Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings.

BACKGROUND: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. METHODS: We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. RESULTS: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. LIMITATIONS: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. CONCLUSION: Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.

White matter microstructure and developmental improvement of hyperactive/impulsive symptoms in attention-deficit/hyperactivity disorder.

BACKGROUND: A developmental improvement of symptoms in attention-deficit/hyperactivity disorder (ADHD) is frequently reported, but the underlying neurobiological substrate has not been identified. The aim of this study was to determine whether white matter microstructure is related to developmental improvement of ADHD symptoms. METHODS: A cross-sectional magnetic resonance imaging (MRI) analysis was embedded in a prospective follow-up of an adolescent cohort of ADHD and control subjects (NeuroIMAGE). Mean age at baseline was 11.9 years, mean interval of follow-up was 5.9 years. About 75.3% of the original cohort was retained successfully. Data of 101 participants with ADHD combined type at baseline and 40 healthy controls were analysed. ADHD symptoms were measured with semistructured, investigator-based interviews and Conners' questionnaires, on the basis of DSM-IV criteria. Fractional anisotropy (FA) and mean diffusivity (MD) indices of white matter microstructure were measured using whole brain diffusion tensor imaging at follow-up only. In a dimensional analysis FA and MD were related to change in ADHD symptoms. To link this analysis to DSM-IV diagnoses, a post hoc categorical group analysis was conducted comparing participants with persistent (n = 59) versus remittent (n = 42) ADHD and controls. RESULTS: Over time, participants with ADHD showed improvement mainly in hyperactive/impulsive symptoms. This improvement was associated with lower FA and higher MD values in the left corticospinal tract at follow-up. Findings of the dimensional and the categorical analysis strongly converged. Changes in inattentive symptoms over time were minimal and not related to white matter microstructure. CONCLUSIONS: The corticospinal tract is important in the control of voluntary movements, suggesting the importance of the motor system in the persistence of hyperactive/impulsive symptoms.

Differential effects of the ApoE4 genotype on brain structure and function.

The apolipoprotein E ε4 allele is a well established genetic risk factor for sporadic Alzheimer's disease. It is associated with structural and functional brain changes in healthy young, middle-aged and elderly subjects. In the current study, we assessed the impact of the ApoE genotype on brain macro- and microstructure, cognitive functioning and brain activity in fifty healthy young subjects (25 ApoE ε4 (ε4+) carriers and 25 non-carriers (ε4-), mean age 26.4±4.6years). We used diffusion tensor imaging (DTI) and voxel based morphometry (VBM) to assess brain structure, an extensive neuropsychological battery to test cognitive functioning and event-related functional magnetic resonance imaging (fMRI) to capture brain activity during episodic memory encoding and retrieval. ApoE ε4 carriers differed from non-carriers in fMRI activations but not in cognitive performance nor in brain micro- and macrostructure. These results suggest functional alterations in the episodic memory network that are modulated by the ε4 allele and might precede clinical or structural neurodegeneration.

Patterns of autobiographical memory in bipolar disorder examined by psychometric and functional neuroimaging methods.

This is the first study to combine psychometric and functional neuroimaging methods to study altered patterns of autobiographical memory in bipolar disorder (BD). All participants were interviewed with an expanded version of the Bielefelder Autobiographical Memory Inventory (Bielefelder Autobiographisches Gedächtnis Inventar 2004;Lisse: Swets and Zeitlinger). We then acquired functional magnetic resonance imaging data during a task of individually designed autobiographical recall. Compared with healthy controls, BD patients reported a stronger emotionality of autobiographical memories and more frequent recollections of autobiographical events during their everyday life. Furthermore, they failed to deactivate areas in the cuneus and lingual gyrus and showed decreased activation in the inferior frontal and precentral areas compared with the control group. More frequent intrusions from a person's past, which had a neural correlate in the lack of deactivation in some default mode network areas in BD patients, may contribute to manic or depressive symptoms.

Linear assemblies of magnetic nanoparticles as MRI contrast agents.

Using a one-step procedure we have prepared magnetic fluids comprising of polyelectrolyte stabilized magnetite nanoparticles. These nanocomposites are comprised of linear, chain-like assemblies of magnetic nanoparticles, which can be aligned in parallel arrays by an external magnetic field. We have shown the potential use of these materials as contrast agents by measuring their MR response in live rats. The new magnetic fluids have demonstrated good biocompatibility and potential for in vivo MRI diagnostics.

