Family Discordance in Gender Identification Is Not Associated with Increased Depression and Anxiety Among Trans Youth.

Purpose: We examined the relationship between parent- and child-reported gender identity of the youth with internalizing symptoms in transgender and gender-diverse (TGD) youth. In addition, we investigated differences in sex assigned at birth ratios and pubertal development stages in TGD and cisgender youth. Methods: We analyzed longitudinal data from the Adolescent Brain Cognitive Development study (ABCD), corresponding to baseline and 1st-to-3rd-year follow-up interviews (n = 6030 to n = 9743, age range [9-13]). Sociodemographic variables, self- and parent-reported gender identity, and clinical measures were collected. Results: TGD youth showed higher levels of internalizing symptoms compared with cisgender youth. However, this was not worsened by discordance in gender identification between TGD youth and parents. Over the 3-year follow-up period, the proportion of TGD participants increased from 0.8% (95% confidence interval (CI) [0.6-1.0]) at baseline to 1.4% (95% CI [1.1-1.7]) at the 3rd-year follow-up (χ2 = 10.476, df = 1, false discovery rate (FDR)-adjusted p = 0.00256), particularly among those assigned female at birth (AFAB) in relation to people assigned male at birth (AMAB) (AMAB:AFAB at baseline: 1:1.9 vs. AMAB:AFAB at 3rd-year follow-up: 1:4.7, χ2 = 40.357, df = 1, FDR-adjusted p < 0.0001). Conclusions: TGD youth in ABCD reported higher internalizing symptoms than cisgender youth, although this was not affected by parental discordance in gender identification. A substantial increase over time in TGD children AFAB was documented. More research is needed to understand the clinical implications of these preliminary results, for which the longitudinal design of ABCD will be crucial.

A longitudinal resource for studying connectome development and its psychiatric associations during childhood.

Most psychiatric disorders are chronic, associated with high levels of disability and distress, and present during pediatric development. Scientific innovation increasingly allows researchers to probe brain-behavior relationships in the developing human. As a result, ambitions to (1) establish normative pediatric brain development trajectories akin to growth curves, (2) characterize reliable metrics for distinguishing illness, and (3) develop clinically useful tools to assist in the diagnosis and management of mental health and learning disorders have gained significant momentum. To this end, the NKI-Rockland Sample initiative was created to probe lifespan development as a large-scale multimodal dataset. The NKI-Rockland Sample Longitudinal Discovery of Brain Development Trajectories substudy (N = 369) is a 24- to 30-month multi-cohort longitudinal pediatric investigation (ages 6.0-17.0 at enrollment) carried out in a community-ascertained sample. Data include psychiatric diagnostic, medical, behavioral, and cognitive phenotyping, as well as multimodal brain imaging (resting fMRI, diffusion MRI, morphometric MRI, arterial spin labeling), genetics, and actigraphy. Herein, we present the rationale, design, and implementation of the Longitudinal Discovery of Brain Development Trajectories protocol.

Cerebro-cerebellar Dysconnectivity in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Abnormal cerebellar development has been implicated in attention-deficit/hyperactivity disorder (ADHD), although cerebro-cerebellar functional connectivity (FC) has yet to be examined in ADHD. Our objective is to investigate the disturbed cerebro-cerebellar FC in children and adolescents with ADHD. METHOD: We analyzed a dataset of 106 individuals with ADHD (68 children, 38 adolescents) and 62 healthy comparison individuals (34 children, 28 adolescents) from the publicly available ADHD-200 dataset. We identified 7 cerebellar subregions based on cerebro-cerebellar FC and subsequently obtained the FC maps of cerebro-cerebellar networks. The main effects of ADHD and age and their interaction were examined using 2-way analysis of variance. RESULTS: Compared to comparisons, ADHD showed higher cerebro-cerebellar FC in the superior temporal gyrus within the somatomotor network. Interactions of diagnosis and age were identified in the supplementary motor area and postcentral gyrus within the somatomotor network and middle temporal gyrus within the ventral attention network. Follow-up Pearson correlation analysis revealed decreased cerebro-cerebellar FC in these regions with increasing age in comparisons, whereas the opposite pattern of increased cerebro-cerebellar FC occurred in ADHD. CONCLUSION: Increased cerebro-cerebellar FC in the superior temporal gyrus within the somatomotor network could underlie impairments in cognitive control and somatic motor function in ADHD. In addition, increasing cerebro-cerebellar FC in older participants with ADHD suggests that enhanced cerebellar involvement may compensate for dysfunctions of the cerebral cortex in ADHD.

