Examining Treatment Outcomes Across Contexts: How Do Child Baseline Characteristics Impact Measurement of Treatment Response?

The evaluation of the overlap between the ADOS BOSCC and Standard BOSCC as well as the exploration of child characteristics that may predict change are important steps in consolidating data-driven definitions of "improvement". Participants were seen between 2 and 5 times with Standard BOSCC and ADOS BOSCC observations over the course of early intervention trials (Grzadzinski et al. in J Autism Dev Disord 46:2464, 2016; Kim et al. in Autism 23:5, 2019). Results showed consistency between the Standard BOSCC and ADOS BOSCC, highlighting the utility of both as metrics of change and treatment outcome across contexts. Baseline characteristics may play a role in the tailoring of early intervention to maximize treatment outcome and may offer guidance when determining which outcome measures to use.

A Data-Driven Approach in an Unbiased Sample Reveals Equivalent Sex Ratio of Autism Spectrum Disorder-Associated Impairment in Early Childhood.

BACKGROUND: Sex differences in the prevalence of neurodevelopmental disorders are particularly evident in autism spectrum disorder (ASD). Heterogeneous symptom presentation and the potential of measurement bias hinder early ASD detection in females and may contribute to discrepant prevalence estimates. We examined trajectories of social communication (SC) and restricted and repetitive behaviors (RRBs) in a sample of infant siblings of children with ASD, adjusting for age- and sex-based measurement bias. We hypothesized that leveraging a prospective elevated familial likelihood sample, deriving data-driven behavioral constructs, and accounting for measurement bias would reveal less discrepant sex ratios than are typically seen in ASD. METHODS: We conducted direct assessments of ASD symptoms at 6 to 9, 12 to 15, 24, and 36 to 60 months of age (total nobservations = 1254) with infant siblings of children with ASD (n = 377) and a lower ASD-familial-likelihood comparison group (n = 168; nobservations = 527). We established measurement invariance across age and sex for separate models of SC and RRB. We then conducted latent class growth mixture modeling with the longitudinal data and evaluated for sex differences in trajectory membership. RESULTS: We identified 2 latent classes in the SC and RRB models with equal sex ratios in the high-concern cluster for both SC and RRB. Sex differences were also observed in the SC high-concern cluster, indicating that girls classified as having elevated social concerns demonstrated milder symptoms than boys in this group. CONCLUSIONS: This novel approach for characterizing ASD symptom progression highlights the utility of assessing and adjusting for sex-related measurement bias and identifying sex-specific patterns of symptom emergence.

Multilevel growth curve analyses of behavioral activation for anhedonia (BATA) and mindfulness-based cognitive therapy effects on anhedonia and resting-state functional connectivity: Interim results of a randomized trial✰.

BACKGROUND: The neural mechanisms associated with anhedonia treatment response are poorly understood. Additionally, no study has investigated changes in resting-state functional connectivity (rsFC) accompanying psychosocial treatment for anhedonia. METHODS: We evaluated a novel psychotherapy, Behavioral Activation Therapy for Anhedonia (BATA, n = 38) relative to Mindfulness-Based Cognitive Therapy (MBCT, n = 35) in a medication-free, transdiagnostic, anhedonic sample in a parallel randomized controlled trial. Participants completed up to 15 sessions of therapy and up to four 7T MRI scans before, during, and after treatment (n = 185 scans). Growth curve models estimated change over time in anhedonia and in rsFC using average region-of-interest (ROI)-to-ROI connectivity within the default mode network (DMN), frontoparietal network (FPN), salience network, and reward network. Changes in rsFC from pre- to post-treatment were further evaluated using whole-network seed-to-voxel and ROI-to-ROI edgewise analyses. RESULTS: Growth curve models showed significant reductions in anhedonia symptoms and in average rsFC within the DMN and FPN over time, across BATA and MBCT. There were no differences in anhedonia reductions between treatments. Within-person, changes in average rsFC were unrelated to changes in anhedonia. Between-person, higher than average FPN rsFC was related to less anhedonia across timepoints. Seed-to-voxel and edgewise rsFC analyses corroborated reductions within the DMN and between the DMN and FPN over time, across the sample. CONCLUSIONS: Reductions in rsFC within the DMN, FPN, and between these networks co-occurred with anhedonia improvement across two psychosocial treatments for anhedonia. Future anhedonia clinical trials with a waitlist control group should disambiguate treatment versus time-related effects on rsFC.

