The Tower of London task in children and adolescents with neuropsychiatric disorders.

The Tower of London, Drexel Version, Second Edition (TOL-DX) is purported to measure multiple aspects of executive functions, although it also possesses inherent non-executive demands. Such complexity makes it useful in detecting impairment but difficult in interpreting the neurocognitive cause of impairment, particularly in children. This study investigated the developmental, neurocognitive, and symptom correlates of the TOL-DX in children and adolescents with neuropsychiatric disorders. Two-hundred and thirty-three children and adolescents (7-21 years old) completed the TOL-DX during a neuropsychological evaluation as part of clinical care within a children's psychiatric hospital. Pearson correlation, regression models, and receiver operating characteristic curve (ROC) analyses examined the association among variables. Visuospatial and executive functions (EF) were most consistently related to total moves, execution time, and violations. TOL-DX variables were associated with attention in younger participants and EF in older participants. No TOL-DX scores were related to parent-reported symptoms. The TOL-DX possesses inherent visuospatial and attention/executive demands in children and adolescents which are difficult to differentiate, differ by age group, and not associated to clinical symptoms. Taken together, the TOL-DX is complex to interpret, but psychometrically sound and sensitive to neurocognitive impairment in children and adolescents with transdiagnostic neuropsychiatric disorders.

Early childhood trauma exposure and neurocognitive and emotional processes: Associations in young children in a partial hospital program.

Early childhood trauma has been linked to neurocognitive and emotional processing deficits in older children, yet much less is known about these associations in young children. Early childhood is an important developmental period in which to examine relations between trauma and executive functioning/emotion reactivity, given that these capacities are rapidly developing and are potential transdiagnostic factors implicated in the development of psychopathology. This cross-sectional study examined associations between cumulative trauma, interpersonal trauma, and components of executive functioning, episodic memory, and emotion reactivity, conceptualized using the RDoC framework and assessed with observational and performance-based measures, in a sample of 90 children (ages 4-7) admitted to a partial hospital program. Children who had experienced two or more categories of trauma had lower scores in episodic memory, global cognition, and inhibitory control as measured in a relational (but not computerized) task, when compared to children with less or no trauma. Interpersonal trauma was similarly associated with global cognition and relational inhibitory control. Family contextual factors did not moderate associations. Findings support examining inhibitory control in both relationally significant and decontextualized paradigms in early childhood, and underscore the importance of investigating multiple neurocognitive and emotional processes simultaneously to identify potential targets for early intervention.

Frontoparietal beta event characteristics are associated with early life stress and psychiatric symptoms in adults.

Recent work has found that the presence of transient, oscillatory burst-like events, particularly within the beta band (15-29 Hz), is more closely tied to disease state and behavior across species than traditional electroencephalography (EEG) power metrics. This study sought to examine whether features of beta events over frontoparietal electrodes were associated with early life stress (ELS) and the related clinical presentation. Eighteen adults with documented ELS (n = 18; ELS + ) and eighteen adults without documented ELS (n = 18; ELS-) completed eyes-closed resting state EEG as part of their participation in a larger childhood stress study. The rate, power, duration, and frequency span of transient oscillatory events were calculated within the beta band at five frontoparietal electrodes. ELS variables were positively associated with beta event rate at Fp2 and beta event duration at Pz, in that greater ELS was associated with higher resting rates and longer durations. These beta event characteristics were used to successfully distinguish between ELS + and ELS- groups. In an independent clinical dataset (n = 25), beta event power at Pz was positively correlated with ELS. Beta events deserve ongoing investigation as a potential disease marker of ELS and subsequent psychiatric treatment outcomes.

Childhood stress, gender, and cognitive control: Midline theta power.

