Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.

BACKGROUND: Dysregulation of nucleocytoplasmic shuttling of histone deacetylase 4 (HDAC4) is associated with several neurodevelopmental and neurodegenerative disorders. Consequently, understanding the roles of nuclear and cytoplasmic HDAC4 along with the mechanisms that regulate nuclear entry and exit is an area of concerted effort. Efficient nuclear entry is dependent on binding of the transcription factor MEF2, as mutations in the MEF2 binding region result in cytoplasmic accumulation of HDAC4. It is well established that nuclear exit and cytoplasmic retention are dependent on 14-3-3-binding, and mutations that affect binding are widely used to induce nuclear accumulation of HDAC4. While regulation of HDAC4 shuttling is clearly important, there is a gap in understanding of how the nuclear and cytoplasmic distribution of HDAC4 impacts its function. Furthermore, it is unclear whether other features of the protein including the catalytic site, the MEF2-binding region and/or the ankyrin repeat binding motif influence the distribution and/or activity of HDAC4 in neurons. Since HDAC4 functions are conserved in Drosophila, and increased nuclear accumulation of HDAC4 also results in impaired neurodevelopment, we used Drosophila as a genetic model for investigation of HDAC4 function. RESULTS: Here we have generated a series of mutants for functional dissection of HDAC4 via in-depth examination of the resulting subcellular distribution and nuclear aggregation, and correlate these with developmental phenotypes resulting from their expression in well-established models of neuronal morphogenesis of the Drosophila mushroom body and eye. We found that in the mushroom body, forced sequestration of HDAC4 in the nucleus or the cytoplasm resulted in defects in axon morphogenesis. The actions of HDAC4 that resulted in impaired development were dependent on the MEF2 binding region, modulated by the ankyrin repeat binding motif, and largely independent of an intact catalytic site. In contrast, disruption to eye development was largely independent of MEF2 binding but mutation of the catalytic site significantly reduced the phenotype, indicating that HDAC4 acts in a neuronal-subtype-specific manner. CONCLUSIONS: We found that the impairments to mushroom body and eye development resulting from nuclear accumulation of HDAC4 were exacerbated by mutation of the ankyrin repeat binding motif, whereas there was a differing requirement for the MEF2 binding site and an intact catalytic site. It will be of importance to determine the binding partners of HDAC4 in nuclear aggregates and in the cytoplasm of these tissues to further understand its mechanisms of action.

The "make or break" impact of family dynamics on psychological outcomes in focal epilepsy.

OBJECTIVE: Living with epilepsy can shape the dynamics of the whole family unit. The first objective of this study was to establish the reliability and validity of our purpose-built online family mapping tool: "Living with Epilepsy." Our second objective was to identify distinct patterns of emotional closeness between family members (family typologies), and to explore (1) whether family typologies are shaped by epilepsy-related factors, and (2) which typologies confer optimal psychological outcomes to people with epilepsy. METHODS: Ninety-one adults with chronic epilepsy and their caregivers (n = 56) participated and 70 similarly aged healthy controls and 36 caregiver controls (N = 253). Purpose-built software assessed a range of epilepsy-specific psychosocial issues, including family mapping. Questionnaires validated for epilepsy evaluated mood and quality of life (QOL). RESULTS: The reliability and validity of the family mapping tool was established. Family maps revealed three typologies varying in emotional closeness, each with distinct patterns of healthy vs maladaptive family behavior: Extremely Close (32%), Close (54%), and Fractured (14%). There was no difference in the frequency of typology between epilepsy and control families (p > .05). Within the epilepsy cohort, however, patients with seizure onset in childhood largely belonged to the extreme typologies: Extremely Close (47%) or Fractured (42%). In comparison, those with adolescent or adult onset commonly belonged to the moderate typology: Close (53%). People with epilepsy from Extremely Close families reported significantly higher QOL (p = .013) and lower mood symptoms (p = .008) relative to other typologies; no such association was found for controls or caregivers (p > .05). SIGNIFICANCE: These findings suggest that adults whose epilepsy commenced in childhood are likely to have extreme family dynamics characterized by either being brought closer together or driven apart. Extremely close families appear highly adaptive for people with epilepsy, bringing benefits for mood and QOL not seen in their caregivers or controls. The results provide strong empirical support for the value of an emotionally supportive family when living with epilepsy and suggest that fostering healthy connections within epilepsy families can optimize long-term patient well-being.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

