Faculty Bibliography

BACKGROUND:Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence. METHODS:For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task. RESULTS:Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict. CONCLUSIONS:Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development.

We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.

BACKGROUND:GLUT1 deficiency syndrome is a rare, genetically determined neurological disorder for which Ketogenic Dietary Treatment represents the gold standard and lifelong treatment. Patient registries are powerful tools providing insights and real-world data on rare diseases. OBJECTIVE:To describe the implementation of a national web-based registry for GLUT1-DS. METHODS:This is a retrospective and prospective, multicenter, observational registry developed in collaboration with the Italian GLUT1-DS association and based on an innovative, flexible and configurable cloud computing technology platform, structured according to the most rigorous requirements for the management of patient's sensitive data. The Glut1 Registry collects baseline and follow-up data on the patient's demographics, history, symptoms, genotype, clinical, and instrumental evaluations and therapies. RESULTS:Five Centers in Italy joined the registry, and two more Centers are currently joining. In the first two years of running, data from 67 patients (40 females and 27 males) have been collected. Age at symptom onset was within the first year of life in most (40, 60%) patients. The diagnosis was formulated in infancy in almost half of the cases (34, 51%). Symptoms at onset were mainly paroxysmal (mostly epileptic seizure and paroxysmal ocular movement disorder) or mixed paroxysmal and fixed symptoms (mostly psychomotor delay). Most patients (53, 79%) are currently under Ketogenic dietary treatments. CONCLUSIONS:We describe the principles behind the design, development, and deployment of the web-based nationwide GLUT1-DS registry. It represents a stepping stone towards a more comprehensive understanding of the disease from onset to adulthood. It also represents a virtuous model from a technical, legal, and organizational point of view, thus representing a possible paradigmatic example for other rare disease registry implementation.

Attention-deficit/hyperactivity disorder (ADHD) often co-occurs with substance use (SU) and/or substance use disorder (SUD). Individuals with concurrent ADHD and SU/SUD can have complex presentations that may complicate diagnosis and treatment. This can be further complicated by the context in which services are delivered. Also, when working with young people and adults with co-existing ADHD and SU/SUD, there is uncertainty among healthcare practitioners on how best to meet their needs. In February 2022, the United Kingdom ADHD Partnership hosted a meeting attended by multidisciplinary experts to address these issues. Following presentations providing attendees with an overview of the literature, group discussions were held synthesizing research evidence and clinical experience. Topics included: (1) A review of substances and reasons for use/misuse; (2) identification, assessment and treatment of illicit SU/SUD in young people and adults with ADHD presenting in community services; and (3) identification, assessment and treatment of ADHD in adults presenting in SU/SUD community and inpatient services. Dis-cussions highlighted inter-service barriers and fragmentation of care. It was concluded that a multimodal and multi-agency approach is needed. The consensus group generated a table of practice recommendations providing guidance on: identification and assessment; pharmacological and psychological treatment; and multi-agency interventions.

In Kenya, there is a treatment gap for depression and alcohol use that is especially large for fathers, which has consequences for families. While treatments exist, there are challenges to implementation. This study aimed to understand barriers and facilitators to implementing a treatment for fathers' depression and alcohol use in Eldoret, Kenya. Guided by the Consolidated Framework for Implementation Research and the Integrated Sustainability Framework, we conducted 18 key informant interviews and 7 focus group discussions (31 total participants) with stakeholders in Eldoret (hospital leaders, policy makers, mental health providers, community leaders, fathers, lay providers, and patients previously engaged in treatment). Interviews were analyzed using the framework method; themes were matrixed by framework domains. Participants identified barriers and facilitators, and opportunities for implementation, in the following domains: innovation, outer setting, inner setting, individual, sustainability, and characteristics of systems. Barriers included a lack of resources, stigma, masculine norms, cost of services, and alcohol dependence. Facilitators included community buy-in, family support, providers with lived experience, government support, and relevant treatment content. Findings will inform implementation strategy development for an intervention for fathers with depression and alcohol use, and family problems with local relevance and scalable potential.

Electroencephalography (EEG) continues to be a pivotal investigation in children with epilepsy, providing diagnostic evidence and supporting syndromic classification. In the pediatric population, electroencephalographic recordings are frequently performed during sleep, since this procedure reduces the number of artifacts and activates epileptiform abnormalities. To date, no shared guidelines are available for sleep induction in EEG. Among the interventions used in the clinical setting, melatonin and sleep deprivation represent the most used methods. The main purpose of this study is to test the non-inferiority of 3-5 mg melatonin versus sleep deprivation in achieving sleep in nap electroencephalography in children and young adult patients with epilepsy. To test non-inferiority, a randomized crossover trial is proposed where 30 patients will be randomized to receive 3-5 mg melatonin or sleep deprivation. Each enrolled subject will perform EEG recordings during sleep in the early afternoon for a total of 60 EEGs. In the melatonin group, the study drug will be administered a single oral dose 30 min prior to the EEG recording. In the sleep deprivation group, parents will be required to subject the child to sleep deprivation the night before registration. Urinary and salivary concentrations of melatonin and of its main metabolite 6-hydroxymelatonin will be determined by using a validated LC-MS method. The present protocol aims to offer a standardized protocol for sleep induction to be applied to EEG recordings in those of pediatric age. In addition, melatonin metabolism and elimination will be characterized and its potential interference in interictal abnormalities will be assessed.

