From hype to hope: Considerations in conducting robust microbiome science.

Microbiome science has been one of the most exciting and rapidly evolving research fields in the past two decades. Breakthroughs in technologies including DNA sequencing have meant that the trillions of microbes (particularly bacteria) inhabiting human biological niches (particularly the gut) can be profiled and analysed in exquisite detail. This microbiome profiling has profound impacts across many fields of research, especially biomedical science, with implications for how we understand and ultimately treat a wide range of human disorders. However, like many great scientific frontiers in human history, the pioneering nature of microbiome research comes with a multitude of challenges and potential pitfalls. These include the reproducibility and robustness of microbiome science, especially in its applications to human health outcomes. In this article, we address the enormous promise of microbiome science and its many challenges, proposing constructive solutions to enhance the reproducibility and robustness of research in this nascent field. The optimisation of microbiome science spans research design, implementation and analysis, and we discuss specific aspects such as the importance of ecological principals and functionality, challenges with microbiome-modulating therapies and the consideration of confounding, alternative options for microbiome sequencing, and the potential of machine learning and computational science to advance the field. The power of microbiome science promises to revolutionise our understanding of many diseases and provide new approaches to prevention, early diagnosis, and treatment.

Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression.

BACKGROUND: Pre-pregnancy obesity is an emerging risk factor for perinatal depression. However, the underlying mechanisms remain unclear. We investigated the association between pre-pregnancy body mass index (BMI) and perinatal depressive symptoms in a large population-based pre-birth cohort, the Barwon Infant Study. We also assessed whether the levels of circulating inflammatory markers during pregnancy mediated this relationship. METHODS: Depressive symptoms were assessed in 883 women using the Edinburgh Postnatal Depression Scale (EPDS) and psychological stress using the Perceived Stress Scale (PSS) at 28 weeks gestation and 4 weeks postpartum. Glycoprotein acetyls (GlycA), high-sensitivity C-reactive protein (hsCRP) and cytokines were assessed at 28 weeks gestation. We performed regression analyses, adjusted for potential confounders, and investigated mediation using nested counterfactual models. RESULTS: The estimated effect of pre-pregnancy obesity (BMI ≥ 30 kg/m2) on antenatal EPDS scores was 1.05 points per kg/m2 increase in BMI (95% CI: 0.20, 1.90; p = 0.02). GlycA, hsCRP, interleukin (IL) -1ra and IL-6 were higher in women with obesity, compared to healthy weight women, while eotaxin and IL-4 were lower. Higher GlycA was associated with higher EPDS and PSS scores and partially mediated the association between pre-pregnancy obesity and EPDS/PSS scores in unadjusted models, but this association attenuated upon adjustment for socioeconomic adversity. IL-6 and eotaxin were negatively associated with EPDS/PSS scores, however there was no evidence for mediation. CONCLUSIONS: Pre-pregnancy obesity increases the risk of antenatal depressive symptoms and is also associated with systemic inflammation during pregnancy. While discrete inflammatory markers are associated with antenatal depressive symptoms and perceived stress, their role in mediating the effects of pre-pregnancy obesity on antenatal depression requires further investigation.

A cross-sectional investigation of cognition and epileptiform discharges in juvenile absence epilepsy.

