Faculty Bibliography

OBJECTIVE:Impaired multisensory integration in autism spectrum disorder (ASD) may arise from functional dysconnectivity among brain systems. Our study examines the functional connectivity integration between primary modal sensory regions and heteromodal processing cortex in ASD, and whether abnormalities in network integration relate to clinical severity. METHOD/METHODS:We studied a sample of 55 high-functioning ASD and 64 healthy controls (HC) male children and adolescents (total n = 119, age range 7-18). Stepwise functional connectivity analysis (SFC) was applied to resting state functional magnetic resonance images (rsfMRI) to characterize the connectivity paths that link primary sensory cortices to higher-order brain cognitive functional circuits and relate alterations in functional connectivity integration with three clinical scales: Social Communication Questionnaire, Social Responsiveness Scale, and Vineland Adaptive Behavior Scales. RESULTS:HC displayed typical functional connectivity transitions from primary sensory systems to association areas, but the ASD group showed altered patterns of multimodal sensory integration to heteromodal systems. Specifically, compared to the HC group, the ASD group showed (1) hyper-connectivity in visual cortex at initial link step distances; (2) hyper-connectivity between sensory unimodal regions and regions of the default mode network; and (3) hypo-connectivity between sensory unimodal regions and areas of the fronto-parietal and attentional networks. These patterns of hyper- and hypo-connectivity were associated with increased clinical severity in ASD. CONCLUSION/CONCLUSIONS:Network-wise reorganization in high-functioning ASD individuals affects strategic regions of unimodal-to-heteromodal cortical integration predicting clinical severity. Additionally, SFC analysis appears to be a promising approach for studying the neural pathophysiology of multisensory integration deficits in ASD.

Background: Serotonin and dopamine are neurotransmitters associated with multiple psychiatric disorders. How they interact during development to affect subsequent behavior remains unknown. Knockout of the serotonin transporter or administration of selective-serotonin-reuptake inhibitors (SSRIs) during early-life lead to novelty-induced exploration deficits in adulthood.
Method(s): Using a combination of optogenetics, behavioral testing and electrophysiology we tested the effects of perinatal exposure to fluoxetine (PN-FLX) on dopaminergic system's function in the adult. Between 10 to 15 mice per group, male and female, were administered with saline or fluoxetine (10 mg/kg IP) from P2 to P11. Mice were tested after 8 weeks of age.
Result(s): Here we show that Raphe nucleus serotonin neurons activate ventral tegmental area (VTA) dopamine neurons via glutamate cotransmission and that this cotransmission is impaired in postnatally SSRI treated animals. Moreover, we show that the SSRI-induced hypolocomotion is mimicked by blocking serotonin neuron glutamate cotransmission. Optogenetic activation of dopamine neurons rescued this hypolocomotor phenotype.
Conclusion(s): Our data demonstrate that serotonin neurons modulate dopaminergic activity via glutamate cotransmission and that this pathway is developmentally malleable, with high serotonin levels during early life blunting this capacity, resulting in reduced novelty-induced exploration in adulthood

Background: Reduced endocannabinoid "tone" has been posited in the pathophysiology of ASD animal models; children with ASD have been found to have lower peripheral endocannabinoid levels. Additionally, anecdotal reports suggest cannabinoids may be beneficial for some aspects of ASD.
Method(s): Double-blind placebo-controlled comparison (NCT02956226) of whole plant cannabis extract containing cannabidiol (CBD) and DELTA9-tetrahydrocannabinol (THC) in a 20:1 ratio and (2) purified CBD and THC in the same ratio. Participants were 150 children and adolescents with ASD, both males (80%) and females (mean age 11.8 +/-4.1 yrs). They received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout, and crossed-over to receive another treatment for 12 weeks to further assess tolerability.
Result(s): There were no treatment related severe or serious adverse events. None of the outcomes differed significantly between cannabinoid preparation, in either treatment period. Considering cannabinoids together, in the first period, 43% of 90 children who received cannabinoids were either much or very much improved on the CGI-I compared with 21% of 47 on placebo (p = 0.009). Placebo-cannabinoid differences were not significant on the other primary outcome, the Home Situations Questionnaire for ASD (HSQ-ASD). A positive response on the Social Responsiveness Scale-2 (SRS-2) was defined as 15% decrease or better from baseline. In the first treatment period, 44% of participants who received cannabinoids had a positive response compared with 19% on placebo (p = 0.013). In terms of possible mediators of treatment effects on the SRS-2, male sex and milder ASD symptoms at baseline were independently associated with better response to cannabinoid treatment.
Conclusion(s): Novel pharmacological treatments for the core and comorbid symptoms of ASD are urgently needed. Preclinical studies implicate the endocannabinoid system in the pathophysiology of ASD. In a controlled study of 150 children, a combination of CBD and THC, in a 20:1 ratio, either as a whole plant extract or as pure cannabinoids, improved disruptive behaviors and an index of ASD core symptoms, with relatively few adverse events. These data suggest that further investigation of cannabinoids in ASD is likely to be promising

