Neurobiology of attention-deficit hyperactivity disorder: historical challenges and emerging frontiers.

Extensive investigations spanning multiple levels of inquiry, from genetic to behavioural studies, have sought to unravel the mechanistic foundations of attention-deficit hyperactivity disorder (ADHD), with the aspiration of developing efficacious treatments for this condition. Despite these efforts, the pathogenesis of ADHD remains elusive. In this Review, we reflect on what has been learned about ADHD while also providing a framework that may serve as a roadmap for future investigations. We emphasize that ADHD is a highly heterogeneous disorder with multiple aetiologies that necessitates a multifactorial dimensional phenotype, rather than a fixed dichotomous conceptualization. We highlight new findings that suggest a more brain-wide, 'global' view of the disorder, rather than the traditional localizationist framework, which asserts that a limited set of brain regions or networks underlie ADHD. Last, we underscore how underpowered studies that have aimed to associate neurobiology with ADHD phenotypes have long precluded the field from making progress. However, a new age of ADHD research with refined phenotypes, advanced methods, creative study designs and adequately powered investigations is beginning to put the field on a good footing. Indeed, the field is at a promising juncture to advance the neurobiological understanding of ADHD and fulfil the promise of clinical utility.

Neurosurgical Residency Training at Veterans Affairs Medical Centers, the Resident Perspective.

BACKGROUND AND OBJECTIVE: Department of Veteran's Affairs (VA) Medical Centers play a crucial role in training neurosurgery residents. Although previous studies have examined the impact of VA rotations from the attending perspective, the resident experience remains unexplored. We present a national survey of neurosurgery residents to assess their perceptions of VA rotations, focusing on operative experience, call burden, longitudinal patient care experiences, and overall strengths and limitations. METHODS: A 33-question survey was distributed by email to all neurosurgery residents who had previously completed a VA rotation within the past 7 years. RESULTS: Responses were received from 77 residents, representing 36 out of 40 neurosurgical residency programs with an active VA rotation. Most residents (79.2%) found their VA rotations adequate in length, having spent a median of 5 months at the VA. Residents completed an average of 11.7 (SD 7.2) cases per month while at the VA, including 8.9 (SD 5.5) spine, 1.7 (SD 2.0) cranial, and 1.4 (SD 1.6) peripheral nerve cases. Many residents reported completing a greater proportion of spine and peripheral nerve cases at the VA compared with their primary clinical sites. Across all postgraduate years, residents felt that the VA offered increased operative autonomy (79.0% agreement) at the expense of total operative volume (98.7% agreement) and complexity (81.9% agreement). Importantly, 94.8% of residents participated in longitudinal patient care experiences, and 59.7% followed all patients longitudinally. CONCLUSION: The resident experience at the VA varies, presenting both strengths and limitations. Addressing these factors could enhance the overall effectiveness of VA rotations in neurosurgical training programs in the future.

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

From Operating Room to Courtroom: Analyzing Malpractice Trajectories in Cranial Neurosurgery.

BACKGROUND AND OBJECTIVES: Nearly all neurosurgeons in the United States will be named defendants in a malpractice claim before retirement. We perform an assessment of national malpractice trends in cranial neurosurgery to inform neurosurgeons on current outcomes, trends over time, benchmarks for malpractice coverage needs, and ways to mitigate lawsuits. METHODS: The Westlaw Edge and LexisNexis databases were searched to identify medical malpractice cases relating to open cranial surgery between 1987 and 2023. Extracted data included date of verdict, jurisdiction, outcome, details of sustained injuries, and any associated award/settlement figures. RESULTS: Of 1550 cases analyzed, 252 were identified as malpractice claims arising from open cranial surgery. The median settlement amount was $950 000 and the average plaintiff ruling was $2 750 000. The highest plaintiff ruling resulted in an award of $28.1 million. Linear regression revealed no significant relationship between year and defendant win (P-value = .43). After adjusting for inflation, award value increased with time (P-value = .01). The most common cranial subspecialties were tumor (67 cases, 26.6%), vascular (54 cases, 21.4%), infection (23 cases, 9.1%), and trauma (23 cases, 9.1%). Perioperative complications was the most common litigation category (96 cases, 38.1%), followed by delayed treatment (40 cases, 15.9%), failure to diagnose (38 cases, 15.1%), and incorrect choice of procedure (29 cases, 11.5%). The states with most claims were New York (40 cases, 15.9%), California (24 cases, 9.5%), Florida (21 cases, 8.3%), and Pennsylvania (20 cases, 7.9%). CONCLUSION: Although a stable number of cases were won by neurosurgeons, an increase in award sizes was observed in the 37-year period assessed. Perioperative complications and delayed treatment/diagnosis were key drivers of malpractice claims.

