A small number of abnormal brain connections predicts adult autism spectrum disorder

abstract: Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum.The final version of this article, as published in Nature Communications, can be viewed online at: https://www.nature.com/articles/ncomms1125

The homotopic connectivity of the functional brain: a meta-analytic approach

Abstract Homotopic connectivity (HC) is the connectivity between mirror areas of the brain hemispheres. It can exhibit a marked and functionally relevant spatial variability, and can be perturbed by several pathological conditions. The voxel-mirrored homotopic connectivity (VMHC) is a technique devised to enquire this pattern of brain organization, based on resting state functional connectivity. Since functional connectivity can be revealed also in a meta-analytical fashion using co-activations, here we propose to calculate the meta-analytic homotopic connectivity (MHC) as the meta-analytic counterpart of the VMHC. The comparison between the two techniques reveals their general similarity, but also highlights regional differences associated with how HC varies from task to rest. Two main differences were found from rest to task: (i) regions known to be characterized by global hubness are more similar than regions displaying local hubness; and (ii) medial areas are characterized by a higher degree of homotopic connectivity, while lateral areas appear to decrease their degree of homotopic connectivity during task performance. These findings show that MHC can be an insightful tool to study how the hemispheres functionally interact during task and rest conditions

Psychoses, language and brain asymmetry: fMRI connectivity alterations in bipolar disorders.

INTRODUCTION A mood characterised by alternating mania and depression have been matter of curiosity and attention since ancient times. According to T.J. Crow’s theory on psychosis, Schizophrenia is strictly linked to the development of the faculty of language (begun in hominids from 6 to 4.2 million years ago) which depends by (anatomical and functional) asymmetry observable between the two cerebral hemispheres (Crow 2004). Several data in the recent (and older) (Griesinger 1845) scientific literature support the hypothesis that schizophrenia and bipolar disorder are similar due to a large number of partially common features: symptomatology, genetics, cognitive features, neurobiology, connectivity alteration, etc.. A brief historical account about how often the classification of this disease changed across the last two centuries may suggest how the knowledge underling this diagnostic category is still fragile. AIM OF THE RESEARCH The goal of this paper is to study Functional Connectivity (FC) among bipolar patients and to test the compatibility of Crow’s paradigm with Bipolar Disorder, verifying the potential presence of hemispheric asymmetry alteration (left dominance deficit) through fMRI analysis. MATERIALS AND METHODS 18 outpatients of the Mood Disorders Unit at the Psychiatric Clinic of the University of Padua have been recruited. All subjects had a diagnosis of Bipolar Disorder type I or type II, according to the criteria of the DSM-IV-TR). 16 healthy individuals were chosen matched for age, sex and education. Clinical and psychological conditions at the time of the experiment were investigated through some psychometric scales widely used for the evaluation of mood, anxiety and other psychopathologic aspects. All subjects underwent a MRI scan both in resting state and while they were attending two tasks: a phonemic (verbal fluency) exercise and a visuo-spatial test (mental rotations). RESULTS From the neuropsychological point of view the phonemic task revealed no significant (p<0.05) differences between groups; on the contrary patients group showed decreased performance at the visuo-spatial task. MRI FC was analysed using two different techniques. Independent Component Analysis (ICA) showed mainly a volume within the Dorsal Attention Network located in left Precuneus (Brodmann Area 7) where patient group presented a reduction of FC compared to controls. Graph analysis brought to light a number of inter-hemispheric and left intra-hemispheric connections revealed to be significantly less active in patients compared to controls, on the contrary substantial conservation of indices at the Network Level was observed

Disentangling Brain Networks in Adult ADHD: Studies with fMRI and TMS

Attention Deficit/ Hyperactivity Disorder (ADHD) is not only limited to young patients. It is increasingly diagnosed in adults. Although the estimated prevalence in Europe ranges between 2 and 3% (48), the knowledge about adult ADHD pathophysiology and its neurobiological basis developed only in the past two decades, primarily stimulated by the rapid developments in modern genetic and imaging techniques. ADHD in adulthood leads to an array of major psychosocial problems such as social maladaptation, academic underachieving, antisocial and aggressive behaviour, relation problems, high risk sexual behaviour and car accidents (11,12;55;67;66). These factors in total lead to a negative impact on social and economic well-being of the individual

