Decision-making under conditions of explicit risk and uncertainty in autistic and typically developing adolescents and young adults.

Adolescence has been characterized as a period of risky and possibly suboptimal decision-making, yet the development of decision-making in autistic adolescents is not well understood. To investigate decision-making in autism, we evaluated performance on 2 computerized tasks capturing decision-making under explicit risk and uncertainty in autistic and non-autistic adolescents/young adults ages 12-22 years. Participants completed the Game of Dice Task (32 IQ-matched participant pairs) to assess decision-making under explicit risk and the modified Iowa Gambling Task (35 IQ-matched pairs) to assess decision-making under uncertainty. Autistic participants overall made riskier decisions than non-autistic participants on the Game of Dice Task, and the odds of making riskier decisions varied by age and IQ. In contrast, the autistic group showed comparable levels of learning over trial blocks to the non-autistic group on the modified Iowa Gambling Task. For both tasks, younger autistic participants performed poorer than their non-autistic counterparts, while group differences diminished in older ages. This age-related pattern suggests positive development during adolescence on risk assessment and decision-making in autism but also implies differential developmental trajectories between groups. These findings also suggest differential performance by the risk type, with additional complex influences of IQ and fluid cognition, which warrants further investigations.

EEG Microstates as Markers for Cognitive Impairments in Fragile X Syndrome.

Fragile X syndrome (FXS) is one of the most common inherited causes of intellectual disabilities. While there is currently no cure for FXS, EEG is considered an important method to investigate the pathophysiology and evaluate behavioral and cognitive treatments. We conducted EEG microstate analysis to investigate resting brain dynamics in FXS participants. Resting-state recordings from 70 FXS participants and 71 chronological age-matched typically developing control (TDC) participants were used to derive microstates via modified k-means clustering. The occurrence, mean global field power (GFP), and global explained variance (GEV) of microstate C were significantly higher in the FXS group compared to the TDC group. The mean GFP was significantly negatively correlated with non-verbal IQ (NVIQ) in the FXS group, where lower NVIQ scores were associated with greater GFP. In addition, the occurrence, mean duration, mean GFP, and GEV of microstate D were significantly greater in the FXS group than the TDC group. The mean GFP and occurrence of microstate D were also correlated with individual alpha frequencies in the FXS group, where lower IAF frequencies accompanied greater microstate GFP and occurrence. Alterations in microstates C and D may be related to the two well-established cognitive characteristics of FXS, intellectual disabilities and attention impairments, suggesting that microstate parameters could serve as markers to study cognitive impairments and evaluate treatment outcomes in this population. Slowing of the alpha peak frequency and its correlation to microstate D parameters may suggest changes in thalamocortical dynamics in FXS, which could be specifically related to attention control. (250 words).

Commentary: The challenges and promises of competitively employing autistic adults in the United States.

Current United States statistics suggest that autistic individuals will experience high unemployment and underemployment rates throughout their lives. Furthermore, despite the passage of federal legislation to employ young autistic adults in competitive integrated settings, where they work alongside non-disabled workers and earn at least minimum wage, most individuals receiving state services still are placed in day programs or sheltered workshops. Since meaningful employment is the most important determinant of life satisfaction, this failure is a critical societal problem, exerting increasing pressure for systems change. But the news is not all bad. Private sector companies have increased their hiring of disabled workers, producing a growing base of expertise in the recruitment, on-boarding, training, and management of autistic employees. This has led to a growing recognition that autistic individuals can be ideal workers. Autism researchers have advanced the field by investigating these private industry programs as well as conducting efficacy trials of interventions and services that help autistic individuals in the workplace. However, gaps in knowledge persist stemming from the heterogeneity of autistic workers, limited knowledge about those not receiving state services, and a system of federal services that is fragmented, poorly coordinated, difficult to navigate, and over-taxed. Autism researchers can continue to improve outcomes of autistic workers through investigations of the fit between autistic workers, their preferences, and the characteristics of available jobs, and through effectiveness trails of promising employment interventions and services that promote systems change that help break down the barriers to better integration of existing state services and resources in the United States.

Neural correlates of irritability symptom relief in adolescents pre- and post-trauma-focused cognitive behavioral therapy: A pilot study on reward processing.

