Faculty Bibliography

OBJECTIVE/UNASSIGNED:To examine the effects of Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) on ADHD symptoms throughout the day in adults with DSM-5 ADHD. METHOD/UNASSIGNED:This was a 6-week pilot study that included 3 weeks of open label treatment with SDX/d-MPH (39.2/7.8 mg/day to 52.3/10.4 mg/day in clinical titration) after completion of a one-week screening period and a two-week observation period in seventeen adults with ADHD. Two subjects were discontinued from the trial, one for being placebo-responder and another for exhibiting blood pressure lability during the observation period. Of the remaining 15 subjects, one dropped out after one week on 39.2/7.8 mg/day, while all others completed the trial. All fifteen participants were included in the data analyses. RESULTS/UNASSIGNED:There were substantial effects of SDX/d-MPH on all clinical measures, including investigator symptom scores (AISRS); self-report (ASRS) scores, time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A) and measures of medication smoothness (AMSES). SDX/d-MPH was generally well tolerated. CONCLUSIONS/UNASSIGNED:This pilot study is the first systematic treatment effect trial data for SDX/d-MPH in adults with DSM-5 ADHD. The data preliminarily supports the clinical efficacy of DSM/d-MPH in adult ADHD and its ability to ameliorate symptoms throughout the day.

Sharp wave-ripples (SPW-Rs) are critical to hippocampal function, and the same is true of gonadal steroids, but the interactions are unclear. We find that surgical removal of the gonads greatly reduces SPW rates in both sexes. Ripples are greatly reduced also. Testosterone treatment rescues SPW and ripple rates in males, and 17β-estradiol restores SPW rates in females. We also find that male SPW rates are higher than females but have less power. Furthermore, in intact females, SPW rates fluctuate with the stage of the ovarian cycle. These data demonstrate that hippocampal SPWs are significantly affected by gonadal removal, testosterone, and 17β-estradiol. In addition, there are sex differences. The data are consistent with past demonstrations that testosterone and 17β-estradiol play central roles in hippocampus and significantly expand the views of hormone action and SPW-Rs.

BACKGROUND/OBJECTIVES/OBJECTIVE:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies with a challenging prognosis, especially for patients with Neurofibromatosis type 1 (NF1). Their low incidence necessitates comprehensive studies to investigate the survival outcome. METHODS:We conducted a systematic review and meta-analysis, including data from 16 studies and 4265 patients, to explore surgical outcomes and survival rates, focusing on time-related outcomes, including overall survival (OS), progression-free survival (PFS), and recurrence rate. RESULTS:The analysis revealed that the OS rate was 86% [95% CI: 75-97%] at 1 year, decreasing to 60% [95% CI: 45-75%] at 3 years, and further declining to 47% [95% CI: 35-58%] by 5 years. For PFS, the 1-year rate was 61% [95% CI: 25-98%], which remained similar at 62% [95% CI: 35-89%] for 3 and 5 years. In NF1-associated MPNSTs, the 1-year OS was relatively high at 93% [95% CI: 83-100%], but it dropped to 68% [95% CI: 53-84%] at 3 years and further to 50% [95% CI: 31-68%] at 5 years. Additionally, the hazard ratio indicated a 38% lower survival rate in NF1 patients than those with sporadic MPNSTs when data were presented in the same study. Recurrence rates were high, with 56% of patients experiencing a relapse, primarily as local recurrences (70.6%). Mortality was significant, with over 50% of patients dying within an average follow-up period of 33.45 months. CONCLUSIONS:MPNSTs, particularly in NF1 patients, are associated with poor prognosis and high recurrence rates. These results underline the necessity of targeted therapeutic strategies and improved programs for screening, mainly through a multidisciplinary approach to optimize management.

The subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD). Its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. We used a large multi-site cross-sectional sample (1660 patients with MDD vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT) to systematically delineate case-control difference maps of sgACC-FC. We explored the potential impact of group-level abnormality profiles on TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided, individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to individually localize TMS targets. We found enhanced sgACC-DLPFC FC in patients with MDD compared with healthy controls (HC). These group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. We showed that the magnitude of case-control differences in the sgACC-FC was related to clinical improvement in two independent clinical samples. This targeting algorithm may generate targets demonstrating stronger associations with clinical efficiency than group-level targets. We reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets.

Preterm birth can significantly impact cognitive development, particularly executive functions (EF). This study investigated hot (with emotional/motivational aspects) and cool (purely neutral/cognitive) EF trajectories in preterm and full-term children, examining brain-behavior relationships. It included 3508 participants aged 9-10 years (mean age 10.0 years) at baseline from the Adolescent Brain and Cognitive Development (ABCD®) study, evenly split between preterm and full-term births (54.36 % males; 1.05 % Asian American, 10.69 % Black, 15.68 % Hispanic, 61.57 % White, 11.09 % other). Participants were followed for 4 years, completing MRI scans and a cool EF task at baseline and at the 2-year follow-up, as well as hot/cool and hot EF tasks at the 1- and 3-year follow-ups. Linear mixed models showed varying effects of preterm birth across the different EF tasks. Specifically, preterm children showed persistent cool EF deficits and a catch-up pattern for hot EF, while performance on the hot/cool task showed no association with preterm birth. Brain-behavior bivariate latent change score analyses identified distinct bidirectional relationships in specific regions, suggesting altered cognitive-brain maturation interactions in preterm children. These findings highlight the complex nature of EF development following preterm birth: while cool EF deficits persist, hot EF shows catch-up growth in preterm children during early adolescence. This emphasizes the need for tailored interventions and long-term follow-up in this population.

BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) symptomatology in childhood is associated with a high risk of suicide attempt later in life. However, symptom presentation in ADHD is heterogeneous, and little is known about how suicide risk varies according to different profiles of ADHD symptoms and sex. OBJECTIVE:The aim was to investigate the longitudinal associations between childhood profiles of ADHD symptoms (ie, hyperactivity-impulsivity and inattention) and youth suicide attempt in males and females, separately. METHODS:This population-based cohort study used data from three longitudinal cohorts: the Quebec Longitudinal Study of Child Development (QLSCD), the Quebec Longitudinal Study of Kindergarten Children (QLSKC) and the Quebec Newborn Twin Study (QNTS) for a total of 4399 participants (1490 from the QLSCD, 2134 from the QLSKC and 775 from the QNTS; 50% females) followed up from ages 6-23 years. Symptoms of hyperactivity-impulsivity and inattention were assessed by teachers five times from ages 6-12 years. Suicide attempt in adolescence and young adulthood (by age 23) was self-reported. Multitrajectory modelling was used to identify profiles of ADHD symptoms, and regression analysis was used to test their association with suicide attempt, adjusting for childhood socioeconomic and clinical characteristics. FINDINGS/RESULTS:We identified four ADHD symptom profiles with distinct associations with suicide attempt for males and females. Compared with those with persistently low symptoms, females with persistently high inattention and hyperactivity-impulsivity (OR: 2.54, CI 1.39 to 4.63) or high inattention and low hyperactivity-impulsivity (OR: 1.81, CI 1.21 to 2.70) were at higher risk of suicide attempt, while, among males, only those with decreasing hyperactivity-impulsivity and inattention over time (OR: 2.23, CI 1.20 to 4.13) were at higher risk of suicide attempt. CONCLUSIONS:Risk of suicide attempt in children with ADHD symptoms varies according to both symptom profile and sex, the highest risk being for females with high inattention symptoms (with or without hyperactivity), and males with decreasing symptoms. CLINICAL IMPLICATIONS/CONCLUSIONS:Taking into account differences in both sex and ADHD symptoms profile may be relevant to more accurately identify and manage suicide risk in individuals with high ADHD symptoms, though caution is needed when generalising our population-based findings to clinical populations.

Fetal iron status has long-lasting effects on neurodevelopmental outcomes and risk of psychopathology. Although prenatal exposure to maternal psychological stress has been linked to offspring peripheral iron status at birth, it is unknown whether maternal prenatal stress is related to fetal brain iron during gestation. We utilized 86 multi-echo functional magnetic resonance imaging (fMRI) scans from 52 fetuses (23 females; gestational age [GA] 24-38 weeks) to estimate R2* relaxometry as a proxy for fetal brain iron levels. Our results showed that greater maternal anxiety symptoms were associated with higher estimated fetal iron levels in the left cerebellar vermis after controlling for fetal sex and GA. Our finding suggests that fetal brain iron levels may be sensitive to exposure to maternal stress in utero. In a subset of participants with available infant outcome data (n = 31), no significant associations were found between fetal brain iron levels and later cognitive, language, and motor development during infancy. Overall, this study presents the first evidence of associations between maternal prenatal stress and fetal brain iron, which lays the groundwork for future investigations of biological embedding of prenatal maternal stress on the fetal brain and later neurodevelopment through prenatal iron accumulation as a potential mechanism.

A long-standing theory for Alzheimer's disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition.

Assessment of psychiatric symptoms relies on subjective self-report, which can be unreliable. Digital phenotyping collects data from smartphones to provide near-continuous behavioral monitoring. It can be used to provide objective information about an individual's mental state to improve clinical decision-making for both diagnosis and prognostication. The goal of this study was to evaluate the feasibility and acceptability of smartphone-based digital phenotyping for long-term mental health monitoring in adolescents with bipolar disorder and typically developing peers. Participants (aged 14-19) with bipolar disorder (BD) or with no mental health diagnoses were recruited for an 18-month observational study. Participants installed the Beiwe digital phenotyping app on their phones to collect passive data from their smartphone sensors and thrice-weekly surveys. Participants and caregivers were interviewed monthly to assess changes in the participant's mental health. Analyses focused on 48 participants who had completed participation. Average age at baseline was 15.85 years old (SD = 1.37). Approximately half (54%) identified as female, and 54% identified with a minoritized racial/ethnic background. Completion rates across data types were high, with 99% (826/835) of clinical interviews completed, 89% of passive data collected (22,233/25,029), and 47% (4,945/10,448) of thrice-weekly surveys submitted. The proportion of days passive data were collected was consistent over time for both groups; the clinical interview and active survey completion decreased over the study course. Results of this study suggest digital phenotyping has significant potential as a method of long-term mental health monitoring in adolescents. In contrast to traditional methods, including interview and self-report, it is lower burden and provides more complete data over time. A necessary next step is to determine how well the digital data capture changes in mental health to determine the clinical utility of this approach.