Importance/UNASSIGNED:An increasing prevalence of adult attention-deficit/hyperactivity disorder (ADHD) diagnosis and treatment has been reported in clinical settings and administrative data in the United States. However, there are limited data on recent trends of adult ADHD diagnosis among racial/ethnic subgroups. Objective/UNASSIGNED:To examine trends, including associated demographic characteristics, psychiatric diagnoses, and negative outcomes, in the prevalence and incidence of adult ADHD diagnosis among 7 racial/ethnic groups during a 10-year period. Design, Setting, and Participants/UNASSIGNED:This cohort study investigated trends in the diagnosis of ADHD in adults who identified as African American or black, Native American, Pacific Islander, Latino or Hispanic, non-Hispanic white, Asian American, or other using the Kaiser Permanente Northern California health plan medical records. A total of 5 282 877 adult patients and 867 453 children aged 5 to 11 years who received care at Kaiser Permanente Northern California from January 1, 2007, to December 31, 2016, were included. Data analysis was performed from January 2017 through September 2019. Exposures/UNASSIGNED:Period of ADHD diagnosis. Main Outcomes and Measures/UNASSIGNED:Prevalence and incidence of licensed mental health clinician-diagnosed ADHD in adults and prevalence of licensed mental health clinician-diagnosed ADHD in children aged 5 to 11 years. Results/UNASSIGNED:Of 5 282 877 adult patients (1 155 790 [21.9%] aged 25-34 years; 2 667 562 [50.5%] women; 2 204 493 [41.7%] white individuals), 59 371 (1.12%) received diagnoses of ADHD. Prevalence increased from 0.43% in 2007 to 0.96% in 2016. Among 867 453 children aged 5 to 11 years (424 449 [48.9%] girls; 260 236 [30.0%] white individuals), prevalence increased from 2.96% in 2007 to 3.74% in 2016. During the study period, annual adult ADHD prevalence increased for every race/ethnicity, but white individuals consistently had the highest prevalence rates (white individuals: 0.67%-1.42%; black individuals: 0.22%-0.69%; Native American individuals: 0.56%-1.14%; Pacific Islander individuals: 0.11%-0.39%; Hispanic or Latino individuals: 0.25%-0.65%; Asian American individuals: 0.11%-0.35%; individuals from other races/ethnicities: 0.29%-0.71%). Incidence of ADHD diagnosis per 10 000 person-years increased from 9.43 in 2007 to 13.49 in 2016. Younger age (eg, >65 years vs 18-24 years: odds ratio [OR], 0.094; 95% CI, 0.088-0.101; P < .001), male sex (women: OR, 0.943; 95% CI, 0.928-0.959; P < .001), white race (eg, Asian patients vs white patients: OR, 0.248; 95% CI, 0.240-0.257; P < .001), being divorced (OR, 1.131; 95% CI, 1.093-1.171; P < .001), being employed (eg, retired vs employed persons: OR, 0.278; 95% CI, 0.267-0.290; P < .001), and having a higher median education level (OR, 2.156; 95% CI, 2.062-2.256; P < .001) were positively associated with odds of ADHD diagnosis. Having an eating disorder (OR, 5.192; 95% CI, 4.926-5.473; P < .001), depressive disorder (OR, 4.118; 95% CI, 4.030-4.207; P < .001), bipolar disorder (OR, 4.722; 95% CI, 4.556-4.894; P < .001), or anxiety disorder (OR, 2.438; 95% CI, 2.385-2.491; P < .001) was associated with higher odds of receiving an ADHD diagnosis. Adults with ADHD had significantly higher odds of frequent health care utilization (OR, 1.303; 95% CI, 1.272-1.334; P < .001) and sexually transmitted infections (OR, 1.289; 95% CI 1.251-1.329; P < .001) compared with adults with no ADHD diagnosis. Conclusions and Relevance/UNASSIGNED:This study confirmed the reported increases in rates of ADHD diagnosis among adults, showing substantially lower rates of detection among minority racial/ethnic subgroups in the United States. Higher odds of negative outcomes reflect the economic and personal consequences that substantiate the need to improve assessment and treatment of ADHD in adults.