Funtional Near Infrared Spectroscopy Study of Language, Joint Attention and Motor Skills

Near infrared spectroscopy (NIRS) is an emerging non-invasive optical neuro imaging technique that monitors the hemodynamic response to brain activation with ms-scale temporal resolution and sub-cm spatial resolution. The overall goal of my dissertation was to develop and apply NIRS towards investigation of neurological response to language, joint attention and planning and execution of motor skills in healthy adults. Language studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal and fronto-temporal cortex of healthy adults in response to language reception and expression. The mathematical model developed based on granger causality explicated the directional flow of information during the processing of language stimuli by the fronto-temporal cortex. Joint attention and planning/ execution of motor skill studies were performed to investigate the hemodynamic response, synchrony and dominance feature of the frontal cortex of healthy adults and in children (5-8 years old) with autism (for joint attention studies) and individuals with cerebral palsy (for planning/execution of motor skills studies). The joint attention studies on healthy adults showed differences in activation as well as intensity and phase dependent connectivity in the frontal cortex during joint attention in comparison to rest. The joint attention studies on typically developing children showed differences in frontal cortical activation in comparison to that in children with autism. The planning and execution of motor skills studies on healthy adults and individuals with cerebral palsy (CP) showed difference in the frontal cortical dominance, that is, bilateral and ipsilateral dominance, respectively. The planning and execution of motor skills studies also demonstrated the plastic and learning behavior of brain wherein correlation was found between the relative change in total hemoglobin in the frontal cortex and the kinematics of the activity performed by the participants. Thus, during my dissertation the NIRS neuroimaging technique was successfully implemented to investigate the neurological response of language, joint attention and planning and execution of motor skills in healthy adults as well as preliminarily on children with autism and individuals with cerebral palsy. These NIRS studies have long-term potential for the design of early stage interventions in children with autism and customized rehabilitation in individuals with cerebral palsy

A behavioural and electrophysiological investigation of cognitive and executive dysfunction in older adults with Williams syndrome

Williams syndrome (WS) is a rare developmental disorder accompanied by mild–moderate learning difficulties. The literature focusing on older adults with WS is limited, thus the thesis examined cognitive and executive dysfunction in adults with WS aged 35+ years, adopting behavioural and electrophysiological methodologies. Claims of premature cognitive ageing, investigated with paired-associates paradigms to measure associative memory ability (Chapter 2), were not supported, rather they highlighted atypicalities capitalising on semantic memory and implementing spontaneous semantic encoding strategies. Further investigation of semantic memory (Levels of Processing paradigm, Chapter 3) showed better recall for ‘deep’ encoded items; however, effect sizes identified atypical access to semantic memory. Importantly, both studies were characterised with greater false alarms and reaction time for rejecting new items, indicative of poor error monitoring, and deficits in executive processes of inhibitory control and attention in WS. Chapter 4 adopted The Sustained Attention to Response Task which is highly sensitive to inhibition and attentional lapse. The WS group showed inhibitory deficits failing to withhold a response, and problems re-engaging attentional control after making an error. Chapters 5 and 6 investigated the neural mechanisms underpinning attentional / inhibitory deficits, employing the Oddball paradigm (ERP), and analysis of the alpha and beta frequency bands during resting states (EEG). The WS group showed a) compromised early monitoring of perceptual input, and inefficient task irrelevant stimulus evaluation, and b) low EEG alpha power indicative of reduced inhibitory control, atypical topographical distributions, and low variability; the latter is associated with poorer behavioural performance. Overall, the thesis has demonstrated how cognitive deficits observed in older adults with WS are grounded in atypicalities in the executive processes of attention and inhibition. It has added to theoretical understanding by advancing our knowledge of both the behavioural and eletrophysiological profiles in older adults with WS, and which sub-serve these atypicalities

Augmentation of Brain Function: Facts, Fiction and Controversy. Volume III: From Clinical Applications to Ethical Issues and Futuristic Ideas

