordance (c) statistic = .77) and excellent predictive accuracy (c = .85) in identifying patients with impairments on traditional memory measures. The Words and Faces tests also demonstrated reasonable discrimination for impairments in non-memory domains including executive function, language, attention, processing speed, and visuospatial ability (c = .62 -.70). Importantly, the Words and Faces Immediate Index performed just as well as the Total Score (which included delayed memory performance), suggesting a short version of this measure is sufficient for identifying patients with cognitive impairment. CONCLUSIONS: The Words and Faces tests are valid, computerized tools that can be used to screen for memory and other cognitive impairment in adults with epilepsy.

Polygenic burden and its association with baseline cognitive function and postoperative cognitive outcome in temporal lobe epilepsy.

OBJECTIVE: Demographic and disease factors are associated with cognitive deficits and postoperative cognitive declines in adults with pharmacoresistant temporal lobe epilepsy (TLE), but the role of genetic factors in cognition in TLE is not well understood. Polygenic scores (PGS) for neurological and neuropsychiatric disorders and IQ have been associated with cognition in patient and healthy populations. In this exploratory study, we examined the relationship between PGS for Alzheimer's disease (AD), depression, and IQ and cognitive outcomes in adults with TLE. METHODS: 202 adults with pharmacoresistant TLE had genotyping and completed neuropsychological evaluations as part of a presurgical work-up. A subset (n = 116) underwent temporal lobe resection and returned for postoperative cognitive testing. Logistic regression was used to determine if PGS for AD, depression, and IQ predicted baseline domain-specific cognitive function and cognitive phenotypes as well as postoperative language and memory decline. RESULTS: No significant findings survived correction for multiple comparisons. Prior to correction, higher PGS for AD and depression (i.e., increased genetic risk for the disorder), but lower PGS for IQ (i.e., decreased genetic likelihood of high IQ) appeared possibly associated with baseline cognitive impairment in TLE. In comparison, higher PGS for AD and IQ appeared as possible risk factors for cognitive decline following temporal lobectomy, while the possible relationship between PGS for depression and post-operative cognitive outcome was mixed. SIGNIFICANCE: We did not observe any relationships of large effect between PGS and cognitive function or postsurgical outcome; however, results highlight several promising trends in the data that warrant future investigation in larger samples better powered to detect small genetic effects.

Utility of the Brief Assessment of Cognitive Health (BACH) computerized screening tool in identifying MS-related cognitive impairment.

BACKGROUND: Current guidelines recommend that individuals with MS are screened annually for processing speed deficits, often using the Symbol Digit Modalities Test (SDMT). However, given the heterogeneity of cognitive deficits in individuals with MS, other screening measures that assess a range of cognitive domains are necessary. The current cross-sectional study aimed to examine the ability of the computerized, self-administered Brief Assessment of Cognitive Health (BACH) screening measure to detect the presence of cognitive impairment in adults with MS as determined by performance on a standard neuropsychological test battery. METHODS: Seventy-two individuals with MS completed the BACH and a comprehensive neuropsychological test battery. Receiver operating characteristic (ROC) analyses were conducted to investigate the ability of the BACH to identify cognitively impaired and cognitively intact individuals. ROC analyses were also conducted to compare the ability of the SDMT to discriminate between cognitively intact and cognitively impaired groups as a comparison with the BACH. RESULTS: Cognitive impairment was observed in 56 % of the sample. The BACH showed acceptable ability to discriminate between cognitively intact and cognitively impaired groups (AUC = 0.78). Additionally, the BACH was able to adequately predict cognitive impairment in domains other than processing speed (AUC = 0.71). The SDMT also demonstrated adequate utility in identifying individuals with cognitive impairment (AUC = 0.73); however, the SDMT was not able to adequately predict cognitive impairment in domains other than processing speed (AUC = 0.56). CONCLUSION: The BACH showed adequate ability to detect cognitive impairment in individuals with MS. The BACH was able to identify impairments across various assessed cognitive domains, including individuals with and without processing speed deficits.

