Everyday Executive Functioning Research Articles

The Role of Everyday Executive Function in Observed Social Symptoms of Autism Spectrum Disorder.

Recent research suggests there may be differences in the social presentations of autistic males and females. Camouflaging is believed to account for some of these differences and executive function (EF) may support compensatory social behaviors. As few studies have explored the role of sex and everyday EF when evaluating specific social difficulties among autistic youth, the present study seeks to address this. The Social Responsiveness Scale-2 (SRS-2) was used to measure types of social difficulties and the Behavioral Rating Inventory of Executive Function-2 (BRIEF-2) served as a measure of everyday EF. Four three-step hierarchical multiple regressions were conducted with SRS-2 social subscales as dependent variables. Autism symptom severity, BRIEF-2 EF Indices (i.e., behavioral, emotional, and cognitive regulation), and sex served as independent variables. Types of EF impairment significantly predicted social symptoms of autism. Behavioral dysregulation predicted all social symptoms assessed, cognitive dysregulation predicted social awareness and communication challenges, and emotion dysregulation predicted social motivation and communication difficulties. Sex significantly predicted social communication and cognition challenges, beyond the contributions of age, IQ, autism severity, and EF impairment. Findings from this study provide evidence for the contribution of EF to observed social symptoms of autism. Results suggest there may be sex-based differences in the relationship between EF and social problems for autistic youth. Implications and future directions are discussed.

Comparing Executive Functions in Children and Adolescents with Autism and ADHD-A Systematic Review and Meta-Analysis.

Two neurodevelopmental conditions, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), have been associated with executive function (EF) impairments but the specificity of their impairments is still controversial. The present meta-analysis aimed to identify the differences in EF profiles of ASD, ADHD, and ASD+ADHD in relation to a control group of individuals with typical development (TD) and to understand whether the EF performance could change depending upon the type of measure used to assess EF (performance tests vs. questionnaires). Results from 36 eligible studies revealed that ADHD and ASD showed more difficulties than the TD group in tests and, particularly, in questionnaires. No significant differences in the EF profile emerged between ASD and ADHD when assessed through neuropsychological tests (d = 0.02), while significant differences emerged when assessed through questionnaires, with ADHD having higher ratings than ASD (d = -0.34). EF questionnaires and neuropsychological tests may catch two different constructs of EF, with the former being more predictive of everyday life EF impairments. The comparison between the double diagnosis group (ADHD+ASD) and the clinical groups pointed out that the former has a more similar EF profile to the ADHD-alone one and that it shows more difficulties than ASD-alone.

Executive functioning, behavior, and white matter microstructure in the chronic phase after pediatric mild traumatic brain injury: results from the adolescent brain cognitive development study.

Mild traumatic brain injury (mTBI) is common in children. Long-term cognitive and behavioral outcomes as well as underlying structural brain alterations following pediatric mTBI have yet to be determined. In addition, the effect of age-at-injury on long-term outcomes is largely unknown. Children with a history of mTBI (n = 406; Mage = 10 years, SDage = 0.63 years) who participated in the Adolescent Brain Cognitive Development (ABCD) study were matched (1:2 ratio) with typically developing children (TDC; n = 812) and orthopedic injury (OI) controls (n = 812). Task-based executive functioning, parent-rated executive functioning and emotion-regulation, and self-reported impulsivity were assessed cross-sectionally. Regression models were used to examine the effect of mTBI on these domains. The effect of age-at-injury was assessed by comparing children with their first mTBI at either 0-3, 4-7, or 8-10 years to the respective matched TDC controls. Fractional anisotropy (FA) and mean diffusivity (MD), both MRI-based measures of white matter microstructure, were compared between children with mTBI and controls. Children with a history of mTBI displayed higher parent-rated executive dysfunction, higher impulsivity, and poorer self-regulation compared to both control groups. At closer investigation, these differences to TDC were only present in one respective age-at-injury group. No alterations were found in task-based executive functioning or white matter microstructure. Findings suggest that everyday executive function, impulsivity, and emotion-regulation are affected years after pediatric mTBI. Outcomes were specific to the age at which the injury occurred, suggesting that functioning is differently affected by pediatric mTBI during vulnerable periods. Groups did not differ in white matter microstructure.

Everyday executive function issues from the perspectives of autistic adolescents and their parents: Theoretical and empirical implications.

