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BackgroundDespite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all

BackgroundTo assess whether patients with Persistent Depressive Disorder (PDD) have abnormal levels of N-acetyl-aspartate (NAA) and whether those levels normalize following treatment with the antidepressant medication duloxetine. Furthermore, we conducted post hoc analyses of other important brain metabolites to understand better the cellular and physiological determinants for changes in NAA levels.MethodsWe acquired proton (1H) magnetic resonance spectroscopic imaging (MRSI) data on a 3 Tesla (3T), GE Magnetic Resonance Imaging (MRI) scanner in 41 patients (39.9±10.4 years, 22 males) with PDD at two time points: before the start and at the end of a 10-week, placebo-controlled, double-blind, randomized controlled trial (RCT) of the antidepressant medication duloxetine. Patients were randomized such that 21 patients received the active medication and 20 patients received placebo during the 10 week period of the trial. In addition, we acquire 1H MRSI data once in 29 healthy controls (37.7±11.2 years, 17 males).FindingsPatients had significantly higher baseline concentrations of NAA across white matter (WM) pathways and subcortical gray matter, and in direct proportion to the severity of depressive symptoms. NAA concentrations declined in duloxetine-treated patients over the duration of the trial in the direction toward healthy values, whereas concentrations increased in placebo-treated patients, deviating even further away from healthy values. Changes in NAA concentration did not mediate medication effects on reducing symptom severity, however; instead, changes in symptom severity partially mediated the effects of medication on NAA concentration, especially in the caudate and putamen.InterpretationThese findings, taken together, suggest that PDD is not a direct consequence of elevated NAA concentrations, but that a more fundamental pathophysiological process likely causes PDD and determines the severity of its symptoms. The findings also suggest that although duloxetine normalized NAA concentrations in patients, it did so by modulating the severity of depressive symptoms. Medication presumably reduced depressive symptoms through other, as yet unidentified, brain processes.Trial registrationClinicalTrials.gov NCT00360724.

Background Methods Results Conclusions The real‐world effectiveness of exposure‐based therapies for youth depends on the willingness and ability of young people to tolerate confronting their fears, which can be experienced as highly aversive and create problems with treatment engagement and acceptance. Recently, neuroscientific research on the nonconscious basis of fear has been translated into novel exposure interventions that bypass conscious processing of feared stimuli and that thus do not cause phobic youth to experience distress. We present a review of these unconscious exposure interventions.A PRISMA‐based search yielded 20 controlled experiments based on three paradigms that tested if fear‐related responses could be reduced without conscious awareness in highly phobic, transition‐age youth: 14 randomized controlled trials (RCTs), 5 fMRI studies (1 was also an RCT), 4 psychophysiological studies (3 were also RCTs), and 1 ERP study. We conducted meta‐analyses of outcomes where feasible.Unconscious exposure interventions significantly (1) reduced avoidance behavior (range of Cohen's d = 0.51–0.95) and self‐reported fear (d = 0.45–1.25) during in vivo exposure to the feared situation; (2) reduced neurobiological indicators of fear (d = 0.54–0.62) and concomitant physiological arousal (d = 0.55–0.64); (3) activated neural systems supporting fear regulation more strongly than visible exposure to the same stimuli (d = 1.2–1.5); (4) activated regions supporting fear regulation that mediated the reduction of avoidance behavior (d = 0.70); (5) evoked ERPs suggesting encoding of extinction memories (d = 2.13); and (6) had these effects without inducing autonomic arousal or subjective fear.Unconscious exposure interventions significantly reduce a variety of symptomatic behaviors with mostly moderate effect sizes in transition‐age youth with specific phobias. fMRI and physiological findings establish a neurophysiological basis for this efficacy, and suggest it occurs through extinction learning. Unconscious exposure was well tolerated, entirely unassociated with drop out, and is highly scalable for clinical practice. However, a number of limitations must be addressed to assess potential clinical impacts, including combining unconscious exposure with exposure therapy to boost treatment acceptance and efficacy. [ABSTRACT FROM AUTHOR]