RNAi-mediated reversible opening of the blood-brain barrier.

BACKGROUND: The blood-brain barrier (BBB) contains tight junctions (TJs) which reduce the space between adjacent endothelial cells lining the fine capillaries of the microvasculature of the brain to form a selective and regulatable barrier. METHODS: Using a hydrodynamic approach, we delivered siRNA targeting the TJ protein claudin-5 to the endothelial cells of the BBB in mice. RESULTS: We have shown a significant decrease in claudin-5 mRNA levels 24 and 48 hours post-delivery of siRNA, with levels of protein expression decreasing up to 48 hours post-injection compared to uninjected, phosphate-buffered saline (PBS)-injected and non-targeting siRNA-injected mice. We observed increased permeability at the BBB to molecules up to 742 Da, but not 4400 Da, using tracer molecule perfusion and MRI analysis. To illustrate the functional efficacy of size-selective and transient barrier opening, we have shown that enhanced delivery of the small neuropeptide thyrotropin-releasing hormone (TRH) (MW 360 Da) to the brains of mice 48 hours post-injection of siRNA targeting claudin-5 significantly modifies behavioural output. CONCLUSIONS: These data demonstrate that it is now possible to transiently and size-selectively open the BBB in mice, allowing in principle the delivery of a wide range of agents for the establishment and treatment of experimental mouse models of neurodegenerative, neuropsychiatric and malignant diseases.

Supporting Innovation through Regulation and Science: Ireland as an Innovation Hub for Health Products.

New technologies and our ever-increasing knowledge provide an exciting potential to develop innovative health products that can address challenges such as chronic diseases and ultimately improve outcomes for patients. Ireland has a strategic focus on supporting innovation and offers an ideal environment for health product innovation. This is due to the expertise and experience that is available within the life sciences sector and an established national infrastructure which supports the translation of research into health products in a collaborative manner. The Health Products Regulatory Authority (HPRA) is committed to supporting innovation for health products. Anyone developing an innovative health product can obtain regulatory guidance via the HPRA's Innovation Office. Scientific advice and a product classification service are also available. The HPRA is actively engaging with innovators through an outreach programme to discuss how regulation can support innovation and to raise awareness of available supports. In order to facilitate the appropriate regulation of innovative therapies, the HPRA is performing horizon scanning to identify innovations at an early stage of development, so that proactive action can be taken to put in place any additional regulatory tools or develop any expertise required to regulate such products and provide safe and timely access for patients.

The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders.

BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies.

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation.

BACKGROUND: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. METHODS: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. RESULTS: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. CONCLUSIONS: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials.

Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings.

Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children's Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.

Diffusion-MRI in neurodegenerative disorders.

The ability to image the whole brain through ever more subtle and specific methods/contrasts has come to play a key role in understanding the basis of brain abnormalities in several diseases. In magnetic resonance imaging (MRI), "diffusion" (i.e. the random, thermally-induced displacements of water molecules over time) represents an extraordinarily sensitive contrast mechanism, and the exquisite structural detail it affords has proven useful in a vast number of clinical as well as research applications. Since diffusion-MRI is a truly quantitative imaging technique, the indices it provides can serve as potential imaging biomarkers which could allow early detection of pathological alterations as well as tracking and possibly predicting subtle changes in follow-up examinations and clinical trials. Accordingly, diffusion-MRI has proven useful in obtaining information to better understand the microstructural changes and neurophysiological mechanisms underlying various neurodegenerative disorders. In this review article, we summarize and explore the main applications, findings, perspectives as well as challenges and future research of diffusion-MRI in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and degenerative ataxias.

Distinct effects of ASD and ADHD symptoms on reward anticipation in participants with ADHD, their unaffected siblings and healthy controls: a cross-sectional study.

