Functional neuroimaging of treatment effects in psychiatry: methodological challenges and recommendations.

Functional magnetic resonance imaging (fMRI) has helped to elucidate the neurobiological bases of psychiatric and neurodevelopmental disorders by localizing etiologically-relevant aberrations in brain function. Functional MRI also has shown great promise to help understand potential mechanisms of action of effective treatments for a range of psychiatric and neurodevelopmental disorders, including mood and anxiety disorders, schizophrenia, and autism. However, the use of fMRI to probe intervention effects in psychiatry is associated with unique methodological considerations, including the psychometric properties of repeated fMRI scans, how to assess potential relations between the effects of an intervention on symptoms and on specific brain activation patterns, and how to best make causal inferences about intervention effects on brain function. Additionally, the study of treatment effects in neurodevelopmental disorders presents additional unique challenges related to brain maturation, analysis methods, and the potential for motion artifacts. We review these methodological considerations and provide recommendations for best practices for each of these topics.

Evaluating the Feasibility of The NIH Toolbox Cognition Battery for Autistic Children and Adolescents.

This study evaluates the feasibility of the NIH Toolbox Cognition Battery (NIH-TCB) for use in autism spectrum disorder (ASD). 116 autistic children and adolescents and 80 typically developing (TD) controls, ages 3-17 years, completed four NIH-TCB tasks related to inhibitory control, cognitive flexibility, processing speed, and episodic memory. While the majority of autistic and TD children completed all four tasks, autistic children experienced greater difficulties with task completion. Across autistic and TD children, performance on NIH-TCB tasks was highly dependent on IQ, but significant performance differences related to ASD diagnosis were found for two of four tasks. These findings highlight the potential strengths and limitations of the NIH-TCB for use with autistic children.

Measuring the Functional Impact of Behavioral Inflexibility in Children with Autism Using the Behavioral Inflexibility Scale: Clinical Interview (BIS-CI).

For individuals with autism spectrum disorder (ASD), behavioral inflexibility can affect multiple domains of functioning and family life. The objective of this study was to develop and validate a clinical interview version of the Behavioral Inflexibility Scale. Trained interviewers conducted interviews with parents of 144 children with ASD and 70 typically developing children (ages: 3-17 years). Using exploratory factor analysis, the Behavioral Inflexibility Scale-Clinical Interview (BIS-CI) was found to be unidimensional. Reliability data indicated the measure was internally consistent (α = 0.80), achieved excellent inter-rater reliability (ICC = 0.97) and test-retest reliability (ICC = 0.87). These findings demonstrate that the BIS-CI is a reliable and valid measure to determine the functional impact of behavioral inflexibility.

Behavioral Inflexibility Across Two Neurogenetic Conditions: Down Syndrome and Fragile X Syndrome.

Behavioral inflexibility (BI) has been highlighted to occur across genetic and neurodevelopmental disorders. This study characterized BI in two common neurogenetic conditions: Fragile X syndrome (FXS) and Down syndrome (DS). Caregivers of children with FXS (N = 56; with ASD = 28; FXS only = 28) and DS (N = 146) completed the Behavioral Inflexibility Scale (BIS) via an online survey. Total BIS scores were higher in FXS+ASD than both FXS only and DS (p <.001). Most endorsed items were similar across the three groups, but scores were higher in the FXS+ASD group. In all groups, BI associated with other clinical variables (receptive behaviors, anxiety, social communication). The current data suggest that BI is variable across neurogenetic conditions and higher in individuals with comorbid ASD.

Atypical neural processing during the execution of complex sensorimotor behavior in autism.

Stereotyped behavior is rhythmic, repetitive movement that is essentially invariant in form. Stereotypy is common in several clinical disorders, such as autism spectrum disorders (ASD), where it is considered maladaptive. However, it also occurs early in typical development (TD) where it is hypothesized to serve as the foundation on which complex, adaptive motor behavior develops. This transition from stereotyped to complex movement in TD is thought to be supported by sensorimotor integration. Stereotypy in clinical disorders may persist due to deficits in sensorimotor integration. The present study assessed whether differences in sensorimotor processing may limit the expression of complex motor behavior in individuals with ASD and contribute to the clinical stereotypy observed in this population. Adult participants with ASD and TD performed a computer-based stimulus-tracking task in the presence and absence of visual feedback. Electroencephalography was recorded during the task. Groups were compared on motor performance (root mean square error), motor complexity (sample entropy), and neural complexity (multiscale sample entropy of the electroencephalography signal) in the presence and absence of visual feedback. No group differences were found for motor performance or motor complexity. The ASD group demonstrated greater neural complexity and greater differences between feedback conditions than TD individuals, specifically in signals relevant to sensorimotor processing. Motor performance and motor complexity correlated with clinical stereotypy in the ASD group. These findings support the hypothesis that individuals with ASD have differences in sensorimotor processing when executing complex motor behavior and that stereotypy is associated with low motor complexity.