Prior studies of mother-infant interaction have generally used a variable-centered approach to associate face-to-face communication with psychosocial outcomes. Herein, we use a person-centered approach to identify clusters of infants who exhibit similar behavioral profiles during face-to-face communication with their mothers. Four infant communication channels were examined--gaze, facial affect, vocal affect, and head orientation--coded from videotape at a 1-s temporal resolution. We used k-means clustering to classify community infants (N = 132) into 10 groups, based on variation in the intercept and the autocorrelation function at the first time lag, representing respectively the overall level of behavior and the predictability of the infant's moment-by-moment behavioral stream, in each of the 4 communication channels. In this exploratory study, 10 clusters were identified, some with unusual levels or predictability of behavior in varying channels, and clusters associated differentially with risk outcomes (infant 4-month temperament and 12-month attachment). Distinct forms of affective dysregulation were identified: sustained negative vocal affect associated with degree of disorganization; random vocal affect associated with attachment resistance; random facial affect and vocal affect, irrespective of positive/negative valence, associated with infant difficult temperament. Clustering multiple channels of infant communication generated unique behavioral profiles and predicted 4- and 12-month outcomes, suggesting that these clusters may indeed represent natural types of infant communicative behavior, not easily observed with the naked eye, that may be useful behavioral markers of clinical risk.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants. [ABSTRACT FROM AUTHOR]

Identifying reliable indicators of cognitive functioning prior to age five has been challenging. Prior studies have shown that maternal cognition, as indexed by intellectual quotient (IQ) and years of education, predict child intelligence at school age. We examined whether maternal full scale IQ, education, and inhibitory control (index of executive function) are associated with newborn brain measures and toddler language outcomes to assess potential indicators of early cognition. We hypothesized that maternal indices of cognition would be associated with brain areas implicated in intelligence in school-age children and adults in the newborn period. Thirty-seven pregnant women and their newborns underwent an MRI scan. T2-weighted images and surface-based morphometric analysis were used to compute local brain volumes in newborn infants. Maternal cognition indices were associated with local brain volumes for infants in the anterior and posterior cingulate, occipital lobe, and pre/postcentral gyrus -- regions associated with IQ, executive function, or sensori-motor functions in children and adults. Maternal education and executive function, but not maternal intelligence, were associated with toddler language scores at 12 and 24 months. Newborn brain volumes did not predict language scores. Overall, the pre/postcentral gyrus and occipital lobe may be unique indicators of early intellectual development in the newborn period. Given that maternal executive function as measured by inhibitory control has robust associations with the newborn brain and is objective, brief, and easy to administer, it may be a useful predictor of early developmental and cognitive capacity for young children. [ABSTRACT FROM AUTHOR]

Objective: This study explores the impact of maternal pre‐pregnancy BMI on infant neurodevelopment at 24 months in low‐income Latino families. It also investigates whether infant diet mediates this relationship. Methods: Latino mother‐infant pairs (n = 163) were enrolled at 1 month post partum and were followed for 2 years, with assessments at 6‐month intervals. Maternal pre‐pregnancy anthropometrics were self‐reported at baseline, and child neurodevelopment was assessed at 24 months using the Bayley Scales of Infant Development. Diet quality of infants was measured using the Healthy Eating Index (HEI)‐2015 and HEI‐Toddlers‐2020 scores at multiple time points. Mediation and regression models that adjust for maternal factors were used to examine the associations. Results: Pre‐pregnancy BMI showed significant negative associations with child cognitive scores (β = −0.1, 95% CI: −0.2 to −0.06, p < 0.001) and language scores (β = −0.1, 95% CI: −0.2 to −0.03, p = 0.01) at 24 months. Infant HEI‐2015 scores at 24 months partly mediated these associations, explaining 23% and 30% of the total effect on cognitive and language subscales, respectively. No specific dietary components in infants mediated the relationship, except for the total HEI‐2015 score. Conclusions: Managing maternal obesity pre‐pregnancy is crucial for improving infant neurodevelopmental outcomes, especially in low‐income Latino families. Promoting healthy weight and enhancing infant diet quality can enhance neurodevelopment in these populations. [ABSTRACT FROM AUTHOR]