Despite that Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) is a first-line, evidence-based treatment for youths experiencing trauma-related symptoms, treatment responses vary and it remains unclear for whom and how this treatment works. In this context, we examined pre-treatment neural reward processing and pre- vs. post-treatment changes in neural reward processing, in relation to irritability - a transdiagnostic and dimensional feature present in multiple trauma-related syndromes, following TF-CBT. Adolescents (N = 22) with childhood trauma history completed a child-friendly monetary incentive delay task during fMRI acquisition, prior to and after the treatment, and irritability symptoms were assessed at five time points over the course of the treatment. Individual irritability slopes (i.e., irritability change rate) and intercepts (i.e., initial irritability level), generated by linear growth curve modeling, were integrated with fMRI data. Repeated ANCOVAs demonstrated that both pre-treatment neural response to reward and pre- vs. post-treatment changes in neural reward processing correlated with irritability symptom relief, such that opposite baseline neural reward processing profiles and differential changing patterns were observed in individuals showing irritability symptom relief vs. not. Together, our findings provide proof of concept that integrating brain information with clinical information has the potential to identify predictors and mechanisms of symptom relief.

Multisensory integration and interactions across vision, hearing, and somatosensation in autism spectrum development and typical development.

Most prior studies of multisensory integration (MSI) in autism have measured MSI in only a single combination of modalities - typically audiovisual integration. The present study used onset reaction times (RTs) and 125-channel electroencephalography (EEG) to examine different forms of bimodal and trimodal MSI based on combinations of auditory (noise burst), somatosensory (finger tap), and visual (flash) stimuli presented in a spatially-aligned manner using a custom desktop apparatus. A total of 36 autistic and 19 non-autistic adolescents between the ages of 11-14 participated. Significant RT multisensory facilitation relative to summed unisensory RT was observed in both groups, as were significant differences between summed unisensory and multisensory ERPs. Although the present study's statistical approach was not intended to test effect latencies, these interactions may have begun as early as ∼45 ms, constituting "early" (<100 ms) MSI. RT and ERP measurements of MSI appeared independent of one another. Groups did not significantly differ in multisensory RT facilitation, but we found exploratory evidence of group differences in the magnitude of audiovisual interactions in ERPs. Future research should make greater efforts to explore MSI in under-represented populations, especially autistic people with intellectual disabilities and nonspeaking/minimally-verbal autistic people.

A Multidimensional Investigation of Sensory Processing in Autism: Parent- and Self-Report Questionnaires, Psychophysical Thresholds, and Event-Related Potentials in the Auditory and Somatosensory Modalities.

Background: Reconciling results obtained using different types of sensory measures is a challenge for autism sensory research. The present study used questionnaire, psychophysical, and neurophysiological measures to characterize autistic sensory processing in different measurement modalities. Methods: Participants were 46 autistic and 21 typically developing 11- to 14-year-olds. Participants and their caregivers completed questionnaires regarding sensory experiences and behaviors. Auditory and somatosensory event-related potentials (ERPs) were recorded as part of a multisensory ERP task. Auditory detection, tactile static detection, and tactile spatial resolution psychophysical thresholds were measured. Results: Sensory questionnaires strongly differentiated between autistic and typically developing individuals, while little evidence of group differences was observed in psychophysical thresholds. Crucially, the different types of measures (neurophysiological, psychophysical, questionnaire) appeared to be largely independent of one another. However, we unexpectedly found autistic participants with larger auditory Tb ERP amplitudes had reduced hearing acuity, even though all participants had hearing acuity in the non-clinical range. Limitations: The autistic and typically developing groups were not matched on cognitive ability, although this limitation does not affect our main analyses regarding convergence of measures within autism. Conclusion: Overall, based on these results, measures in different sensory modalities appear to capture distinct aspects of sensory processing in autism, with relatively limited convergence between questionnaires and laboratory-based tasks. Generally, this might reflect the reality that laboratory tasks are often carried out in controlled environments without background stimuli to compete for attention, a context which may not closely resemble the busier and more complex environments in which autistic people's atypical sensory experiences commonly occur. Sensory questionnaires and more naturalistic laboratory tasks may be better suited to explore autistic people's real-world sensory challenges. Further research is needed to replicate and investigate the drivers of the unexpected association we observed between auditory Tb ERP amplitudes and hearing acuity, which could represent an important confound for ERP researchers to consider in their studies.

White matter integrity in adolescent irritability: A preliminary study.