A family study implicates GBE1 in the etiology of autism spectrum disorder.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with an estimated heritability of >60%. Family-based genetic studies of ASD have generally focused on multiple small kindreds, searching for de novo variants of major effect. We hypothesized that molecular genetic analysis of large multiplex families would enable the identification of variants of milder effects. We studied a large multigenerational family of European ancestry with multiple family members affected with ASD or the broader autism phenotype (BAP). We identified a rare heterozygous variant in the gene encoding 1,4-ɑ-glucan branching enzyme 1 (GBE1) that was present in seven of seven individuals with ASD, nine of ten individuals with the BAP, and none of four tested unaffected individuals. We genotyped a community-acquired cohort of 389 individuals with ASD and identified three additional probands. Cascade analysis demonstrated that the variant was present in 11 of 13 individuals with familial ASD/BAP and neither of the two tested unaffected individuals in these three families, also of European ancestry. The variant was not enriched in the combined UK10K ASD cohorts of European ancestry but heterozygous GBE1 deletion was overrepresented in large ASD cohorts, collectively suggesting an association between GBE1 and ASD.

"Do I still have epilepsy?" Epilepsy identity 15-20 years after anterior temporal lobectomy.

OBJECTIVE: Identity is a multifaceted construct, comprising personal identity (sense of being a unique individual) and social identity (the sense-of-self derived from membership of social groups). Social identity involves explicit identification with a group ("I am …") and implicit behaviors or attitudes associated with group membership. Following successful treatment with surgery, patients with epilepsy can undergo a complex and lasting change in personal identity. To date, there has been no research into postoperative social epilepsy identity (SEI). We sought to examine SEI 15-20 years post-surgery, and the relationship between SEI and satisfaction with surgery, psychosocial improvements, mood, and health-related quality of life (HRQoL). METHODS: Thirty-two patients who underwent anterior temporal lobectomy (ATL; 19 female) were recruited, with a median follow-up of 18 years (interquartile range [IQR] = 2.5). Using a novel interactive online program, we collected data on SEI, satisfaction with surgery, and perceived psychosocial improvements, alongside standardized measures of mood (Neurological Disorders Depressio Inventory-Epilepsy; Patient Health Questionnaire-Generalised Anxiety Disorder-7 item) and HRQoL (Quality of Life in Epilepsy-31 item). Non-parametric analyses were used to analyse the data. RESULTS: Twenty-five percent of patients were free of disabling seizures since surgery, yet 65% stated they no longer had epilepsy and >90% reported satisfaction with surgery. Explicitly discarding SEI was positively associated with HRQoL at long-term follow-up, over and above seizure outcome. Implicit SEI was expressed as (a) acceptance of epilepsy, (b) a sense of belonging to the epilepsy community, and (c) difficulty disclosing and discussing epilepsy. Difficulty disclosing and discussing epilepsy was associated with increased anxiety and lower HRQoL. SIGNIFICANCE: At long-term follow-up, over half of our patients reported an explicit change in SEI, which could promote better HRQoL. In contrast, difficulty with disclosure of epilepsy was associated with increased anxiety and reduced HRQoL, possibly reflecting the ongoing effects of stigma. These findings highlight the importance of understanding changes in patient social identity for promoting long-term well-being after surgery.

ILAE clinical practice recommendations for the medical treatment of depression in adults with epilepsy.

The aim of this document is to provide evidence-based recommendations for the medical treatment of depression in adults with epilepsy. The working group consisted of members of an ad hoc Task Force of the International League Against Epilepsy (ILAE) Commission on Psychiatry, ILAE Executive and the International Bureau for Epilepsy (IBE) representatives. The development of these recommendations is based on a systematic review of studies on the treatment of depression in adults with epilepsy, and a formal adaptation process of existing guidelines and recommendations of treatment of depression outside epilepsy using the ADAPTE process. The systematic review identified 11 studies on drug treatments (788 participants, class of evidence III and IV); 13 studies on psychological treatments (998 participants, class of evidence II, III and IV); and 2 studies comparing sertraline with cognitive behavioral therapy (CBT; 155 participants, class of evidence I and IV). The ADAPTE process identified the World Federation of Societies of Biological Psychiatry guidelines for the biological treatment of unipolar depression as the starting point for the adaptation process. This document focuses on first-line drug treatment, inadequate response to first-line antidepressant treatment, and duration of such treatment and augmentation strategies within the broader context of electroconvulsive therapy, psychological, and other treatments. For mild depressive episodes, psychological interventions are first-line treatments, and where medication is used, selective serotonin reuptake inhibitors (SSRIs) are first-choice medications (Level B). SSRIs remain the first-choice medications (Level B) for moderate to severe depressive episodes; however, in patients who are partially or non-responding to first-line treatment, switching to venlafaxine appears legitimate (Level C). Antidepressant treatment should be maintained for at least 6 months following remission from a first depressive episode but it should be prolonged to 9 months in patients with a history of previous episodes and should continue even longer in severe depression or in cases of residual symptomatology until such symptoms have subsided.