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma.

Background: Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes. Methods: An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry. Results: HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Conclusions: A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.

A precision functional atlas of personalized network topography and probabilities.

Although the general location of functional neural networks is similar across individuals, there is vast person-to-person topographic variability. To capture this, we implemented precision brain mapping functional magnetic resonance imaging methods to establish an open-source, method-flexible set of precision functional network atlases-the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. This atlas is an evolving resource comprising 53,273 individual-specific network maps, from more than 9,900 individuals, across ages and cohorts, including the Adolescent Brain Cognitive Development study, the Developmental Human Connectome Project and others. We also generated probabilistic network maps across multiple ages and integration zones (using a new overlapping mapping technique, Overlapping MultiNetwork Imaging). Using regions of high network invariance improved the reproducibility of executive function statistical maps in brain-wide associations compared to group average-based parcellations. Finally, we provide a potential use case for probabilistic maps for targeted neuromodulation. The atlas is expandable to alternative datasets with an online interface encouraging the scientific community to explore and contribute to understanding the human brain function more precisely.

Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Cumulative Effects of Resting-State Connectivity Across All Brain Networks Significantly Correlate with Attention-Deficit Hyperactivity Disorder Symptoms.

Identification of replicable neuroimaging correlates of attention-deficit hyperactivity disorder (ADHD) has been hindered by small sample sizes, small effects, and heterogeneity of methods. Given evidence that ADHD is associated with alterations in widely distributed brain networks and the small effects of individual brain features, a whole-brain perspective focusing on cumulative effects is warranted. The use of large, multisite samples is crucial for improving reproducibility and clinical utility of brain-wide MRI association studies. To address this, a polyneuro risk score (PNRS) representing cumulative, brain-wide, ADHD-associated resting-state functional connectivity was constructed and validated using data from the Adolescent Brain Cognitive Development (ABCD, N = 5,543, 51.5% female) study, and was further tested in the independent Oregon-ADHD-1000 case-control cohort (N = 553, 37.4% female). The ADHD PNRS was significantly associated with ADHD symptoms in both cohorts after accounting for relevant covariates (p < 0.001). The most predictive PNRS involved all brain networks, though the strongest effects were concentrated among the default mode and cingulo-opercular networks. In the longitudinal Oregon-ADHD-1000, non-ADHD youth had significantly lower PNRS (Cohen's d = -0.318, robust p = 5.5 × 10-4) than those with persistent ADHD (age 7-19). The PNRS, however, did not mediate polygenic risk for ADHD. Brain-wide connectivity was robustly associated with ADHD symptoms in two independent cohorts, providing further evidence of widespread dysconnectivity in ADHD. Evaluation in enriched samples demonstrates the promise of the PNRS approach for improving reproducibility in neuroimaging studies and unraveling the complex relationships between brain connectivity and behavioral disorders.

Brain tumors in United States military veterans.

BACKGROUND: Comprehensive analysis of brain tumor incidence and survival in the Veteran population has been lacking. METHODS: Veteran data were obtained from the Veterans Health Administration (VHA) Medical Centers via VHA Corporate Data Warehouse. Brain tumor statistics on the overall US population were generated from the Central Brain Tumor Registry of the US data. Cases were individuals (≥18 years) with a primary brain tumor, diagnosed between 2004 and 2018. The average annual age-adjusted incidence rates (AAIR) and 95% confidence intervals were estimated per 100 000 population and Kaplan-Meier survival curves evaluated overall survival outcomes among Veterans. RESULTS: The Veteran population was primarily white (78%), male (93%), and between 60 and 64 years old (18%). Individuals with a primary brain tumor in the general US population were mainly female (59%) and between 18 and 49 years old (28%). The overall AAIR of primary brain tumors from 2004 to 2018 within the Veterans Affairs cancer registry was 11.6. Nonmalignant tumors were more common than malignant tumors (AAIR:7.19 vs 4.42). The most diagnosed tumors in Veterans were nonmalignant pituitary tumors (AAIR:2.96), nonmalignant meningioma (AAIR:2.62), and glioblastoma (AAIR:1.96). In the Veteran population, survival outcomes became worse with age and were lowest among individuals diagnosed with glioblastoma. CONCLUSIONS: Differences between Veteran and US populations can be broadly attributed to demographic composition differences of these groups. Prior to this, there have been no reports on national-level incidence rates and survival outcomes for Veterans. These data provide vital information that can drive efforts to understand disease burden and improve outcomes for individuals with primary brain tumors.