OBJECTIVES: Despite the prevalence of cognitive symptoms in the idiopathic generalized epilepsies (IGEs), cognitive dysfunction in juvenile absence epilepsy (JAE), a common yet understudied IGE subtype, remains poorly understood. This descriptive study provides a novel, comprehensive characterization of cognitive functioning in a JAE sample and examines the relationship between cognition and 24-h epileptiform discharge load. METHOD: Forty-four individuals diagnosed with JAE underwent cognitive assessment using Woodcock Johnson III Test of Cognitive Abilities with concurrent 24-h ambulatory EEG monitoring. Generalized epileptiform discharges of any length, and prolonged generalized discharges ≥3 s were quantified across wakefulness and sleep. The relationship between standardized cognitive scores and epileptiform discharges was assessed through regression models. RESULTS: Cognitive performances in overall intellectual ability, acquired comprehension-knowledge, processing speed, long-term memory storage and retrieval, and executive processes were 0.63-1.07 standard deviation (SD) units lower in the JAE group compared to the population reference mean, adjusted for educational attainment. Prolonged discharges (≥3 s) were recorded in 20 patients (47.6%) from 42 available electroencephalography (EEG) studies and were largely unreported. Duration and number of prolonged discharges were associated with reduced processing speed and long-term memory storage and retrieval. SIGNIFICANCE: Cognitive dysfunction is seen in patients with JAE across various cognitive abilities, including those representing more stable processes like general intellect. During 24-h EEG, prolonged epileptiform discharges are common yet underreported in JAE despite treatment, and they show moderate effects on cognitive abilities. If epileptiform burden is a modifiable predictor of cognitive dysfunction, therapeutic interventions should consider quantitative 24-h EEG with routine neuropsychological screening. The growing recognition of the spectrum of neuropsychological comorbidities of IGE highlights the value of multidisciplinary approaches to explore the causes and consequences of cognitive deficits in epilepsy.

Challenges and priorities for researching the gut microbiota in individuals living with anorexia nervosa.

OBJECTIVE: The gut microbiota is implicated in several symptoms and biological pathways relevant to anorexia nervosa (AN). Investigations into the role of the gut microbiota in AN are growing, with a specific interest in the changes that occur in response to treatment. Findings suggest that microbial species may be associated with some of the symptoms common in AN, such as depression and gastrointestinal disturbances (GID). Therefore, researchers believe the gut microbiota may have therapeutic relevance. Whilst research in this field is rapidly expanding, the unique considerations relevant to conducting gut microbiota research in individuals with AN must be addressed. METHOD: We provide an overview of the published literature investigating the relationship between the gut microbiota and symptoms and behaviors present in AN, discuss important challenges in gut microbiota research, and offer recommendations for addressing these. We conclude by summarizing research design priorities for the field to move forward. RESULTS: Several ways exist to reduce participant burden and accommodate challenges when researching the gut microbiota in individuals with AN. DISCUSSION: Recommendations from this article are foreseen to encourage scientific rigor and thoughtful protocol planning for microbiota research in AN, including ways to reduce participant burden. Employing such methods will contribute to a better understanding of the role of the gut microbiota in AN pathophysiology and treatment. PUBLIC SIGNIFICANCE: The field of gut microbiota research is rapidly expanding, including the role of the gut microbiota in anorexia nervosa. Thoughtful planning of future research will ensure appropriate data collection for meaningful interpretation while providing a positive experience for the participant. We present current challenges, recommendations for research design and priorities to facilitate the advancement of research in this field.

Feasibility, Acceptability, and Safety of Faecal Microbiota Transplantation in the Treatment of Major Depressive Disorder: A Pilot Randomized Controlled Trial.

OBJECTIVES: Perturbations of the intestinal microbiota have been associated with mental health disorders, including major depressive disorder (MDD). Therefore, faecal microbiota transplantation (FMT) holds promise as a microbiota-modulating treatment for MDD. Yet, to date, there are no published controlled studies evaluating the use of FMT for MDD. This study aimed to address this gap by evaluating the feasibility, acceptability, and safety of FMT for MDD. METHODS: The study was an 8-week, double-blind, 2:1 parallel group, randomized controlled pilot trial (n = 15) of enema-delivered FMT (n = 10) compared with a placebo enema (n = 5) in adults with moderate-to-severe MDD. RESULTS: Recruitment was completed within 2 months, with 0% attrition and 100% attendance at key study appointments. There were no major protocol deviations. The placebo and blinding strategies were considered successful; nurses and participants correctly guessing their treatment allocation at a rate similar to that anticipated by chance. No serious or severe adverse events were reported in either group, and there were no significant differences in mild-to-moderate adverse events between groups (median of 2 adverse events per participant reported in both groups). Furthermore, the 12/15 participants who completed the Week 2 participant satisfaction survey agreed or strongly agreed that the enema delivery was tolerable and that they would have the treatment again if required. Whilst the study was not designed to measure clinical outcomes, exploratory data also suggested that the active FMT treatment may lead to improvements in gastrointestinal symptoms and quality of life in this population, noting that irritable bowel syndrome is commonly comorbid with MDD. CONCLUSIONS: All feasibility targets were met or exceeded. This study found that enema-delivered FMT is feasible, acceptable, well-tolerated, and safe in patients with MDD. The findings of this study support further research to evaluate clinical efficacy, and the use of this protocol is supported.