Irritability is a prevalent, impairing transdiagnostic symptom, especially during adolescence, yet little is known about irritability's neural mechanisms. A few studies examined the integrity of white matter tracts that facilitate neural communication in irritability, but only with extreme, disorder-related symptom presentations. In this preliminary study, we used a group connectometry approach to identify white matter tracts correlated with transdiagnostic irritability in a community/clinic-based sample of 35 adolescents (mean age = 14 years, SD = 2.0). We found positive and negative associations with irritability in local white matter tract bundles including sections of the longitudinal fasciculus; frontoparietal, parolfactory, and parahippocampal cingulum; corticostriatal and thalamocortical radiations; and vertical occipital fasciculus. Our findings support functional neuroimaging studies that implicate widespread neural pathways, particularly emotion and reward networks, in irritability. Our findings of positive and negative associations reveal a complex picture of what is "good" white matter connectivity. By characterizing irritability's neural underpinnings, targeted interventions may be developed.

EEG microstates suggest atypical resting-state network activity in high-functioning children and adolescents with autism spectrum development.

EEG microstates represent transient electrocortical events that reflect synchronized activities of large-scale networks, which allows investigations of brain dynamics with sub-second resolution. We recorded resting EEG from 38 children and adolescents with Autism Spectrum Development (ASD) and 48 age, IQ, sex, and handedness-matched typically developing (TD) participants. The EEG was segmented into a time series of microstates using modified k-means clustering of scalp voltage topographies. The frequency and global explained variance (GEV) of a specific microstate (type C) were significantly lower in the ASD group compared to the TD group while the duration of the same microstate was correlated with the presence of ASD-related behaviors. The duration of this microstate was also positively correlated with participant age in the TD group, but not in the ASD group. Further, the frequency and duration of the microstate were significantly correlated with the overall alpha power only in the TD group. The signal strength and GEV for another microstate (type G) was greater in the ASD group than the TD group, and the associated topographical pattern differed between groups with greater variations in the ASD group. While more work is needed to clarify the underlying neural sources, the existing literature supports associations between the two microstates and the default mode and salience networks. The current study suggests specific alterations of temporal dynamics of the resting cortical network activities as well as their developmental trajectories and relationships to alpha power, which has been proposed to reflect reduced neural inhibition in ASD.

Neural Hyperexcitability in Autism Spectrum Disorders.

Despite the progress that has been made in research on autism spectrum disorders (ASD), the understanding of the biological basis of ASD to identify targets for novel, effective treatment remains limited. One of the leading biological theories of autism is a model of cortical hyperexcitability. While numerous genetic and epigenetic studies support this model, how this particular biological alteration relates to known phenotypes in ASD is not well established. Using examples of sensory processing alterations, this review illustrates how cortical excitability may affect neural processes to result eventually in some core clinical phenotypes in ASD. Applications of the cortical excitability model for translational research and drug development are also discussed.

Neurophysiological hyperresponsivity to sensory input in autism spectrum disorders.

BACKGROUND: Atypical sensory processing is a common clinical observation in autism spectrum disorder (ASD). Neural hyperexcitability has been suggested as the cause for sensory hypersensitivity, a frequently reported clinical observation in ASD. We examined visual evoked responses to parametric increases in stimulus contrast in order to model neural responsivity of sensory systems in ASD. METHODS: Thirteen high-functioning individuals with ASD and 12 typically developing (TD) individuals completed a steady-state visual evoked potential study. Stimuli were vertical circular gratings oscillating at 3.76 Hz at varying contrasts (5, 10, 20,…, 90 % contrast, 10 levels). The average spectral power at the stimulus oscillation frequency was calculated for each contrast level. RESULTS: The magnitude of evoked sensory responses increased at a significantly greater rate and resulted in disproportionately elevated activation with higher contrasts in the ASD group. Approximately 45 % of ASD participants had rates of response increases greater than any TD participant. This alteration was highly associated with parental reports of these participants' sensory difficulties. CONCLUSIONS: Greater increases in visual responses over contrast manipulation suggest heightened excitability in the sensory cortex in ASD participants. Heightened neural excitability was observed in a substantial portion but not all of the ASD participants. This pattern suggests that individuals with higher excitability may constitute a neurobiologically distinct subgroup requiring individualized treatment interventions.

Visual motion processing and visual sensorimotor control in autism.