A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism.

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [11C]raclopride, voxel-wise binding potential (BPND) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BPND differences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.

Sensory Reactivity at 1 and 2 Years Old is Associated with ASD Severity During the Preschool Years.

Children with Autism Spectrum Disorder (ASD) often display atypical sensory reactivity within the first years of life, prior to a diagnosis. This study examined sensory reactivity patterns at 14 months, changes from 14 to 23 months, and later ASD severity at 3 to 5 years of age in children (n = 87) at elevated likelihood of ASD. Results indicated that observed hyporeactivity at 14 months and increases from 14 to 23 months were related to higher ASD severity during the preschool years. Parent report of hyperreactivity at 14 months was associated with higher ASD severity in the RRB domain during the preschool years. Early hypo and hyperreactivity may predict later severity of ASD and aid in subtyping and developing individualized treatments.

Does local dynamic stability during unperturbed walking predict the response to balance perturbations? An examination across age and falls history.

BACKGROUND: Older adults are at an exceptionally high risk of falls, and most falls occur during locomotor activities such as walking. Reduced local dynamic stability in old age is often interpreted to suggest a lessened capacity to respond to more significant balance challenges encountered during walking and future falls risk. However, it remains unclear whether local dynamic stability during normal, unperturbed walking predicts the response to larger external balance disturbances. RESEARCH QUESTION: We tested the hypothesis that larger values of local dynamic instability during unperturbed walking would positively correlate with larger changes thereof due to optical flow balance perturbations. METHODS: We used trunk kinematics collected in subjects across a spectrum of walking balance integrity - young adults, older non-fallers, and older fallers - during walking with and without mediolateral optical flow perturbations of four different amplitudes. RESULTS: We first found evidence that optical flow perturbations of sufficient amplitude appear capable of revealing independent effects of aging and falls history that are not otherwise apparent during normal, unperturbed walking. We also reject our primary hypothesis; a significant negative correlation only in young adults indicated that individuals with more local dynamic instability during normal, unperturbed walking exhibited smaller responses to optical flow perturbations. In contrast, most prominently in older fallers, the response to optical flow perturbations appeared independent of their baseline level of dynamic instability. SIGNIFICANCE: We propose that predicting the response to balance perturbations in older fallers, at least that measured using local dynamic stability, likely requires measuring that response directly.

Subcortical Brain and Behavior Phenotypes Differentiate Infants With Autism Versus Language Delay.

BACKGROUND: Younger siblings of children with autism spectrum disorder (ASD) are themselves at increased risk for ASD and other developmental concerns. It is unclear if infants who display developmental concerns, but are unaffected by ASD, share similar or dissimilar behavioral and brain phenotypes to infants with ASD. Most individuals with ASD exhibit heterogeneous difficulties with language, and their receptive-expressive language profiles are often atypical. Yet, little is known about the neurobiology that contributes to these language difficulties. METHODS: In this study, we used behavioral assessments and structural magnetic resonance imaging to investigate early brain structures and associations with later language skills. High-risk infants who were later diagnosed with ASD (n = 86) were compared with high-risk infants who showed signs of early language delay (n = 41) as well as with high- and low-risk infants who did not have ASD or language delay (n = 255 and 143, respectively). RESULTS: Results indicated that diminished language skills were evident at 12 months in infants with ASD and infants with early language delay. At 24 months of age, only the infants with ASD displayed atypical receptive-expressive language profiles. Associations between 12-month subcortical volumes and 24-month language skills were moderated by group status, indicating disordinal brain-behavior associations among infants with ASD and infants with language delay. CONCLUSIONS: These results suggest that there are different brain mechanisms influencing language development in infants with ASD and infants with language delay, and that the two groups likely experience unique sets of genetic and environmental risk factors.