Maternal inflammatory and omega-3 fatty acid pathways mediate the association between socioeconomic disadvantage and childhood cognition.

Poor cognitive outcomes in early childhood predict poor educational outcomes and diminished health over the life course. We sought to investigate (i) whether maternal metabolites predict child cognition, and (ii) if maternal metabolomic profile mediates the relationship between environmental exposures and child cognition. Metabolites were measured using nuclear magnetic resonance-based metabolomics in pregnant women from a population-derived birth cohort. Child cognition was measured at age 2 years. In 662 mother-child pairs, elevated inflammatory markers (ß = -2.62; 95% CI -4.10, -1.15; P = 0.0005) and lower omega-3 fatty acid-related metabolites (ß = 0.49; 95% CI 0.09, 0.88; P = 0.02) in the mother were associated with lower child cognition and partially mediated the association between lower child cognition and multiple risk factors common to socioeconomic disadvantage. Modifying maternal prenatal metabolic pathways related to inflammation and omega-3 fatty acids may offset the adverse associations between prenatal risk factors related to socioeconomic disadvantage and low child cognition.

The effect of vitamin D supplementation on depressive symptoms in adults: A systematic review and meta-analysis of randomized controlled trials.

Neurosteroid and immunological actions of vitamin D may regulate depression-linked physiology. Meta-analyses investigating the effect of vitamin D on depression have been inconsistent. This meta-analysis investigated the efficacy of vitamin D in reducing depressive symptoms among adults in randomized placebo-controlled trials (RCT). General and clinical populations, and studies of ill individuals with systemic diseases were included. Light therapy, co-supplementation (except calcium) and bipolar disorder were exclusionary. Databases Medline, PsycINFO, CINAHL and The Cochrane Library were searched to identify relevant articles in English published before April 2022. Cochrane risk-of-bias tool (RoB 2) and GRADE were used to appraise studies. Forty-one RCTs (n = 53,235) were included. Analyses based on random-effects models were performed with the Comprehensive Meta-analysis Software. Results for main outcome (n = 53,235) revealed a positive effect of vitamin D on depressive symptoms (Hedges' g = -0.317, 95% CI [-0.405, -0.230], p < 0.001, I2 = 88.16%; GRADE: very low certainty). RoB assessment was concerning in most studies. Notwithstanding high heterogeneity, vitamin D supplementation ≥ 2,000 IU/day appears to reduce depressive symptoms. Future research should investigate possible benefits of augmenting standard treatments with vitamin D in clinical depression. PROSPERO registration number: CRD42020149760. Funding: Finnish Medical Foundation, grant 4120 and Juho Vainio Foundation, grant 202100353.

Associations between dairy consumption and constipation in adults: A cross-sectional study.