Investigating the Relationship Between Childhood Music Practice and Pitch-Naming Ability in Professional Musicians and a Population-Based Twin Sample.

The relationship between pitch-naming ability and childhood onset of music training is well established and thought to reflect both genetic predisposition and music training during a critical period. However, the importance of the amount of practice during this period has not been investigated. In a population sample of twins (N = 1447, 39% male, 367 complete twin pairs) and a sample of 290 professional musicians (51% male), we investigated the role of genes, age of onset of playing music and accumulated childhood practice on pitch-naming ability. A significant correlation between pitch-naming scores for monozygotic (r = .27, p < .001) but not dizygotic twin pairs (r = -.04, p = .63) supported the role of genetic factors. In professional musicians, the amount of practice accumulated between ages 6 and 11 predicted pitch-naming accuracy (p = .025). In twins, age of onset was no longer a significant predictor once practice was considered. Combined, these findings are in line with the notion that pitch-naming ability is associated with both genetic factors and amount of early practice, rather than just age of onset per se. This may reflect a dose-response relation between practice and pitch-naming ability in genetically predisposed individuals. Alternatively, children who excel at pitch-naming may have an increased tendency to practice.

Understanding long-term changes in patient identity 15-20 years after surgery for temporal lobe epilepsy.

OBJECTIVE: Following epilepsy surgery, patients can experience complex psychosocial changes. We recently described a longer term adjustment and reframing ("meaning-making") process 15-20 years following surgery for temporal lobe epilepsy, which could involve an ongoing sense of being a "different" person for some patients. Here, we quantitatively examine identity at long-term follow-up and how this relates to meaning-making and postoperative seizure outcome. METHODS: Eighty-seven participants were included: 39 who underwent anterior temporal lobectomy (ATL) 15-20 years ago (59% female; median age = 49.2 years, interquartile range [IQR] = 10; median follow-up = 18.4 years, IQR = 4.4) and 48 surgically naïve focal epilepsy patients (56% female; median age = 34.5 years, IQR = 19). We captured approach to meaning-making by coding for key narrative features identified in our previous qualitative work. Nonparametric tests and correspondence analysis were then used to explore relationships between a quantitative measure of identity and meaning-making, as well as seizure outcome, mood, and health-related quality of life (HRQOL). RESULTS: Patients 15-20 years post-ATL demonstrated a shift toward increasing identity commitment and exploration compared to the surgically naïve cohort, with this shift significantly linked to seizure outcome. Examining the relationship between identity and meaning-making also revealed three groups: (1) those who embraced self-change (29%), (2) those who continued to struggle with this process (60.5%), and (3) those who showed minimal engagement (10.5%). Those who "embraced change" were significantly younger at regular seizure onset and demonstrated a trend toward higher HRQOL. SIGNIFICANCE: Findings suggest that ATL patients show a more developed identity profile compared to surgically naïve controls; however, the majority still struggled with postoperative identity change at long-term follow-up. Approximately one third of patients demonstrated positive psychological growth following surgery, reflected in the ability to embrace change. Findings highlight the importance of understanding the impact of surgery on patient identity to maximize the psychosocial benefits.

Metabolic patterns and seizure outcomes following anterior temporal lobectomy.

OBJECTIVE: We investigated the relationship between the interictal metabolic patterns, the extent of resection of 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) hypometabolism, and seizure outcomes in patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection. METHODS: Eighty-two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant 18 FDG-PET hypometabolism, and at least 2 years of postoperative follow-up were included in this 2-center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre- and postoperative MRI scans coregistered with interictal 18 FDG-PET. RESULTS: Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). INTERPRETATION: The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1-10 ANN NEUROL 2019;85:241-250.

Positive illusions determine quality of life in drug-resistant epilepsy.