Autism researchers have a long-time interest in a set of skills called executive function. These skills include planning, inhibition, and switching between one activity and another. There was a theory that these skills explained the social and thinking difficulties autistic people might have. After years of study into this, the evidence is confusing and contradictory. Autistic people tend to report struggling quite a lot with these skills. Yet, when researchers test these skills, they do not tend to find such big difficulties. In this study, we spoke to 12 autistic teenagers and seven of their mothers about this. We asked them what they thought about their own, or their child's, executive function skills. We wanted to know about things they were good at and things they struggled with. They told us that their skills were very changeable from one context to the next and from one time to the next. According to their reports, their skills depended on how motivated they were by doing the task. Another thing that influenced their skills were how anxious they felt at the time they needed to use the skill. Finally, they told us that sometimes they think differently about how best to perform a task. We discuss what these insights mean for autism researchers who study these skills. In future, research should ask people about their experiences alongside testing their abilities in different contexts. Combining these information sources will give us a better understanding of autistic people's everyday skills as well as how best to support them.

Parent-Report Sleep Disturbances and Everyday Executive Functioning Difficulties in Children with Tourette Syndrome

ABSTRACT There is an increasing need to identify and treat sleep disturbances in Tourette syndrome (TS), a neurodevelopmental condition characterized by tics. This study explored sleep, tics, and executive functioning in children with TS (n=136) and neurotypical controls (n=101) through parent-report scales and open-ended questions. 85% of children with TS scored in the clinical range for a sleep disorder. Higher tic severity predicted increased sleep disturbances and executive difficulties. Qualitative insights indicated a bidirectional link between sleep and tics, which warrants consideration in clinical settings. Further research is needed to explore causal links.

BRIEF-A: Factor structure and measurement invariance across self-report and informant forms

Objective This study analyzes the psychometric properties of the two forms (self-report and informant) of the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A) in a sample of healthy Portuguese adults. Method The participants were 608 adults, 304 of whom answered the self-report form (ages 18–59; 137 male and 167 female) and 304 who answered the informant form (ages 18–70; 110 male and 194 female). Results The internal consistency for the indexes and the Global Executive Composite was very good (≥.90), whereas for the scales they were either acceptable (between .70 and .80) or good (≥.80), except for the Inhibit scale in both forms. Confirmatory factor analysis was used to test seven competing factor models for each of the forms. The original two-factor model (Behavioral Regulation and Metacognition Indexes) showed a slightly better model fit than the three-factor model (Behavioral Regulation, Emotional Regulation, and Metacognition Indexes) in both forms. The multiple-group analysis of the two-correlated-factor model across forms was supported (configural, metric, and partial scalar invariance). Conclusions Overall, the BRIEF-A showed adequate psychometric properties, suggesting that it is a useful instrument to assess everyday executive functioning in healthy Portuguese adults.

Improvement of anxiety in ADHD following goal-focused cognitive remediation: a randomized controlled trial.

Despite the high prevalence and detrimental consequences of cognitive and executive dysfunction in ADHD, the evidence base of cognitive remediation in the adult ADHD population is sparse. Executive problems can increase both anxiety and depression in ADHD. Thcus, it is important to develop treatment options for adults with ADHD, aiming to improve goal-directed behavior and mood. Goal Management Training (GMT) is an intervention that has received empirical support in improving executive functions and mood in normal aging and for various neurological and psychiatric conditions. The present randomized controlled trial investigated the effects of a goal-focused intervention combining 1) group-based GMT incorporating psychoeducation about ADHD and 2) guidance in implementing individual goals for coping with executive problems in everyday life, compared to treatment as usual (TAU). The primary outcome was perceived executive functioning in everyday life. Secondary outcomes included psychological well-being (anxiety, depression, and coping with ADHD symptoms). We recruited 81 adult participants with a verified ADHD diagnosis (Mage = 31 years). Inclusion was based upon the presence of executive functioning complaints. The participants were randomly assigned to either the intervention or TAU. The intervention group (n = 41) received 16 hours of GMT and psychoeducation, in addition to 4 individual sessions focusing on formulating goals. The goals were assessed in 6 bi-weekly phone calls in the first three months following the group sessions. Participants in the TAU group (n = 40) received standard, individually-adapted follow-up in an outpatient psychiatric health care setting. All participants were assessed at baseline, post-intervention, and at 8-month follow-up (main measurement time point). Significant improvements in everyday executive functioning, psychological wellbeing, and symptoms of ADHD from baseline to 8-month follow-up were reported in both groups. The intervention group reported a significantly higher reduction in symptoms of anxiety compared to TAU. Conclusions. Our findings provide support for considering cognitive remediation as a treatment option for patients with ADHD.Clinical Trial Registration: https://clinicaltrials.gov/study/NCT04638283?term=NCT04638283&rank=1, identifier: NCT04638283.