OBJECTIVE: The current study aimed to assess the association between dairy consumption and constipation in the general adult population. DESIGN: Data from the Geelong Osteoporosis Study were used to assess the association between dairy consumption and constipation in women (n=632) and men (n=609). Information on milk, yogurt and cheese, and constipation were self-reported. Total dairy was calculated by summing the intake of milk, yogurt and cheese and expressed as servings per day. Multivariable logistic regression models adjusted for irritable bowel syndrome, major depressive disorders, mobility, body mass index, age and fibre intake were used to examine the odds ratio (OR) and 95% confidence interval (CI) between the consumption of categories of total dairy, milk, yogurt, cheese, and constipation. RESULTS: In women, consumption of 1-2 servings/d of total dairy was associated with reduced odds for constipation (OR: 0.49; 95% CI: 0.26-0.90; P=0.021) compared to consuming <1 serving/d of total dairy after adjusting for covariates. Also, consumption of 1-4 servings/d of milk was associated with marginally reduced odds for constipation (OR: 0.63; 95% CI: 0.39-1.02; P=0.058) compared to women who consumed <1 serving/d of milk after adjusting for covariates. There were no significant associations detected between other types of dairy consumption and constipation in women, and none in men. CONCLUSION: In women, consumption of moderate amounts of dairy is associated with reduced odds for constipation whereas in men no associations were detected between dairy consumption and constipation. Further studies are warranted to confirm results.

Inhibition, excitation and bilateral transfer following a unilateral complex finger-tapping task in young and older adults.

Neuroplasticity underpins motor learning, with abnormal neuroplasticity related to age-associated motor declines. Bilateral transfer of motor learning, through rehabilitation, may mitigate these declines; however, the magnitude of transfer may be reduced in older populations. This study investigated excitatory and inhibitory pathways in the trained and untrained hemispheres following unilateral training of a complex finger-tapping task across ageing. Fifteen young (26.2 ± 3.8 years) and 11 older adults (63.7 ± 15.4 years) received transcranial magnetic stimulation, although surface electromyography was recorded from the extensor digitorum communis (EDC) and abductor pollicis brevis (APB), before and after practicing a complex finger-tapping task with the dominant hand. Excitability, inhibition (expressed as percent change scores from pre- to post-training), motor task performance and bilateral transfer were assessed between groups. Investigation of hemispheric differences within each group was completed for measures that significantly differed between groups. There were no between-group differences in task performance or bilateral transfer, with task performance improving post-training irrespective of group for both hands (p < 0.05). Pre- to post-inhibition change scores of the untrained EDC muscle increased (p = 0.034) in older compared with younger adults, indicating reduced inhibition in older adults. Inhibition change scores significantly differed between hemispheres for the young group only (p = 0.037). Only the younger group presented with hemispheric lateralisation, providing some support for the Hemispheric Asymmetry Reduction in OLDer adults (HAROLD) hypothesis. Whether this reduction is evidence of de-differentiation or compensation will need to be confirmed with additional measures.

Gut Microbiome Diversity and Composition Are Associated with Habitual Dairy Intakes: A Cross-Sectional Study in Men.

BACKGROUND: At a population level, the relation between dairy consumption and gut microbiome composition is poorly understood. OBJECTIVES: We sought to study the cross-sectional associations between individual dairy foods (i.e., milk, yogurt, and cheese), as well as total dairy intake, and the gut microbiome composition in a large, representative sample of men living in south-eastern Australia. METHODS: Data on 474 men (mean ± SD: 64.5 ± 13.5 y old) from the Geelong Osteoporosis Study were used to assess the cross-sectional association between dairy consumption and gut microbiome. Information on dairy intake was self-reported. Men were categorized as consumers and nonconsumers of milk, yogurt, cheese, and high- and low-fat milk. Milk, yogurt, and cheese intakes were summed to calculate the total dairy consumed per day and categorized into either low (<2.5 servings/d) or high (≥2.5 servings/d) total dairy groups. Fecal samples were analyzed using bacterial 16S ribosomal RNA (rRNA) gene sequencing. After assessment of α and ß diversity, differential abundance analysis was performed to identify bacterial taxa associated with each of milk, yogurt, and cheese consumption compared with nonconsumption, low compared with high total dairy, and low- compared with high-fat milk consumption. All analyses were adjusted for potential confounders. RESULTS: α Diversity was not associated with consumption of any of the dairy groups. Differences in ß diversity were observed between milk and yogurt consumption compared with nonconsumption. Taxa belonging to the genera Ruminococcaceae UCG-010 and Bifidobacterium showed negative and weak positive associations with milk consumption, respectively. A taxon from the genus Streptococcus was positively associated with yogurt consumption, whereas a taxon from the genus Eisenbergiella was negatively associated with cheese consumption. No specific taxa were associated with low- compared with high-fat milk nor low compared with high total dairy consumption. CONCLUSIONS: In men, community-level microbiome differences were observed between consumers and nonconsumers of milk and yogurt. Bacterial taxon-level associations were detected with milk, yogurt, and cheese consumption. Total dairy consumption was not associated with any microbiome measures, suggesting that individual dairy foods may have differential roles in shaping the gut microbiome in men.

Gastrointestinal symptoms following treatment for anorexia nervosa: A systematic literature review.

OBJECTIVE: Gastrointestinal (GI) disturbances are a frequent and burdensome experience for patients with anorexia nervosa (AN). How GI symptoms respond to current interventions is not well characterized, yet is critical to facilitate treatment success, and to inform the development of new treatments for AN. Therefore, the aim of this systematic review was to identify which treatments are effective in improving GI symptoms in patients with AN. METHOD: A systematic search for studies of AN treatments measuring GI symptoms pre- and post-treatment was conducted in May 2020 (PROSPERO ID: CRD42020181328). After removal of duplicates, title and abstracts of 3,370 studies were screened. Methodological quality was assessed using National Institute of Health Quality Assessment Tool. RESULTS: Following full-text screening, 13 studies (12 observational studies and 1 randomized double-blind placebo-controlled trial) with 401 participants met eligibility criteria and were included. All observational studies included a component of nutritional rehabilitation, with half (n = 6) involving concurrent psychological treatment. The randomized controlled trial reported a drug therapy. Eleven studies reported an improvement in all (n = 6) or at least one (n = 5) patient-reported GI symptom following treatment. Two studies reported no change. Methodological quality was fair or poor across all studies. DISCUSSION: This is the first systematic review to synthesize available evidence on the trajectory of patient-reported GI symptoms from commencement to end of treatment for AN. The results suggest that most studies showed improvement in one or more GI symptom in response to current treatments. Future therapeutic approaches should consider GI symptoms within their design for optimal treatment adherence and outcomes.

OBJETIVO: Las alteraciones gastrointestinales (GI) son una experiencia frecuente y gravosa para los pacientes que padecen anorexia nerviosa (AN). La forma en que los síntomas gastrointestinales responden a las intervenciones actuales no está bien caracterizada, sin embargo es fundamental para facilitar el éxito del tratamiento, e informar el desarrollo de nuevos tratamientos para la AN. Por lo tanto, el objetivo de esta revisión sistemática fue identificar qué tratamientos son eficaces para mejorar los síntomas gastrointestinales en pacientes que padecen AN. MÉTODO: En mayo de 2020 se llevó a cabo una búsqueda sistemática de estudios de tratamientos para AN que midieron los síntomas gastrointestinales antes y después del tratamiento (PROSPERO ID: CRD42020181328). Después de la eliminación de duplicados, se examinaron el título y los resúmenes de 3370 estudios. La calidad metodológica fue evaluada utilizando la Herramienta de Evaluación de la Calidad del Instituto Nacional de Salud. RESULTADOS: Después de la detección completa de texto, 13 estudios (12 estudios observacionales y un ensayo aleatorizado doble ciego controlado con placebo) con 401 participantes cumplieron con los criterios de elegibilidad y fueron incluidos. Todos los estudios observacionales incluyeron un componente de rehabilitación nutricional, con la mitad (n=6) involucrando un tratamiento psicológico simultáneo. El ensayo controlado aleatorizado reportó tratamiento farmacológico. Once studies informaron de una mejora en todos (n=6) o al menos un (n=5) paciente reportó síntomas gastrointestinales después del tratamiento. Dos estudios no reportaron ningún cambio. La calidad metodológica fue justa o pobre en todos los estudios. DISCUSIÓN: Esta es la primera revisión sistemática que sintetiza la evidencia disponible sobre la trayectoria de los síntomas GI notificados por el paciente desde el inicio hasta el final del tratamiento para la AN. Los resultados sugieren que la mayoría de los estudios mostraron mejoría en uno o más síntomas gastrointestinales en respuesta a los tratamientos actuales. Los futuros abordajes terapéuticos deben considerar los síntomas gastrointestinales dentro de su diseño para una adherencia y resultados óptimos en el tratamiento.

