Design and methodology for a proof of mechanism study of individualized neuronavigated continuous Theta burst stimulation for auditory processing in adolescents with autism spectrum disorder.

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.

Transcranial Magnetic Stimulation Across the Lifespan: Impact of Developmental and Degenerative Processes.

Transcranial magnetic stimulation (TMS) has emerged as a pivotal noninvasive technique for investigating cortical excitability and plasticity across the lifespan, offering valuable insights into neurodevelopmental and neurodegenerative processes. In this review, we explore the impact of TMS applications on our understanding of normal development, healthy aging, neurodevelopmental disorders, and adult-onset neurodegenerative diseases. By presenting key developmental milestones and age-related changes in TMS measures, we provide a foundation for understanding the maturation of neurotransmitter systems and the trajectory of cognitive functions throughout the lifespan. Building on this foundation, the paper delves into the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, and adolescent depression. Highlighting recent findings on altered neurotransmitter circuits and dysfunctional cortical plasticity, we underscore the potential of TMS as a valuable tool for unraveling underlying mechanisms and informing future therapeutic interventions. We also review the emerging role of TMS in investigating and treating the most common adult-onset neurodegenerative disorders and late-onset depression. By outlining the therapeutic applications of noninvasive brain stimulation techniques in these disorders, we discuss the growing body of evidence supporting their use as therapeutic tools for symptom management and potentially slowing disease progression. The insights gained from TMS studies have advanced our understanding of the underlying mechanisms in both healthy and disease states, ultimately informing the development of more targeted diagnostic and therapeutic strategies for a wide range of neuropsychiatric conditions.

Childhood stress, gender, and cognitive control: Midline theta power.

The emergence of psychiatric symptoms is a common consequence of childhood stress exposure. However, there are a dearth of reliable clinical hallmarks or physiological biomarkers to predict post-trauma symptom emergence. The objective of this study was to examine if childhood stressors and stress-related symptoms are associated with altered midline theta power (MTP) during cognitive control demands, and how these associations interact with gender and early adversity. N = 53 children (ages 9-13 years old) from a longitudinal study of children maltreated during early childhood and non-maltreated children participated in this study. EEG recorded neural activity during a Zoo-Themed Go/No-Go task. Stress-related symptoms, recent stressful events, and other adversity experiences were identified. MTP was analyzed with clinical variables in a series of follow-up analyses. The number of stressors in the past six months was negatively correlated with MTP in those with low preschool adversity, but not in those with high preschool adversity. MTP was higher in girls than in boys, and the associations of MTP with stressors and symptoms were moderated by gender. MTP was negatively associated with stressors in the past six months in girls, while in boys, MTP was associated with stress-related symptoms. Childhood stressful events were associated with reduced MTP during cognitive control demands, and this was finding was moderated by gender and early life adversity. These preliminary findings suggest that boys and girls may process stressful experiences in distinct ways, and preschool adversity may potentially blunt the interaction between current stress and neural dynamics. However, ongoing investigation is needed.

The use of noninvasive brain stimulation techniques in autism spectrum disorder.

Noninvasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have recently emerged as alternative, nonpharmacological interventions for a variety of psychiatric, neurological, and neurodevelopmental conditions. NIBS is beginning to be applied in both research and clinical settings for the treatment of core and associated symptoms of autism spectrum disorder (ASD) including social communication deficits, restricted and repetitive behaviors, irritability, hyperactivity, depression and impairments in executive functioning and sensorimotor integration. Though there is much promise for these targeted device-based interventions, in other disorders (including adult major depressive disorder (MDD) and obsessive compulsive disorder (OCD) where rTMS is FDA cleared), data on the safety and efficacy of these interventions in individuals with ASD is limited especially in younger children when neurodevelopmental interventions typically begin. Most studies are open-label, small scale, and/or focused on a restricted subgroup of individuals with ASD. There is a need for larger, randomized controlled trials that incorporate neuroimaging in order to develop predictive biomarkers of treatment response and optimize treatment parameters. We contend that until such studies are conducted, we do not have adequate estimates of the safety and efficacy of NIBS interventions in children across the spectrum. Thus, broad off-label use of these techniques in this population is not supported by currently available evidence. Here we discuss the existing data on the use of NIBS to treat symptoms related to ASD and discuss future directions for the field.