Revisión escéptica del estado de la neuroimagen en el trastorno por déficit de atención e hiperactividad / Skeptical review of the state of neuroimaging in attention deficit hyperactivity disorder

Resumen El trastorno por déficit de atención e hiperactividad (TDAH) ha sido estudiado por medio de resonancia magnética durante más de 30 años, superando 2200 artículos en PubMed. Sin embargo, todavía no se entienden bien las bases cerebrales del TDAH. Esto refleja la dificultad de replicar resultados, que afecta a casi todos los esfuerzos científicos. Los factores que contribuyen a resultados falsos positivos incluyen tamaños de muestra pequeños y la superabundancia de métodos analíticos. En el campo de la genética mole cular, estos retos conllevaron a la adopción del requisito de compartir los datos genéticos inmediatamente para que la comunidad pueda trabajar de forma conjunta, y que se apliquen métodos rigurosos tomando en cuenta la verdadera cantidad de pruebas estadísticas. Esto ha producido resultados más creíbles, aunque con tamaños de efecto muy reducidos respecto a los anteriores. En este breve resumen se usan dos consorcios, uno internacional llamado ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis), y el otro norteamericano llamado ABCD (Adolescent and Cognitive Behavior Development Study), para ilustrar este movimiento a la ciencia abier ta. Aquí se revisa la primera cosecha de hallazgos, aunque todavía limitados a análisis transversales. Ya que ABCD fue diseñado como esfuerzo longitudinal, la combinación con la maduración continua del campo promete transformar nuestro entendimiento de la patofisiología de TDAH (probablemente también alterando la definición diagnostica al largo plazo) para acercarnos al día en el cual la neuroimagen sea útil en la clínica.

Abstract Attention-deficit/hyperactivity disorder (ADHD) has been the focus of magnetic resonance imaging studies for more than 30 years, with more than 2200 articles listed in PubMed. Nevertheless, the brain substrates of ADHD remain poorly understood. This reflects the crisis of replicability across nearly all scientific endeavors, deriving from factors such as small sample sizes combined with a proliferation in analytical approaches, yielding high rates of false positive results. The field of molecular genetics confronted this by adopting open and immedi ate sharing of raw data and insistence on rigorous corrections for multiple comparisons. These strategies are yielding more robust genetic findings, albeit with much smaller effect sizes than before. This brief review focuses on two recent consortium efforts, i.e., the international Enhancing Neuro-Imaging Genetics through Meta-Analysis (ENIGMA), and the U.S. Adolescent Behavior & Cognitive Developm ent Study (ABCD). Both embrace the culture of open science, and are beginning to yield credible findings, despite being limited initially to cross-sectional analyses. As the field continues to mature, these and other ongoing longitudinal large-scale studies are poised to transform our understanding of the pathophysiology of ADHD to bring closer the day when neuroimaging can contribute to clinical utility.

[Skeptical review of the state of neuroimaging in attention deficit hyperactivity disorder]. / Revisión escéptica del estado de la neuroimagen en el trastorno por déficit de atención e hiperactividad.

Attention-deficit/hyperactivity disorder (ADHD) has been the focus of magnetic resonance imaging studies for more than 30 years, with more than 2200 articles listed in PubMed. Nevertheless, the brain substrates of ADHD remain poorly understood. This reflects the crisis of replicability across nearly all scientific endeavors, deriving from factors such as small sample sizes combined with a proliferation in analytical approaches, yielding high rates of false positive results. The field of molecular genetics confronted this by adopting open and immediate sharing of raw data and insistence on rigorous corrections for multiple comparisons. These strategies are yielding more robust genetic findings, albeit with much smaller effect sizes than before. This brief review focuses on two recent consortium efforts, i.e., the international Enhancing Neuro-Imaging Genetics through Meta-Analysis (ENIGMA), and the U.S. Adolescent Behavior & Cognitive Developm ent Study (ABCD). Both embrace the culture of open science, and are beginning to yield credible findings, despite being limited initially to cross-sectional analyses. As the field continues to mature, these and other ongoing longitudinal large-scale studies are poised to transform our understanding of the pathophysiology of ADHD to bring closer the day when neuroimaging can contribute to clinical utility.