OBJECTIVE: Humans use a complex system of protective cognitive biases or "positive illusions" that foster emotional well-being and subjective quality of life. This study examined the role of positive illusions in patient adjustment to drug-resistant epilepsy and its surgical treatment. METHODS: One hundred fifty people participated, including 93 focal epilepsy patients being evaluated for surgery and 57 sociodemographically matched healthy controls. We purpose-built computer software, "Living With Epilepsy," to assess the impact of positive illusions on patient perceptions of their current life, and administered well-validated questionnaires of depression (Neurological Disorders Depression Inventory for Epilepsy), anxiety (Patient Health Questionnaire for Generalized Anxiety Disorder-7 items), and health-related quality of life (HRQOL; Epilepsy Surgery Inventory-55) before and at 3 and 12 months after surgery. RESULTS: We identified two patient groups: those with "high positive illusions" (53%) about their epilepsy and those with "low positive illusions" (47%), with no differences between sociodemographic or epilepsy variables (all P > .05). Before epilepsy surgery, patients with high positive illusions exhibited fewer symptoms of depression (P < .001) and anxiety (P = .002) and higher HRQOL (P ≥ .002 ≤ 0.046) than those with low positive illusions. A subset of patients proceeded with surgery (n = 34 at 3 months; n = 26 at 12 months). They showed that the beneficial impact of having high positive illusions re-emerged 12 months postsurgery, with patients reporting lower depression and anxiety (P = .006) and elevated HRQOL (P = .036) compared to low positive illusions patients, independent of seizure outcome (P > .05). SIGNIFICANCE: These findings point to an active psychological process in drug-resistant patients, where approximately half generate strong positive illusions about their life with epilepsy, maintaining their mood and subjective well-being. Those who use this psychological mechanism show better adjustment 12 months postsurgery independent of seizure outcome, providing a potential new target for psychological treatment in patients with epilepsy.

Music training is neuroprotective for verbal cognition in focal epilepsy.

Focal epilepsy is a unilateral brain network disorder, providing an ideal neuropathological model with which to study the effects of focal neural disruption on a range of cognitive processes. While language and memory functions have been extensively investigated in focal epilepsy, music cognition has received less attention, particularly in patients with music training or expertise. This represents a critical gap in the literature. A better understanding of the effects of epilepsy on music cognition may provide greater insight into the mechanisms behind disease- and training-related neuroplasticity, which may have implications for clinical practice. In this cross-sectional study, we comprehensively profiled music and non-music cognition in 107 participants; musicians with focal epilepsy (n = 35), non-musicians with focal epilepsy (n = 39), and healthy control musicians and non-musicians (n = 33). Parametric group comparisons revealed a specific impairment in verbal cognition in non-musicians with epilepsy but not musicians with epilepsy, compared to healthy musicians and non-musicians (P = 0.029). This suggests a possible neuroprotective effect of music training against the cognitive sequelae of focal epilepsy, and implicates potential training-related cognitive transfer that may be underpinned by enhancement of auditory processes primarily supported by temporo-frontal networks. Furthermore, our results showed that musicians with an earlier age of onset of music training performed better on a composite score of melodic learning and memory compared to non-musicians (P = 0.037), while late-onset musicians did not differ from non-musicians. For most composite scores of music cognition, although no significant group differences were observed, a similar trend was apparent. We discuss these key findings in the context of a proposed model of three interacting dimensions (disease status, music expertise, and cognitive domain), and their implications for clinical practice, music education, and music neuroscience research.

A patient-centered approach to understanding long-term psychosocial adjustment and meaning-making, 15 to 20 years after epilepsy surgery.