Influence of psychological factors on the relationship between subjective and objective memory in adults with pharmacoresistant temporal lobe epilepsy.

PURPOSE: Many adults with temporal lobe epilepsy (TLE) report subjective cognitive impairment; however, prior studies have shown a discrepancy between these subjective complaints and objective cognitive deficits on neuropsychological measures. Mood disorders/symptoms are also common in TLE and have been linked to greater subjective cognitive difficulties. To further understand these relationships, this retrospective study sought to determine if symptoms of depression and anxiety moderate or mediate the relationship between subjective cognitive impairment and objective cognitive performance in adults with TLE. METHOD: Participants were 345 adults (mean age = 40.7; 55 % female) with pharmacoresistant TLE who completed self-report screening measures of depression, anxiety, and subjective cognitive function along with objective memory measures as part of a pre-surgical clinical neuropsychological evaluation. A series of linear regression analyses was conducted to examine the potential moderating and mediating effects of mood on the relationship between subjective and objective memory function after adjusting for relevant covariates. RESULTS: Consistent with existing literature, self-reported depression and anxiety symptoms were significantly correlated with subjective memory difficulties across all scales (all p < .001). Subjective memory impairment was also significantly correlated with objective memory performance on neuropsychological measures, albeit with small effect sizes (estimate range 0.04-0.20). Contrary to our hypothesis, depression and anxiety did not moderate or mediate the relationship between subjective memory complaints and objective memory performance. CONCLUSIONS: While symptoms of depression and anxiety were associated with subjective memory ability in this cohort of adults with TLE, this study suggests that mood symptoms do not fully explain the relationship between subjective and objective memory function, likely reflecting the complex and multifactorial relationships among these variables. Nevertheless, our results highlight the importance of screening for depression and anxiety symptoms and assessing patients' subjective memory complaints as part of a neuropsychological evaluation as each of these factors tap into a different aspect of the patient functioning.

Contralaterally controlled functional electrical stimulation video game therapy for hand rehabilitation after stroke: a randomized controlled trial.

PURPOSE: To estimate the effect of integrating custom-designed hand therapy video games (HTVG) with contralaterally controlled functional electrical stimulation (CCFES) therapy. METHODS: Fifty-two stroke survivors with chronic (>6 months) upper limb hemiplegia were randomized to 12 weeks of CCFES or CCFES + HTVG. Treatment involved self-administration of technology-mediated therapy at home plus therapist-administered CCFES-assisted task practice in the lab. Pre- and post-treatment assessments were made of hand dexterity, upper limb impairment and activity limitation, and cognitive function. RESULTS: No significant between-group differences were found on any outcome measure, and the average magnitudes of improvement within both groups were small. The incidence of technical problems with study devices at home was greater for the CCFES + HTVG group. This negatively affected adherence and may partially explain the absence of effect of HTVG. At end-of-treatment, large majorities of both treatment groups had positive perceptions of treatment efficacy and expressed enthusiasm for the treatments. CONCLUSION: This study makes an important contribution to the research literature on the importance of environmental factors, concomitant impairments, and technology simplification when designing technology-based therapies intended to be self-administered at home. This study failed to show any added benefit of HTVG to CCFES therapy.Clinicaltrials.gov (NCT03058796).

Contralaterally controlled functional electrical stimulation (CCFES) is an emerging therapy for upper limb rehabilitation after stroke that is designed, in part, to be self-administered at home.While movement-soliciting video games have shown promise in rehabilitation, this study failed to show a significant added benefit of integrating CCFES with hand therapy video games.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of making every component of rehabilitation technology as user friendly and trouble-free as possible.For technology-based therapies intended to be self-administered at home, this study brings to light the importance of assuring that the home environment is conducive to home-based therapy.

Molecular subtypes of epilepsy associated with post-surgical seizure recurrence.

Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P < 0.20). A total of 551 microRNAs and 2486 messenger RNAs were associated with clusters A1 and B4, respectively (adjusted P < 0.05). Clustering of brain-tissue messenger RNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated messenger RNA transcripts with cluster B4. Clusters A1, B4 and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which microRNA and messenger RNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4 and C2 reveal both known and novel microRNA and messenger RNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples and could potentially serve as biomarkers for surgical resection outcomes.

Application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to frontal lobe epilepsy using multicenter data.

RATIONALE: The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS: Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS: The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS: These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.

The relationship between mood and anxiety and cognitive phenotypes in adults with pharmacoresistant temporal lobe epilepsy.

OBJECTIVE: Patients with temporal lobe epilepsy (TLE) are often at a high risk for cognitive and psychiatric comorbidities. Several cognitive phenotypes have been identified in TLE, but it is unclear how phenotypes relate to psychiatric comorbidities, such as anxiety and depression. This observational study investigated the relationship between cognitive phenotypes and psychiatric symptomatology in TLE. METHODS: A total of 826 adults (age = 40.3, 55% female) with pharmacoresistant TLE completed a neuropsychological evaluation that included at least two measures from five cognitive domains to derive International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) cognitive phenotypes (i.e., intact, single-domain impairment, bi-domain impairment, generalized impairment). Participants also completed screening measures for depression and anxiety. Psychiatric history and medication data were extracted from electronic health records. Multivariable proportional odds logistic regression models examined the relationship between IC-CoDE phenotypes and psychiatric variables after controlling for relevant covariates. RESULTS: Patients with elevated depressive symptoms had a greater odds of demonstrating increasingly worse cognitive phenotypes than patients without significant depressive symptomatology (odds ratio [OR] = 1.123-1.993, all corrected p's < .05). Number of psychotropic (OR = 1.584, p < .05) and anti-seizure medications (OR = 1.507, p < .001), use of anti-seizure medications with mood-worsening effects (OR = 1.748, p = .005), and history of a psychiatric diagnosis (OR = 1.928, p < .05) also increased the odds of a more severe cognitive phenotype, while anxiety symptoms were unrelated. SIGNIFICANCE: This study demonstrates that psychiatric factors are not only associated with function in specific cognitive domains but also with the pattern and extent of deficits across cognitive domains. Results suggest that depressive symptoms and medications are strongly related to cognitive phenotype in adults with TLE and support the inclusion of these factors as diagnostic modifiers for cognitive phenotypes in future work. Longitudinal studies that incorporate neuroimaging findings are warranted to further our understanding of the complex relationships between cognition, mood, and seizures and to determine whether non-pharmacologic treatment of mood symptoms alters cognitive phenotype.

Validation of Self-Administered Visual and Verbal Episodic Memory Tasks in Healthy Controls and a Clinical Sample.

This study evaluated the performance characteristics, construct validity, and reliability of two computerized, self-administered verbal and visual recognition memory tests based on the Remember-Know paradigm. Around 250 healthy control participants and 440 patients referred for neuropsychological assessment used an iPad to complete the Words and Faces recognition memory tests before or after concurrent neuropsychological testing. Performance accuracy was high but without ceiling effects. Education, but not age, was related to overall performance for both samples while the influence of gender and race differed across samples. In the clinical sample, overall performance was worse in those patients demonstrating memory impairment on clinical assessment. Words and Faces subtests demonstrated the strongest correlations with neuropsychological measures of verbal and nonverbal memory, respectively. Both showed moderate correlations with processing speed while Faces was also correlated with visuospatial skills. The memory tests showed good test-retest reliability over two testing sessions. These findings demonstrate acceptable psychometric properties in clinical and community samples and suggest that this computerized format is feasible for memory assessment in clinical contexts.

Development of webcam-collected and artificial-intelligence-derived social and cognitive performance measures for neurodevelopmental genetic syndromes.