1 Executive Functioning and Anxiety/Depressive Symptoms as Mediators Between ADHD and Quality of Life: A 10-year Longitudinal Study

Objective:Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with impaired executive functioning and anxiety/depressive symptoms, which may contribute to reduced quality of life. We tested the hypotheses that (1) a childhood diagnosis of ADHD is related to reduced quality of life in emerging adulthood and that (2) this relationship is mediated by impaired executive functioning and anxiety/depressive symptoms.Participants and Methods:We assessed 85 children and adolescents with ADHD and 50 typically developing peers at baseline (Mean age = 11.6 years, 58% males), two-year follow-up, and 10-year follow-up with neuropsychological tests of executive functioning, the Behavioral Rating Inventory of Executive Function (BRIEF), the Short Moods and Feelings Questionnaire (SMFQ), and the Revised Children’s Manifest Anxiety Scale, second edition (RCMAS-2), as well as the Perceived Quality of Life scale (PQoL) at the 10-year follow-up. Four neuropsychological tests of executive functioning, the Letter-Number Sequencing test (working memory), the Color-Word Interference test condition 3 (response inhibition), the Color-Word Interference test condition 4 (shifting), and the trail making test condition 4 (cognitive flexibility) were combined into a neuropsychological executive functioning composite score based on high factor loadings (> .73). the parent-reported BRIEF indexes, the behavioral regulation index, and the metacognition index were used as measures of everyday executive functioning. We conducted independent samples t-tests to compare the groups and simple and parallel mediation analyses with full information maximum likelihood estimation to examine whether the different executive functioning measures and anxiety/depressive symptoms at two-year follow-up mediated the relationship between baseline ADHD and self-reported quality of life at 10-year follow-up.Results:Baseline ADHD was associated with more difficulties with executive functioning on a composite measure of neuropsychological tests (p < .001, Hedges g = .79) and parent-reported everyday metacognitive (p < .001, Hedges g = 2.37) and behavioral regulation executive functioning (p < .001, Hedges g = 1.55), as well as self-reported anxiety (p < .001, Hedges g = 1.05) and depressive symptoms (p < .001, Hedges g = 1.00) at two-year follow-up. Baseline ADHD was associated with lower self-reported quality of life (p = .001, Hedges g = -.67) at 10-year follow-up. The mediation analysis showed that everyday metacognitive executive functioning (p = .011, ß = -.497) and an anxiety/depressive symptoms composite (p < .001, ß = -.404) parallelly mediated the relationship between ADHD and quality of life.Conclusions:Impaired everyday executive functioning and anxiety/depressive symptoms may represent two distinct pathways to reduced quality of life in emerging adults with a childhood diagnosis of ADHD. These findings stress the importance of targeting both cognitive and emotional aspects in interventions for children and adolescents with ADHD to improve later quality of life.

70 Uncovering Comorbid Neuropsychological Disorders in Children with Unilateral Hearing Loss Under Consideration for Cochlear Implantation