OBJECTIVE: Different psychosocial trajectories have been identified following treatment with epilepsy surgery, as patients adjust to possible changes in seizure frequency and the subsequent impact on their psychosocial functioning. Qualitative research has been key to understanding this adjustment process, particularly in the short-term (2-5 years). Currently, however, there is a lack of qualitative research examining longer-term (>15 years) outcomes, precluding the same rich, detailed understanding of longer-term psychosocial outcomes. Using a grounded theory approach, we explored how patients reflected on and made sense of their adjustment trajectories, 15 to 20 years after surgery. This included the impact of surgery on their sense of self and broader psychosocial functioning. METHODS: We recruited 40 adult patients who had undergone anterior temporal lobectomy (ATL) 15 to 20 years ago (24 females; 26 left-sided). Median age at habitual seizure onset was 9.7 years (Interquartile range; IQR = 13.8), and at surgery was 31 years (IQR = 12). Median length of follow-up was 18.4 years (IQR = 4.3). Comprehensive one-on-one interviews (median time = 86 min, IQR = 28) were used to elicit patient experiences of their surgery and subsequent psychosocial outcomes. Data were analyzed using a grounded theory inductive-deductive process. RESULTS: Patient narratives revealed a common process of psychosocial change and meaning-making triggered by surgery, which was often perceived as a major turning point in life. Patients reflected on moving through an early postsurgical period (<5 years) of upheaval and psychological disequilibrium. While this period was often remembered as stressful, difficulties were softened and/or reframed in hindsight. Through this process of reframing and meaning-making, patients were able to reestablish equilibrium and a sense of normality. Differences were evident in how patients navigated the process of meaning-making, and the extent to which they felt surgery had changed their self-identity. DISCUSSION: We propose a model of postsurgical meaning-making, evident in the narratives of patients who have undergone ATL, providing a new perspective on long-term psychosocial outcomes. This model contributes to our understanding of patient well-being and quality of life, by acknowledging the active role that patients play in seeking to create their own sense of normality after epilepsy surgery.

Contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy.

"My memory is terrible!" is a common refrain among people with epilepsy, but such complaints are not reliably linked to poor performances on standard tests of memory. Negative affect like depression and anxiety are the most robust predictor of these complaints; however, neither do they entirely account for the phenomenon. The contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy has not been well-explored despite autobiographic memory impairments being common in patients with epilepsy, and the face validity of relating day-to-day memory failings to such a personally relevant form of memory. The current study sought to clarify whether autobiographic memory dysfunction contributes to subjective complaints in epilepsy, above and beyond negative affect, objective memory impairment, and epileptological factors in a large sample of patients with drug-resistant focal epilepsy relative to healthy controls (N = 135). Patients were stratified into groups with mesial temporal (MT; n = 40) versus nonmesial temporal (NMT; n = 46) foci. Compared to controls (n = 46), both patient groups reported more bitter subjective memory complaints (p < 0.001, large effect size), demonstrated poorer episodic (p = 0.001, large effect size) and semantic autobiographical recall (p = 0.004, medium effect size), and had higher levels of depressive symptomatology (p = 0.011, medium effect size), and trait neuroticism (p = 0.015, medium effect size). Contrary to expectations, multiple regression analyses revealed that autobiographic memory function was not an independent predictor of subjective memory complaints in either group with epilepsy. In people with epilepsy with MT foci, objective verbal memory dysfunction, neuroticism, and female gender predicted memory complaints (R2 = 0.70, p = 0.015), whereas only neuroticism predicted memory complaints in people with epilepsy with NMT foci (R2 = 0.21, p = 0.001). Although patients' poor recall of their autobiographical memories did not contribute to their concerns about their day-to-day memory function, the findings indicate that the location of the epileptogenic focus can provide clues as to the underlying contributors to subjective memory complaints in focal epilepsy. Important clinical implications to stem from these findings include the need for clinicians to adopt a patient-tailored, multifactorial lens when managing memory complaints in people with epilepsy, taking into account both psychological and cognitive factors.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

Tracing Autism Traits in Large Multiplex Families to Identify Endophenotypes of the Broader Autism Phenotype.

Families comprising many individuals with Autism Spectrum Disorders (ASD) may carry a dominant predisposing mutation. We implemented rigorous phenotyping of the "Broader Autism Phenotype" (BAP) in large multiplex ASD families using a novel endophenotype approach for the identification and characterisation of distinct BAP endophenotypes. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 110 individuals, including two large multiplex families (Family A: 30; Family B: 35) and an independent sample of small families (n = 45). Our protocol identified four distinct psychological endophenotypes of the BAP that were evident across these independent samples, and showed high sensitivity (97%) and specificity (82%) for individuals classified with the BAP. Patterns of inheritance of identified endophenotypes varied between the two large multiplex families, supporting their utility for identifying genes in ASD.

Bilateral volume reduction in posterior hippocampus in psychosis of epilepsy.

OBJECTIVE: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research. METHODS: In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). RESULTS: Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups. CONCLUSION: Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.

Pediatric epilepsy surgery patients show normal psychosocial development at long-term follow-up despite dissatisfying family dynamics.