This study focused on the development and initial psychometric evaluation of a set of online, webcam-collected, and artificial intelligence-derived patient performance measures for neurodevelopmental genetic syndromes (NDGS). Initial testing and qualitative input was used to develop four stimulus paradigms capturing social and cognitive processes, including social attention, receptive vocabulary, processing speed, and single-word reading. The paradigms were administered to a sample of 375 participants, including 163 with NDGS, 56 with idiopathic neurodevelopmental disability (NDD), and 156 neurotypical controls. Twelve measures were created from the four stimulus paradigms. Valid completion rates varied from 87 to 100% across measures, with lower but adequate completion rates in participants with intellectual disability. Adequate to excellent internal consistency reliability (α = 0.67 to 0.95) was observed across measures. Test-retest reproducibility at 1-month follow-up and stability at 4-month follow-up was fair to good (r = 0.40-0.73) for 8 of the 12 measures. All gaze-based measures showed evidence of convergent and discriminant validity with parent-report measures of other cognitive and behavioral constructs. Comparisons across NDGS groups revealed distinct patterns of social and cognitive functioning, including people with PTEN mutations showing a less impaired overall pattern and people with SYNGAP1 mutations showing more attentional, processing speed, and social processing difficulties relative to people with NFIX mutations. Webcam-collected performance measures appear to be a reliable and potentially useful method for objective characterization and monitoring of social and cognitive processes in NDGS and idiopathic NDD. Additional validation work, including more detailed convergent and discriminant validity analyses and examination of sensitivity to change, is needed to replicate and extend these observations.

Convolutional Neural Network Algorithm to Determine Lateralization of Seizure Onset in Patients With Epilepsy: A Proof-of-Principle Study.

BACKGROUND AND OBJECTIVES: A new frontier in diagnostic radiology is the inclusion of machine-assisted support tools that facilitate the identification of subtle lesions often not visible to the human eye. Structural neuroimaging plays an essential role in the identification of lesions in patients with epilepsy, which often coincide with the seizure focus. In this study, we explored the potential for a convolutional neural network (CNN) to determine lateralization of seizure onset in patients with epilepsy using T1-weighted structural MRI scans as input. METHODS: Using a dataset of 359 patients with temporal lobe epilepsy (TLE) from 7 surgical centers, we tested whether a CNN based on T1-weighted images could classify seizure laterality concordant with clinical team consensus. This CNN was compared with a randomized model (comparison with chance) and a hippocampal volume logistic regression (comparison with current clinically available measures). Furthermore, we leveraged a CNN feature visualization technique to identify regions used to classify patients. RESULTS: Across 100 runs, the CNN model was concordant with clinician lateralization on average 78% (SD = 5.1%) of runs with the best-performing model achieving 89% concordance. The CNN outperformed the randomized model (average concordance of 51.7%) on 100% of runs with an average improvement of 26.2% and outperformed the hippocampal volume model (average concordance of 71.7%) on 85% of runs with an average improvement of 6.25%. Feature visualization maps revealed that in addition to the medial temporal lobe, regions in the lateral temporal lobe, cingulate, and precentral gyrus aided in classification. DISCUSSION: These extratemporal lobe features underscore the importance of whole-brain models to highlight areas worthy of clinician scrutiny during temporal lobe epilepsy lateralization. This proof-of-concept study illustrates that a CNN applied to structural MRI data can visually aid clinician-led localization of epileptogenic zone and identify extrahippocampal regions that may require additional radiologic attention. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with drug-resistant unilateral temporal lobe epilepsy, a convolutional neural network algorithm derived from T1-weighted MRI can correctly classify seizure laterality.