Objective:Children with unilateral hearing loss (UHL) have difficulty hearing in noisy environments and localizing sounds, impacting learning and social opportunities across contexts. Using a visible device like a cochlear implant (CI) may improve functioning but can also create psychological risk. Audiological measures alone are insufficient for predicting social, emotional, educational, adaptive, and quality-of-life post-operative outcomes, which are highly variable in this population and can also be impacted by a secondary diagnosis. Extending beyond audition to consider the “whole child” through neuropsychological evaluation may produce a sharper picture of potential outcomes, with or without surgical/audiological intervention. Given recent FDA approval for CI in children with UHL, more are receiving this elective surgery despite difficulties predicting who will experience significant benefit. Here we describe neuropsychological profiles of children with UHL who underwent CI candidacy evaluation at a tertiary pediatric hospital.Participants and Methods:During pre-operative clinical care, CI candidates completed targeted neuropsychological evaluation to identify patient- and family-level factors that could impact CI use and outcomes from surgery. Cognitive, language, attention/executive, visuoperceptual/visuomotor, academic, adaptive, and emotional/behavioral functioning were assessed. Evaluations integrated history, observations, caregiver report forms, and performance-based test data.Results:18 individuals were evaluated (age 7-months to 16-years). Most had left-sided UHL (67%) and were male (61%). Known hearing loss etiologies were congenital cytomegalovirus (n=5), enlarged vestibular aqueduct (n=1), traumatic brain injury (n=1), meningitis (n=1), cholesteatoma (n=1), neurofibromatosis type 1 (n=1), and Waardenburg syndrome (n=1). Indices of general cognitive ability were generally low average to average. Patterns of cognitive impairment were not restricted to language-based tasks (e.g., Beery VMI-6 range 56-109, M=89.42, SD=16.27). Standardized parent ratings of everyday executive functioning, social/emotional/behavioral functioning, and adaptive skills were collected. Eight (44%) had a behavioral health diagnosis: Attention Deficit Hyperactivity Disorder (n=2), Global Developmental Delay (n=2), Unspecified Neurodevelopmental Disorder (n=2), Autism Spectrum Disorder (n=1), and Depression (n=1). Thirteen (72%) received or will receive a CI, of whom 38% had a behavioral health diagnosis. Average Area Deprivation Index (a marker of socio-economic status) was lower for individuals who ultimately received CIs (M=18%tile) compared to those who did not (M=25%tile).Conclusions:There may be increased rates of neurodevelopmental/psychological conditions among children with UHL, especially when the etiology involves the central nervous system. Albeit preliminary, results align with findings from bilateral hearing loss samples. Findings highlight the importance of routine neuropsychological screening in children with UHL and close interdisciplinary collaboration for optimal outcomes. Socio-economic disparities among those who do and do not receive CI need further exploration as those who did not receive CIs tended to be from less resourced neighborhoods. Additional research is warranted to understand the full range of risk and protective factors for children with UHL and how these relate to outcomes for those who opt for cochlear implantation.

A - 52 Self-Reports and Informant-Reports of Everyday Functioning as Predictors of Objective Cognition in Mild Cognitive Impairment and Dementia.

The objective of the current study was to investigate self- and informant-reports of everyday functioning and whether they predicted objective cognitive functioning. Participants included 65 persons with mild cognitive impairment (MCI), 18 individuals with dementia, and 58 healthy older controls. Self-reports and informant-reports were taken on the Everyday Cognition Scales (E-Cog), which included seven subscales: everyday language, memory, executive functioning (EF) planning, EF organization, EF divided attention, visual-spatial/perceptual abilities, and attention. Participants also completed a neuropsychological battery, and composite scores were calculated for each cognitive domain. Regression analyses revealed that in healthy older controls, self-reported EF organization significantly predicted objective executive functions. Additionally, informant-reported language significantly predicted objective language. In the MCI group, self- and informant-reports on the E-Cog did not predict objective cognition. For the dementia group, informant-reported EF planning, EF organization, and EF divided attention significantly predicted objective executive functions. Furthermore, informant-reported language significantly predicted objective language. Overall, informant-reports of everyday language predicted objective language in healthy aging and dementia. Self-reports were only predictive of objective cognition in healthy older controls, with self-reported everyday executive functions predicting objective executive functions. Interestingly, in MCI, self- and informant-reports were not predictive of any domain of objective cognitive skill. These results indicate that when the cognitive impairment is more subtle than in dementia, objective neuropsychological assessment will be even more important, as self- and informant-reports are not associated with actual cognitive functioning.

Self-reported symptoms of everyday executive dysfunction, daytime sleepiness, and fatigue and health status among adults with congenital aniridia: a descriptive study

ABSTRACT Background Congenital aniridia is a rare genetic disorder of the eye characterized by visual impairment and progressive vision loss. While prior research has focused on ocular manifestations in individuals with aniridia, there is a dearth of research on impacts on cognition and mental health. The aims of this study were to describe subjective symptoms of everyday executive functioning, fatigue and sleepiness in adults with aniridia and to compare self-reported health status with that of a normative reference group. Methods Twenty-nine adults (aged 18–79 years) with congenital aniridia were included in this online survey, of whom 52% were females. Participants completed self-report measures of executive functioning (The Behavior Rating Inventory of Executive Function–Adult Version), sleepiness, fatigue, and health status (EQ-5D-5L). Results Participants reported relatively few problems in everyday executive functioning, with only 14% experiencing impaired executive functioning. Scores on the five EQ-5D-5L domains (mobility, self-care, usual activities, pain, and anxiety/depression) did not differ from those of the normative reference group. The frequencies of excessive daytime sleepiness and severe fatigue were 17% and 38%, respectively. Ocular pain was experienced by 62% of participants. Conclusions The findings show that cognitive problems are related to and reflect self-reported health status and extent of fatigue. Moreover, those who suffered from ocular pain reported more difficulties with executive functioning, sleepiness and fatigue. These findings are important for understanding this disorder and supporting patients.