El trastorno por déficit de atención e hiperactividad (TDAH) ha sido estudiado por medio de resonancia magnética durante más de 30 años, superando 2200 artículos en PubMed. Sin embargo, todavía no se entienden bien las bases cerebrales del TDAH. Esto refleja la dificultad de replicar resultados, que afecta a casi todos los esfuerzos científicos. Los factores que contribuyen a resultados falsos positivos incluyen tamaños de muestra pequeños y la superabundancia de métodos analíticos. En el campo de la genética molecular, estos retos conllevaron a la adopción del requisito de compartir los datos genéticos inmediatamente para que la comunidad pueda trabajar de forma conjunta, y que se apliquen métodos rigurosos tomando en cuenta la verdadera cantidad de pruebas estadísticas. Esto ha producido resultados más creíbles, aunque con tamaños de efecto muy reducidos respecto a los anteriores. En este breve resumen se usan dos consorcios, uno internacional llamado ENIGMA (Enhancing Neuro-Imaging Genetics through Meta-Analysis), y el otro norteamericano llamado ABCD (Adolescent and Cognitive Behavior Development Study), para ilustrar este movimiento a la ciencia abierta. Aquí se revisa la primera cosecha de hallazgos, aunque todavía limitados a análisis transversales. Ya que ABCD fue diseñado como esfuerzo longitudinal, la combinación con la maduración continua del campo promete transformar nuestro entendimiento de la patofisiología de TDAH (probablemente también alterando la definición diagnostica al largo plazo) para acercarnos al día en el cual la neuroimagen sea útil en la clínica.

Predicting multiscan MRI outcomes in children with neurodevelopmental conditions following MRI simulator training.

Pediatric brain imaging holds significant promise for understanding neurodevelopment. However, the requirement to remain still inside a noisy, enclosed scanner remains a challenge. Verbal or visual descriptions of the process, and/or practice in MRI simulators are the norm in preparing children. Yet, the factors predictive of successfully obtaining neuroimaging data remain unclear. We examined data from 250 children (6-12 years, 197 males) with autism and/or attention-deficit/hyperactivity disorder. Children completed systematic MRI simulator training aimed to habituate to the scanner environment and minimize head motion. An MRI session comprised multiple structural, resting-state, task and diffusion scans. Of the 201 children passing simulator training and attempting scanning, nearly all (94%) successfully completed the first structural scan in the sequence, and 88% also completed the following functional scan. The number of successful scans decreased as the sequence progressed. Multivariate analyses revealed that age was the strongest predictor of successful scans in the session, with younger children having lower success rates. After age, sensorimotor atypicalities contributed most to prediction. Results provide insights on factors to consider in designing pediatric brain imaging protocols.

Cannabinoid treatment for autism: a proof-of-concept randomized trial.