A Distinct Three-Factor Structure of Restricted and Repetitive Behaviors in an Epidemiologically Sound Sample of Preschool-Age Children with Autism Spectrum Disorder.

Prior studies investigating restricted and repetitive behavior (RRB) subtypes within autism spectrum disorder (ASD) have found varied factor structures for symptom groupings, in part, due to variation in symptom measurement and broad sample age ranges. This study examined RRBs among 827 preschool-age children, ages 35 to 71 months, through an exploratory factor analysis of RRB items from the Autism Diagnostic Interview-Revised (ADI-R) collected through the Study to Explore Early Development. The factor structures of RRBs among children with confirmed ASD versus those with non-autism developmental concerns were qualitatively compared. Correlations between RRB factors and participant characteristics were examined in the ASD group. Three conceptually well-defined factors characterized as repetitive sensorimotor behaviors (RSMB), insistence on sameness (IS), and a novel stereotyped speech (SPEECH) factor emerged for the ASD group only. Distinct factors were supported by different clinical correlates. Findings have implications for improving differential diagnosis and understanding of ASD symptomatology in this age range.

Cataloguing and characterizing interests in typically developing toddlers and toddlers who develop ASD.

Intense interests are common in children with and without autism spectrum disorder (ASD), and little research has characterized aspects of interests that are unique to or shared among children with and without ASD. We aimed to characterize interests in a sample of infants at high-familial-risk (HR) and low-familial-risk (LR) for ASD using a novel interview. Participants included HR siblings who were diagnosed with ASD at 24 months (HR-ASD, n = 56), HR siblings who did not receive an ASD diagnosis at 24 months (HR-Neg, n = 187), and a LR comparison group (n = 109). We developed and collected data with the Intense Interests Inventory at 18- and 24-months of age, a semi-structured interview that measures intensity and peculiarity of interests in toddlers and preschool-aged children. Intensity of interests differed by familial risk at 24 months, with HR-ASD and HR-Neg groups demonstrating equivalent intensity of interests that were higher than the LR group. By contrast, peculiarity of interest differed by ASD diagnosis, with the HR-ASD group showing more peculiar interests than the HR-Neg and LR groups at 24 months. At 18 months the HR-ASD group had more peculiar interests than the LR group, though no differences emerged in intensity of interests. This measure may be useful in identifying clinically-relevant features of interests in young children with ASD. We also replicated previous findings of males showing more intense interests at 18 months in our non-ASD sample. These results reveal new information about the nature of interests and preoccupations in the early autism phenotype. LAY SUMMARY: Intense interests are common in young children with autism and their family members. Intense interests are also prevalent among typically-developing children, and especially boys. Here we catalog interests and features of these interests in a large sample of toddlers enriched for autism risk. Children who had family members with autism had more intense interests, and those who developed autism themselves had more unusual interests at 24 months. These results highlight the importance of different aspects of interest in autism.

Adults with Autism and Adults with Depression Show Similar Attentional Biases to Social-Affective Images.

Individuals with ASD have increased rates of depression compared to the general population. Repetitive cognition is a core feature of ASD; in typically developing adults, repetitive cognition has been associated with attentional biases to negative emotional material and increased prospective depression risk. We compared adults with ASD to typically developing adults with depression and never-depressed controls, using a paired preference paradigm sensitive to affective biases in the context of repetitive cognition. Both clinical cohorts oriented faster to negative social-emotional material and spent less time overall on positive material, compared to healthy controls. Exploratory analyses within ASD revealed specific influences of repetitive behavior on patterns of affective bias. Findings help pinpoint susceptibilities in ASD that may confer increased risk for depression.

Auditory event-related potentials index faster processing of natural speech but not synthetic speech over nonspeech analogs in children.