Association of Neighborhood Deprivation With Cognitive and Mood Outcomes in Adults With Pharmacoresistant Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: Temporal lobe epilepsy (TLE) is the most common adult form of epilepsy and is associated with a high risk of cognitive deficits and depressed mood. However, little is known about the role of environmental factors on cognition and mood in TLE. This cross-sectional study examined the relationship between neighborhood deprivation and neuropsychological function in adults with TLE. METHODS: Neuropsychological data were obtained from a clinical registry of patients with TLE and included measures of intelligence, attention, processing speed, language, executive function, visuospatial skills, verbal/visual memory, depression, and anxiety. Home addresses were used to calculate the Area Deprivation Index (ADI) for each individual, which were separated into quintiles (i.e., quintile 1 = least disadvantaged and quintile 5 = most disadvantaged). Kruskal-Wallis tests compared quintile groups on cognitive domain scores and mood and anxiety scores. Multivariable regression models, with and without ADI, were estimated for overall cognitive phenotype and for mood and anxiety scores. RESULTS: A total of 800 patients (median age 38 years; 58% female) met all inclusion criteria. Effects of disadvantage (increasing ADI) were observed across nearly all measured cognitive domains and with significant increases in symptoms of depression and anxiety. Furthermore, patients in more disadvantaged ADI quintiles had increased odds of a worse cognitive phenotype (p = 0.013). Patients who self-identified as members of minoritized groups were overrepresented in the most disadvantaged ADI quintiles and were 2.91 (95% CI 1.87-4.54) times more likely to be in a severe cognitive phenotype than non-Hispanic White individuals (p < 0.001). However, accounting for ADI attenuated this relationship, suggesting neighborhood deprivation may account for some of the relationship between race/ethnicity and cognitive phenotype (ADI-adjusted proportional odds ratio 1.82, 95% CI 1.37-2.42). DISCUSSION: These findings highlight the importance of environmental factors and regional characteristics in neuropsychological studies of epilepsy. There are many potential mechanisms by which neighborhood disadvantage can adversely affect cognition (e.g., fewer educational opportunities, limited access to health care, food insecurity/poor nutrition, and greater medical comorbidities). Future research will seek to investigate these potential mechanisms and determine whether structural and functional alterations in the brain moderate the relationship between ADI and cognition.

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes.

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

Characterization and Prediction of Short-term Outcomes in Memory After Temporal Lobe Resection in Children With Epilepsy.

BACKGROUND AND OBJECTIVES: The aim of this study was to characterize short-term outcomes in episodic memory, as assessed by the Children's Memory Scale (CMS), after temporal lobe resection in children with epilepsy using empirical methods for assessing cognitive change (i.e., reliable change indices [RCI] and standardized regression-based change scores [SRB]) and develop and internally validate clinically applicable models to predict postoperative memory decline. METHODS: This retrospective cohort study included children aged 6-16 years who underwent resective epilepsy surgery that included the temporal lobe (temporal only: "temporal" and multilobar: "temporal plus") and who completed preoperative and postoperative neuropsychological assessments including the CMS. Change scores on the CMS delayed memory subtests (Faces, Stories, and Word Pairs) were classified as decline, no change, or improvement using epilepsy-specific RCI and SRB. Logistic regression models for predicting postoperative memory decline were developed and internally validated with bootstrapping. RESULTS: Of the 126 children included, most of them demonstrated either no significant change (54%-69%) or improvement (8%-14%) in memory performance using RCI on individual measures at a median of 7 months after surgery. A subset of children (23%-33%) showed postoperative declines. Change distributions obtained using RCI and SRB were not statistically significantly different from each other. Preoperative memory test score, surgery side, surgery extent, and preoperative full-scale IQ were predictors of memory decline. Prediction models for memory decline included subsets of these variables with bias-corrected concordance statistics ranging from 0.70 to 0.75. The models were well calibrated although slightly overestimated the probability of verbal memory decline in high-risk patients. DISCUSSION: This study used empiric methodology to characterize memory outcome in children after temporal lobe resection. Provided online calculator and nomograms may be used by clinicians to estimate the risk of postoperative memory decline for individual patients before surgery.