The emergence of psychiatric symptoms is a common consequence of childhood stress exposure. However, there are a dearth of reliable clinical hallmarks or physiological biomarkers to predict post-trauma symptom emergence. The objective of this study was to examine if childhood stressors and stress-related symptoms are associated with altered midline theta power (MTP) during cognitive control demands, and how these associations interact with gender and early adversity. N = 53 children (ages 9-13 years old) from a longitudinal study of children maltreated during early childhood and non-maltreated children participated in this study. EEG recorded neural activity during a Zoo-Themed Go/No-Go task. Stress-related symptoms, recent stressful events, and other adversity experiences were identified. MTP was analyzed with clinical variables in a series of follow-up analyses. The number of stressors in the past six months was negatively correlated with MTP in those with low preschool adversity, but not in those with high preschool adversity. MTP was higher in girls than in boys, and the associations of MTP with stressors and symptoms were moderated by gender. MTP was negatively associated with stressors in the past six months in girls, while in boys, MTP was associated with stress-related symptoms. Childhood stressful events were associated with reduced MTP during cognitive control demands, and this was finding was moderated by gender and early life adversity. These preliminary findings suggest that boys and girls may process stressful experiences in distinct ways, and preschool adversity may potentially blunt the interaction between current stress and neural dynamics. However, ongoing investigation is needed.

Christianson Syndrome across the Lifespan: An International Longitudinal Study in Children, Adolescents, and Adults.

Mutations in the X-linked endosomal Na+/H+ Exchanger 6 (NHE6) causes Christianson Syndrome (CS). In the largest study to date, we examine genetic diversity and clinical progression, including cerebellar degeneration, in CS into adulthood. Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. Forty-four individuals with 31 unique NHE6 mutations, age 2 to 32 years, were followed prospectively, herein reporting baseline, 1-year follow-up, and retrospective natural history. We present data on the CS phenotype with regard to physical growth, adaptive and motor regression, and across the lifespan, including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model: the rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined: a majority of adult (18+ years) participants lost gross and fine motor skills over a 1-year follow-up. Previously defined core diagnostic criteria for CS (present in >85%) - namely nonverbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia - were universally present in age 6 to 16; however, an additional core feature of high pain tolerance was added (present in 91%), and furthermore, evolution of symptoms were noted across the lifespan, such that postnatal microcephaly, ataxia and high pain threshold were often not apparent prior to age 6, and hyperkinesis decreased after age 16. While neurologic exams were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study. In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype, thereby identifying critical targets for treatment.

Pre-treatment frontal beta events are associated with executive dysfunction improvement after repetitive transcranial magnetic stimulation for depression: A preliminary report.

Repetitive transcranial magnetic stimulation (rTMS) is an established clinical treatment for major depressive disorder (MDD) that has also been found to improve aspects of executive functioning. The objective of this study was to examine whether oscillatory burst-like events within the beta band (15-29 Hz) prior to treatment could predict subsequent change in self-reported executive dysfunction (EDF) across a clinical course of rTMS for MDD. Twenty-eight adults (64% female) with MDD completed the self-report Frontal Systems Behavior Scale (FrSBe) and provided eyes-closed resting-state electroencephalography (EEG) before and after a clinical course of rTMS therapy for primary MDD. The rate, power, duration, and frequency span of transient EEG measured oscillatory beta events were calculated. Events within delta/theta and alpha bands were examined to assess for beta specificity. After controlling for improvement in primary depressive symptoms, a lower rate of beta events at F3, Fz, F4, and Cz prior to rTMS treatment was associated with a larger improvement in EDF after rTMS treatment. In addition, a decrease in beta event rate at Fz pre-to-post treatment was associated with a larger improvement in EDF after treatment. Results were largely specific to the beta band. In this study, the rate of frontrocentral beta events prior to treatment significantly predicted the likelihood of subsequent improvement in EDF symptoms following a clinical course of rTMS for MDD. These preliminary findings suggest the potential utility of EEG measured beta events and rTMS for targeting EDF across an array of neuropsychiatric disorders.

Moderators of Age of Diagnosis in > 20,000 Females with Autism in Two Large US Studies.

The objective of this study was to determine the clinical features that moderate a later age at ASD diagnosis in females in a large sample of females with ASD. Within two large and independent ASD datasets (> 20,000 females), females were first diagnosed with ASD 14-months later relative to males. This later age at diagnosis was moderated by a mild or atypical presentation, wherein repetitive behaviors were limited, IQ and language were broadly intact, and recognized symptoms emerged later in development. Females are at risk for a later age at ASD diagnosis and treatment implementation, and modification of early childhood ASD screening methods for females may be warranted.