Given the crucial role of speech sounds in human language, it may be beneficial for speech to be supported by more efficient auditory and attentional neural processing mechanisms compared to nonspeech sounds. However, previous event-related potential (ERP) studies have found either no differences or slower auditory processing of speech than nonspeech, as well as inconsistent attentional processing. We hypothesized that this may be due to the use of synthetic stimuli in past experiments. The present study measured ERP responses during passive listening to both synthetic and natural speech and complexity-matched nonspeech analog sounds in 22 8-11-year-old children. We found that although children were more likely to show immature auditory ERP responses to the more complex natural stimuli, ERP latencies were significantly faster to natural speech compared to cow vocalizations, but were significantly slower to synthetic speech compared to tones. The attentional results indicated a P3a orienting response only to the cow sound, and we discuss potential methodological reasons for this. We conclude that our results support more efficient auditory processing of natural speech sounds in children, though more research with a wider array of stimuli will be necessary to confirm these results. Our results also highlight the importance of using natural stimuli in research investigating the neurobiology of language.

Children With Autism Produce a Unique Pattern of EEG Microstates During an Eyes Closed Resting-State Condition.

Although fMRI studies have produced considerable evidence for differences in the spatial connectivity of resting-state brain networks in persons with autism spectrum disorder (ASD) relative to typically developing (TD) peers, little is known about the temporal dynamics of these brain networks in ASD. The aim of this study was to examine the EEG microstate architecture in children with ASD as compared to TD at rest in two separate conditions - eyes-closed (EC) and eyes-open (EO). EEG microstate analysis was performed on resting-state data of 13 ASD and 13 TD children matched on age, gender, and IQ. We found that children with ASD and TD peers produced topographically similar canonical microstates at rest. Group differences in the duration and frequency of these microstates were found primarily in the EC resting-state condition. In line with previous fMRI findings that have reported differences in spatial connectivity within the salience network (previously correlated with the activity of microstate C) in ASD, we found that the duration of activation of microstate C was increased, and the frequency of microstate C was decreased in ASD as compared to TD in EC resting-state. Functionally, these results may be reflective of alterations in interoceptive processes in ASD. These results suggest a unique pattern of EEG microstate architecture in ASD relative to TD during resting-states and also that EEG microstate parameters in ASD are susceptible to differences in resting-state conditions.

Degranulated mast cells in the skin of adults with self-injurious behavior and neurodevelopmental disorders.

The role of nociceptive processes in relation to chronic, tissue-damaging self-injury among individuals with neurodevelopmental disorders is poorly understood. Scientific investigation has been limited, in part, by the clinical reality that the majority of individuals with severe intellectual impairments have co-morbid communicative impairments making it difficult to ascertain information regarding pain. Recently, we found abnormal patterns of peripheral epidermal nerve fiber (ENF) innervation and increased neuropeptide (substance P; SP) content among a subset of individuals with chronic self-injury. Here, we provide initial evidence for peripheral neuro-immune activity specific to self-injury. Skin samples from non-injury body-matched sites were compared between non-verbal adults with and without self-injury matched on gender and disability level. Relative to disability-matched controls, individuals with chronic self-injury had significantly more degranulated mast cells and were more responsive to tactile stimulation during a sensory testing procedure. Thus, nociceptive mechanisms and peripheral afferent sensitization may play a part in mediating and maintaining chronic self-injury.

Age-related differences in restricted repetitive behaviors in autism spectrum disorders.

Restricted repetitive behaviors (RRBs) were examined in a large group of children, adolescents and adults with ASD in order to describe age-related patterns of symptom change and association with specific contextual factors, and to examine if the patterns of change are different for the various types of RRBs. Over 700 individuals with ASD were rated on the Repetitive Behavior Scale-Revised. RRBs were less frequent and less severe among older than younger individuals, corroborating that autism symptoms abate with age. Our findings further suggest that repetitive behaviors are a heterogeneous group of behaviors, with the subtypes of RRBs having their own individual patterns across the lifespan, and in some cases, a differential association with age depending on intellectual functioning.

Visual feedback during motor performance is associated with increased complexity and adaptability of motor and neural output.