The effect of blueberry interventions on cognitive performance and mood: A systematic review of randomized controlled trials.

Blueberries are rich in polyphenols that may be beneficial to cognitive performance and mood. The aim of this systematic review was to evaluate randomized controlled trials investigating the effects of blueberries and blueberry products on measures of cognition and mood. In total, eleven articles (that included 12 studies) were identified using freeze-dried blueberries (n = 9 studies), whole blueberries (n = 2) and blueberry concentrate (n = 1). These studies were conducted in children (n = 5), young adults (n = 1), and older people with either no known cognitive impairment (n = 4) or indicated cognitive impairment (n = 2). Eight studies reported blueberry consumption or supplementation at various doses and time lengths to improve measures of cognitive performance, particularly short- and long-term memory and spatial memory. For mood, one study reported significant between-group improvements in positive affect from blueberry products, whereas four studies reported no improvement. Low risk of bias were observed across all studies. Based on the current evidence, blueberries may improve some measures of cognitive performance. However, considerable differences in study design, dosages, and anthocyanin content hinder between-study comparison. The use of standardized blueberry interventions, consideration of placebo formulations, and consistently reported cognitive performance tools are recommended in future trials. PROSPERO registration no. CRD42018100888.

An intermittent hypercaloric diet alters gut microbiota, prefrontal cortical gene expression and social behaviours in rats.

Objectives: Excessive consumption of high fat and high sugar (HFHS) diets alters reward processing, behaviour, and changes gut microbiota profiles. Previous studies in gnotobiotic mice also provide evidence that these gut microorganisms may influence social behaviour. To further investigate these interactions, we examined the impact of the intermittent access to a HFHS diet on social behaviour, gene expression and microbiota composition in adolescent rats. Methods: Male rats were permitted intermittent daily access (2 h / day) to a palatable HFHS chow diet for 28 days across adolescence. Social interaction, social memory and novel object recognition were assessed during this period. Following testing, RT-PCR was conducted on hippocampal and prefrontal cortex (PFC) samples. 16S ribosomal RNA amplicon sequencing was used for identification and relative quantification of bacterial taxa in faecal samples. Results: We observed reduced social interaction behaviours, impaired social memory and novel object recognition in HFHS diet rats compared to chow controls. RT-PCR revealed reduced levels of monoamine oxidase A (Maoa), catechol-O-methyltransferase (Comt) and brain derived neurotrophic factor (Bdnf) mRNA in the PFC of HFHS diet rats. Faecal microbiota analysis demonstrated that the relative abundance of a number of specific bacterial taxa differed significantly between the two diet groups, in particular, Lachnospiraceae and Ruminoccoceae bacteria. Discussion: Intermittent HFHS diet consumption evoked physiological changes to the brain, particularly expression of mRNA associated with reward and neuroplasticity, and gut microbiome. These changes may underpin the observed alterations to social behaviours.

Unravelled facets of milk derived opioid peptides: a focus on gut physiology, fractures and obesity.