Everyday executive functioning in pediatric obsessive-compulsive disorder: diagnostic specificity, clinical correlations, and outcome

BackgroundObsessive-compulsive disorder (OCD) typically onsets during childhood or adolescence and difficulties with executive functioning (EF) may be involved in its onset and maintenance. Yet, few studies have examined everyday EF difficulties in youth with OCD and no study has compared EF in youth with OCD to EF in youth with anxiety disorders, leaving the diagnostic specificity of EF unclear.MethodsIn this study, parents of treatment-seeking children and adolescents with OCD (n = 96, Mage = 13.3, SD = 2.7, 59% girls) or anxiety disorders (n = 67, Mage = 14.0, SD = 2.6, 78% girls) reported on their children’s everyday EF using the Behavior Rating Inventory of Executive Function (BRIEF) measure.ResultsCompared to community youth, the two clinical groups showed moderately elevated EF deficits but did not differ significantly from each other. EF deficits were not associated with the major symptom dimensions of OCD, age of OCD symptom onset, duration of OCD symptoms, and OCD severity, and did not predict treatment outcome in OCD.ConclusionsCompared to peers, youth with OCD show moderate difficulties with EF, but very similar difficulties are seen in youth with anxiety disorders, and it is unclear whether these difficulties are of clinical relevance. Among youth with OCD, EF difficulties were not differentially associated with the major symptom dimensions of OCD, which is inconsistent with findings from adults. Difficulties with EF did not predict treatment outcome, indicating that integrating EF modules into OCD treatment may be of limited value, although EF may be important for treatment planning in individual cases.

The Relationship between Trait Impulsivity and Everyday Executive Functions among Patients with Type 2 Diabetes Mellitus: The Mediating Effect of Negative Emotions.

In recent years, the incidence of type 2 diabetes mellitus (T2DM) has dramatically increased, imposing a heavy financial burden on society and individuals. The most cost-effective way to control diabetes is diabetes self-management, which depends on patients' executive functions (EFs). However, the level of EFs among patients with T2DM varies greatly. In addition to diabetes-related factors contributing to a decline in EFs, trait impulsivity as a relatively stable personality trait may explicate individual differences in EFs. The objective of this study was to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs among patients with T2DM in China. A total of 305 patients with T2DM were enrolled consecutively from the endocrinology departments of three tertiary hospitals in China using convenience sampling. The participants completed the Sociodemographic Questionnaire, Mini-Mental State Examination (MMSE), Barratt Impulsiveness Scale-Brief (BIS-Brief), Depression Anxiety and Stress Scales with 21 items (DASS-21), and Behavior Rating Inventory of Executive Function-Adult (BRIEF-A) version. A structural equation modeling was used to verify the mediating effect of negative emotions on the relationship between trait impulsivity and EFs. A total of 32.46% of the participants experienced at least one aspect of daily EF decline. The mediating effect of trait impulsivity on the Behavioral Regulation Index (BRI) of EFs through negative emotions was significant, accounting for 29.57% of the total effect. The mediating effect of trait impulsivity on the Metacognitive Index (MI) of EFs through negative emotions was significant, accounting for 31.67% of the total effect. Trait impulsivity can positively predict EF decline, which can be alleviated by improving the negative emotions of patients with T2DM. Future research exploring interventions to improve the EFs of patients with T2DM should therefore consider their trait impulsivity and negative emotions.

Early and stable difficulties of everyday executive functions predict autism symptoms and emotional/behavioral problems in preschool age children with autism: a 2-year longitudinal study.