Complex motor behavior is believed to be dependent on sensorimotor integration - the neural process of using sensory input to plan, guide, and correct movements. Previous studies have shown that the complexity of motor output is low when sensory feedback is withheld during precision motor tasks. However, much of this research has focused on motor behavior rather than neural processing, and therefore, has not specifically assessed the role of sensorimotor neural functioning in the execution of complex motor behavior. The present study uses a stimulus-tracking task with simultaneous electroencephalography (EEG) recording to assess the effect of visual feedback on motor performance, motor complexity, and sensorimotor neural processing in healthy adults. The complexity of the EEG signal was analyzed to capture the information content in frequency bands (alpha and beta) and scalp regions (central, parietal, and occipital) that are associated with sensorimotor processing. Consistent with previous literature, motor performance and its complexity were higher when visual feedback was provided relative to when it was withheld. The complexity of the neural signal was also higher when visual feedback was provided. This was most robust at frequency bands (alpha and beta) and scalp regions (parietal and occipital) associated with sensorimotor processing. The findings show that visual feedback increases the information available to the brain when generating complex, adaptive motor output.

Development of a mouse test for repetitive, restricted behaviors: relevance to autism.

Repetitive behavior, a core symptom of autism, encompasses stereotyped responses, restricted interests, and resistance to change. These studies investigated whether different components of the repetitive behavior domain could be modeled in the exploratory hole-board task in mice. Four inbred mouse strains, C57BL/6J, BALB/cByJ, BTBR T+tf/J, and FVB/NJ, and mice with reduced expression of Grin1, leading to NMDA receptor hypofunction (NR1neo/neo mice), were tested for exploration and preference for olfactory stimuli in an activity chamber with a 16-hole floor-board. Reduced exploration and high preference for holes located in the corners of the chamber were observed in BALB/cByJ and BTBR T+tf/J mice. All inbred strains had initial high preference for a familiar olfactory stimulus (clean cage bedding). BTBR T+tf/J was the only strain that did not demonstrate a shift in hole preference towards an appetitive olfactory stimulus (cereal or a chocolate chip), following home cage exposure to the food. The NR1neo/neo mice showed lower hole selectivity and aberrant olfactory stimulus preference, in comparison to wildtype controls. The results indicate that NR1neo/neo mice have repetitive nose poke responses that are less modified by environmental contingencies than responses in wildtype mice. 25-30% of NMDA receptor hypomorphic mice also show self-injurious responses. Findings from the olfactory studies suggest that resistance to change and restricted interests might be modeled in mice by a failure to alter patterns of hole preference following familiarization with an appetitive stimulus, and by high preference persistently demonstrated for one particular olfactory stimulus. Further work is required to determine the characteristics of optimal mouse social stimuli in the olfactory hole-board test.

Evidence for three subtypes of repetitive behavior in autism that differ in familiality and association with other symptoms.

BACKGROUND: Restricted repetitive behaviors (RRBs) are a core feature of autism and consist of a variety of behaviors, ranging from motor stereotypies to complex circumscribed interests. The objective of the current study was to examine the structure of RRBs in autism using relevant items from the Autism Diagnostic Interview-Revised in a sample of 316 individuals with autistic disorder. METHODS/RESULTS: Using exploratory factor analysis, three distinct factors were identified: Repetitive Motor Behaviors (RMB), Insistence on Sameness (IS), and Circumscribed Interests (CI). RMB were found to be associated with a variety of subject characteristics such as IQ, age, social/communication impairments, and the presence of regression. IS was associated with social and communication impairments whereas CI appeared to be independent of subject characteristics, suggesting CI may be particularly useful in subsetting samples. Based on sib-pair correlations, IS and CI (but not RMB) appear to be familial. Analysis of the data at the case level suggests that the presence of multiple forms of RRB in an individual is associated with more impairment in the social and communication domains, suggesting a more severe presentation of autistic disorder. CONCLUSIONS: There appears to be considerable structure within repetitive behavior in autism. The finding that these behaviors are differentially related to subject characteristics and familiality adds to their validity.

Brief report: exposure and response prevention for obsessive compulsive disorder in a 12-year-old with autism.

Obsessive Compulsive Disorder (OCD) involves exaggerated or excessive worry about threatening and non-threatening stimuli coupled with impairing rituals believed to reduce anxiety. Autism Spectrum Disorders (ASD) are characterized by impairment in social and communicative activities as well as restricted and repetitive behaviors. Approximately 2% of children with ASD are also diagnosed with OCD. Although there is extensive research demonstrating the effectiveness of behavioral interventions for pediatric OCD, little is known about how effective these treatments are for children who have a dual diagnosis of OCD and ASD. This report describes a 12-year-old male with Autism who was treated successfully with cognitive behavioral therapy with exposure and response prevention. This case study provides initial support that cognitive-behavioral therapy is effective in symptom reduction for children with comorbid autism and OCD.

Brief report: feasibility of social cognition and interaction training for adults with high functioning autism.