Beyond being a source of key nutrients, bovine milk influences physiological functions by synthesising bioactive peptides during the process of digestion. Some of the claimed negative health outcomes associated with milk consumption, such as cardiovascular diseases and type 1 diabetes may be attributed to an opioid peptide, beta-casomorphin-7 (BCM-7), derived from A1 beta-casein. BCM-7 exerts its function by binding to the µ-opioid receptors in the body. It is hypothesised that activation of the µ-opioid receptors in the gut can alter gut microbial composition, impair gut barrier integrity and bile acid metabolism, in addition to increasing gastrointestinal transit time and gut inflammation. Further, it is hypothesised that BCM-7 may influence fractures and obesity via µ-opioid receptor pathways. In conclusion, it appears that BCM-7 might have multiple functions pertinent to human health; however, the evidence is limited and warrants further pre-clinical and clinical studies for hypothesis confirmation.

Self and informant report ratings of psychopathology in genetic generalized epilepsy.

The psychological sequelae of genetic generalized epilepsies (GGE) is of growing research interest, with up to a third of all adults with GGE experiencing significant psychiatric comorbidity according to a recent systematic review. A number of unexplored questions remain. Firstly, there is insufficient evidence to determine relative prevalence of psychopathology between GGE syndromes. Secondly, the degree to which self-report and informant-report questionnaires accord in adults with epilepsy is unknown. Finally, while epilepsy severity is one likely predictor of worse psychopathology in GGE, evidence regarding other possible contributing factors such as epilepsy duration and antiepileptic drugs (AEDs) has been equivocal. The potential impact of subclinical epileptiform discharges remains unexplored. Self-report psychopathology symptoms across six DSM-Oriented Subscales were prospectively measured in 60 adults with GGE, with informant-report provided for a subset of 47. We assessed the burden of symptoms from both self- and informant-report, and the relationship between clinical epilepsy variables and self-reported symptoms. Results showed elevated symptoms in almost half of the sample overall. Depression and anxiety were the most commonly reported types of symptoms. There was a trend towards greater symptoms endorsement by self-report, and relatively modest interrater agreement. Symptoms of ADHD were significantly positively associated with number of AEDs currently prescribed. Other psychopathology symptoms were not significantly predicted by epilepsy duration, seizure-free duration or total duration of epileptiform discharges over a 24-hour period. The high prevalence of psychological needs suggests that routine screening of psychopathology and provision of psychoeducation may be essential to improving patient care and outcomes. Further investigation is required to better understand predictive and causal factors for psychopathology in GGE.

Epilepsy beyond seizures: Predicting enduring cognitive dysfunction in genetic generalized epilepsies.

Reduced cognitive functioning has been documented in the genetic generalized epilepsies (GGE). Among a number of hypothesized causal mechanisms, some evidence from other epilepsy syndromes suggests the impact of epileptiform discharges. This study investigates the relationship between cognitive function in GGE and burden of epileptiform discharges within a 24-hour EEG recording, controlling for variables relevant to cognitive function in epilepsy. As part of a larger prospective cohort study, 69 patients with EEG-confirmed GGE (11-58years) underwent 24-hour EEG and detailed neuropsychological assessment using the Woodcock Johnson III Tests. Ten-second pages of the EEG were marked manually page-by-page on longitudinal bipolar montage with 0.5 to 70Hz bandwidth by an experienced EEG reader. Multiple regression analyses were conducted. Epileptiform discharges were detected in 90% of patients. Less than 0.01% of electrophysiological events of two or more seconds were recognized by patients. Regression analysis demonstrated that the cumulative duration of epileptiform discharges over a 24-hour period predicted overall cognitive ability and memory function, accounting for 9.6% and 11.8% of adjusted variance, respectively. None of the epilepsy covariates included in multiple regression analysis added significantly to the model. Duration of epileptiform discharges negatively predicts overall cognitive ability and memory function, even after accounting for other known determinants of cognition. Prolonged epileptiform discharges are common and remain unreported by patients, raising important questions regarding the management of GGE syndromes and their associated comorbidities. Further research is required to investigate causal mechanisms if we are to improve cognitive outcomes in this common group of epilepsies.