The final volume in this tripartite series on Brain Augmentation is entitled “From Clinical Applications to Ethical Issues and Futuristic Ideas”. Many of the articles within this volume deal with translational efforts taking the results of experiments on laboratory animals and applying them to humans. In many cases, these interventions are intended to help people with disabilities in such a way so as to either restore or extend brain function. Traditionally, therapies in brain augmentation have included electrical and pharmacological techniques. In contrast, some of the techniques discussed in this volume add specificity by targeting select neural populations. This approach opens the door to where and how to promote the best interventions. Along the way, results have empowered the medical profession by expanding their understanding of brain function. Articles in this volume relate novel clinical solutions for a host of neurological and psychiatric conditions such as stroke, Parkinson’s disease, Huntington’s disease, epilepsy, dementia, Alzheimer’s disease, autism spectrum disorders (ASD), traumatic brain injury, and disorders of consciousness. In disease, symptoms and signs denote a departure from normal function. Brain augmentation has now been used to target both the core symptoms that provide specificity in the diagnosis of a disease, as well as other constitutional symptoms that may greatly handicap the individual. The volume provides a report on the use of repetitive transcranial magnetic stimulation (rTMS) in ASD with reported improvements of core deficits (i.e., executive functions). TMS in this regard departs from the present-day trend towards symptomatic treatment that leaves unaltered the root cause of the condition. In diseases, such as schizophrenia, brain augmentation approaches hold promise to avoid lengthy pharmacological interventions that are usually riddled with side effects or those with limiting returns as in the case of Parkinson’s disease. Brain stimulation can also be used to treat auditory verbal hallucination, visuospatial (hemispatial) neglect, and pain in patients suffering from multiple sclerosis. The brain acts as a telecommunication transceiver wherein different bandwidth of frequencies (brainwave oscillations) transmit information. Their baseline levels correlate with certain behavioral states. The proper integration of brain oscillations provides for the phenomenon of binding and central coherence. Brain augmentation may foster the normalization of brain oscillations in nervous system disorders. These techniques hold the promise of being applied remotely (under the supervision of medical personnel), thus overcoming the obstacle of travel in order to obtain healthcare. At present, traditional thinking would argue the possibility of synergism among different modalities of brain augmentation as a way of increasing their overall effectiveness and improving therapeutic selectivity. Thinking outside of the box would also provide for the implementation of brain-to-brain interfaces where techniques, proper to artificial intelligence, could allow us to surpass the limits of natural selection or enable communications between several individual brains sharing memories, or even a global brain capable of self-organization. Not all brains are created equal. Brain stimulation studies suggest large individual variability in response that may affect overall recovery/treatment, or modify desired effects of a given intervention. The subject’s age, gender, hormonal levels may affect an individual’s cortical excitability. In addition, this volume discusses the role of social interactions in the operations of augmenting technologies. Finally, augmenting methods could be applied to modulate consciousness, even though its neural mechanisms are poorly understood. Finally, this volume should be taken as a debate on social, moral and ethical issues on neurotechnologies. Brain enhancement may transform the individual into someone or something else. These techniques bypass the usual routes of accommodation to environmental exigencies that exalted our personal fortitude: learning, exercising, and diet. This will allow humans to preselect desired characteristics and realize consequent rewards without having to overcome adversity through more laborious means. The concern is that humans may be playing God, and the possibility of an expanding gap in social equity where brain enhancements may be selectively available to the wealthier individuals. These issues are discussed by a number of articles in this volume. Also discussed are the relationship between the diminishment and enhancement following the application of brain-augmenting technologies, the problem of “mind control” with BMI technologies, free will the duty to use cognitive enhancers in high-responsibility professions, determining the population of people in need of brain enhancement, informed public policy, cognitive biases, and the hype caused by the development of brain- augmenting approaches

Investigating structural and functional neural correlates in children and adolescents with antisocial behavior