The goal of this study was to evaluate the feasibility and utility of a group-based cognitive behavioral intervention to improve social-cognitive functioning in adults with high-functioning autism (HFA). We modified the treatment manual of a previously validated intervention, Social Cognition and Interaction Training (SCIT), for optimal use with HFA adults (SCIT-A). We then conducted a pilot study to compare SCIT-A (n = 6) to treatment as usual (TAU) (n = 5) for adults with HFA. Feasibility was supported; attendance was high (92%) and satisfaction reports were primarily positive. Participants in SCIT-A showed significant improvement in theory-of-mind skills and trend level improvements in social communication skills; TAU participants did not show these improvements. Findings indicate SCIT-A shows promise as an intervention for adults with HFA.

Subgrouping Autism Based on Symptom Severity Leads to Differences in the Degree of Convergence Between Core Feature Domains.

Existing models of autism spectrum disorder (ASD) disagree as to whether the core features should be conceptualized as convergent (related) or divergent (unrelated), and the few previous studies addressing this question have found conflicting results. We examined standardized parent ratings of symptoms from three domains (social, communication, repetitive behaviors) in large samples of typically developing children, children with ASD, and ASD subgroups. Our results suggest that the most evidence for divergence lies in typically developing children and lower severity ASD cases, while more evidence for convergence is found in a subset of cases with more severe impairment on any core feature. These results highlight the importance of subgrouping ASD given the degree of phenotypic heterogeneity present across the autism spectrum.

Pupil response to social-emotional material is associated with rumination and depressive symptoms in adults with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is marked by repetitive thinking and high rates of depression. Understanding the extent to which repetitive negative thinking in ASD reflects autistic stereotypy versus general depressive thinking patterns (e.g., rumination) could help guide treatment research to improve emotional health in ASD. We compared associations between rumination, depressive symptoms, and pupil response to social-emotional material in adults with ASD and typically developing (TD) adults with and without depression. METHODS: N = 53 verbally fluent young adults were recruited to three cohorts: ASD, n = 21; TD-depressed, n = 13; never-depressed TD-controls, n = 19. Participants completed Ruminative Response Scale and Beck Depression Inventory self-reports and a passive-viewing task employing emotionally-expressive faces, during which pupillary motility was assessed to quantify cognitive-affective load. Main and interactive effects of cohort, emotion condition, and time on pupil amplitude were tested via a linear mixed effects analysis of variance using restricted maximum likelihood estimation. Similar procedures were used to test for effects of rumination and depressive symptoms on pupil amplitude over time within ASD. RESULTS: Responsive pupil dilation in the ASD cohort tended to be significantly lower than TD-depressed initially but increased to comparable levels by trial end. When viewing sad faces, individuals with ASD who had higher depression scores resembled TD-depressed participants' faster, larger, and sustained pupil response. Within ASD, depressive symptoms uniquely predicted early pupil response to sad faces, while rumination and depression scores each independently predicted sustained pupil response. CONCLUSIONS: People with elevated depressive symptoms appear to have faster and greater increases in pupil-indexed neural activation following sad stimuli, regardless of ASD status, suggesting the utility of conceptualizing rumination as depression-like in treatment. Ruminative processes may increase more slowly in ASD, suggesting the potential utility of interventions that decrease reactions before they are uncontrollable. Findings also reinforce the importance of testing for effects of internalizing variables in broader ASD research.

Animal models of restricted repetitive behavior in autism.

Restricted, repetitive behavior, along with deficits in social reciprocity and communication, is diagnostic of autism. Animal models relevant to this domain generally fall into three classes: repetitive behavior associated with targeted insults to the CNS; repetitive behavior induced by pharmacological agents; and repetitive behavior associated with restricted environments and experience. The extant literature provides potential models of the repetitive behavioral phenotype in autism rather than attempts to model the etiology or pathophysiology of restricted, repetitive behavior, as these are poorly understood. This review focuses on our work with deer mice which exhibit repetitive behaviors associated with environmental restriction. Repetitive behaviors are the most common category of abnormal behavior observed in confined animals and larger, more complex environments substantially reduce the development and expression of such behavior. Studies with this model, including environmental enrichment effects, suggest alterations in cortical-basal ganglia circuitry in the development and expression of repetitive behavior. Considerably more work needs to be done in this area, particularly in modeling the development of aberrant repetitive behavior. As mutant mouse models continue to proliferate, there should be a number of promising genetic models to pursue.