Evaluating barriers and facilitators to healthcare providers' use of an emergency department electronic referral portal for high-risk children with asthma using the Theoretical Domains Framework.

OBJECTIVE: Urban children with asthma are at risk for frequent emergency department (ED) visits and suboptimal asthma management. ED visits provide an opportunity for referrals to community-based asthma management services. Electronic medical record-based referral portals have been shown to improve quality of care but use of these portals by healthcare providers (HCPs) is variable. The purpose of the study was to investigate facilitators, barriers, and recommendations to improve the use of an electronic referral portal to connect children presenting with asthma exacerbations in an urban pediatric ED to community-based education and case management services. METHODS: The study was grounded in the Theoretical Domains Framework, an implementation provided the theoretical basis of the study. All ED HCPs were invited to complete qualitative interviews; twenty-three HCPs participated. Interviews were coded using directed content analysis. RESULTS: Facilitators to portal use included its relative ease of use and HCP beliefs regarding the importance of such referrals for preventive asthma care. Barriers included insufficient time to make referrals, lack of information regarding the community agency and challenges communicating the value of the referral to patients and/or their caregivers. CONCLUSIONS: Successfully engaging HCPs working in ED settings to use electronic portals to refer children with asthma to community agencies for health services may involve helping providers increase their comfort and knowledge of the external provider agency, ensuring organizational leaders support the need for preventive asthma care and provision of feedback to HCPs on the success of such referrals in meeting the needs of those families served.

Landmine Injury Resulting in Comminuted Lumbar Facet Fracture as a Cause of Lumbar Stenosis and Spondylolisthesis.

Lumbar facet fractures are rarely reported and have been linked to sports and spine surgery. We describe the case of a 77-year-old patient who sustained an injury from multiple landmine blasts during the Vietnam War. He had low back pain since that time, which was initially managed conservatively. However, the pain progressed over decades to severe neurogenic claudication that greatly restricted his quality of life. Neuroimaging revealed the presence of bone fragments impinging on the spinal canal at the L5/6 level (transitional anatomy) that resulted from a comminuted fracture of the lumbar facet at the inferior articular process. We performed an L5/6 decompressive laminectomy, with removal of these fragments, and posterior instrumented fusion, with substantial improvement in symptoms. This case illustrates a unique mechanism of lumbar facet fracture and the biomechanic origination, natural history, and optimal treatment of this entity. We expand on the spectrum of lumbosacral injuries associated with the combat blast injury that have only increased in prevalence in recent conflicts.

Late Subacute Cerebral Hematoma Mimicking a Metastasis on PSMA PET/CT.

ABSTRACT: A 64-year-old man with history of prostate cancer was found to have rising prostate-specific antigen after radical prostatectomy. 18 F-DCFPyL PET/CT demonstrated a prostate-specific membrane antigen-avid brain lesion in the left frontal lobe and no other findings to account for rising prostate-specific antigen. Brain MRI demonstrated a small intraparenchymal hematoma with late subacute features in this location. The patient reported a seizure 3 weeks before but was otherwise asymptomatic, and neurologic examination was normal. Follow-up MRI demonstrated gradual decrease in size of the hematoma without treatment.

Price Transparency for Cervical Spinal Fusion Among High-Performing Spine Centers in the United States.

BACKGROUND AND OBJECTIVES: As of January 1, 2021, all US hospitals are required by the Hospital Price Transparency Final Rule (HPTFR) to publish standard charges for all items and services, yet the state of price transparency for cervical spinal fusion is unknown. Here, we assess the nationwide price transparency landscape for cervical spinal fusion among high-performing spine centers in the United States. METHODS: In this cross-sectional economic evaluation, we queried publicly available price transparency websites of 332 "high-performing" spine centers, as defined by the US News and World Report. We extracted variables including gross charges for cervical spinal fusion, payor options, price reporting methodology, and prices relevant to consumers including listed cash prices and minimum and maximum negotiated charges. RESULTS: While nearly all 332 high-performing spine surgery centers (99.4%) had an online cost estimation tool, the HPTFR compliance rate was only 8.4%. Gross charges for cervical spinal fusion were accessible for 68.1% of hospitals, discounted cash prices for 46.4% of hospitals, and minimum and maximum charges for 10.8% of hospitals. There were large IQRs for gross charges ($48 491.98-$99 293.37), discounted cash prices ($26 952.25-$66 806.63), minimum charges ($10 766.11-$21 248.36), and maximum charges ($39 280.49-$89 035.35). There was geographic variability in the gross charges of cervical spinal fusion among high-performing spine centers within and between states. There was a significant association between "excellent" discharge to home status and lower mean gross charges. CONCLUSION: Although online cost reporting has drastically increased since implementation of the HPTFR, data reported for cervical spinal fusion remain inadequate and difficult to interpret by both providers and patients.

