Stefanos Maltezos

Describing the Brain in Autism in Five Dimensions—Magnetic Resonance Imaging-Assisted Diagnosis of Autism Spectrum Disorder Using a Multiparameter Classification Approach

Autism spectrum disorder (ASD) is a neurodevelopmental condition with multiple causes, comorbid conditions, and a wide range in the type and severity of symptoms expressed by different individuals. This makes the neuroanatomy of autism inherently difficult to describe. Here, we demonstrate how a multiparameter classification approach can be used to characterize the complex and subtle structural pattern of gray matter anatomy implicated in adults with ASD, and to reveal spatially distributed patterns of discriminating regions for a variety of parameters describing brain anatomy. A set of five morphological parameters including volumetric and geometric features at each spatial location on the cortical surface was used to discriminate between people with ASD and controls using a support vector machine (SVM) analytic approach, and to find a spatially distributed pattern of regions with maximal classification weights. On the basis of these patterns, SVM was able to identify individuals with ASD at a sensitivity and specificity of up to 90% and 80%, respectively. However, the ability of individual cortical features to discriminate between groups was highly variable, and the discriminating patterns of regions varied across parameters. The classification was specific to ASD rather than neurodevelopmental conditions in general (e.g., attention deficit hyperactivity disorder). Our results confirm the hypothesis that the neuroanatomy of autism is truly multidimensional, and affects multiple and most likely independent cortical features. The spatial patterns detected using SVM may help further exploration of the specific genetic and neuropathological underpinnings of ASD, and provide new insights into the most likely multifactorial etiology of the condition.

A Spatiotemporal Profile of In Vivo Cerebral Blood Flow Changes Following Intranasal Oxytocin in Humans

BACKGROUND Animal and human studies highlight the role of oxytocin in social cognition and behavior and the potential of intranasal oxytocin (IN-OT) to treat social impairment in individuals with neuropsychiatric disorders such as autism. However, extensive efforts to evaluate the central actions and therapeutic efficacy of IN-OT may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain. METHODS In a placebo-controlled study, we used arterial spin labeling to measure IN-OT-induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. The rCBF data were acquired 15 min before and up to 78 min after onset of treatment onset (40 IU of IN-OT or placebo). The data were analyzed using mass univariate and multivariate pattern recognition techniques. RESULTS We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histologic evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. Pattern recognition on rCBF maps indicated that IN-OT-induced changes were sustained over the entire posttreatment observation interval (25-78 min) and consistent with a pharmacodynamic profile showing a peak response at 39-51 min. CONCLUSIONS Our study provides the first visualization and quantification of IN-OT-induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behavior and guide future experiments (e.g., regarding the timing of experimental manipulations).

Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study

There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD—the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)—and one ‘control’ region—the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal ‘control’ region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate–glutamine levels are not explained by use of stimulant medication.

Rates of undiagnosed attention deficit hyperactivity disorder in London drug and alcohol detoxification units

BackgroundADHD is a common childhood onset mental health disorder that persists into adulthood in two-thirds of cases. One of the most prevalent and impairing comorbidities of ADHD in adults are substance use disorders. We estimate rates of ADHD in patients with substance abuse disorders and delineate impairment in the co-morbid group.MethodScreening for ADHD followed by a research diagnostic interview in people attending in-patient drug and alcohol detoxification units.ResultsWe estimated prevalence of undiagnosed ADHD within substance use disorder in-patients in South London around 12%. Those individuals with substance use disorders and ADHD had significantly higher self-rated impairments across several domains of daily life; and higher rates of substance abuse and alcohol consumption, suicide attempts, and depression recorded in their case records.ConclusionsThis study demonstrates the high rates of untreated ADHD within substance use disorder populations and the association of ADHD in such patients with greater levels of impairment. These are likely to be a source of additional impairment to patients and represent an increased burden on clinical services.