Impairments in visual motion perception and use of visual motion information to guide behavior have been reported in autism, but the brain alterations underlying these abnormalities are not well characterized. We performed functional magnetic resonance imaging (fMRI) studies to investigate neural correlates of impairments related to visual motion processing. Sixteen high-functioning individuals with autism and 14 age and IQ-matched typically developing individuals completed two fMRI tasks using passive viewing to examine bottom-up responses to visual motion and visual pursuit tracking to assess top-down modulation of visual motion processing during sensorimotor control. The autism group showed greater activation and faster hemodynamic decay in V5 during the passive viewing task and reduced frontal and V5 activation during visual pursuit. The observations of increased V5 activation and its faster decay during passive viewing suggest alterations in local V5 circuitries that may be associated with reduced GABAergic tone and inhibitory modulation. Reduced frontal and V5 activation during active pursuit suggest reduced top-down modulation of sensory processing. These results suggest that both local intrinsic abnormalities in V5 and more widely distributed network level abnormalities are associated with visual motion processing in autism.

Resting state EEG abnormalities in autism spectrum disorders.

Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD.

A cross-sectional study of the development of volitional control of spatial attention in children with chromosome 22q11.2 deletion syndrome.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) results from a 1.5- to 3-megabase deletion on the long arm of chromosome 22 and occurs in approximately 1 in 4000 live births. Previous studies indicate that children with 22q11.2DS are impaired on tasks involving spatial attention. However, the degree to which these impairments are due to volitionally generated (endogenous) or reflexive (exogenous) orienting of attention is unclear. Additionally, the efficacy of these component attention processes throughout child development in 22q11.2DS has yet to be examined. METHODS: Here we compared the performance of a wide age range (7 to 14 years) of children with 22q11.2DS to typically developing (TD) children on a comprehensive visual cueing paradigm to dissociate the contributions of endogenous and exogenous attentional impairments. Paired and two-sample t-tests were used to compare outcome measures within a group or between groups. Additionally, repeated measures regression models were fit to the data in order to examine effects of age on performance. RESULTS: We found that children with 22q11.2DS were impaired on a cueing task with an endogenous cue, but not on the same task with an exogenous cue. Additionally, it was younger children exclusively who were impaired on endogenous cueing when compared to age-matched TD children. Older children with 22q11.2DS performed comparably to age-matched TD peers on the endogenous cueing task. CONCLUSIONS: These results suggest that endogenous but not exogenous orienting of attention is selectively impaired in children with 22q11.2DS. Additionally, the age effect on cueing in children with 22q11.2DS suggests a possible altered developmental trajectory of endogenous cueing.

Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome.

Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them toward the lower end of dopamine turnover on the nonlinear function. A common polymorphism with valine to methionine substitution alters COMT activity that results in higher enzyme activity in the valine variant. Twenty-seven children with 22q11.2DS between 7 and 14 years old, and 21 age-matched typically developing children, performed a modified version of the Attention Network Test. Children with a single valine allele showed a reduction in response times when trials with incongruent flankers were repeated, whereas those who were hemizygous for the methionine allele did not show the same context-based response facilitation. Our results support that a single gene, COMT, could modulate PFC-dependent cognition.

Patterns of visual sensory and sensorimotor abnormalities in autism vary in relation to history of early language delay.

Visual motion perception and pursuit eye movement deficits have been reported in autism. However, it is unclear whether these impairments are related to each other or to clinical symptoms of the disorder. High-functioning individuals with autism (41 with and 36 without delayed language acquisition) and 46 control subjects participated in the present study. All three subject groups were matched on chronological age and Full-Scale IQ. The autism group with delayed language acquisition had bilateral impairments on visual motion discrimination tasks, whereas the autism group without delay showed marginal impairments only in the left hemifield. Both autism groups showed difficulty tracking visual targets, but only the autism group without delayed language acquisition showed increased pursuit latencies and a failure to show the typical rightward directional advantage in pursuit. We observed correlations between performance on the visual perception and pursuit tasks in both autism groups. However, pursuit performance was correlated with manual motor skills only in the autism group with delayed language, suggesting that general sensorimotor or motor disturbances are a significant additional factor related to pursuit deficits in this subgroup. These findings suggest that there may be distinct neurocognitive phenotypes in autism associated with patterns of early language development.

Atypical involvement of frontostriatal systems during sensorimotor control in autism.