Context: Correct diagnosis is essential for the appropriate clinical management of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Objective: This systematic review provides an overview of the available diagnostic tools. Data sources: We identified diagnostic accuracy studies in 12 databases published from 1980 through June 2023. Study selection: Any ADHD tool evaluation for the diagnosis of ADHD, requiring a reference standard of a clinical diagnosis by a mental health specialist. Data extraction: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. Results: In total, 231 studies met eligibility criteria. Studies evaluated parental ratings, teacher ratings, youth self-reports, clinician tools, neuropsychological tests, biospecimen, EEG, and neuroimaging. Multiple tools showed promising diagnostic performance, but estimates varied considerably across studies, with a generally low strength of evidence. Performance depended on whether ADHD youth were being differentiated from neurotypically developing children or from clinically referred children. Limitations: Studies used different components of available tools and did not report sufficient data for meta-analytic models. Conclusions: A valid and reliable diagnosis of ADHD requires the judgment of a clinician who is experienced in the evaluation of youth with and without ADHD, along with the aid of standardized rating scales and input from multiple informants across multiple settings, including parents, teachers, and youth themselves. [ABSTRACT FROM AUTHOR]

Context: Effective treatment of attention-deficit/hyperactivity disorder (ADHD) is essential to improving youth outcomes. Objectives: This systematic review provides an overview of the available treatment options. Data sources: We identified controlled treatment evaluations in 12 databases published from 1980 to June 2023; treatments were not restricted by intervention content. Study selection: Studies in children and adolescents with clinically diagnosed ADHD, reporting patient health and psychosocial outcomes, were eligible. Publications were screened by trained reviewers, supported by machine learning. Data extraction: Data were abstracted and critically appraised by 1 reviewer and checked by a methodologist. Data were pooled using random-effects models. Strength of evidence and applicability assessments followed Evidence-based Practice Center standards. Results: In total, 312 studies reported in 540 publications were included. We grouped evidence for medication, psychosocial interventions, parent support, nutrition and supplements, neurofeedback, neurostimulation, physical exercise, complementary medicine, school interventions, and provider approaches. Several treatments improved ADHD symptoms. Medications had the strongest evidence base for improving outcomes, including disruptive behaviors and broadband measures, but were associated with adverse events. Limitations: We found limited evidence of studies comparing alternative treatments directly and indirect analyses identified few systematic differences across stimulants and nonstimulants. Identified combination of medication with youth-directed psychosocial interventions did not systematically produce better results than monotherapy, though few combinations have been evaluated. Conclusions: A growing number of treatments are available that improve ADHD symptoms and other outcomes, in particular for school-aged youth. Medication therapies remain important treatment options but are associated with adverse events. [ABSTRACT FROM AUTHOR]

Typically twin studies are used to investigate the aggregate effects of genetic and environmental influences on brain phenotypic measures. Although some phenotypic measures are highly heritable in twin studies, SNPs (single nucleotide polymorphisms) identified by genome-wide association studies (GWAS) account for only a small fraction of the heritability of these measures. We mapped the genetic variation (the proportion of phenotypic variance explained by variation among SNPs) of volumes of pre-defined regions across the whole brain, as explained by 512,905 SNPs genotyped on 747 adult participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found that 85% of the variance of intracranial volume (ICV) (p = 0.04) was explained by considering all SNPs simultaneously, and after adjusting for ICV, total grey matter (GM) and white matter (WM) volumes had genetic variation estimates near zero (p = 0.5). We found varying estimates of genetic variation across 93 non-overlapping regions, with asymmetry in estimates between the left and right cerebral hemispheres. Several regions reported in previous studies to be related to Alzheimer's disease progression were estimated to have a large proportion of volumetric variance explained by the SNPs.