The Analgesic Effect of Oxytocin in Humans: A Double-Blind, Placebo-Controlled Cross-Over Study Using Laser-Evoked Potentials

Oxytocin is a neuropeptide regulating social‐affiliative and reproductive behaviour in mammals. Despite robust preclinical evidence for the antinociceptive effects and mechanisms of action of exogenous oxytocin, human studies have produced mixed results regarding the analgesic role of oxytocin and are yet to show a specific modulation of neural processes involved in pain perception. In the present study, we investigated the analgesic effects of 40 IU of intranasal oxytocin in 13 healthy male volunteers using a double‐blind, placebo‐controlled, cross‐over design and brief radiant heat pulses generated by an infrared laser that selectively activate Aδ‐ and C‐fibre nerve endings in the epidermis, at the same time as recording the ensuing laser‐evoked potentials (LEPs). We predicted that oxytocin would reduce subjective pain ratings and attenuate the amplitude of the N1, N2 and P2 components. We observed that oxytocin attenuated perceived pain intensity and the local peak amplitude of the N1 and N2 (but not of P2) LEPs, and increased the latency of the N2 component. Importantly, for the first time, the present study reports an association between the analgesic effect of oxytocin (reduction in subjective pain ratings) and the oxytocin‐induced modulation of cortical activity after noxious stimulation (attenuation of the N2 LEP). These effects indicate that oxytocin modulates neural processes contributing to pain perception. The present study reports preliminary evidence that is consistent with electrophysiological studies in rodents showing that oxytocin specifically modulates Aδ/C‐fibre nociceptive afferent signalling at the spinal level and provides further specificity to evidence obtained in humans indicating that oxytocin may be modulating pain experience by modulating activity in the cortical areas involved in pain processing.

Validation of the Mind Excessively Wandering Scale and the relationship of mind wandering to impairment in adult ADHD

Objective: This study investigates excessive mind wandering (MW) in adult ADHD using a new scale: the Mind Excessively Wandering Scale (MEWS). Method: Data from two studies of adult ADHD was used in assessing the psychometric properties of the MEWS. Case-control differences in MW, the association with ADHD symptoms, and the contribution to functional impairment were investigated. Results: The MEWS functioned well as a brief measure of excessive MW in adult ADHD, showing good internal consistency (α > .9), and high sensitivity (.9) and specificity (.9) for the ADHD diagnosis, comparable with that of existing ADHD symptom rating scales. Elevated levels of MW were found in adults with ADHD, which contributed to impairment independently of core ADHD symptom dimensions. Conclusion: Findings suggest excessive MW is a common co-occurring feature of adult ADHD that has specific implications for the functional impairments experienced. The MEWS has potential utility as a screening tool in clinical practice to assist diagnostic assessment.

Assessment of mental health problems in people with autism

The general public and professionals from a range of backgrounds have increasingly become interested in autism spectrum disorders. This interest is particularly relevant to learning disability practitioners. Both autism and learning disabilities are independently associated with increased risk of mental health problems. Thus, when a person has learning disabilities and an autism spectrum disorder, a comprehensive assessment for mental health problems is of paramount importance. This paper provides an overview of the assessment of mental health problems in adults and children with neurodevelopmental disorders. The general assessment principles are outlined followed by assessment issues related to specific conditions such as psychoses, mood disorders and attention deficit hyperactivity disorder. Finally conclusions on the clinical implications are drawn.

Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis

Background Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. Aims To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). Method Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD–ASD (n = 16) and healthy controls (n = 78). Results Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures. Conclusions Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.

Attention-Deficit Hyperactivity Disorder (ADHD)

People with intellectual disability (ID) are more susceptible to mental disorders including mental illness and developmental disorders, such as autism and attention-deficit hyperactivity disorder (ADHD). Identification of such comorbidities is important, as it has implications for diagnosis as well as treatment and prognosis. In this chapter the association between ADHD and ID is explored. The evidence for the validity of the diagnosis of ADHD in ID is reviewed. Subsequently, the assessment and diagnosis of ADHD in the context of ID is discussed. Finally, issues of treatment and management are highlighted.

The clinical presentation of ADHD in adults with Learning Disability: experience from a National Specialist Adult ADHD clinic

There is growing evidence that ADHD is more common inchildren and adults with Learning Disabilities (LD) andthat it can be successfully treated even if diagnosis can bedifficult because of ‘diagnostic overshadowing’. This studyprovides empirical data about the ADHD symptoms in LDand non-LD populations.