Drug-resistant pediatric epilepsy involves unpredictable seizures and long-term medical management. Both factors can alter a child's psychosocial development and the dynamics of the family, to the detriment of patient and family wellbeing. While drug-resistant pediatric epilepsy can be successfully treated by neurosurgery in some cases, the outlook for psychosocial and family functioning after surgery remains unclear. A total of 163 participants across four groups took part in the current study: these were (i) individuals who had undergone surgical treatment of drug-resistant focal seizures approximately five years prior as children, and were now largely adolescents or young adults ('Patients'; n = 23), (ii) their caregivers ('Patient Caregivers'; n = 27), (iii) healthy individuals of similar age and gender to the Patients ('Controls'; n = 53), and (iv) their caregivers ('Control Caregivers'; n = 60). Based on similar software validated in adults, we built an interactive computer program, 'Living with Epilepsy', to evaluate the achievement of age-specific developmental tasks in Patients relative to their peers. The Family Adaptability and Cohesion Scale measured family dynamics. The findings showed that in the context of seizure freedom, after pediatric epilepsy surgery, Patients are similar to their healthy peers in terms of attaining developmental tasks, with no differences between the Patient and Control groups (P > .05). Family dynamics, however, seemed resistant to postsurgical adaptation, with Patients reporting lower levels of balanced family dynamics (cohesion, flexibility) and higher rates of unbalanced family dynamics (disengagement, chaos, rigidity, enmeshment) relative to Patient Caregivers (P < .001-0.041), and the Controls (P = .011-0.034). Patients also reported reduced family satisfaction compared with that of Patient Caregivers (P = .002), which was associated with polytherapy prior to surgery; that is, more drug-resistant seizures. These findings suggested that childhood-onset epilepsy has a lasting effect on family functioning, even when the child has an optimal medical and psychosocial outcome. These initial findings have significant implications for the provision of pre- to postoperative family support in pediatric epilepsy cases.

The Role of Emotional Intelligence in Community Integration and Return to Work After Acquired Brain Injury.

OBJECTIVE: To investigate whether emotional intelligence (EI) skills measured via the Perceiving, Understanding, and Managing Emotions branches of the Mayer-Salovey-Caruso Emotional Intelligence Test V2.0 are associated with community integration (CI) and return to work (RTW) after moderate-to-severe acquired brain injury (ABI), after accounting for other established predictors. DESIGN: Retrospective cohort study. SETTING: Outpatient follow-up services within 2 specialist ABI rehabilitation centers in Melbourne, Australia. PARTICIPANTS: Individuals (N=82) with moderate-to-severe ABI discharged from inpatient rehabilitation and living in the community (2mo to 7y postinjury). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Community Integration Questionnaire scores for the total sample (N=82; age range 18-80) and RTW status (employed vs not employed) for the subset of participants employed prior to ABI (n=71; age range 19-66). RESULTS: Hierarchical logistic and multiple regression analyses were used to examine the unique contribution of Perceiving, Understanding, and Managing Emotions scores to RTW and CI, after controlling for demographic, injury-related, psychological, and cognitive predictors. As a set, the 3 EI variables did not explain incremental variance in outcomes. However, individually, Understanding Emotions predicted RTW (adjusted odds ratio=3.10, P=.03), χ2 (12)=35.52, P<.001, and Managing Emotions predicted CI (ß=0.23, P=.036), F12,69=5.14, P<.001. CONCLUSION: Although the EI constructs in combination did not improve prediction beyond the effects of established variables, individual components of strategic EI may be important for specific participation outcomes after ABI.

Systematic review of structural and functional brain alterations in psychosis of epilepsy.

This systematic review critically assesses structural and functional neuroimaging studies of psychosis of epilepsy (POE). We integrate findings from 18 studies of adults with POE to examine the prevailing view that there is a specific relationship between temporal lobe epilepsy (TLE) and POE, and that mesial temporal lobe pathology is a biomarker for POE. Our results show: (1) conflicting evidence of volumetric change in the hippocampus and amygdala; (2) distributed structural pathology beyond the mesial temporal lobe; and (3) changes in frontotemporal functional network activation. These results provide strong evidence for a revised conceptualisation of POE as disorder of brain networks, and highlight that abnormalities in mesial temporal structures alone are unlikely to account for its neuropathogenesis. Understanding POE as a disease of brain networks has important implications for neuroimaging research and clinical practice. Specifically, we suggest that future neuroimaging studies of POE target structural and functional networks, and that practitioners are vigilant for psychotic symptoms in all epilepsies, not just TLE.