Faculty Bibliography

Preliminary evidence suggests a possible association between Attention-Deficit/Hyperactivity Disorder and Restless Legs Syndrome with or without Periodic Limb Movements during Sleep. When comorbid, Restless Legs Syndrome/Periodic Limb Movements during Sleep might aggravate Attention-Deficit/Hyperactivity Disorder symptoms. Pharmacological treatment of Attention-Deficit/Hyperactivity Disorder may be associated, at least in some cases, with adverse cardiovascular events, including clinically significant elevation in heart rate and systemic blood pressure. However, the characteristics of patients with Attention-Deficit/Hyperactivity Disorder at risk for cardiovascular events during pharmacological treatment are poorly understood. Here, we hypothesize that Restless Legs Syndrome and/or Periodic Limb Movements during Sleep comorbid with Attention-Deficit/Hyperactivity Disorder increase cardiovascular risk via imbalance in activity of the autonomic nervous system. Such an imbalance of the could be related to alterations of sleep microarchitecture also detected by cyclic alternating pattern analysis. If empirical studies confirm our hypothesis, the clinician would be advised to systematically screen for and effectively treat Restless Legs Syndrome/Periodic Limb Movements during Sleep even before starting treatment with Attention-Deficit/Hyperactivity Disorder drugs. The management of Restless Legs Syndrome/Periodic Limb Movements during Sleep might reduce cardiovascular risk during pharmacological treatment of Attention-Deficit/Hyperactivity Disorder.

The aim of this paper was to review the neuroimaging literature on attention-deficit/hyperactivity disorder (ADHD), with a focus on structural and functional magnetic resonance imaging (MRI) studies. We surveyed in particular studies of structural voxel based morphometry MRI and diffusion tensor imaging, as well as of task-based functional and resting state MRI. The overall evidence points to dysfunctions in frontoparietal, striatal, thalamic, and cerebellar networks in ADHD, but also to dysfunctional interactions among the default network and top-down regulatory networks, and visual and sensorimotor cortex.Therefore, the classic model of ADHD pathophysiology focused on fronto-striatal circuits should be expanded to include a broader set of dysfunctional interactions within and among brain networks. Available neuroimaging studies also show that ADHD pharmacological treatments and, possibly, non-pharmacological approaches, tend to normalize structural and functional brain abnormalities. To date, results from neuroimaging studies do not have a direct application in the day-to-day clinical practice at the single patient level; however, it is hoped that the introduction of machine learning techniques, in particular support vector machine, may contribute to the use of neuroimaging in the clinical practice in terms of prediction of diagnosis for challenging cases and, perhaps more importantly, prediction of outcome and response to treatment

The neuroimaging literature on attention-deficit/hyperactivity disorder (ADHD) is growing rapidly. Here, we provide a critical overview of neuroimaging studies published recently, highlighting perspectives that may be of relevance for clinicians. After a comprehensive search of PubMed, Ovid, Web of Science, and EMBASE, we located 41 pertinent papers published between January 2011 and April 2012, comprising both structural and functional neuroimaging studies. This literature is increasingly contributing to the notion that the pathophysiology of ADHD reflects abnormal interplay among large-scale brain circuits. Moreover, recent studies have begun to reveal the mechanisms of action of pharmacological treatment. Finally, imaging studies with a developmental perspective are revealing the brain correlates of ADHD over the lifespan, complementing clinical observations on the phenotypic continuity and discontinuity of the disorder. However, despite the increasing potential to eventually inform clinical practice, current imaging studies do not have validated applications in day-to-day clinical practice. Although novel analytical techniques are likely to accelerate the pace of translational applications, at the present we advise caution regarding inappropriate commercial misuse of imaging techniques in ADHD.

OBJECTIVE: The authors performed a comprehensive meta-analysis of task-based functional MRI studies of attention deficit hyperactivity disorder (ADHD). METHOD: The authors searched PubMed, Ovid, EMBASE, Web of Science, ERIC, CINAHAL, and NeuroSynth for studies published through June 30, 2011. Significant differences in brain region activation between individuals with ADHD and comparison subjects were detected using activation likelihood estimation meta-analysis. Dysfunctional regions in ADHD were related to seven reference neuronal systems. The authors performed a set of meta-analyses focused on age groups (children and adults), clinical characteristics (history of stimulant treatment and presence of psychiatric comorbidities), and specific neuropsychological tasks (inhibition, working memory, and vigilance/attention). RESULTS: Fifty-five studies were included (39 for children and 16 for adults). In children, hypoactivation in ADHD relative to comparison subjects was observed mostly in systems involved in executive function (frontoparietal network) and attention (ventral attentional network). Significant hyperactivation in ADHD relative to comparison subjects was observed predominantly in the default, ventral attention, and somatomotor networks. In adults, ADHD-related hypoactivation was predominant in the frontoparietal system, while ADHD-related hyperactivation was present in the visual, dorsal attention, and default networks. Significant ADHD-related dysfunction largely reflected task features and was detected even in the absence of comorbid mental disorders or a history of stimulant treatment. CONCLUSIONS: A growing literature provides evidence of ADHD-related dysfunction in multiple neuronal systems involved in higher-level cognitive functions but also in sensorimotor processes, including the visual system, and in the default network. This meta-analytic evidence extends early models of ADHD pathophysiology that were focused on prefrontal-striatal circuits.