Here we report on detailed three-dimensional quantitative maps of brain surface and gray matter density asymmetry patterns during normal adolescent development and show how these anatomical features of the brain are disrupted as a result of prenatal exposure to large quantities of alcohol. We studied two independent samples of normally developing children, adolescents, and young adults, totaling 83 subjects from two different research groups, and compared them to 21 individuals with heavy prenatal alcohol exposure. Surface-based image analysis techniques allowed us to match cortical anatomy across subjects and between hemispheres based on manually delineated sulcal landmarks. Quantitative maps of brain surface asymmetry reveal prominent peri-Sylvian hemispheric differences in which the superior temporal and inferior parietal cortices are shifted backward in the left relative to the right hemisphere in both normal and alcohol-exposed subjects. Cortical surface gray matter asymmetry, mapped here in adolescent populations, is most prominent in the posterior inferior temporal lobes (right greater than left), and this effect does not differ between groups of normally developing children, adolescents, or young adults. Alcohol-exposed individuals show a significant reduction in this asymmetry, whether studied with surface-based or more traditional volumetric region of interest analyses. This region of cortex, near the junction of Brodmann's areas 21, 22, and 37, primarily subserves language functions that are known to be impaired on average in the alcohol-exposed subjects. Our findings elucidate regional patterns of brain surface and gray matter asymmetry during normal development and may contribute to a more comprehensive understanding of the neural substrates of cognitive dysfunction after heavy prenatal alcohol exposure.

Introduction: Repetitive, subconcussive events may adversely affect the brain and cognition during sensitive periods of development. Prevention of neurocognitive consequences of concussion in high school football is therefore an important public health priority. We aimed to identify the player positions and demographic, behavioral, cognitive, and impact characteristics that predict the frequency and acceleration of head impacts in high school football players. Methods: In this prospective study, three cohorts of adolescent male athletes (N = 53, 28.3% Hispanic) were recruited over three successive seasons in a high school American football program. Demographic and cognitive functioning were assessed at baseline prior to participating in football. Helmet sensors recorded impact frequency and acceleration. Each head impact was captured on film from five different angles. Research staff verified and characterized on-field impacts. Player-level Poisson regressions and year-level and impact-level linear mixed-effect models were used to determine demographic, behavioral, cognitive, and impact characteristics as predictors of impact frequency and acceleration. Results: 4,678 valid impacts were recorded. Impact frequency positively associated with baseline symptoms of hyperactivity-impulsivity [β(SE) = 1.05 impacts per year per unit of symptom severity (1.00), p = 0.01] and inattentiveness [β(SE) = 1.003 impacts per year per T-score unit (1.001), p = 0.01]. Compared to quarterbacks, the highest acceleration impacts were sustained by kickers/punters [β(SE) = 21.5 g's higher (7.1), p = 0.002], kick/punt returners [β(SE) = 9.3 g's higher (4.4), p = 0.03], and defensive backs [β(SE) = 4.9 g's higher (2.5), p = 0.05]. Impacts were more frequent in the second [β(SE) = 33.4 impacts (14.2), p = 0.02)] and third [β(SE) = 50.9 impacts (20.1), p = 0.01] year of play. Acceleration was highest in top-of-the-head impacts [β(SE) = 4.4 g's higher (0.8), p<0.001]. Conclusion: Including screening questions for Attention-Deficit/Hyperactivity Disorder in pre-participation evaluations can help identify a subset of prospective football players who may be at risk for increased head impacts. Position-specific strategies to modify kickoffs and correct tackling and blocking may also reduce impact burden. [ABSTRACT FROM AUTHOR]