Autism is a neurodevelopmental disorder involving dysmaturation of widely distributed brain systems. Accordingly, behaviors that depend on distributed systems, such as higher level cognition and sensorimotor control, are compromised in the disorder. The current study investigated alterations in neural systems underlying sensorimotor disturbances in autism. An fMRI investigation was conducted using saccadic and pursuit eye movement paradigms with 13 high functioning individuals with autism and 14 age- and IQ-matched typically developing individuals. Individuals with autism had reduced activation in cortical eye fields and cerebellar hemispheres during both eye movement tasks. When executing visually guided saccades, individuals with autism had greater activation bilaterally in a frontostriatal circuit including dorsolateral prefrontal cortex, caudate nucleus, medial thalamus, anterior and posterior cingulate cortex, and right dentate nucleus. The increased activation in prefrontal-striatal-thalamocortical circuitry during visually guided saccades indicates that systems typically dedicated to cognitive control may need to compensate for disturbances in lower-level sensorimotor systems. Reduced activation throughout visual sensorimotor systems may contribute to saccadic and pursuit disturbances that have been reported in autism. These findings document that neurodevelopmental disturbances in autism affect widely distributed brain systems beyond those mediating language and social cognition.

Oculomotor studies of cerebellar function in autism.

Histopathological, neuroimaging and genetic findings indicate cerebellar abnormalities in autism, but the extent of neurophysiological dysfunction associated with those findings has not been systematically examined. Suppression of intrusive saccades (square wave jerks) and the ability to sustain eccentric gaze, two phenomena requiring intact cerebellar function, were examined in 52 high-functioning individuals with autism and 52 age- and IQ-matched healthy subjects during visual fixation of static central and peripheral targets. Rates of intrusive saccades were not increased in autism during visual fixation, and foveopetal ocular drift was also not increased when subjects held an eccentric gaze. The absence of gross disturbances of visual fixation associated with cerebellar disease in individuals with autism, such as increased square wave jerk rates and foveopetal drift when holding eccentric gaze, indicates that the functional integrity of cerebellar--brainstem networks devoted to oculomotor control is preserved in autism despite reported anatomic variations. However, increased amplitude of intrusive saccades and reduced latency of target refixation after intrusive saccades were observed in individuals with autism, especially when subjects maintained fixation of remembered target locations without sensory guidance. The atypical metrics of intrusive saccades that were observed may be attributable to faulty functional connectivity in cortico-cerebellar networks.

Pursuit eye movement deficits in autism.

Oculomotor studies provide a novel strategy for evaluating the functional integrity of multiple brain systems and cognitive processes in autism. The current study compared pursuit eye movements of 60 high-functioning individuals with autism and 94 intelligence quotient, age and gender matched healthy individuals using ramp and oscillating target tasks. Individuals with autism had normal pursuit latency, but reduced closed-loop pursuit gain when tracking both oscillating and ramp targets. This closed-loop deficit was similar for leftward and rightward pursuit, but the difference between individuals with autism and their age-matched peers was more apparent after mid-adolescence, suggesting reduced maturational achievement of the pursuit system in autism. Individuals with autism also had lower open-loop pursuit gain (initial 100 ms of pursuit) and less accurate initial catch-up saccades during a foveofugal step-ramp task, but these deficits were only seen when targets moved into the right visual field. Pursuit performance in both open- and closed-loop phases was correlated with manual praxis in individuals with autism. Bilateral disturbances in the ability to use internally generated extraretinal signals for closed-loop pursuit implicate frontostriatal or cerebellar circuitry. The hemifield specific deficit in open-loop pursuit demonstrates a lateralized disturbance in the left extrastriate areas that extract visual motion information, or in the transfer of visual motion information to the sensorimotor areas that transform visual information into appropriate oculomotor commands.

Eye movements in neurodevelopmental disorders.

PURPOSE OF REVIEW: The aim of this paper is to review the literature on eye-movement abnormalities associated with neurodevelopmental disorders. Eye-movement testing is a non-invasive quantitative approach for evaluating brain systems across the age spectrum. It thus provides a promising methodology for characterizing and documenting maturational abnormalities in brain systems associated with neurodevelopmental disorders. RECENT FINDINGS: Recent oculomotor studies have made significant contributions to the understanding of neurodevelopmental disorders, most notably in autism, attention-deficit/hyperactivity disorder, and Tourette's syndrome. Notably different patterns of deficits have been found in these disorders and have helped to clarify their pathophysiology. SUMMARY: Eye-movement studies have begun to serve as a useful approach for studying cognitive and neurophysiological aspects of neurodevelopmental disorders. They also have potential as a strategy for establishing quantitative endophenotypes for genetic research, and for monitoring beneficial and adverse effects of pharmacotherapies. Studies are needed that involve larger patient populations, longitudinal characterization of developmental failures, patients free from central nervous system-active medications, and that use functional imaging, as patients perform eye-movement tasks, for direct identification of clinically relevant abnormalities in brain systems.