BRAIN CONNECTIVITY AND TREATMENT RESPONSE IN ADULT ADHD:understanding the relationship between individual differences in fronto-parietal and fronto-striatal brain networks and response to chronic treatment with methylphenidate

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, characterised by disrupted anatomical and/or functional connectivity, mainly in the fronto-striatal and fronto-parietal networks. Stimulants, such as methylphenidate (MPH), represent a first-line treatment in ADHD, but one third of patients fail to respond, with severe consequences for the individual and the society at large. Hence, a comprehensive understanding of the relationship between individual differences in brain abnormalities and treatment response is needed.This thesis focused on two main brain networks: the fronto-striatal network, a central theme in ADHD research, and the fronto-parietal attentive network, formed by the three branches of the superior longitudinal fasciculus (SLF). The SLF branches have been only recently described in humans, and there is no detailed analysis of their distinct functional roles and involvement in disorders such as ADHD. Therefore, I first investigated the functional anatomy of the SLF branches by combining a meta-analytic approach with tractography, and revealed novel findings about the anatomical and functional segregation and integration of brain functions within fronto-parietal networks. Then, I showed, for the first time, that the three SLF branches are all significantly right-lateralised in ADHD patients but not in controls, and provided preliminary evidence that the pattern of lateralisation of the SLF I may be related to poor attentive performance in ADHD patients.Finally, I conducted functional and structural connectivity analysis to test whether a relationship exists between brain abnormalities and treatment response in adult ADHD. I employed a longitudinal crossover follow-up design. 60 non-medicated adult ADHD patients were recruited and underwent behavioural assessment (Qb test) and magnetic resonance imaging (MRI) scanning twice, once under placebo and once under a clinically effective dose of MPH. Clinical and behavioural response was measured after two months of treatment with MPH. I demonstrated for the first time that there is a relationship between ‘connectivity’ abnormalities within fronto-parietal networks and treatment response in adult ADHD, both at the anatomical and functional level.Ultimately, my investigation contributed towards the identification of potential biomarkers of treatment response, which in the future may help clinicians deliver more individualised treatments.<br/

Long-term central nervous system (CNS) consequences of COVID-19 in children

Introduction: neurological/neuropsychiatric symptoms are commonly reported by children/young people with long COVID, especially headache, fatigue, cognitive deficits, anosmia and ageusia, dizziness, mood symptoms, and sleep problems. However, reported prevalence estimates are highly variable due to study heterogeneity and often small sample size; most studies only considered short-term follow-ups; and, apart from mood and sleep problems, neuropsychiatric conditions have received less attention. Considering the potential debilitating effects of neurological/neuropsychiatric conditions, a comprehensive review of the topic is timely, and needed to support clinical recognition as well as to set the direction for future research.Areas covered: the authors discuss neurological/neuropsychiatric manifestations of long COVID in pediatric populations, with a focus on prevalence, associated demographic characteristics, and potential pathogenetic mechanisms.Expert opinion: children/young people may develop persistent neurological/neuropsychiatric symptoms following acute SARS-CoV-2 infection, which may affect daily functioning and well-being. Studies in larger samples with longer follow-ups are needed to clarify prevalence and symptom duration; as well as less investigated risk factors, including genetic predisposition, ethnicity, and comorbidities. Controlled studies may help separate infection-related direct effects from pandemic-related psychosocial stressors. Clarifying pathogenetic mechanisms is paramount to develop more targeted and effective treatments; whilst screening programs and psychoeducation may enhance early recognition.</p

Computerized cognitive training in attention-deficit/hyperactivity disorder (ADHD): a meta-analysis of randomized controlled trials with blinded and objective outcomes

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

White matter alterations in Attention-Deficit/Hyperactivity Disorder (ADHD):a systematic review of 129 diffusion imaging studies with meta-analysis

Aberrant anatomical brain connections in attention-deficit/hyperactivity disorder (ADHD) are reported inconsistently across diffusion weighted imaging (DWI) studies. Based on a pre-registered protocol (Prospero: CRD42021259192), we searched PubMed, Ovid, and Web of Knowledge until 26/03/2022 to conduct a systematic review of DWI studies. We performed a quality assessment based on imaging acquisition, preprocessing, and analysis. Using signed differential mapping, we meta-analyzed a subset of the retrieved studies amenable to quantitative evidence synthesis, i.e., tract-based spatial statistics (TBSS) studies, in individuals of any age and, separately, in children, adults, and high-quality datasets. Finally, we conducted meta-regressions to test the effect of age, sex, and medication-naïvety. We included 129 studies (6739 ADHD participants and 6476 controls), of which 25 TBSS studies provided peak coordinates for case-control differences in fractional anisotropy (FA)(32 datasets) and 18 in mean diffusivity (MD)(23 datasets). The systematic review highlighted white matter alterations (especially reduced FA) in projection, commissural and association pathways of individuals with ADHD, which were associated with symptom severity and cognitive deficits. The meta-analysis showed a consistent reduced FA in the splenium and body of the corpus callosum, extending to the cingulum. Lower FA was related to older age, and case-control differences did not survive in the pediatric meta-analysis. About 68% of studies were of low quality, mainly due to acquisitions with non-isotropic voxels or lack of motion correction; and the sensitivity analysis in high-quality datasets yielded no significant results. Findings suggest prominent alterations in posterior interhemispheric connections subserving cognitive and motor functions affected in ADHD, although these might be influenced by non-optimal acquisition parameters/preprocessing. Absence of findings in children may be related to the late development of callosal fibers, which may enhance case-control differences in adulthood. Clinicodemographic and methodological differences were major barriers to consistency and comparability among studies, and should be addressed in future investigations. © 2023, The Author(s).11Nsciescopu