Psychiatric Outcomes of Childhood Maltreatment: A Retrospective Chart Review from a Children's Psychiatric Inpatient Program.

Childhood maltreatment is linked to deleterious outcomes, whereby post-traumatic stress disorder (PTSD) has been identified as one of the most debilitating. This retrospective chart review examined whether self-reported affective measures (anxiety, depression, trauma), type of maltreatment (sexual, physical, emotional/verbal abuses), and demographics predicted a diagnosis of anxiety or PTSD among 169 children in a psychiatric inpatient hospital. Secondly, this study identified significant predictors of a PTSD diagnosis. Results indicated self-reported anxiety predicted a diagnosis of PTSD, while self-reported depression predicted PTSD only in maltreated children. Self-reported trauma predicted an anxiety diagnosis. PTSD risk variables including duration of stay, sex, self-reported anxiety, presence of sexual abuse, and presence of emotional/verbal abuse, showed sound sensitivity/specificity as predictors of risk for a PTSD diagnosis in an inpatient setting. Clinical implications are discussed.

Parental age and autism severity in the Rhode Island Consortium for Autism Research and Treatment (RI-CART) study.

Advanced parental age at offspring birth has been associated with autism spectrum disorder (ASD). The objective of the current study was to investigate associations between parental age at birth and autism severity. The Rhode Island Consortium for Autism Research and Treatment (RI-CART) study represents a community-based sample with a range of autism severity, including participants with and without ASD. This study involved participants (n = 1178) enrolled in RI-CART with available mother and father ages at birth. Primary data points included the age of mother and father at the participant's birth and results from the Autism Diagnostic Observation Schedule - Second Edition (ADOS-2). Mothers were 1.7 years older at the time of birth of the child with ASD, as compared to mothers of offspring without ASD. Fathers of children with ASD were 1.6 years older at the time of birth than fathers of children without ASD. The age of both parents at offspring birth displayed a positive, statistically significant association with overall ASD severity and the severity of restricted/repetitive behaviors. This finding was driven by the association between parental age and the severity of compulsions or rituals. Intelligence and adaptive functioning did not moderate the relationship between parental age and ASD severity. This study extends prior research to show that advanced parental age at birth is associated with the severity as well as the presence of ASD in offspring.

The association between neurocognition and sexual abuse within a children's psychiatric inpatient program.

Objective: The aim of this study was to understand the detrimental effects of sexual abuse on neuropsychological variables including child's intelligence, executive functioning (EF), and learning/memory within a pediatric inpatient population.Method: This study examined the effect of sexual abuse on children's intelligence, EF, and learning/memory by conducting a retrospective chart review for 144 children (aged 7-12) who completed a neuropsychological assessment during a psychiatric inpatient hospitalization. Of the 144 children, participants were matched two to one by gender and age, with one group (n = 52) categorized by reported sexual abuse and the other group (n = 92) categorized by no reported sexual abuse. The neuropsychological measures included the Wechsler Abbreviated Scale of Intelligence (WASI-I/II) or Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), Wide Range Assessment of Memory and Learning - Second Edition (WRAML-2): Story Memory Immediate/Delayed Recall and Delayed Recognition, Trail Making Test-B, Stroop Interference Test: Color-Word Condition, WRAML-2: Sentence Memory and Conners Continuous Performance Test-Second Edition.Results: Statistical analysis showed that participants with reported sexual abuse had significantly (p< .05) lower intelligence, EF, and learning/memory skills than those without reported sexual abuse. Only working memory and cognitive flexibility differences remained after controlling for clinical variables (e.g., PTSD, amount of total abuse types).Conclusions: These findings contributed to the limited research on the detrimental effects of sexual abuse in a pediatric inpatient population. They demonstrated a relationship between early sexual abuse and neuropsychological deficits, specifically executive function and IQ deficits.

Cognitive Control Deficits in Depression: A Novel Target to Improve Suboptimal Outcomes in Childhood.