Rumination is strongly and consistently correlated with depression. Although multiple studies have explored the neural correlates of rumination, findings have been inconsistent and the mechanisms underlying rumination remain elusive. Functional brain imaging studies have identified areas in the default mode network (DMN) that appear to be critically involved in ruminative processes. However, a meta-analysis to synthesize the findings of brain regions underlying rumination is currently lacking. Here, we conducted a meta-analysis consisting of experimental tasks that investigate rumination by using Signed Differential Mapping of 14 fMRI studies comprising 286 healthy participants. Furthermore, rather than treat the DMN as a unitary network, we examined the contribution of three DMN subsystems to rumination. Results confirm the suspected association between rumination and DMN activation, specifically implicating the DMN core regions and the dorsal medial prefrontal cortex subsystem. Based on these findings, we suggest a hypothesis of how DMN regions support rumination and present the implications of this model for treating major depressive disorder characterized by rumination.

Cortical development is characterized by distinct spatial and temporal patterns of maturational changes across various cortical shape measures. There is a growing interest in summarizing complex developmental patterns into a single index, which can be used to characterize an individual's brain age. We conducted this study with two primary aims. First, we sought to quantify covariation patterns for a variety of cortical shape measures, including cortical thickness, gray matter volume, surface area, mean curvature, and travel depth, as well as white matter volume, and subcortical gray matter volume. We examined these measures in a sample of 869 participants aged 5-18 from the Healthy Brain Network (HBN) neurodevelopmental cohort using the Joint and Individual Variation Explained (Lock et al., 2013) method. We validated our results in an independent dataset from the Nathan Kline Institute - Rockland Sample (NKI-RS; N = 210) and found remarkable consistency for some covariation patterns. Second, we assessed whether covariation patterns in the brain can be used to accurately predict a person's chronological age. Using ridge regression, we showed that covariation patterns can predict chronological age with high accuracy, reflected by our ability to cross-validate our model in an independent sample with a correlation coefficient of 0.84 between chronologic and predicted age. These covariation patterns also predicted sex with high accuracy (AUC = 0.85), and explained a substantial portion of variation in full scale intelligence quotient (R²â€¯= 0.10). In summary, we found significant covariation across different cortical shape measures and subcortical gray matter volumes. In addition, each shape measure exhibited distinct covariations that could not be accounted for by other shape measures. These covariation patterns accurately predicted chronological age, sex and general cognitive ability. In a subset of NKI-RS, test-retest (<1 month apart, N = 120) and longitudinal scans (1.22 ± 0.29 years apart, N = 77) were available, allowing us to demonstrate high reliability for the prediction models obtained and the ability to detect subtle differences in the longitudinal scan interval among participants (median and median absolute deviation of absolute differences between predicted age difference and real age difference = 0.53 ± 0.47 years, r = 0.24, p-value = 0.04).

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10-4), rs2282794-FGF1 (A allele; p = 1.33 × 10-2), rs2122642-ADGRL3 (C allele, p = 3.5 × 10-2), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, Ppermuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease.