Dysfunctions in brain networks supporting empathy: an fMRI study in adults with autism spectrum disorders

The present study aimed at identifying dysfunctions in brain networks that may underlie disturbed empathic behavior in autism spectrum disorders (ASD). During functional magnetic resonance imaging, subjects were asked to identify the emotional state observed in a facial stimulus (other-task) or to evaluate their own emotional response (self-task). Behaviorally, ASD subjects performed equally to the control group during the other-task, but showed less emotionally congruent responses in the self-task. Activations in brain regions related to theory of mind were observed in both groups. Activations of the medial prefrontal cortex (MPFC) were located in dorsal subregions in ASD subjects and in ventral areas in control subjects. During the self-task, ASD subjects activated an additional network of frontal and inferior temporal areas. Frontal areas previously associated with the human mirror system were activated in both tasks in control subjects, while ASD subjects recruited these areas during the self-task only. Activations in the ventral MPFC may provide the basis for one's "emotional bond" with other persons' emotions. Such atypical patterns of activation may underlie disturbed empathy in individuals with ASD. Subjects with ASD may use an atypical cognitive strategy to gain access to their own emotional state in response to other people's emotions.     

Autism spectrum disorders and underlying brain pathology in CHARGE association

The rate of autism spectrum disorders (ASDs) and brain abnormalities was analyzed in 31 individuals (15 males, 16 females; age range 1mo to 31y, mean age 8y 11mo) with CHARGE association, as part of a multidisciplinary study. A meticulous neuropsychiatric examination was performed, including standardized autism diagnostic interviews. Judgement regarding ASDs was impossible in three infants and three patients who were deaf and blind. Five individuals met diagnostic criteria for autism, five for an autistic-like condition, and seven for autistic traits. Brain abnormalities were indicated in almost three-quarters of examined individuals, and midline abnormalities of the forebrain in one-third. Awareness of the coexistence of CHARGE and ASDs is important in habilitation care in CHARGE. Moreover, the results indicate that a subgroup of ASDs may be associated with errors in early embryonic brain development.     

Decreased centrality of cortical volume covariance networks in autism spectrum disorders

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions characterized by atypical structural and functional brain connectivity. Complex network analysis has been mainly used to describe altered network-level organization for functional systems and white matter tracts in ASD. However, atypical functional and structural connectivity are likely to be also linked to abnormal development of the correlated structure of cortical gray matter. Such covariations of gray matter are particularly well suited to the investigation of the complex cortical pathology of ASD, which is not confined to isolated brain regions but instead acts at the systems level. In this study, we examined network centrality properties of gray matter networks in adults with ASD (n = 84) and neurotypical controls (n = 84) using graph theoretical analysis. We derived a structural covariance network for each group using interregional correlation matrices of cortical volumes extracted from a surface-based parcellation scheme containing 68 cortical regions. Differences between groups in closeness network centrality measures were evaluated using permutation testing. We identified several brain regions in the medial frontal, parietal and temporo-occipital cortices with reductions in closeness centrality in ASD compared to controls. We also found an association between an increased number of autistic traits and reduced centrality of visual nodes in neurotypicals. Our study shows that ASD are accompanied by atypical organization of structural covariance networks by means of a decreased centrality of regions relevant for social and sensorimotor processing. These findings provide further evidence for the altered network-level connectivity model of ASD.     

Neurofeedback in autism spectrum disorders

Aim  To review current studies on the effectiveness of neurofeedback as a method of treatment of the core symptoms of autism spectrum disorders (ASD). Method  Studies were selected based on searches in PubMed, Ovid MEDLINE, EMBASE, ERIC, and CINAHL using combinations of the following keywords: ‘Neurofeedback’ OR ‘EEG Biofeedback’ OR ‘Neurotherapy’ OR ‘Mu‐Rhythm’ OR ‘SMR’ AND ‘Autism’ OR ‘Autism Spectrum Disorder’ OR ‘Pervasive Developmental Disorder’. Results  The existing evidence does not support the use of neurofeedback in the treatment of ASD. Studies with outcomes in favour of neurofeedback might be showing an improvement in comorbid attention‐deficit–hyperactivity disorder symptoms rather than a true improvement in core ASD symptoms. Interpretation  Limitations of this review are those inherent in the studies available, including small sample size, short duration, variable diagnostic criteria, and insufficient control interventions, all causing a lack of generalizability.     

Epilepsy in autism spectrum disorders

Epilepsy is quite common in autism spectrum disorders, and it is increasingly recognized as an additional clinical problem that must be dealt with. The rate of comorbidity varies, depending upon the age and type of disorder, and currently the conservative estimate of comorbidity cases is 20–25% of the whole spectrum. Major risk factors for seizure occurrence are mental retardation and additional neurological disorders, as well as some specific associated medical conditions. Autism with regression has been reported in one-third of children with previously normal or nearly normal development. In an unknown proportion of these subjects, epileptic disorders are concomitant, leading to so-called autistic epileptiform regression. Furthermore, epileptiform abnormalities without seizures are frequent in this population and their role in the development of the nuclear disturbances of autism is controversial. The therapeutic approaches to epilepsy in autism are conventional treatments, yet when seizures are not evident, there is still controversy. Anticonvulsant medications could also potentially interfere with mood and behavioral disturbances frequently observed in ASD. The current understanding of the association between epilepsy and autism is still limited, but from a clinical point of view this association should not be overlooked, and it should be routinely investigated.     