Incidence, treatment and outcomes of coronary artery dissection during percutaneous coronary intervention.

BACKGROUND: Coronary artery dissection is a feared and potentially life-threatening complication of percutaneous coronary intervention (PCI). METHODS: We examined the clinical, angiographic, and procedural characteristics, and outcomes of coronary dissection at a tertiary care institution. RESULTS: Between 2014 and 2019, unplanned coronary dissection occurred in 141 of 10,278 PCIs (1.4%). Median patient age was 68 (60, 78) years, 68% were men, and 83% had hypertension. The prevalence of diabetes (29%), and prior PCI (37%) was high. Most target vessels were significantly diseased: 48% had moderate/severe tortuosity and 62% had moderate/severe calcification. The most common cause of dissection was guidewire advancement (30%), followed by stenting (22%), balloon angioplasty (20%), and guide-catheter engagement (18%). TIMI flow was 0 in 33% and 1-2 in 41% of cases. Intravascular imaging was used in 17% of the cases. Stenting was used to treat the dissection in 73% of patients. There was no consequence of dissection in 43% of patients. Technical and procedural success was 65% and 55%, respectively. In-hospital major adverse cardiovascular events occurred in 23% of patients: 13 (9%) had an acute myocardial infarction (MI), 3 (2%) had emergency coronary artery bypass graft surgery, and 10 (7%) died. During a mean follow up of 1612 days, 28 (20%) patients died, and the rate of target lesion revascularization was 11.3% (n=16). CONCLUSION: Coronary artery dissection is an infrequent complication of PCI, but is associated with adverse clinical outcomes, such as death and acute MI.

Joint polygenic and environmental risks for childhood attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom dimensions.

Background: attention-deficit/hyperactivity disorder (ADHD) is associated with both polygenic liability and environmental exposures, both intrinsic to the family, such as family conflict, and extrinsic, such as air pollution. However, much less is known about the interplay between environmental and genetic risks relevant to ADHD-a better understanding of which could inform both mechanistic models and clinical prediction algorithms. Methods: Two independent data sets, the population-based Adolescent Brain Cognitive Development Study (ABCD) (N = 11,876) and the case-control Oregon-ADHD-1000 (N = 1449), were used to examine additive (G + E) and interactive (GxE) effects of selected polygenic risk scores (PRS) and environmental factors in a cross-sectional design. Genetic risk was measured using PRS for nine mental health disorders/traits. Exposures included family income, family conflict/negative sentiment, and geocoded measures of area deprivation, lead exposure risk, and air pollution exposure (nitrogen dioxide and fine particulate matter). Results: ADHD PRS and family conflict jointly predicted concurrent ADHD symptoms in both cohorts. Additive-effects models, including both genetic and environmental factors, explained significantly more variation in symptoms than any individual factor alone (joint R 2 = .091 for total symptoms in ABCD; joint R 2 = .173 in Oregon-ADHD-1000; all delta-R 2 p-values <2e-7). Significant effect size heterogeneity across ancestry groups was observed for genetic and environmental factors (e.g., Q = 9.01, p = .011 for major depressive disorder PRS; Q = 13.34, p = .001 for area deprivation). GxE interactions observed in the full ABCD cohort suggested stronger environmental effects when genetic risk is low, though they did not replicate. Conclusions: Reproducible additive effects of PRS and family environment on ADHD symptoms were found, but GxE interaction effects were not replicated and appeared confounded by ancestry. Results highlight the potential value of combining exposures and PRS in clinical prediction algorithms. The observed differences in risks across ancestry groups warrant further study to avoid health care disparities.

Clinical characterization of the mutational landscape of 24,639 real-world samples from patients with myeloid malignancies.

