Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system.

Previous studies have suggested that risk of psychotic events may be increased in children exposed to methylphenidate (MPH). However, this risk has not been fully examined, and the possibility of confounding factors has not been excluded. Patients aged 6-19 years who received at least one MPH prescription were identified using Hong Kong population-based electronic medical records on the Clinical Data Analysis and Reporting System (2001-2014). Using the self-controlled case series design, relative incidence of psychotic events was calculated comparing periods when patients were exposed to MPH with non-exposed periods. Of 20,586 patients prescribed MPH, 103 had an incident psychotic event; 72 (69.9%) were male and 31 (30.1%) female. The mean age at commencement of observation was 6.95 years and the mean follow-up per participant was 10.16 years. On average, each participant was exposed to MPH for 2.17 years. The overall incidence of psychotic events during the MPH exposure period was 6.14 per 10,000 patient-years. No increased risk was found during MPH-exposed compared with non-exposed periods (incidence rate ratio (IRR) 1.02 (0.53-1.97)). However, an increased risk was found during the pre-exposure period (IRR 4.64 (2.17-9.92)). Results were consistent across all sensitivity analyses. This study does not support the hypothesis that MPH increases risk of incident psychotic events. It does indicate an increased risk of psychotic events before the first prescription of MPH, which may be because of an association between psychotic events and the behavioural and attentional symptoms that led to psychiatric assessment and initiation of MPH treatment.

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study.

INTRODUCTION: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. METHODS AND ANALYSIS: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. TRIAL REGISTRATION NUMBER: NCT01470261.

Inefficient cerebral recruitment as a vulnerability marker for schizophrenia.

BACKGROUND: Patients with schizophrenia and their first-degree relatives exhibit both abnormally diminished and increased neural activation during cognitive tasks. In particular, excessive task-related activity is often observed when tasks are easy, suggesting that inefficient cerebral recruitment may be a marker of vulnerability for schizophrenia. This hypothesis might best be tested using a very easy task, thus avoiding confounding by individual differences in task difficulty. METHOD: Eighteen people with schizophrenia, 18 unaffected full siblings of patients with schizophrenia and 26 healthy controls performed an easy auditory target-detection task in a 3-T magnetic resonance imaging (MRI) scanner. Groups were matched for accuracy on the task. Blood oxygen level-dependent (BOLD) responses to non-target stimuli in participants with vulnerability for schizophrenia (siblings and patients) were compared with those of healthy controls, and those of patients with those of unaffected siblings. BOLD responses to targets were compared with baseline, across groups. RESULTS: Subjects with vulnerability for schizophrenia showed significant hyperactivation to non-targets in brain areas activated by targets in all groups, in addition to reduced deactivation to non-targets in areas suppressed by targets in all groups. Siblings showed greater activation than patients to non-targets in the medial frontal cortex. Patients exhibited significantly longer reaction times (RTs) than unaffected siblings and healthy controls. CONCLUSIONS: Inefficient cerebral recruitment is a vulnerability marker for schizophrenia, marked by reduced suppression of brain areas normally deactivated in response to task stimuli, and increased activation of areas normally activated in response to task stimuli. Moreover, siblings show additional activation in the medial frontal cortex that may be protective.

Task induced modulation of neural oscillations in electrophysiological brain networks.

In recent years, one of the most important findings in systems neuroscience has been the identification of large scale distributed brain networks. These networks support healthy brain function and are perturbed in a number of neurological disorders (e.g. schizophrenia). Their study is therefore an important and evolving focus for neuroscience research. The majority of network studies are conducted using functional magnetic resonance imaging (fMRI) which relies on changes in blood oxygenation induced by neural activity. However recently, a small number of studies have begun to elucidate the electrical origin of fMRI networks by searching for correlations between neural oscillatory signals from spatially separate brain areas in magnetoencephalography (MEG) data. Here we advance this research area. We introduce two methodological extensions to previous independent component analysis (ICA) approaches to MEG network characterisation: 1) we show how to derive pan-spectral networks that combine independent components computed within individual frequency bands. 2) We show how to measure the temporal evolution of each network with millisecond temporal resolution. We apply our approach to ~10h of MEG data recorded in 28 experimental sessions during 3 separate cognitive tasks showing that a number of networks could be identified and were robust across time, task, subject and recording session. Further, we show that neural oscillations in those networks are modulated by memory load, and task relevance. This study furthers recent findings on electrodynamic brain networks and paves the way for future clinical studies in patients in which abnormal connectivity is thought to underlie core symptoms.