Longitudinal studies of autistic children show that autism symptoms and emotional/behavioral problems vary and change over time. However, the factors that affect this variability remain far from certain and very little is known about what take place in the preschool period and the role of executive functions (EF). Here, we test the influence of stable difficulties in everyday executive functioning (EEF) during early childhood across 2 years on autistic symptoms and emotional and behavioral problems. Twenty-nine autistic children (24 males and 5 females) were assessed twice within the space of 2 years. At baseline (M = 29 months, SD =5.6 months), participants were assessed for EEF, cognitive development, autistic symptoms, and emotional/behavioral problems. At follow-up, we repeated the same assessment except for cognitive development. The group with stable difficulties (across 2 years) in EEF during early childhood showed a worsening in the severity of autistic symptoms and emotional and behavioral problems compared with children without EEF difficulties (p < 0.05), and these effects cannot be attributable to cognitive development. Our results suggest that early and stable EEF plays the role of a modifier by interacting with the core domains of autism, in particular with the social affect domain (SA CSS), influencing social cognition and exacerbating or lessening symptom expression and emotional behavioral problems. These short-term longitudinal and preliminary findings underscore the importance of EEF as necessary target for early intervention in children with autism.

Fenfluramine: A Review in Dravet and Lennox-Gastaut Syndromes.

Fenfluramine (Fintepla®) is an oral anti-seizure medication (ASM) with a novel mechanism of action consisting of activity in the serotonergic system coupled with positive allosteric modulation effects at sigma-1 receptors. Originally approved for use at high doses as an appetite suppressant, it was subsequently withdrawn after being linked to valvular heart disease (VHD) and pulmonary arterial hypertension (PAH), before being investigated for use at low doses as an adjunctive ASM in patients with developmental epileptic encephalopathies, including Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) who have pharmacoresistant seizures. In clinical trials, treatment with adjunctive fenfluramine markedly reduced convulsive seizure frequency in patients with DS that were sustained for up to 3 years, and reduced drop seizure frequency in patients with LGS that were sustained for up to 1 year. Notably, fenfluramine was also associated with clinically meaningful improvements in aspects of everyday executive functioning (EF) not entirely explainable by seizure reduction alone. Furthermore, it was generally well tolerated with, importantly, no reports of VHD or PAH. Thus, adjunctive fenfluramine is a novel and effective treatment for pharmacoresistant seizures associated with DS and LGS that may also improve aspects of everyday EF in some patients.

Improving adaptive behaviors for autistic adults without intellectual disability through executive function training.

Executive functioning (EF) is a cognitive process used to perform various daily activities throughout one's lifespan. Autistic adults without intellectual disabilities (ID) also experience difficulties with EF, which is closely associated with adaptive behaviors. For this reason, it is important to improve adaptive behaviors through enhanced use of EF for autistic adults to transition into adulthood successfully. This study aims to conduct a randomized controlled trial to evaluate the effectiveness of a newly developed and modified intervention program. Thirty autistic adults without ID were randomly assigned to the treatment or waitlist group. The participants and caregivers completed various assessments and self-report questionnaires to measure everyday EF and adaptive behaviors. We performed linear mixed-effect modeling to compare the two groups. Data collected at pre-, middle, post-, and follow-up based on participants who completed the program were used to explore changes across time. While there were significant differences in the EF utility-scale (F=5.46, p=.027) between the treatment and waitlist groups, no group x time interactions were detected in other measures. Everyday EF and adaptive behaviors improved when comparing measurements at different time points (p<.001). Our program is Korea's first evidence-based intervention to improve everyday EF and adaptive behaviors for autistic adults without ID.

Fenfluramine: a plethora of mechanisms?

Developmental and epileptic encephalopathies are rare, treatment-resistant epilepsies with high seizure burden and non-seizure comorbidities. The antiseizure medication (ASM) fenfluramine is an effective treatment for reducing seizure frequency, ameliorating comorbidities, and potentially reducing risk of sudden unexpected death in epilepsy (SUDEP) in patients with Dravet syndrome and Lennox-Gastaut syndrome, among other rare epilepsies. Fenfluramine has a unique mechanism of action (MOA) among ASMs. Its primary MOA is currently described as dual-action sigma-1 receptor and serotonergic activity; however, other mechanisms may be involved. Here, we conduct an extensive review of the literature to identify all previously described mechanisms for fenfluramine. We also consider how these mechanisms may play a role in the reports of clinical benefit in non-seizure outcomes, including SUDEP and everyday executive function. Our review highlights the importance of serotonin and sigma-1 receptor mechanisms in maintaining a balance between excitatory (glutamatergic) and inhibitory (γ-aminobutyric acid [GABA]-ergic) neural networks, and suggests that these mechanisms may represent primary pharmacological MOAs in seizures, non-seizure comorbidities, and SUDEP. We also describe ancillary roles for GABA neurotransmission, noradrenergic neurotransmission, and the endocrine system (especially such progesterone derivatives as neuroactive steroids). Dopaminergic activity underlies appetite reduction, a common side effect with fenfluramine treatment, but any involvement in seizure reduction remains speculative. Further research is underway to evaluate promising new biological pathways for fenfluramine. A better understanding of the pharmacological mechanisms for fenfluramine in reducing seizure burden and non-seizure comorbidities may allow for rational drug design and/or improved clinical decision-making when prescribing multi-ASM regimens.

Beyond the rubicon: a continuum approach to investigating the impact of ADHD like characteristics on everyday executive function in children with Tourette Syndrome

ABSTRACT Across a range of neurodevelopmental conditions, a diagnosis of attention deficit hyperactivity disorder (ADHD) has been shown to be associated with executive function impairment. However, the DSM-V emphasis upon viewing psychological characteristics as existing on a continuous distributed quantitative dimension has enabled the opportunity to consider the influence of sub-diagnostic or sub-referral levels of these psychological characteristics upon cognitive function. This study adopted a continuum approach to the consideration of this ADHD influence and examined the extent to which the difference in parental reported executive functions between children with Tourette syndrome (TS) or typically developing children could be mediated by a concurrent group difference in the possession of sub-referral levels of ADHD-like characteristics. A total of 146 children, 58 with reported TS diagnosis, participated. Parental report measures of ecological executive functioning, the Child Executive Functioning Inventory, and the Vanderbilt ADHD Diagnostic Parent Rating Scale were employed. The analyses with a full sample and a sub-referral sample revealed significant group differences in most of the key measures. In addition, these measures were highly correlated even when controlling for age and gender. A series of mediation analyses indicated that in all models, the ADHD-like measures significantly mediated the group difference in executive function. These results suggest that sub-referrals levels of ADHD-like characteristics continue to contribute to executive challenges in TS. Future intervention research targeting these executive functions should consider the presence of ADHD-like characteristics at sub-referral levels of possession.

Fenfluramine Treatment Is Associated With Improvement in Everyday Executive Function in Adults With Lennox-Gastaut Syndrome: Post-Hoc Analysis of Dose Effects From a Phase 3 Trial Rationale (P11-1.001)

Fenfluramine Treatment Is Associated With Improvement in Everyday Executive Function in Adults With Lennox-Gastaut Syndrome: Post-Hoc Analysis of Dose Effects From a Phase 3 Trial Rationale (P11-1.001)

Executive functions in daily living skills: A study in adults with autism spectrum disorder.

Adults with autism and adults with schizophrenia show difficulties in adaptive skills, especially those related to daily functioning. Some studies suggest that adaptive skills are associated with deficits in executive functions (EF), while others indicate that intelligence quotient (IQ) might also play a role. Literature suggests that autistic symptoms further affect adaptive skills. The interest of the current study, therefore, was to explore to what extent IQ, EFs as well as core autistic symptoms predict adaptive skills. To do this, 25 controls, 24 adults with autism, and 12 with schizophrenia were assessed on IQ (Wechsler Adult Intelligence Scale), and executive functioning. The EF was measured with neuropsychological tasks (inhibition, updating, and task switching) and with the Dysexecutive-Spanish Questionnaire (DEX-Sp) which assessed everyday life EF problems. Core ASD symptoms were measured using the Autism Diagnostic Observation Schedule, the Autism Spectrum Quotient-Short version (AQ-S), and the Repetitive Behavior Questionnaire - 3 (RBQ-3). The results indicated EF difficulties in both, autism and schizophrenia. The IQ explained a high percentage of the variance found in adaptive skills, but only in the autism group. We can conclude, therefore, that high IQ is associated with low adaptive skills levels and EFs affect adaptive functioning in people with autism; however, this does not explain the difficulties in adaptive functioning in the schizophrenia group. Core features of autism assessed with self-report questionnaires (but not the ADOS-2) predicted low scores on the adaptive skills, only in the autism group. Both EF measures predicted adaptive skills scores in autism, but not in schizophrenia. Our results suggest that different factors affect the adaptive functioning in each disorder. For instance, the EFs should be a central focus for improvement, especially for individuals with autism.