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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.

Research on unconscious fear responses has recently been translated into experimental paradigms for reducing fear that bypass conscious awareness of the phobic stimulus and thus do not induce distress. These paradigms stand in contrast to exposure therapies for anxiety disorders, which require direct confrontation of feared situations and thus are distressing. We systematically review these unconscious exposure paradigms. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-based search yielded 39 controlled experiments based on 10 paradigms that tested whether exposure without awareness can reduce fear-related responses. In randomized controlled trials of phobic participants, unconscious exposure interventions: (a) reduced behavioral avoidance (weighted mean d = 0.77, N = 469) and self-reported fear (d = 0.78, N = 329) during in vivo exposure to feared situations; (b) reduced neurobiological indicators of fear and enhanced such indicators of fear regulation (d = 0.81, N = 205); (c) had significantly stronger effects on reducing symptomatic behaviors and enhancing neurobiological indicators of fear regulation than did conscious exposure (d = 0.78, N = 342); and (d) produced these effects without inducing subjective fear. In fear-conditioned participants, unconscious exposureinduced extinction learning (d = 0.80, N = 420), even during sleep, and yielded somewhat stronger extinction learning than conscious exposure did (d = 0.44, N = 438). We organize these findings within a neuroscientific framework and evaluate alternative mechanisms for unconscious exposure. The use of incommensurate outcome measures across exposure paradigms and nonreporting of relevant statistics limited meta-analyses. Despite steps taken to address publication bias, 25.6% of included studies came from a single laboratory. We propose potential clinical applications of these findings. Future research should clarify underlying mechanisms, use common outcome measures, and explore effects on other anxiety disorders. Public Significance Statement: Phobias are among the most common psychological disorders. Most sufferers avoid or drop out of the frontline treatment, which requires them to directly confront their fears. We report findings supporting the efficacy of a new generation of interventions that address these problems by exposing phobic persons to their feared stimulus without conscious awareness, and thus without causing them to experience distress. If clinical trials support the efficacy of unconscious exposure interventions, their public health impact will be considerable, as they could be widely disseminated online. [ABSTRACT FROM AUTHOR]

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.

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]

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.