Neurometabolic disorders and dysfunction in autism spectrum disorders

The cause of autism remains largely unknown because it is likely multifactorial, arising from the interaction of biologic, genetic, and environmental factors. The specific role of metabolic abnormalities also is largely unknown, but current research may provide insight into the pathophysiologic underpinnings of autism, at least in some patients. We review a number of known neurometabolic disorders identified as having an autistic phenotype. We also discuss the possible involvement of mitochondrial disorders and dysfunction as well as a theory regarding an increased vulnerability to oxidative stress, by which various environmental toxins produce metabolic alterations that impair normal cellular function. Finally, we review various strategies for metabolic work-up and treatment. Accurate diagnosis of neurometabolic disorders and a broader understanding of underlying metabolic disturbance even in the absence of known disease have important implications both for individual patients and for research into the etiology of autism.     

Cognitive control in autism spectrum disorders

Cognitive control refers to the ability to flexibly allocate mental resources to guide thoughts and actions in light of internal goals. Given the behavioral inflexibility exhibited by individuals with autism spectrum disorders (ASDs), it would appear they experience cognitive control deficits. Cognitive correlates of this behavioral inflexibility have been elusive in previous investigations. Study goals were to investigate deficits in cognitive control in ASDs; to explore its developmental trajectory; and to test whether control deficits are related to symptoms of inflexible thoughts and/or behaviors, and attention symptoms. Thirty-one children and adolescents aged 8-17 with ASDs and 32 age, IQ, and gender matched control subjects completed cognitive, diagnostic, and behavorial assessments, as well as a measure of cognitive control involving overcoming a prepotent response tendency. Compared with typically developing control subjects, individuals with ASDs exhibited deficits in cognitive control. Younger children with ASDs did not demonstrate age-related improvements in cognitive control. Modest relationships between cognitive control, IQ, and attention problems were found for the sample. Only the relationship between cognitive control and full-scale IQ survived correction for multiple comparisons.     

Recent advances in autism spectrum disorders

OBJECTIVE: This review article provides an overview of the most recent developments in the literature regarding autism spectrum disorders including epidemiology, etiology, assessment, and management/treatment. METHOD: A review of the recent literature was conducted using Medline and the search term "Autism Spectrum Disorders." RESULTS: Autism Spectrum Disorders are more common than previously believed (1 in 166), and etiology appears to be multifaceted including both heritable and non-heritable factors. State of the art treatment includes comprehensive medical monitoring as well as behavioral intervention. CONCLUSIONS: Current and anticipated federal funding, policy changes, and large scale research projects provide promise for increasing knowledge about Autism Spectrum Disorders.     

Face-brain asymmetry in autism spectrum disorders

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.     

Medical conditions in autism spectrum disorders

Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio-pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development.     

Pharmacotherapy of autism spectrum disorders

Although no pharmacological or behavioral therapy has currently proven effective for treating all core symptoms of autism, many dysfunctional behaviors may be treated pharmacologically. Drug treatments should always be part of a comprehensive management plan that includes behavioral and educational interventions, and should be focused on specific targets. Several classes of psychotropic medications have been used to decrease the wide range of “maladaptive” or “interfering” behaviors and associated medical problems that can interfere with relationships and physical health and hinder the implementation of various non-pharmacological interventions. Atypical neuroleptics have been shown to be useful in the treatment of behavioral symptoms in autism. Attention deficit and hyperactivity disorder medications may be effective for counteracting the additional features of hyperactivity and short attention span. Antiepileptic drugs and selective serotonin reuptake inhibitors have shown promising results, but there are no specific indications for them as of yet. With respect to potential drug targets, some clinical features are caused by a dysfunction in neurochemical signaling systems, and thus may improve with selective pharmacological interventions acting on specific abnormal neurobiological pathways. Recent animal studies can be useful models for understanding the common pathogenic pathways leading to autism spectrum disorders (ASDs), and have the potential to offer new biologically focused treatment options.     

Genetics of autism spectrum disorders

Autism spectrum disorders (ASDs) are a clinically complex group of childhood disorders that have firm evidence of an underlying genetic etiology. Many techniques have been used to characterize the genetic bases of ASDs. Linkage studies have identified several replicated susceptibility loci, including 2q24–2q31, 7q, and 17q11–17q21. Association studies and mutation analysis of candidate genes have implicated the synaptic genes NRXN1, NLGN3, NLGN4, SHANK3, and CNTNAP2 in ASDs. Traditional cytogenetic approaches highlight the high frequency of large chromosomal abnormalities (3%–7% of patients), including the most frequently observed maternal 15q11–13 duplications (1%–3% of patients). Newly developed techniques include high-resolution DNA microarray technologies, which have discovered formerly undetectable submicroscopic copy number variants, and genomewide association studies, which allow simultaneous detection of multiple genes associated with ASDs. Although great progress has been made in autism genetics, the molecular bases of most ASDs remains enigmatic.