IMPORTANCE:Early behavior problems in children with developmental delay (DD) are prevalent and impairing, but service barriers persist. Controlled studies examining telehealth approaches are limited, particularly for children with DD. OBJECTIVE:To evaluate the efficacy of a telehealth parenting intervention for behavior problems in young children with DD. DESIGN, SETTING, AND PARTICIPANTS:A randomized clinical trial was conducted from March 17, 2016, to December 15, 2020, in which children with DD and externalizing behavior problems were recruited from early intervention and randomly assigned to a telehealth parenting intervention or control group and evaluated through a 12-month follow-up. Most children were from ethnic or racial minoritized backgrounds. Over one-half of children were in extreme poverty or low income-need ratio categories. INTERVENTIONS:Internet-delivered parent-child interaction therapy (iPCIT), which leverages videoconferencing to provide live coaching of home-based caregiver-child interactions. Families received 20 weeks of iPCIT (provided in English or in Spanish) or referrals as usual (RAU). MAIN OUTCOMES AND MEASURES:Observational and caregiver-report measures of child and caregiver behaviors and caregiving stress were examined at preintervention, midtreatment, and postintervention and at 6- and 12-month follow-ups. RESULTS:The sample included a total of 150 children (mean [SD] age, 36.2 [1.0] months; 111 male children [74%]) and their caregivers with 75 each randomly assigned to iPCIT or RAU groups. Children receiving iPCIT relative to RAU displayed significantly lower levels of externalizing problems (postintervention Cohen d = 0.48; 6-month Cohen d = 0.49; 12-month Cohen d = 0.50) and significantly higher levels of compliance to caregiver direction after treatment. Of those children with data at postintervention, greater clinically significant change was observed at postintervention for children in the iPCIT group (50 [74%]) than for those in the RAU group (30 [42%]), which was maintained at the 6-month but not the 12-month follow-up. iPCIT did not outperform RAU in reducing caregiving stress, but caregivers receiving iPCIT, relative to RAU, showed steeper increases in proportion of observed positive parenting skills (postintervention odds ratio [OR], 1.10; 95% CI, 0.53-2.21; 6-month OR, 1.31; 95% CI, 0.61-2.55; 12-month OR, 1.64; 95% CI, 0.70-3.07) and sharper decreases in proportion of observed controlling/critical behaviors (postintervention OR, 1.40; 95% CI, 0.61-1.52; 6-month OR, 1.72; 95% CI, 0.58-1.46; 12-month OR, 2.23; 95% CI, 0.53-1.37). After treatment, iPCIT caregivers also self-reported steeper decreases in harsh and inconsistent discipline than did than RAU caregivers (postintervention Cohen d = 0.24; 6-month Cohen d = 0.26; 12-month Cohen d = 0.27). CONCLUSIONS AND RELEVANCE:Results of this randomized clinical trial provide evidence that a telehealth-delivered parenting intervention with real-time therapist coaching led to significant and maintained improvements for young children with DD and their caregivers. Findings underscore the promise of telehealth formats for expanding scope and reach of care for underserved families. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03260816.

Separability (a Kronecker product) of a scatter matrix is one of favorable structures when multivariate heavy-tailed data are collected in a matrix form, due to its parsimonious representation. However, little attempt has been made to test separability beyond Gaussianity. In this paper, we present nonparametric separability tests that can be applied to a larger class of multivariate distributions not only including elliptical distributions but also generalized elliptical distributions and transelliptical distributions. The proposed test statistic exploits robustness of Tyler's M (or Kendall's tau) estimator and a likelihood function of a scaled variable. Since its distribution is hard to specify, we approximate the p-value using a permutation procedure, whose unbiasedness is obtained from the permutation invariance of multivariate paired data. Our simulation study demonstrates the efficacy of our method against other alternatives, and we apply it to rhesus monkey data and corpus callosum data.

Fetal motor behavior is an important clinical indicator of healthy development. However, our understanding of associations between fetal behavior and fetal brain development is limited. To fill this gap, this study introduced an approach to automatically and objectively classify long durations of fetal movement from a continuous four-dimensional functional magnetic resonance imaging (fMRI) data set, and paired behavior features with brain activity indicated by the fMRI time series. Twelve-minute fMRI scans were conducted in 120 normal fetuses. Postnatal motor function was evaluated at 7 and 36 months age. Fetal motor behavior was quantified by calculating the frame-wise displacement (FD) of fetal brains extracted by a deep-learning model along the whole time series. Analyzing only low motion data, we characterized the recurring coactivation patterns (CAPs) of the supplementary motor area (SMA). Results showed reduced motor activity with advancing gestational age (GA), likely due in part to loss of space (r = -.51, p < .001). Evaluation of individual variation in motor movement revealed a negative association between movement and the occurrence of coactivations within the left parietotemporal network, controlling for age and sex (p = .003). Further, we found that the occurrence of coactivations between the SMA to posterior brain regions, including visual cortex, was prospectively associated with postnatal motor function at 7 months (r = .43, p = .03). This is the first study to pair fetal movement and fMRI, highlighting potential for comparisons of fetal behavior and neural network development to enhance our understanding of fetal brain organization.

Characterizing the developmental trajectories of children with autism spectrum disorder (ASD) throughout adolescence and across different domains of functioning offers opportunities to improve long-term outcomes. This prospective study explored, for the first time, the evolution of children with ASD-without intellectual disability (ID) in terms of socio-adaptative skills, learning behaviors, executive functioning (EF), and internalizing/externalizing problems, compared to typically developing (TD) peers. Forty-five children with ASD-without ID and 37 matched TD children (aged 7-11) were assessed at baseline and after 5 years. Parents and teachers completed measures on theory of mind (ToM), socialization, daily living skills, learning style, EF, and emotional/behavioural difficulties at both time points. On all the domains assessed, the ASD group performed significantly worse than the TD group, both in childhood and adolescence. Specific changes were noted between baseline and follow-up assessment on adaptive skills, prosocial behavior, emotional control, inhibit, working memory and monitoring. Group membership (ASD/TD) was influenced by peer relationships and inhibit EF variables. These findings have implications for clinical and school settings.