Antisocial behavior is highly prevalent in young and adult populations worldwide and constitutes a major public health problem due to the huge burden on the individual as well as the significant economic burden on society. A better understanding of the underlying neurobiological mechanisms of antisocial behavior is warranted to improve current diagnostics (e.g. early detection of children at risk) and effective prevention/treatment programs. So far, neuroimaging studies have indicated neural atypicalities in youths with antisocial behavior; however, the direction and location of these brain alterations vary across studies. These ambiguities are most likely caused by the heterogeneity of the young samples with antisocial behavior studied, especially regarding sex, clinical diagnoses, and the presence of callous-unemotional traits. The central aim of this dissertation was to further the neuroscientific knowledge of antisocial behavior in children and adolescents by investigating the underlying structural and functional neurobiological characteristics, with an extra focus on possible sex differences and callous-unemotional traits. First, we examined the current neuroimaging literature, through meta-analyses, with the purpose of overcoming the heterogeneity of antisocial behavior and generating a common “overlapping” pattern of structural and functional atypicalities in youths with antisocial behavior. Secondly, the relation between callous-unemotional traits and brain structure was investigated separately for sex and independently of psychiatric comorbidities. Thirdly, this work investigated the white matter integrity within a homogenous group of girls with conduct disorder –the severe variant of antisocial behavior– in comparison to typically developing peers. This work expands our current knowledge on the structural and functional neural correlates in children and adolescents with antisocial behavior in several ways. For one, our meta-analytic results indicate a consistent pattern of gray matter reductions and hypoactivations in brain areas within the prefrontal and limbic cortex. These findings fit a recently proposed neurobiological model that connects alterations within similar brain regions with the behavioral dispositions of antisocial behavior (e.g. dysfunctions in empathy, emotional learning, and decision making). Secondly, we observed a positive relation between callous-unemotional traits and bilateral insula volume in a large international population of typically developing boys, but not in girls, independent of psychiatric disorders. This demonstrates that callous-unemotional traits have a sex-specific neurobiological basis beyond psychiatric samples. Thirdly, this work presents novel findings of white-matter integrity alterations in the body of the corpus callosum of girls with antisocial behavior, indicating possible reduced interhemispheric processing and consequent emotion processing abilities. In short, the present thesis provides original findings regarding the neurobiology of antisocial behavior in youths and emphasizes the importance of callous-unemotional traits and sex differences. Our results encourage future studies to further investigate the developmental trajectories and potential neural markers of antisocial behavior in order to enhance early detection and improve intervention programs, which could ultimately reduce antisocial behavior and delinquency in our society

Neuronal basis of emotion processing and regulation in conduct disorder

Emotion regulation, a key component of healthy development, has been shown to be deficient in several psychiatric conditions, including conduct disorder. Conduct disorder is a neuropsychiatric disorder of childhood and adolescence characterized by severe aggressive behavior and violation of societal norms. It is highly prevalent and results in substantial economic costs and negative social consequences. Neuroimaging evidence has revealed brain activity alterations in several regions, including prefrontal, temporal, and limbic cortex (amygdala, insula, and cingulate gyrus). While the neuronal basis of emotion processing in conduct disorder has been intensely investigated, the brain correlates of implicit and explicit emotion regulation remain unclear. The main aim of this dissertation was to extend current knowledge by investigating the neuronal mechanisms of emotion regulation in children and adolescents with conduct disorder. First, we conducted a meta-analysis in order to identify the neuronal correlates of emotion processing in adolescents with aggressive behavior. We then developed an affective Stroop task designed to investigate the interplay between emotion and cognition in a paediatric population, and validated it in healthy young adults. We then employed the task to study the neuronal characteristics of implicit emotion-cognition interaction in children and adolescents with conduct disorder. Finally, we investigated explicit emotion regulation by cognitive reappraisal (i.e., reinterpretation of the meaning of an emotional stimulus) in conduct disorder. We here present findings on altered brain function during tasks assessing implicit and explicit emotion regulation in adolescents with conduct disorder that are in agreement with behaviorally observed deficits. Our meta-analysis on emotion processing in conduct disorder summarized previous literature indicating prefrontal and limbic brain structure and function alterations. The results from our study employing the affective Stroop task in healthy adults validated the usefulness of our task design and replicated previous findings suggesting that emotion significantly impacts cognition on a behavioral and neuronal level. Using the affective Stroop and cognitive reappraisal tasks in adolescents with conduct disorder revealed neuronal alterations within prefrontal and limbic regions, brain areas implicated in both emotion and cognition. Overall, the results of this dissertation provide novel evidence on the neuronal basis of emotion regulation deficits in conduct disorder. Future studies shall further investigate emotion regulation in specific subgroups of conduct disorder, for example those with psychopathic traits or high levels of anxiety with the ultimate goal of influencing the child’s immediate environment and society as a whole