Myeloid neoplasms represent a broad spectrum of hematological disorders for which somatic mutation status in key driver genes is important for diagnosis, prognosis and treatment. Here we summarize the findings of a targeted, next generation sequencing laboratory developed test in 24,639 clinical myeloid samples. Data were analyzed comprehensively and as part of individual cohorts specific to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). Overall, 48,015 variants were detected, and variants were found in all 50 genes in the panel. The mean number of mutations per patient was 1.95. Mutation number increased with age (Spearman's rank correlation coefficient, ρ = 0.29, P < 0.0001) and was higher in patients with AML than MDS or MPN (Student's t-test, P < 0.0001). TET2 was the most common mutation detected (19.1% of samples; 4,695/24,639) including 7.7% (1,908/24,639) with multi-hit TET2 mutations. Mutation frequency was correlated between patients with cytopenias and MDS (Spearman's, ρ = 0.97, P < 2.2×10-16) with the MDS diagnostic gene SF3B1 being the only notable outlier. This large retrospective study shows the utility of NGS testing to inform clinical decisions during routine clinical care and highlights the mutational landscape of a broad population of myeloid patients.

Trans-ancestry meta-analysis of genome wide association studies of inhibitory control.

Deficits in effective executive function, including inhibitory control are associated with risk for a number of psychiatric disorders and significantly impact everyday functioning. These complex traits have been proposed to serve as endophenotypes, however, their genetic architecture is not yet well understood. To identify the common genetic variation associated with inhibitory control in the general population we performed the first trans-ancestry genome wide association study (GWAS) combining data across 8 sites and four ancestries (N = 14,877) using cognitive traits derived from the stop-signal task, namely - go reaction time (GoRT), go reaction time variability (GoRT SD) and stop signal reaction time (SSRT). Although we did not identify genome wide significant associations for any of the three traits, GoRT SD and SSRT demonstrated significant and similar SNP heritability of 8.2%, indicative of an influence of genetic factors. Power analyses demonstrated that the number of common causal variants contributing to the heritability of these phenotypes is relatively high and larger sample sizes are necessary to robustly identify associations. In Europeans, the polygenic risk for ADHD was significantly associated with GoRT SD and the polygenic risk for schizophrenia was associated with GoRT, while in East Asians polygenic risk for schizophrenia was associated with SSRT. These results support the potential of executive function measures as endophenotypes of neuropsychiatric disorders. Together these findings provide the first evidence indicating the influence of common genetic variation in the genetic architecture of inhibitory control quantified using objective behavioural traits derived from the stop-signal task.

Prediction of Attention-Deficit/Hyperactivity Disorder Diagnosis Using Brief, Low-Cost Clinical Measures: A Competitive Model Evaluation.

Proper diagnosis of ADHD is costly, requiring in-depth evaluation via interview, multi-informant and observational assessment, and scrutiny of possible other conditions. The increasing availability of data may allow the development of machine-learning algorithms capable of accurate diagnostic predictions using low-cost measures to supplement human decision-making. We report on the performance of multiple classification methods used to predict a clinician-consensus ADHD diagnosis. Methods ranged from fairly simple (e.g., logistic regression) to more complex (e.g., random forest), while emphasizing a multi-stage Bayesian approach. Classifiers were evaluated in two large (N>1000), independent cohorts. The multi-stage Bayesian classifier provides an intuitive approach consistent with clinical workflows, and was able to predict expert consensus ADHD diagnosis with high accuracy (>86%)-though not significantly better than other methods. Results suggest that parent and teacher surveys are sufficient for high-confidence classifications in the vast majority of cases, while an important minority require additional evaluation for accurate diagnosis.

Polyneuro risk scores capture widely distributed connectivity patterns of cognition.

Resting-state functional connectivity (RSFC) is a powerful tool for characterizing brain changes, but it has yet to reliably predict higher-order cognition. This may be attributed to small effect sizes of such brain-behavior relationships, which can lead to underpowered, variable results when utilizing typical sample sizes (N∼25). Inspired by techniques in genomics, we implement the polyneuro risk score (PNRS) framework - the application of multivariate techniques to RSFC data and validation in an independent sample. Utilizing the Adolescent Brain Cognitive Development® cohort split into two datasets, we explore the framework's ability to reliably capture brain-behavior relationships across 3 cognitive scores - general ability, executive function, learning & memory. The weight and significance of each connection is assessed in the first dataset, and a PNRS is calculated for each participant in the second. Results support the PNRS framework as a suitable methodology to inspect the distribution of connections contributing towards behavior, with explained variance ranging from 1.0 % to 21.4 %. For the outcomes assessed, the framework reveals globally distributed, rather than localized, patterns of predictive connections. Larger samples are likely necessary to systematically identify the specific connections contributing towards complex outcomes. The PNRS framework could be applied translationally to identify neurologically distinct subtypes of neurodevelopmental disorders.