BACKGROUND: Endocannabinoid dysfunction in animal models of autism spectrum disorder (ASD) and accumulating, albeit anecdotal, evidence for efficacy in humans motivated this placebo-controlled double-blind comparison of two oral cannabinoid solutions in 150 participants (age 5-21 years) with ASD. METHODS: We tested (1) BOL-DP-O-01-W, a whole-plant cannabis extract containing cannabidiol and Δ9-tetrahydrocannabinol at a 20:1 ratio and (2) BOL-DP-O-01, purified cannabidiol and Δ9-tetrahydrocannabinol at the same ratio. Participants (N = 150) received either placebo or cannabinoids for 12-weeks (testing efficacy) followed by a 4-week washout and predetermined cross-over for another 12 weeks to further assess tolerability. Registered primary efficacy outcome measures were improvement in behavioral problems (differences between whole-plant extract and placebo) on the Home Situation Questionnaire-ASD (HSQ-ASD) and the Clinical Global Impression-Improvement scale with disruptive behavior anchor points (CGI-I). Secondary measures were Social Responsiveness Scale (SRS-2) and Autism Parenting Stress Index (APSI). RESULTS: Changes in Total Scores of HSQ-ASD (primary-outcome) and APSI (secondary-outcome) did not differ among groups. Disruptive behavior on the CGI-I (co-primary outcome) was either much or very much improved in 49% on whole-plant extract (n = 45) versus 21% on placebo (n = 47; p = 0.005). Median SRS Total Score (secondary-outcome) improved by 14.9 on whole-plant extract (n = 34) versus 3.6 points after placebo (n = 36); p = 0.009). There were no treatment-related serious adverse events. Common adverse events included somnolence and decreased appetite, reported for 28% and 25% on whole-plant extract, respectively (n = 95); 23% and 21% on pure-cannabinoids (n = 93), and 8% and 15% on placebo (n = 94). Limitations Lack of pharmacokinetic data and a wide range of ages and functional levels among participants warrant caution when interpreting the results. CONCLUSIONS: This interventional study provides evidence that BOL-DP-O-01-W and BOL-DP-O-01, administrated for 3 months, are well tolerated. Evidence for efficacy of these interventions are mixed and insufficient. Further testing of cannabinoids in ASD is recommended. Trial registration ClinicalTrials.gov: NCT02956226. Registered 06 November 2016, https://clinicaltrials.gov/ct2/show/NCT02956226.

Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder.

Previous studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene's relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.

Clinical and Functional Connectivity Outcomes of 5-Hz Repetitive Transcranial Magnetic Stimulation as an Add-on Treatment in Cocaine Use Disorder: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Cocaine use disorder (CUD) is a global condition lacking effective treatment. Repetitive transcranial magnetic stimulation (rTMS) may reduce craving and frequency of cocaine use, but little is known about its efficacy and neural effects. We sought to elucidate short- and long-term clinical benefits of 5-Hz rTMS as an add-on to standard treatment in patients with CUD and discern underlying functional connectivity effects using magnetic resonance imaging. METHODS: A total of 44 patients with CUD were randomly assigned to complete the 2-week double-blind randomized controlled trial (acute phase) (sham [n = 20, 2 female] and active [n = 24, 4 female]), in which they received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (PFC). Subsequently, 20 patients with CUD continued to an open-label maintenance phase for 6 months (two weekly sessions for up to 6 mo). RESULTS: rTMS plus standard treatment for 2 weeks significantly reduced craving (baseline: 3.9 ± 3.6; 2 weeks: 1.5 ± 2.4, p = .013, d = 0.77) and impulsivity (baseline: 64.8 ± 16.8; 2 weeks: 53.1 ± 17.4, p = .011, d = 0.79) in the active group. We also found increased functional connectivity between the left dorsolateral PFC and ventromedial PFC and between the ventromedial PFC and right angular gyrus. Clinical and functional connectivity effects were maintained for 3 months, but they dissipated by 6 months. We did not observe reduction in positive results for cocaine in urine; however, self-reported frequency and grams consumed for 6 months were reduced. CONCLUSIONS: With this randomized controlled trial, we show that 5-Hz rTMS has potential promise as an adjunctive treatment for CUD and merits further research.

DREAM : A Toolbox to Decode Rhythms of the Brain System.

Rhythms of the brain are generated by neural oscillations across multiple frequencies. These oscillations can be decomposed into distinct frequency intervals associated with specific physiological processes. In practice, the number and ranges of decodable frequency intervals are determined by sampling parameters, often ignored by researchers. To improve the situation, we report on an open toolbox with a graphical user interface for decoding rhythms of the brain system (DREAM). We provide worked examples of DREAM to investigate frequency-specific performance of both neural (spontaneous brain activity) and neurobehavioral (in-scanner head motion) oscillations. DREAM decoded the head motion oscillations and uncovered that younger children moved their heads more than older children across all five frequency intervals whereas boys moved more than girls in the age of 7 to 9 years. It is interesting that the higher frequency bands contain more head movements, and showed stronger age-motion associations but weaker sex-motion interactions. Using data from the Human Connectome Project, DREAM mapped the amplitude of these neural oscillations into multiple frequency bands and evaluated their test-retest reliability. The resting-state brain ranks its spontaneous oscillation's amplitudes spatially from high in ventral-temporal areas to low in ventral-occipital areas when the frequency band increased from low to high, while those in part of parietal and ventral frontal regions are reversed. The higher frequency bands exhibited more reliable amplitude measurements, implying more inter-individual variability of the amplitudes for the higher frequency bands. In summary, DREAM adds a reliable and valid tool to mapping human brain function from a multiple-frequency window into brain waves.

Evidence of Altered Habenular Intrinsic Functional Connectivity in Pediatric ADHD.

Objective: The habenula is a small region in the epithalamus that contributes to the regulation of midbrain dopaminergic circuits implicated in attention-deficit hyperactivity disorder (ADHD). This investigation aims to evaluate the intrinsic functional connectivity (iFC) of the habenula in children with ADHD. Method: A total of 112 children (5-9 years; 75 ADHD, 37 healthy comparisons) completed anatomical and resting-state functional magnetic resonance imaging (MRI) scans. Habenula regions of interest (ROIs) were identified individually on normalized T1-weighted anatomical images. Seed-based iFC analyses and group comparisons were conducted for habenula ROIs, as well as thalamic ROIs to test the specificity of habenula findings. Results: Children with ADHD exhibited reduced habenula-putamen iFC compared with healthy comparisons. Group differences in thalamic iFC showed no overlap with habenular findings. Conclusion: These preliminary findings suggest that habenula-putamen iFC may be disrupted in children with ADHD. Further work is needed to confirm and elucidate the role of this circuit in ADHD pathophysiology.

Systematic Review and Meta-analysis: Resting-State Functional Magnetic Resonance Imaging Studies of Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: To conduct a meta-analysis of resting-state functional magnetic resonance imaging (R-fMRI) studies in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and in adults with ADHD to assess spatial convergence of findings from available studies. METHOD: Based on a preregistered protocol in PROSPERO (CRD42019119553), a large set of databases were searched up to April 9, 2019, with no language or article type restrictions. Study authors were systematically contacted for additional unpublished information/data. Resting-state functional magnetic resonance imaging studies using seed-based connectivity (SBC) or any other method (non-SBC) reporting whole-brain results of group comparisons between participants with ADHD and typically developing controls were eligible. Voxelwise meta-analysis via activation likelihood estimation with cluster-level familywise error (voxel-level: p < .001; cluster-level: p < .05) was used. RESULTS: Thirty studies (18 SBC and 12 non-SBC), comprising 1,978 participants (1,094 with ADHD; 884 controls) were retained. The meta-analysis focused on SBC studies found no significant spatial convergence of ADHD-related hyperconnectivity or hypoconnectivity across studies. This nonsignificant finding remained after integrating 12 non-SBC studies into the main analysis and in sensitivity analyses limited to studies including only children or only non-medication-naïve patients. CONCLUSION: The lack of significant spatial convergence may be accounted for by heterogeneity in study participants, experimental procedures, and analytic flexibility as well as in ADHD pathophysiology. Alongside other neuroimaging meta-analyses in other psychiatric conditions, the present results should inform the conduct and publication of future neuroimaging studies of psychiatric disorders.

Stability and similarity of the pediatric connectome as developmental measures.

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6-21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6-21 years) are low (18-44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), cross-state (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n = 119). The first component was significantly correlated with the social skills measure (r=-0.26, p = 0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p = 0.001) and with connectome similarity during MovieDM (r=-0.28, p = 0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to the development of social skills. We infer that the maturation of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs-features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome.

Diffusion kurtosis imaging of gray matter in young adults with autism spectrum disorder.