Sleep disturbances in Phelan-McDermid syndrome: Clinical and metabolic profiling of 56 individuals.

Phelan-McDermid Syndrome (PMS) is caused by deletions at chromosome 22q13.3 or pathogenic/likely pathogenic SHANK3 variants. The clinical presentation is extremely variable and includes global developmental delay/intellectual disability (ID), seizures, neonatal hypotonia, and sleep disturbances, among others. This study investigated the prevalence of sleep disturbances, and the genetic and metabolic features associated with them, in a cohort of 56 individuals with PMS. Sleep data were collected via standardized observer/caregiver questionnaires, while genetic data from array-CGH and sequencing of 9 candidate genes within the 22q13.3 region, and metabolic profiling utilized the Biolog Phenotype Mammalian MicroArray plates. Sleep disturbances were present in 64.3% of individuals with PMS, with the most common problem being waking during the night (39%). Sleep disturbances were more prevalent in individuals with a SHANK3 pathogenic variant (89%) compared to subjects with 22q13.3 deletions of any size (59.6%). Distinct metabolic profiles for individuals with PMS with and without sleep disturbances were also identified. These data are helpful information for recognizing and managing sleep disturbances in individuals with PMS, outlining the main candidate gene for this neurological manifestation, and highlighting potential biomarkers for early identification of at-risk subjects and molecular targets for novel treatment approaches.

Rett Syndrome Behaviour Questionnaire in Children and Adults With Rett Syndrome: Psychometric Characterization and Revised Factor Structure.

Rett syndrome (RTT) is a severe neurodevelopmental disorder associated with multiple neurobehavioral abnormalities. The Rett Syndrome Behaviour Questionnaire (RSBQ) was developed for pediatric RTT observational studies. Because its application has expanded to adult and interventional studies, we evaluated the RSBQ's psychometric properties in six pediatric (n = 323) and five adult (n = 309) datasets. Total and General Mood subscale scores had good reliability. Clinical severity had no influence on RSBQ scores. Exploratory and confirmatory factor analyses yielded 6 pediatric and 7 adult clinically relevant and psychometrically strong factors including the original Breathing Problems and Fear/Anxiety subscales and the novel Emotional and Disruptive Behavior subscale composed of items from the original General Mood and Nighttime Behaviours subscales. The present findings support additional evaluations and improvements of an important RTT behavioral measure.

A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI).

Theta burst stimulation (TBS) is associated with the modulation of a range of clinical, cognitive, and behavioural outcomes, but specific neurobiological effects remain somewhat unclear. This systematic literature review investigated resting-state and task-based functional magnetic resonance imaging (fMRI) outcomes post-TBS in healthy human adults. Fifty studies that applied either continuous-or intermittent-(c/i) TBS, and adopted a pretest-posttest or sham-controlled design, were included. For resting-state outcomes following stimulation applied to motor, temporal, parietal, occipital, or cerebellar regions, functional connectivity generally decreased in response to cTBS and increased in response to iTBS, though there were some exceptions to this pattern of response. These findings are mostly consistent with the assumed long-term depression (LTD)/long-term potentiation (LTP)-like plasticity effects of cTBS and iTBS, respectively. Task-related outcomes following TBS were more variable. TBS applied to the prefrontal cortex, irrespective of task or state, also produced more variable responses, with no consistent patterns emerging. Individual participant and methodological factors are likely to contribute to the variability in responses to TBS. Future studies assessing the effects of TBS via fMRI must account for factors known to affect the TBS outcomes, both at the level of individual participants and of research methodology.

Assessing the mechanisms of brain plasticity by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a non-invasive technique for focal brain stimulation based on electromagnetic induction where a fluctuating magnetic field induces a small intracranial electric current in the brain. For more than 35 years, TMS has shown promise in the diagnosis and treatment of neurological and psychiatric disorders in adults. In this review, we provide a brief introduction to the TMS technique with a focus on repetitive TMS (rTMS) protocols, particularly theta-burst stimulation (TBS), and relevant rTMS-derived metrics of brain plasticity. We then discuss the TMS-EEG technique, the use of neuronavigation in TMS, the neural substrate of TBS measures of plasticity, the inter- and intraindividual variability of those measures, effects of age and genetic factors on TBS aftereffects, and then summarize alterations of TMS-TBS measures of plasticity in major neurological and psychiatric disorders including autism spectrum disorder, schizophrenia, depression, traumatic brain injury, Alzheimer's disease, and diabetes. Finally, we discuss the translational studies of TMS-TBS measures of plasticity and their therapeutic implications.

Preliminary Report of the Safety and Tolerability of 1 Hz Repetitive Transcranial Magnetic Stimulation in Temporal Lobe Epilepsy.

Background: Low frequency (≤1 Hz) repetitive transcranial magnetic stimulation (rTMS) has been shown to suppress cortical excitability and is beginning to be trialed for the treatment of refractory epilepsy. Purpose: As a step toward a larger trial, the current pilot study was aimed to test the tolerability and safety of temporal lobe rTMS using H-coil for the treatment of temporal lobe epilepsy (TLE). Research Design: 1800 pulses of active or sham rTMS were applied 5  days a week for 2 weeks over the temporal lobe of the affected hemisphere. Results: Nine participants were enrolled and randomized to verum or sham stimulation. One participant dropped out from the sham group after 5 rTMS sessions. In-session, 3 patients had typical seizures during sham stimulation. One patient had seizures also during active stimulation (albeit fewer than during sham). Minor reported adverse events during stimulation otherwise included transient neck pain and headache, and were reported in equal numbers in both groups. Major adverse events were not reported. Our results indicate that H-coil rTMS was well-tolerated. Conclusion: Given the relatively high prevalence of individuals with TLE who are treatment-resistant and the preliminary results of this study, we suggest that a larger safety and efficacy trial of 1 Hz rTMS for the treatment of TLE is warranted.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression, Post-Traumatic Stress Disorder, and Suicidal Ideation in Military Populations: A Scholarly Review.

INTRODUCTION: Military mental health conditions, such as depression, PTSD, and suicidal ideation, are currently understudied and undertreated. Repetitive transcranial magnetic stimulation (rTMS) is currently being considered as a treatment for these conditions; however, there exists a paucity of research in this area. This scholarly review will examine the limitations of the existing literature on the use of rTMS to treat depression, PTSD, and suicidal ideation in service members (SMs) and veterans. MATERIALS AND METHODS: Publications that evaluated rTMS for the treatment of depression, PTSD, or suicidal ideation in military samples were identified via a PubMed search. Non-interventional rTMS studies, studies where the sample could not be confirmed to be primarily composed of SMs or veteran participants, studies without psychiatric outcome measures, and studies not published in a peer-reviewed journal were excluded from this review. RESULTS: This literature search identified 20 total publications (eight primary analyses of randomized controlled trials (RCTs), one longitudinal analysis of an RCT, five open label trials, and six retrospective analyses of clinical data), inclusive of 879 participants. Eighteen studies utilized a protocol targeting the prefrontal cortex (PFC), and one of these also targeted the supplementary motor area (SMA) with the PFC (one study did not specify the stimulation site). Eight studies applied standard 10 Hz frequency stimulation, and four applied standard 1 Hz frequency stimulation. The remainder of studies applied alternative stimulation protocols including 5 Hz (two studies), 20 Hz (one study), a combination of 1 and 10 Hz (two studies), and theta burst stimulation (TBS) (two studies). Twelve studies reported significant results, including four RCTs, three open label studies, and five retrospective analyses. CONCLUSIONS: rTMS offers a promising area of research for mental health conditions in military populations. However, the number of studies that focus specifically on this population are few in number and have many notable limitations. Further research is needed to validate the effectiveness of this tool for SMs and veterans.

Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures.

Phelan-McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM-M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand-mal seizures. Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype.

Effects of the sigma-1 receptor agonist blarcamesine in a murine model of fragile X syndrome: neurobehavioral phenotypes and receptor occupancy.

Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.

Modulation of motor cortical excitability by continuous theta-burst stimulation in adults with autism spectrum disorder.

OBJECTIVE: To test whether change in motor evoked potential (ΔMEP) induced by continuous theta-burst stimulation (cTBS) of motor cortex (M1) distinguishes adults with autism spectrum disorder (ASD) from neurotypicals, and to explore the contribution of two common polymorphisms related to neuroplasticity. METHODS: 44 adult neurotypical (NT) participants (age 21-65, 34 males) and 19 adults with ASD (age 21-58, 17 males) prospectively underwent M1 cTBS. Their data were combined with previously obtained results from 35 NT and 35 ASD adults. RESULTS: ΔMEP at 15 minutes post-cTBS (T15) was a significant predictor of diagnosis (p = 0.04) in the present sample (n=63). T15 remained a significant predictor in a larger sample (n=91) and when partially imputed based on T10-T20 from a yet-greater sample (N=133). T15 also remained a significant predictor of diagnosis among brain-derived neurotrophic factor (BDNF) Met+ and apolipoprotein E (APOE) ε4- subjects (p's < 0.05), but not among Met- or ε4+ subjects (p's > 0.19). CONCLUSIONS: ΔMEP at T15 post-cTBS is a significant biomarker for adults with ASD, and its utility is modulated by BDNF and APOE polymorphisms. SIGNIFICANCE: M1 cTBS response is a physiologic biomarker for adults with ASD in large samples, and controlling for BDNF and APOE polymorphisms can improve its diagnostic utility.

Repetitive Transcranial Magnetic Stimulation for Adolescent Major Depressive Disorder: A Focus on Neurodevelopment.

Adolescent depression is a potentially lethal condition and a leading cause of disability for this age group. There is an urgent need for novel efficacious treatments since half of adolescents with depression fail to respond to current therapies and up to 70% of those who respond will relapse within 5 years. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising treatment for major depressive disorder (MDD) in adults who do not respond to pharmacological or behavioral interventions. In contrast, rTMS has not demonstrated the same degree of efficacy in adolescent MDD. We argue that this is due, in part, to conceptual and methodological shortcomings in the existing literature. In our review, we first provide a neurodevelopmentally focused overview of adolescent depression. We then summarize the rTMS literature in adult and adolescent MDD focusing on both the putative mechanisms of action and neurodevelopmental factors that may influence efficacy in adolescents. We then identify limitations in the existing adolescent MDD rTMS literature and propose specific parameters and approaches that may be used to optimize efficacy in this uniquely vulnerable age group. Specifically, we suggest ways in which future studies reduce clinical and neural heterogeneity, optimize neuronavigation by drawing from functional brain imaging, apply current knowledge of rTMS parameters and neurodevelopment, and employ an experimental therapeutics platform to identify neural targets and biomarkers for response. We conclude that rTMS is worthy of further investigation. Furthermore, we suggest that following these recommendations in future studies will offer a more rigorous test of rTMS as an effective treatment for adolescent depression.

Use of Repetitive Transcranial Magnetic Stimulation in the Treatment of Neuropsychiatric and Neurocognitive Symptoms Associated With Concussion in Military Populations.

BACKGROUND: Since the year 2000, over 342 000 military service members have experienced a concussion, often associated with chronic neuropsychiatric and neurocognitive symptoms. Repetitive transcranial magnetic stimulation (rTMS) protocols have been developed for many of these symptoms in the general population. OBJECTIVE: To conduct a scoping review of the literature on rTMS for neuropsychological and neurocognitive symptoms following concussion. METHODS: PubMed and Google Scholar search engines identified 9 articles, written in English, corresponding to the search terms TBI or concussion; and TMS or rTMS; and depression, PTSD, or cognition. Studies that were not therapeutic trials or case reports, did not have neuropsychiatric or neurocognitive primary outcome measures, or described samples where 80% or more of the cohort did not have a TBI were excluded. RESULTS: There were no reports of seizures nor difference in the frequency or quality of other adverse events as compared with the broader rTMS literature, supporting the safety of rTMS in this population. Support for the efficacy of rTMS for the treatment of neuropsychiatric and neurocognitive symptoms, in this population, is limited. CONCLUSIONS: Large-scale, innovative, neuroscience-informed protocols are recommended to elucidate the potential utility of rTMS for the complex neuropsychiatric and neurocognitive symptoms associated with military concussions.

Continuous Theta-Burst Stimulation in Children With High-Functioning Autism Spectrum Disorder and Typically Developing Children.

Objectives: A neurophysiologic biomarker for autism spectrum disorder (ASD) is highly desirable and can improve diagnosis, monitoring, and assessment of therapeutic response among children with ASD. We investigated the utility of continuous theta-burst stimulation (cTBS) applied to the motor cortex (M1) as a biomarker for children and adolescents with high-functioning (HF) ASD compared to their age- and gender-matched typically developing (TD) controls. We also compared the developmental trajectory of long-term depression- (LTD-) like plasticity in the two groups. Finally, we explored the influence of a common brain-derived neurotrophic factor (BDNF) polymorphism on cTBS aftereffects in a subset of the ASD group. Methods: Twenty-nine children and adolescents (age range 10-16) in ASD (n = 11) and TD (n = 18) groups underwent M1 cTBS. Changes in MEP amplitude at 5-60 min post-cTBS and their cumulative measures in each group were calculated. We also assessed the relationship between age and maximum cTBS-induced MEP suppression (ΔMEPMax) in each group. Finally, we compared cTBS aftereffects in BDNF Val/Val (n = 4) and Val/Met (n = 4) ASD participants. Results: Cumulative cTBS aftereffects were significantly more facilitatory in the ASD group than in the TD group (P FDR's < 0.03). ΔMEPMax was negatively correlated with age in the ASD group (r = -0.67, P = 0.025), but not in the TD group (r = -0.12, P = 0.65). Cumulative cTBS aftereffects were not significantly different between the two BDNF subgroups (P-values > 0.18). Conclusions: The results support the utility of cTBS measures of cortical plasticity as a biomarker for children and adolescents with HF-ASD and an aberrant developmental trajectory of LTD-like plasticity in ASD.

Autism Heterogeneity in a Densely Sampled U.S. Population: Results From the First 1,000 Participants in the RI-CART Study.

The objective of this study was to establish a large, densely sampled, U.S. population-based cohort of people with autism spectrum disorder (ASD). The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by ASD. Diagnosis was based on direct behavioral observation via the Autism Diagnostic Observation Schedule, Second Edition. For the first 1,000 participants, ages ranged from 21 months to 64 years. Using Geographic Information System and published prevalence rates, the overall cohort is estimated to represent between 20% and 49% of pediatric age persons in Rhode Island with ASD, with demographics representative of U.S. Census. We observed a high rate of co-occurring medical and psychiatric conditions in affected individuals. Among the most prominent findings of immediate clinical importance, we found that females received a first diagnosis of ASD at a later age than males, potentially due to more advanced language abilities in females with ASD. In summary, this is the first analysis of a large, population-based U.S. cohort with ASD. Given the depth of sampling, the RI-CART study reflects an important new resource for studying ASD in a representative U.S. population. Psychiatric and medical comorbidities in ASD constitute a substantial burden and warrant adequate attention as part of overall treatment. Our study also suggests that new strategies for earlier diagnosis of ASD in females may be warranted. Autism Res 2020, 13: 474-488. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The Rhode Island Consortium for Autism Research and Treatment (RI-CART) represents a unique public-private-academic collaboration involving all major points of service for families in Rhode Island affected by autism spectrum disorder (ASD). In this article, we provide results from the first 1,000 participants, estimated to represent >20% of affected families in the state. Importantly, we find a later age at first diagnosis of ASD in females, which potentially calls attention to the need for improved early diagnosis in girls. Also, we report a high rate of co-occurring medical and psychiatric conditions in affected individuals.