Cortical thickness and oscillatory phase resetting: a proposed mechanism of salience network dysfunction in schizophrenia.

Schizophrenia is characterised by both electrophysiological abnormalities and consistent changes in the structure of cortical grey matter. But the relationship between these two observations is largely unknown. Structural changes reported in schizophrenia include reduced grey matter volume, thickness and surface area in several cortical regions, but most frequently in the insula and anterior cingulate cortex. These two regions together constitute an intrinsic brain circuit known as the "Salience Network", which has a key role in stimulus processing. During stimulus processing tasks, evoked activity is noted using electroencephalography (EEG). Phase resetting of ongoing oscillations contributes to this evoked activity. Neuronal oscillations play a crucial role in cerebral recruitment during cognitive tasks, and influencing the oscillatory phase can modulate cortical excitability and the transition between various cognitive states. At a network level, such a transition or switch is thought to be enabled by the Salience Network. In this study, we investigated the relationship between the cortical thickness in the Salience Network (measured using MRI) and the degree of phase resetting observed during an oddball task (measured using EEG) in 18 medicated male patients in a clinically stable phase of schizophrenia and 20 age and gender matched healthy controls. We obtained a measure of partial phase resetting after a stimulus is presented, and a second measure representing mean evoked activity, using the methods proposed by Martinez-Montes. Using MRI analysis, we have firstly shown that there is a significant loss of cortical thickness of regions that constitute the Salience Network in patients with schizophrenia. EEG analysis revealed that in healthy controls, the expected relationship between phase resetting and evoked electrical activity is observed, but in patients with schizophrenia the theta phase resetting is a weak predictor of the activity evoked by attending to a target stimulus, though the difference between the groups did not reach statistical significance in the present sample. Furthermore, in patients with schizophrenia the reduced thickness in the Salience Network is associated with the inefficient phase resetting of theta oscillations. Our findings suggest that the grey matter reduction seen in the Salience Network in patients with schizophrenia has substantial functional consequences. In particular, the structural defect of the insula that is seen in schizophrenia is likely to be associated with less efficient recruitment of brain circuits for processing information. This implies a possible mechanism by which disruptions in the intrinsic Salience Network can result in a general disturbance in salience detection seen in schizophrenia.

Autistic spectrum disorder traits in children with attention deficit hyperactivity disorder.

BACKGROUND: Current classification systems do not allow for comorbid diagnoses of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD). Children with ADHD are often screened for ASD during clinical assessment and when recruited to clinical trials. We predicted that children with ADHD would have more autistic traits than controls and that certain traits would be more prevalent. METHODS: The clinically referred sample consisted of 30 children with ADHD and 30 matched controls aged 9-15 years. Children were screened for ASD traits using the Social Aptitudes Scale (SAS) and the Social Communication Questionnaire (SCQ). RESULTS: We found that ASD traits were significantly higher in children with ADHD than controls. None of the children received a diagnosis of autism or ASD. However, a large proportion (28% using the SCQ and 62% using the SAS) of children with ADHD reached screening thresholds for a predictive diagnosis of ASD. Relative to controls, children with ADHD had significantly higher levels of communication and social deficits, but not repetitive behaviours. CONCLUSION: Further work is needed to establish whether autistic-like communication and social difficulties in children with ADHD are part of the broader ASD phenotype or are specific to ADHD.