Computerized cognitive training in attention-deficit/hyperactivity disorder (ADHD): a meta-analysis of randomized controlled trials with blinded and objective outcomes

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

Management of sleep problems in people with autism: an updated review

Sleep problems are more common in people with autism spectrum disorder (ASD) as compared to the general population, and may contribute to worsening social functioning, emotional symptoms, and lower quality of life. To support healthcare professionals and researchers in the field, we provide an updated overview of sleep problems in the context of autism across the lifespan and their evidence-based management, as derived from evidence-synthesis studies and the most recent randomized controlled trials. Most studies to date have been conducted in children and adolescents with autism. Several studies suggest that behavioral interventions aiming at improving sleep hygiene and environment may be beneficial, especially when actively involving parents. Furthermore, there is an increasing body of literature showing that melatonin is an effective pharmacological option for improving sleep quality in children and adolescents with autism, in line with reports showing a reduced endogenous synthesis of this hormone. Unfortunately, studies in adults are more limited, and thus, the evidence base around non-pharmacological and pharmacological interventions remains mixed. Finally, there is a growing interest towards the use of complementary interventions or food supplements, but further studies are needed to test their effectiveness. In sum, most studies to date support the use of behavioral interventions and melatonin, especially in children and adolescents with autism. However, findings need to be validated in large-scale, rigorous and blinded trials and extended to the adult population. Non-pharmacological interventions remain the first treatment option and should adopt an individualized approach, considering individual characteristics and needs, including comorbidities, family dynamics, and sleep environment

From neurons to brain networks, pharmacodynamics of stimulant medication for ADHD

Stimulants represent the first line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) and are among the most prescribed psychopharmacological treatments. Their mechanism of action at synaptic level has been extensively studied. However, it is less clear how their mechanism of action determines clinically observed benefits. To help bridge this gap, we provide a comprehensive review of stimulant effects, with an emphasis on nuclear medicine and magnetic resonance imaging (MRI) findings. There is evidence that stimulant-induced modulation of dopamine and norepinephrine neurotransmission optimizes engagement of task-related brain networks, increases perceived saliency, and reduces interference from the default mode network. An acute administration of stimulants may reduce brain alterations observed in untreated individuals in fronto-striato-parieto-cerebellar networks during tasks or at rest. Potential effects of prolonged treatment remain controversial. Overall, neuroimaging has fostered understanding on stimulant mechanism of action. However, studies are often limited by small samples, short or no follow-up, and methodological heterogeneity. Future studies should address age-related and longer-term effects, potential differences among stimulants, and predictors of treatment response

Association between single dose and longer-term clinical response to stimulants in ADHD: a systematic review of randomized controlled trials.: Single dose and long-term ADHD treatment response

Objectives: stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for Attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer-term response. It is unclear whether this also applies to clinical measures. Methods: we carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer-term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD dataset, the European ADHD Guidelines Group (EAGG) RCT Dataset (https://med-adhd.org/), as updated on the 01/02/2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool.Results: 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only one RCT tested the association between acute and longer-term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after four-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy (NIRS), thus did not meet inclusion criteria, and reported an association between brain changes under a single dose and longer-term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single dose effects on neuropsychological, neuroimaging or neurophysiological measures. Conclusion: this systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age and sex-related differences. <br/

Alterations in cortical anatomy are associated with lower response to methylphenidate in adults with ADHD

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A narrative review of the efficacy of interventions for emotional dysregulation, and underlying bio–psycho–social factors

In this narrative, comprehensive, and updated review of the literature, we summarize evidence about the effectiveness of interventions aimed at reducing emotion dysregulation and improving emotion regulation in children, adolescents, and adults. After introducing emotion dysregulation and emotion regulation from a theoretical standpoint, we discuss the factors commonly associated with emotion regulation, including neurobiological and neuropsychological mechanisms, and the role of childhood adverse experiences and psycho–social factors in the onset of emotion dysregulation. We then present evidence about pharmacological and non-pharmacological interventions aiming at improving emotion dysregulation and promoting emotion regulation across the lifespan. Although our review was not intended as a traditional systematic review, and the search was only restricted to systematic reviews and meta-analyses, we highlighted important implications and provided recommendations for clinical practice and future research in this field