The authors systematically reviewed evidence on iron status, as well as studies of iron supplementation, in individuals with attention deficit/hyperactivity disorder (ADHD). PubMed, Ovid, EMBASE and Web of Knowledge were searched on 4 July 2012. Quantitative appraisal of trials was performed using Jadad's score. Most (n = 20) of the retrieved studies assessed an index of peripheral iron status (i.e., serum ferritin), with overall mixed results - that is, both significant and nonsignificant association between ADHD symptoms and serum ferritin levels. One MRI study reported significantly lower indices of thalamic iron in ADHD versus comparison subjects. Two trials, an open-label and a pilot randomized placebo-controlled study with high Jaded score (4), showed improvement in some but not all measures of ADHD symptoms. Three studies showed that children with ADHD plus sleep disorders, in particular restless legs syndrome, are at risk of iron deficiency. Finally, two studies suggested that iron deficiency might decrease the effectiveness of psychostimulant treatment. The authors discussed how the field could move from initial research mainly focused on serum ferritin towards a more comprehensive and translational investigation of iron in ADHD, with the potential to inform clinical practice in terms of screening and treating iron deficiency in individuals with ADHD.

This review, addressed mainly to clinicians, considers commonly asked questions related to the neuroimaging, neurophysiology, neurochemistry and genetics of Attention-Deficit/Hyperactivity Disorder (ADHD). It provides answers based on the most recent meta-analyses and systematic reviews, as well as additional relevant original studies. Empirical findings from neurobiological research into ADHD reflect a shift in the conceptualisation of this disorder from simple theoretical views of a few isolated dysfunctions to more complex models integrating the heterogeneity of the clinical manifestations of ADHD. Thus, findings from structural and functional neuroimaging suggest the involvement of developmentally abnormal brain networks related to cognition, attention, emotion and sensorimotor functions. Brain functioning alterations are confirmed by neurophysiological findings, showing that individuals with ADHD have elevated theta/beta power ratios, and less pronounced responses and longer latencies of event-related potentials, compared with controls. At a molecular level, alterations in any single neurotransmitter system are unlikely to explain the complexity of ADHD; rather, the disorder has been linked to dysfunctions in several systems, including the dopaminergic, adrenergic, serotoninergic and cholinergic pathways. Genetic studies showing a heritability of approximately 60-75% suggest that a plethora of genes, each one with a small but significant effect, interact with environmental factors to increase the susceptibility to ADHD. Currently, findings from neurobiological research do not have a direct application in daily clinical practice, but it is hoped that in the near future they will complement the diagnostic process and contribute to the long-term effective treatment of this impairing condition.

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common childhood-onset neuropsychiatric conditions. Despite extensive research, the etiopathophysiological factors underlying ADHD are not completely understood. It has been suggested that iron deficiency may contribute to ADHD symptoms severity. Whereas evidence from studies based on serum ferritin measures, a marker of peripheral iron status, is somewhat mixed, preliminary recent evidence suggests a deficiency of brain iron in individuals with ADHD. Therefore, it has been proposed that either a deficiency of peripheral iron or a dysfunction of the blood-brain barrier, in the presence of normal peripheral iron levels, may contribute to low brain iron levels, which, in turn, would increase the risk for ADHD symptoms in a subgroup of individuals with this disorder. It has also been found that individuals with ADHD may be at increased risk of severe cardiovascular events during treatment with ADHD drugs, although the extent to which this occurs in ADHD patients compared to non-ADHD individuals is still matter of investigation. Since iron depletion has been recently reported as a risk factor for adverse prognosis in heart failure, iron deficiency might contribute both to ADHD symptoms severity before treatment and to increased risk of severe cardiovascular events during treatment with ADHD drugs in a selected subgroup of patients. Therefore, we hypothesize that the effective treatment of iron deficiency might lead both to improvement of ADHD symptoms severity and to a decrease of the risk of cardiovascular events during treatment with ADHD drugs. If empirical studies confirm this hypothesis, the clinician would be advised to systematically check iron status and effectively treat iron deficiency before starting a pharmacological treatment with ADHD drugs.

We conducted a comprehensive review of studies assessing the efficacy and tolerability of psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorder (encompassing autism disorder, Asperger's syndrome and pervasive developmental disorders not otherwise specified). PubMed, Ovid, EMBASE, Web of Science, ERIC and CINHAL were searched through 3 January 2012. From a pool of 348 potentially relevant references, 12 citations (11 studies) were retained as pertinent. Four of the included studies had a randomized controlled design. Most of the studies assessed methylphenidate immediate release. Despite inter-study heterogeneity, taken together, the results of the selected reports suggest that psychostimulants may be effective for ADHD-like symptoms in autism spectrum disorder individuals. The most common adverse events reported in the included trials were appetite reduction, sleep-onset difficulties, irritability and emotional outbursts. We discuss future directions in the field, including the need for trials assessing more ecological outcomes and combined treatment strategies tailored to the specific individual features.

Abstract Objective. Brain iron deficiency has been supposed to be involved in the pathophysiology of ADHD. Available studies assessing iron in ADHD are based on serum ferritin, a peripheral marker of iron status. To what extent serum ferritin correlates with brain iron (BI) is unclear. The main aim of this study was to compare BI, estimated with magnetic resonance imaging (MRI) in the putamen, pallidum, caudate, and thalamus, between children with and without ADHD. The secondary aim was to assess the correlation between serum ferritin and BI levels. Methods. Thirty-six children (18 with and 18 without ADHD, the latter including nine healthy controls and nine psychiatric controls) completed MRI and blood sampling. Brain iron levels were estimated by imaging T2*. Results. Children with ADHD showed significantly lower estimated BI in right and left thalamus compared to healthy controls. Estimated BI did not differ significantly between children with ADHD and psychiatric controls. Children with ADHD had significantly lower levels of serum ferritin than healthy as well as psychiatric controls. Serum ferritin and T2* values did not correlate significantly in most regions. Conclusions. Low iron in the thalamus may contribute to ADHD pathophysiology.