Carla A. Mazefsky, Ph.D. - US grants

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K23) will enable the candidate to independently conduct research on the development of emotion regulation in autism that integrates clinical and brain findings. The candidate is a licensed child clinical psychologist, specialized in autism, who also has prior genetics training. Her short-term goals are to pursue training in the cognitive and affective neuroscience mechanisms underlying the development of emotion regulation in childhood and adolescence, the use of functional magnetic resonance imaging (fMRI), and methods for eliciting emotion and measuring emotional reactivity. Training will be accomplished via (a) meetings and guided readings with mentors Nancy Minshew, M.D., Kevin Pelphrey, Ph.D., and Ronald Dahl, M.D., and an expert team of internal and external consultants;(b) formal coursework;(c) attendance at local and national conferences, journal clubs, and research meetings, and (d) supervised hands-on experiences in the collection and analysis of data using fMRI methodologies and research on emotion regulation. The University of Pittsburgh School of Medicine and Carnegie Mellon University will be the primary sites of this training, offering a combination of excellence in neuroscience and psychiatric research. A key component of the training is participation in all aspects of the proposed study, which utilizes functional Magnetic Resonance Imaging to explore the cognitive control of emotion in ASD. This particular component of emotion regulation was chosen as the focus based on the applicant's clinical impressions that perseveration often leads to disruptive emotional meltdowns in ASD, and because research in other populations suggests that attentional biases related to emotion regulation may be highly amenable to treatment. Within the infrastructure of the Pittsburgh NIH Autism Center of Excellence (PI Minshew), the proposed research will include 120 12 to 18 year old children, with and without high-functioning autism/Asperger's. Participants will view fear-inducing and neutral film clips while in the scanner. Multiple methods will be used to capture emotional reactivity;most notably, participants will continuously rate their emotional status throughout their time in the scanner. The study aims to: characterize the role of perseveration in emotional responses to negative stimuli in autism;investigate the functioning of the amygdala and pre- frontal cortex, and their interactions, during emotional responses;and gather preliminary data on the impact of age and comorbid mood, anxiety, and inattention symptoms on individual differences in emotional responding in autism. Insights into emotion regulation gained from this study, and the skills that the applicant will attain through the related training, will place the applicant in a strong position to conduct research on emotion regulation in autism that will specify mechanisms of change to inform treatment development and explain varying response to treatment. PUBLIC HEALTH RELEVANCE: Poor emotion regulation in autism often leads to "meltdowns" and worsening of social functioning. This research will identify specific components of emotion regulation that are problematic in autism, and the underlying brain mechanisms related to these difficulties. This information can then be used to develop novel treatments to improve emotional and social functioning in autism.

DESCRIPTION (provided by applicant): Individuals with autism spectrum disorder (ASD) are often in need of psychiatric care due to poor emotion regulation and emotional distress. Only two psychotropic medications have been approved for use in ASD, both to treat irritability expressed as tantrums, outbursts, and aggression. However, the underlying deficits in emotion regulation that lead to these problem behaviors are poorly understood and rarely measured or targeted in treatment. Evidence-based treatment approaches for the full range of emotion dysregulation (e.g. depression, outbursts, meltdowns, etc.) present in ASD do not exist. A major barrier to progress in this area is a lack of validated, treatment sensitive measures of emotional distress for individuals with ASD. This project proposes to refine and validate a new measure of emotional distress and emotion regulation for ASD, called the Emotion Dysregulation Inventory (EDI). Guidelines from the Patient-Reported Outcome Measurement Information System (PROMIS) Project and gold-standard statistical approaches will be utilized to complete calibration and psychometric analysis of the EDI. The primary sample will include caregivers of 1000 children and young adults with ASD from community, outpatient, and psychiatric inpatient settings. Data collection will occur through an online system. Analyses will focus on establishing the EDI's factor structure/dimensionality, developing a less than 10-item short form, establishing convergent and divergent validity, comparing EDI scores among groups whose scores would be expected to differ (e.g. inpatients versus community sample; ASD versus healthy controls), and comparing EDI scores to observational counts of emotion dysregulation episodes displayed by children who are inpatients on two specialized psychiatric units. A subset of the sample will complete the EDI twice to establish test-retest reliability. The EDI's ability to detect treatment change will be determined by comparing both caregiver- and provider-rated EDI scores at admission and discharge across two psychiatric inpatient units that specialize in ASD and 4-week change scores in a stable community sample. The primary outcome of this study will be a user-friendly (e.g. available online, brief), validated, treatment sensitive outcome measure for clinical trials in ASD that is independent of verbal ability. In addition, this study will produce he largest existing dataset on emotion dysregulation in ASD, which will be used to identify emotional profiles and treatment needs in this population. Additional time-course questions in the EDI that tap the individual's history of emotion dysregulation will be useful for clinical conceptualization and helping to understand the boundaries between emotion dysregulation that is inherent in ASD and comorbid psychiatric disorders. Finally, having a sensitive measure of emotion dysregulation in ASD will aid in understanding heterogeneity in genetic and neuroimaging research and will enable cross-population studies