BACKGROUND: Autism spectrum disorder (ASD) traits are continuously distributed throughout the population, and ASD symptoms are also frequently observed in patients with attention-deficit/hyperactivity disorder (ADHD). Both ASD and ADHD have been linked to alterations in reward-related neural processing. However, whether both symptom domains interact and/or have distinct effects on reward processing in healthy and ADHD populations is currently unknown. METHODS: We examined how variance in ASD and ADHD symptoms in individuals with ADHD and healthy participants was related to the behavioural and neural response to reward during a monetary incentive delay (MID) task. Participants (mean age: 17.7 years, range: 10-28 years) from the NeuroIMAGE study with a confirmed diagnosis of ADHD (n = 136), their unaffected siblings (n = 83), as well as healthy controls (n = 105) performed an MID task in a magnetic resonance imaging (MRI) scanner. ASD and ADHD symptom scores were used as predictors of the neural response to reward anticipation and reward receipt. Behavioural responses were modeled using linear mixed models; neural responses were analysed using FMRIB's Software Library (FSL) proprietary mixed effects analysis (FLAMEO). RESULTS: ASD and ADHD symptoms were associated with alterations in BOLD activity during reward anticipation, but not reward receipt. Specifically, ASD scores were related to increased insular activity during reward anticipation across the sample. No interaction was found between this effect and the presence of ADHD, suggesting that ASD symptoms had no differential effect in ADHD and healthy populations. ADHD symptom scores were associated with reduced dorsolateral prefrontal activity during reward anticipation. No interactions were found between the effects of ASD and ADHD symptoms on reward processing. CONCLUSIONS: Variance in ASD and ADHD symptoms separately influence neural processing during reward anticipation in both individuals with (an increased risk of) ADHD and healthy participants. Our findings therefore suggest that both symptom domains affect reward processing through distinct mechanisms, underscoring the importance of multidimensional and multimodal assessment in psychiatry.

Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (ß = -31.92; 95% CI, -52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (ß = -22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (ß = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.

Brain volumetric correlates of autism spectrum disorder symptoms in attention deficit/hyperactivity disorder.

Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children's Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners' ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.

Reduced hippocampal volume in healthy young ApoE4 carriers: an MRI study.

The E4 allele of the ApoE gene has consistently been shown to be related to an increased risk of Alzheimer's disease (AD). The E4 allele is also associated with functional and structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess volumes of deep grey matter structures of 22 healthy younger ApoE4 carriers and 22 non-carriers (20-38 years). Volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen, thalamus and brain stem were calculated by FMRIB's Integrated Registration and Segmentation Tool (FIRST) algorithm. A significant drop in volume was found in the right hippocampus of ApoE4 carriers (ApoE4+) relative to non-carriers (ApoE4-), while there was a borderline significant decrease in the volume of the left hippocampus of ApoE4 carriers. The volumes of no other structures were found to be significantly affected by genotype. Atrophy has been found to be a sensitive marker of neurodegenerative changes, and our results show that within a healthy young population, the presence of the ApoE4+ carrier gene leads to volume reduction in a structure that is vitally important for memory formation. Our results suggest that the hippocampus may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age. Although volume reductions were noted bilaterally in the hippocampus, atrophy was more pronounced in the right hippocampus. This finding relates to previous work which has noted a compensatory increase in right hemisphere activity in ApoE4 carriers in response to preclinical declines in memory function. Possession of the ApoE4 allele may lead to greater predilection for right hemisphere atrophy even in healthy young subjects in their twenties.

Cognitive and behavioural effects of physical exercise in psychiatric patients.

The current review outlines the under-appreciated effects of physical exercise on the course of psychiatric disorders, focussing on recent findings from animal and human research. Several studies have shown that regular physical exercise is significantly beneficial for psychiatric patients both on a biological and a psychological level. Positive effects of controlled exercise include improved metabolic responses, neuro-protection, increased quality of life, and reduced psychopathological symptoms. Studies investigating the effectiveness of various physical training interventions in alleviating severe mental diseases, such as Alzheimer's dementia (AD), schizophrenia (SZ) or major depressive disorder (MDD) indicate that physical exercise can relieve symptoms of depression, psychosis and dementia and more importantly can curtail further progression of these diseases. This review assesses the most effective methods of physical training for specific psychiatric symptoms. Introducing physical exercise in therapeutic regimes would be an innovative approach that could significantly reduce the severity of psychopathological and cognitive symptoms in patients. The positive biological and molecular outcomes associated with physical exercise render it a concrete therapeutic strategy for improving the quality of live and reducing physical illness in psychiatric patients. Therefore, integrating physical activity into a patient's social life may be an effective treatment strategy. Furthermore, exercise might have the potential to be a preventative treatment within the context of multi-modal therapeutic programs.

White matter differences between healthy young ApoE4 carriers and non-carriers identified with tractography and support vector machines.

The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age.