Faculty Bibliography

This meta-analysis investigated the effects of computerized cognitive training (CCT) on clinical, neuropsychological and academic outcomes in individuals with attention-deficit/hyperactivity disorder (ADHD). The authors searched PubMed, Ovid, and Web of Science until 19th January 2022 for parallel-arm randomized controlled trials (RCTs) using CCT in individuals with ADHD. Random-effects meta-analyses pooled standardized mean differences (SMD) between CCT and comparator arms. RCT quality was assessed with the Cochrane Risk of Bias 2.0 tool (PROSPERO: CRD42021229279). Thirty-six RCTs were meta-analysed, 17 of which evaluated working memory training (WMT). Analysis of outcomes measured immediately post-treatment and judged to be "probably blinded" (PBLIND; trial n = 14) showed no effect on ADHD total (SMD = 0.12, 95%CI[-0.01 to -0.25]) or hyperactivity/impulsivity symptoms (SMD = 0.12, 95%[-0.03 to-0.28]). These findings remained when analyses were restricted to trials (n: 5-13) with children/adolescents, low medication exposure, semi-active controls, or WMT or multiple process training. There was a small improvement in inattention symptoms (SMD = 0.17, 95%CI[0.02-0.31]), which remained when trials were restricted to semi-active controls (SMD = 0.20, 95%CI[0.04-0.37]), and doubled in size when assessed in the intervention delivery setting (n = 5, SMD = 0.40, 95%CI[0.09-0.71]), suggesting a setting-specific effect. CCT improved WM (verbal: n = 15, SMD = 0.38, 95%CI[0.24-0.53]; visual-spatial: n = 9, SMD = 0.49, 95%CI[0.31-0.67]), but not other neuropsychological (e.g., attention, inhibition) or academic outcomes (e.g., reading, arithmetic; analysed n: 5-15). Longer-term improvement (at ~6-months) in verbal WM, reading comprehension, and ratings of executive functions were observed but relevant trials were limited in number (n: 5-7). There was no evidence that multi-process training was superior to working memory training. In sum, CCT led to shorter-term improvements in WM, with some evidence that verbal WM effects persisted in the longer-term. Clinical effects were limited to small, setting specific, short-term effects on inattention symptoms.

Differences in visual attention have been documented in ASD, and appear linked to clinical symptoms. However, most research has been conducted in Western cultures. Because striking differences in visual attention patterns have been documented in other cultures, it is important to understand how culture may influence attentional patterns in ASD. This study compared differences in visual attention in ASD across Western and East Asian cultures, where differences in attention to contextual and global information have been repeatedly demonstrated, to investigate potential culturally-specific ASD phenotypes. One hundred thirty-two total participants included individuals with ASD (n = 24) and controls (n = 47) from Hong Kong (HK), along with a previously studied group of age- and IQ-comparable participants from the United States (n = 26 ASD; n = 35 control). Gaze was tracked while participants completed two narrative tasks that differed in social-emotional complexity. Proportions of fixations to face, bodies, and setting were examined across groups using linear mixed-effect models and a series of growth curve models. Cultural differences were found across tasks and groups. Both the ASD and control HK groups attended more to global contextual setting information, more to the body regions, and less toward faces of characters compared to US groups. Growth curve models indicated that these differences attenuated over time in certain stimuli. ASD-related effects were only observed in the more complex stimuli depicting characters with ambiguous facial expressions. Findings indicate a notable cultural influence on visual attention patterns in ASD, and underscore the importance of stimuli complexity in differentiating cultural versus diagnostic effects on attentional styles.

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.