PROJECT SUMMARY Emotion dysregulation (ED) increases risk for psychiatric and behavioral problems, and leads to polypharmacy, crisis interventions, and high rates of suicidality. Rates of clinically elevated ED are particularly high among those with autism spectrum disorder (ASD). Effective treatment of ED could greatly reduce morbidity and costs and significantly improve quality of life for individuals with ASD. Unfortunately, the development of evidence- based interventions for ED in ASD has been limited by the absence of measures that assess ED without being biased by differences in intellectual and verbal ability. The Emotion Dysregulation Inventory (EDI) (R01HD079512) was developed to address this obstacle. The EDI is a caregiver report that measures rapidly escalating, intense, and poorly regulated negative emotion and dysphoria. It was validated on 1755 school- aged verbal and nonverbal ASD youth as well as a sample of 1000 youth representative of the general US population. The EDI is already being used in multiple clinical trials and for screening and treatment monitoring in inpatient and outpatient settings across the U.S. and in 10 other countries. This project will build on the EDI's conceptual and psychometric strengths and apply Patient-Reported Outcomes Measurement Information System (PROMIS®) methods to develop the EDI-Young Child (EDI-YC for ages 2-5) and the EDI Self-Report (EDI-SR for ages 12+). Samples of 800 participants with ASD, 200 with other intellectual and developmental disorders (IDD), and 1000 from the general community will be recruited to complete calibration and psychometric analysis of each measure using Item Response Theory (IRT) and traditional psychometric analyses. The change-sensitivity of the EDI-YC and EDI-SR will be evaluated in the context of funded clinical trials. The availability of the EDI-YC will motivate ED prevention and intervention in early childhood during this critical period of early brain plasticity. The EDI-SR will be developed through a systematic item refinement process to ensure validity even in the context of cognitive impairments or poor emotional awareness, thereby creating new opportunities to incorporate patient perspectives and include the often overlooked but growing population of adults with ASD or IDD in clinical trials when no caregiver is available. Finally, the translational value of this research will be supported by linking specific neural features of ED (e.g., hypo-activation of the lateral prefrontal cortex (LPFC) during frustration and cognitive inflexibility tasks) to ED in ASD as assessed by the EDI. This will be accomplished through neuroimaging via collection of functional near-infrared spectroscopy (fNIRS) and EDI data in a sample of 125 4- to 17-year-olds with ASD. Because of ED's transdiagnostic significance, the impact will span outcomes from aggression to suicide and other critical symptoms related to ED. We will ensure the EDI battery's utility across populations by evaluating the candidate EDI-EC and EDI-SR items in non-ASD IDD samples, as well as through the generation of general norms from large community samples.

7. PROJECT SUMMARY/ABSTRACT Developmental disabilities (DD), including autism spectrum disorder (ASD), Down syndrome, Fragile X syndrome, and other intellectual and developmental disabilities are heterogeneous neurodevelopmental disorders that place considerable burden on individuals, families, and society. Although most research on DD has focused on children, these conditions are life-long with few established treatments to support functioning in adulthood. As a result, many adults with DD experience significant functional impairment represented by low rates of employment, severe social dysfunction and isolation, and a limited ability to live independently and experience autonomy in adult life. The development of interventions to improve adult functional outcomes in social, employment, and independent living domains across DD has lagged far behind those developed for children. A key factor limiting the development of treatments to improve adult functioning in DD is the lack of validated assessments of functional outcome applicable to adulthood. Current studies either use measures relevant to childhood with limited applicability to and treatment sensitivity in adults, or fail to assess this important domain, greatly restricting knowledge on how adult functioning can be improved in DD. We have shown in preliminary studies with adults with ASD that it is possible to develop measures of functional outcome in adulthood that have greater validity and are more sensitive to treatment effects than existing measures adapted from childhood. In response to this major gap in adult outcome measurement in DD and PAR-18-039, ?Outcome Measures for Use in Treatment Trials of Individuals with Intellectual and Developmental Disabilities?, this project proposes to use NIH PROMIS methods to develop and validate proxy- and self-report versions of the Adult Functioning Scale (AFS) for assessing functional outcomes in social, employment, and independent living domains in adults with DD. A pool of potential items will be generated based on our conceptual model, functional outcome measures used in other populations, and input from expert and stakeholder panels. This item pool will then be completed by two calibration samples: Proxy reporters (e.g., parents, clinicians, group home staff) for 1000 adults with DD representative of the full range of verbal and intellectual functioning in DD and 1000 self-reporting adults with DD (N = 500 with ASD, N = 500 with other DD). Advanced psychometric analytics employing exploratory and confirmatory factor analysis and item response theory models will be used to create final calibrated item banks (and static short forms) of the AFS suitable for broad use in clinical trials across heterogeneous DD. The reliability and validity of the AFS caregiver and self-report versions will be examined in the calibration samples, along with a 4-week retest subsample (N = 200). Sensitivity to treatment- related changes will be assessed in longitudinal intervention studies of inpatient and outpatient samples of adults with DD. The results will validate the first measure of functional outcome for use in clinical trials in adult DD and will pave the way for treatment advances to improve functioning in this underserved population.