Prior ex vivo histological postmortem studies of autism spectrum disorder (ASD) have shown gray matter microstructural abnormalities, however, in vivo examination of gray matter microstructure in ASD has remained scarce due to the relative lack of non-invasive methods to assess it. The aim of this work was to evaluate the feasibility of employing diffusional kurtosis imaging (DKI) to describe gray matter abnormalities in ASD in vivo. DKI data were examined for 16 male participants with a diagnosis of ASD and IQ>80 and 17 age- and IQ-matched male typically developing (TD) young adults 18-25 years old. Mean (MK), axial (AK), radial (RK) kurtosis and mean diffusivity (MD) metrics were calculated for lobar and sub-lobar regions of interest. Significantly decreased MK, RK, and MD were found in ASD compared to TD participants in the frontal and temporal lobes and several sub-lobar regions previously associated with ASD pathology. In ASD participants, decreased kurtosis in gray matter ROIs correlated with increased repetitive and restricted behaviors and poor social interaction symptoms. Decreased kurtosis in ASD may reflect a pathology associated with a less restrictive microstructural environment such as decreased neuronal density and size, atypically sized cortical columns, or limited dendritic arborizations.

Charting brain growth in tandem with brain templates at school age.

Brain growth charts and age-normed brain templates are essential resources for researchers to eventually contribute to the care of individuals with atypical developmental trajectories. The present work generates age-normed brain templates for children and adolescents at one-year intervals and the corresponding growth charts to investigate the influences of age and ethnicity using a common pediatric neuroimaging protocol. Two accelerated longitudinal cohorts with the identical experimental design were implemented in the United States and China. Anatomical magnetic resonance imaging (MRI) of typically developing school-age children (TDC) was obtained up to three times at nominal intervals of 1.25 years. The protocol generated and compared population- and age-specific brain templates and growth charts, respectively. A total of 674 Chinese pediatric MRI scans were obtained from 457 Chinese TDC and 190 American pediatric MRI scans were obtained from 133 American TDC. Population- and age-specific brain templates were used to quantify warp cost, the differences between individual brains and brain templates. Volumetric growth charts for labeled brain network areas were generated. Shape analyses of cost functions supported the necessity of age-specific and ethnicity-matched brain templates, which was confirmed by growth chart analyses. These analyses revealed volumetric growth differences between the two ethnicities primarily in lateral frontal and parietal areas, regions which are most variable across individuals in regard to their structure and function. Age- and ethnicity-specific brain templates facilitate establishing unbiased pediatric brain growth charts, indicating the necessity of the brain charts and brain templates generated in tandem. These templates and growth charts as well as related codes have been made freely available to the public for open neuroscience (https://github.com/zuoxinian/CCS/tree/master/H3/GrowthCharts).

Trends in the Prevalence and Incidence of Attention-Deficit/Hyperactivity Disorder Among Adults and Children of Different Racial and Ethnic Groups.

Importance: 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: 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: 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: Period of ADHD diagnosis. Main Outcomes and Measures: 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: 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: 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.

Brain age prediction: Cortical and subcortical shape covariation in the developing human brain.

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 (R2 = 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 ±â€¯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 ±â€¯0.47 years, r = 0.24, p-value = 0.04).

Genetic Variation Underpinning ADHD Risk in a Caribbean Community.

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.

Autism-associated Nf1 deficiency disrupts corticocortical and corticostriatal functional connectivity in human and mouse.

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.

Diffusion weighted imaging evidence of extra-callosal pathways for interhemispheric communication after complete commissurotomy.

The integrity of white matter architecture in the human brain is related to cognitive processing abilities. The corpus callosum is the largest white matter bundle interconnecting the two cerebral hemispheres. "Split-brain" patients in whom all cortical commissures have been severed to alleviate intractable epilepsy demonstrate remarkably intact cognitive abilities despite the lack of this important interhemispheric pathway. While it has often been speculated that there are compensatory alterations in the remaining interhemispheric fibers in split-brain patients several years post-commissurotomy, this has never been directly shown. Here we examined extra-callosal pathways for interhemispheric communication in the brain of a patient who underwent complete cerebral commissurotomy using diffusion weighted imaging tractography. We found that compared with a healthy age-matched comparison group, the split-brain patient exhibited increased fractional anisotropy (FA) of the dorsal and ventral pontine decussations of the cortico-cerebellar interhemispheric pathways. Few differences were observed between the patient and the comparison group with respect to FA of other long-range intrahemispheric fibers. These results point to specific cerebellar anatomical substrates that may account for the spared interhemispheric coordination and intact cognitive abilities that have been extensively documented in this unique patient.