Cognitive control deficits are one of three primary endophenotypes in depression, and the enhanced targeting of these deficits in clinical and research work is expected to lead to improved depression outcomes. Cognitive control is a set of self-regulatory processes responsible for goal-oriented behavior that predicts clinical/functional outcomes across the spectrum of brain-based disorders. In depression, cognitive control deficits emerge by the first depressive episode, persist during symptom remission, and worsen over the course of depression. In addition, the presence of these deficits predicts a poor response to evidence-based depression treatments, including psychotherapy and antidepressant medication. This is particularly relevant to childhood depression, as 1%-2% of children are diagnosed with depression, yet there are very limited evidence-based treatment options. Cognitive control deficits may be a previously underaddressed factor contributing to poor outcomes, although there remains a dearth of research examining the topic. The investigators describe the prior literature on cognitive control in depression to argue for the need for increased focus on this endophenotype. They then describe cognitive control-focused clinical and research avenues that would likely lead to improved treatments and outcomes for this historically undertreated aspect of childhood depression.

Human neurons from Christianson syndrome iPSCs reveal mutation-specific responses to rescue strategies.

Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6, the gene encoding endosomal Na+/H+ exchanger 6 (NHE6). To hasten treatment development, we established induced pluripotent stem cell (iPSC) lines from patients with CS representing a mutational spectrum, as well as biologically related and isogenic control lines. We demonstrated that pathogenic mutations lead to loss of protein function by a variety of mechanisms: The majority of mutations caused loss of mRNA due to nonsense-mediated mRNA decay; however, a recurrent, missense mutation (the G383D mutation) had both loss-of-function and dominant-negative activities. Regardless of mutation, all patient-derived neurons demonstrated reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Phenotype rescue strategies showed mutation-specific responses: A gene transfer strategy was effective in nonsense mutations, but not in the G383D mutation, wherein residual protein appeared to interfere with rescue. In contrast, application of exogenous trophic factors (BDNF or IGF-1) rescued arborization phenotypes across all mutations. These results may guide treatment development in CS, including gene therapy strategies wherein our data suggest that response to treatment may be dictated by the class of mutation.

A preliminary investigation of childhood anxiety/depressive symptomatology and working memory across multiple units of analysis.

This exploratory study examined multiple units of working memory (WM) analysis in a transdiagnostic, treatment-seeking, pediatric sample. This included a) an electroencephalography marker of WM (coupling of theta and gamma oscillations [i.e., theta-gamma coupling] in frontal brain regions), b) WM test performance, and c) parent-reported WM symptoms. A composite score combining each of these units of analysis correlated with self-reported depressive and anxiety symptoms, with only theta-gamma coupling independently predicted anxiety/depressive symptoms. Results confirm prior findings on the association between WM and anxiety/depression, although the majority of this variance was explained by frontal theta-gamma coupling during WM demands.

Assessing performance validity with the TOMM and automatized sequences task in a pediatric psychiatric inpatient setting.

This study examined the performance of children consecutively admitted to an inpatient psychiatric unit on the Test of Memory Malingering (TOMM) (aged 5-12; n = 96) and Automatized Sequences Task (aged 8-12; n = 67). Eighty-three percent of children passed the TOMM Trial 2 (M raw score = 47.7, SD = 4.7) and 76% of children passed the Automatized Sequences Task total time (M = 23.1 seconds; SD = 8.2). The concordance rate between the TOMM and the total time on the Automatized Sequences Task was 73.1%. Receiver operating characteristic curves indicated that of the Automatized Sequences Task subtests, only Counting 1-20 significantly differentiated children who passed Trial 2 of the TOMM from those who did not pass Trial 2 of the TOMM (area under the curve = .756, p = .006). Performance on both PVTs was unrelated to demographic characteristics and measures of psychological and neuropsychological functioning on both the TOMM and Automatized Sequences Task. Further research is needed to determine whether the nearly 1 in 4 children (23.9%) who performed below recommended cutoffs on Automatized Sequences Task reflects genuine suboptimal effort, cognitive difficulties among these children, and/or other factors.

Autism Heterogeneity in a Densely Sampled U.S. Population: Results From the First 1,000 Participants in the RI-CART Study.

The objective of this study was to establish a large, densely sampled, U.S. population-based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co-occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population-based U.S. cohort with ASD. Given the depth of sampling, the RI-CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474-488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co-occurring medical and psychiatric conditions in affected individuals.

Neurocognitive predictors of length of stay within a children's psychiatric inpatient program.

This study investigated the neurocognitive predictors of length of stay (LOS) within a children's psychiatric inpatient program. A medical chart review was conducted for 96 children aged 6-14 years who received a neuropsychological evaluation during hospitalization. Correlation and linear regression analyses examined the influence of neurocognition (memory, construction, executive functioning [EF], and intelligence [IQ]) on subsequent LOS. Impairment/performance was calculated by the standard mean composite score and global deficit score (GDS) approaches for each domain and for overall neurocognition. Rates of impairment were similar between the two approaches (ranging from 22.9% to 45.8% across domains). Overall neurocognition (r = .347 & -.270, respectively), EF (r = .333 & -.261, respectively), and construction (r = .287 & -.240), respectively, were significantly associated with LOS utilizing the GDS and composite approaches. After controlling for clinical/demographic predictors of LOS, GDS-Total, GDS-EF/Construction, and EF/Construction composite scores significantly predicted LOS. Further, receiver operating characteristic (ROC) curve detected the GDS was able to distinguish between those children that would and would not end up having a prolonged hospitalization. The GDS and composite score approaches to neurocognitive impairment detection were similarly able to capture neurocognitive impairment and the association of impairment to LOS within a children's psychiatric inpatient program.

Neurocognitive heterogeneity across the spectrum of psychopathology: need for improved approaches to deficit detection and intervention.

Neurocognition is one of the strongest predictors of clinical and functional outcomes across the spectrum of psychopathology, yet there remains a dearth of unified neurocognitive nosology and available neurocognition-targeted interventions. Neurocognitive deficits manifest in a transdiagnostic manner, with no psychiatric disorder uniquely affiliated with one specific deficit. In fact, recent research has identified that essentially all investigated disorders are comprised of 3-4 neurocognitive profiles. This within-disorder neurocognitive heterogeneity has hampered the development of novel, neurocognition-targeted interventions, as only a portion of patients with any given disorder possess neurocognitive deficits that would warrant neurocognitive intervention. The development of criteria and terminology to characterize these neurocognitive deficit syndromes would provide clinicians with the opportunity to more systematically identify and treat their patients and provide researchers the opportunity to develop neurocognition-targeted interventions for patients. This perspective will summarize recent work and discuss possible approaches for neurocognition-focused diagnosis and treatment in psychiatry.

Measurement of executive functioning with the National Institute of Health Toolbox and the association to anxiety/depressive symptomatology in childhood/adolescence.

INTRODUCTION: Despite preliminary research, there remain inconsistent findings with regard to the role of executive functioning (EF) deficits in childhood anxiety and depression. This report examined the association of The National Institute of Health (NIH) Toolbox to clinical neuropsychological measures and to childhood, anxiety/depressive symptomatology. Methods: One-hundred eight children and adolescents completed the three EF measures from the NIH Toolbox (List Sorting Working Memory Test [LSWMT], Dimensional Change Card Sorting Test [DCCST], and Flanker Test of Attention and Inhibition [Flanker]) in an outpatient neuropsychology program. These tests were compared to established measures of EF in terms of linear correlations and detection of impairment. Heaton's Global Deficit Score (GDS) was utilized to calculate impairment. The Toolbox-EF measures were paired with parent-reported EF symptoms (Behavior Rating Inventory of Executive Function [BRIEF2]) to identify the role of EF in childhood anxiety/depressive symptomatology. RESULTS: Toolbox-EF measures displayed medium sized correlations with their clinically comparable counterparts, and generally did not differ in their detection of impairment. Toolbox-GDS was associated with depression diagnosis and clinically significant child-reported anxiety and depressive symptoms. Together, Toolbox/BRIEF2 accounted for 26.8-30.9% of elevated depressive symptom variance, but only 13.2-14% of elevated anxiety symptom variance. Further, EF impairment was associated with depression across self report, parent report, and clinical diagnosis. DISCUSSION: The NIH Toolbox-EF measures display comparable psychometric properties to clinically available EF measures in a pediatric (primarily psychiatric) neuropsychology setting. The Toolbox appears to display an appropriate ability to detect EF deficits secondary to self-reported depression in childhood.