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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]

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]

Introduction: The false discovery rate (FDR) procedure does not incorporate the geometry of the random field and requires high statistical power at each voxel, a requirement not satisfied by the limited number of participants in imaging studies. Topological FDR, threshold free cluster enhancement (TFCE), and probabilistic TFCE improve statistical power by incorporating local geometry. However, topological FDR requires specifying a cluster defining threshold and TFCE requires specifying transformation weights. Methods: Geometry‐derived statistical significance (GDSS) procedure overcomes these limitations by combining voxelwise p‐values for the test statistic with the probabilities computed from the local geometry for the random field, thereby providing substantially greater statistical power than the procedures currently used to control for multiple comparisons. We use synthetic data and real‐world data to compare its performance against the performance of these other, previously developed procedures. Results: GDSS provided substantially greater statistical power relative to the comparator procedures, which was less variable to the number of participants. GDSS was more conservative than TFCE: that is, it rejected null hypotheses at voxels with much higher effect sizes than TFCE. Our experiments also showed that the Cohen's D effect size decreases as the number of participants increases. Therefore, sample size calculations from small studies may underestimate the participants required in larger studies. Our findings also suggest effect size maps should be presented along with p‐value maps for correct interpretation of findings. Conclusions: GDSS compared with the other procedures provides considerably greater statistical power for detecting true positives while limiting false positives, especially in small sized (<40 participants) imaging cohorts. [ABSTRACT FROM AUTHOR]

Background: Prenatal exposure to air pollution disrupts cognitive, emotional, and behavioral development. The brain disturbances associated with prenatal air pollution are largely unknown. Methods: In this prospective cohort study, we estimated prenatal exposures to fine particulate matter (PM2.5) and polycyclic aromatic hydrocarbons (PAH), and then assessed their associations with measures of brain anatomy, tissue microstructure, neurometabolites, and blood flow in 332 youth, 6–14 years old. We then assessed how those brain disturbances were associated with measures of intelligence, ADHD and anxiety symptoms, and socialization. Results: Both exposures were associated with thinning of dorsal parietal cortices and thickening of postero–inferior and mesial wall cortices. They were associated with smaller white matter volumes, reduced organization in white matter of the internal capsule and frontal lobe, higher metabolite concentrations in frontal cortex, reduced cortical blood flow, and greater microstructural organization in subcortical gray matter nuclei. Associations were stronger for PM2.5 in boys and PAH in girls. Youth with low exposure accounted for most significant associations of ADHD, anxiety, socialization, and intelligence measures with cortical thickness and white matter volumes, whereas it appears that high exposures generally disrupted these neurotypical brain‐behavior associations, likely because strong exposure‐related effects increased the variances of these brain measures. Conclusions: The commonality of effects across exposures suggests PM2.5 and PAH disrupt brain development through one or more common molecular pathways, such as inflammation or oxidative stress. Progressively higher exposures were associated with greater disruptions in local volumes, tissue organization, metabolite concentrations, and blood flow throughout cortical and subcortical brain regions and the white matter pathways interconnecting them. Together these affected regions comprise cortico‐striato‐thalamo‐cortical circuits, which support the regulation of thought, emotion, and behavior. [ABSTRACT FROM AUTHOR]

Background: Psychostimulants are frequently used to treat attention‐deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics. Methods: We conducted a 12‐week, randomized, placebo‐controlled trial (RCT) of a long‐acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6–25 years old. Of the 58 participants who participated in the RCT, 49 completed pre‐ and post‐RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time‐averaged) and dynamic (time‐varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD‐200 Consortium (n = 213). Results: In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated‐ADHD participants relative to HCs. Independent samples yielded similar findings – ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples. Conclusions: Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations. [ABSTRACT FROM AUTHOR]

Background: Identifying the brain bases for phenotypic heterogeneity in Autism Spectrum Disorder (ASD) will advance understanding of its pathogenesis and improve its clinical management. Methods: We compared Diffusion Tensor Imaging (DTI) indices and connectome measures between 77 ASD and 88 Typically Developing (TD) control participants. We also assessed voxel‐wise associations of DTI indices with measures of regional cerebral blood flow (rCBF) and N‐acetylaspartate (NAA) to understand how tissue microstructure associates with cellular metabolism and neuronal density, respectively. Results: Autism Spectrum Disorder participants had significantly lower fractional anisotropy (FA) and higher diffusivity values in deep white matter tracts, likely representing ether reduced myelination by oligodendrocytes or a reduced density of myelinated axons. Greater abnormalities in these measures and regions were associated with higher ASD symptom scores. Participant age, sex and IQ significantly moderated these group differences. Path analyses showed that reduced NAA levels accounted significantly for higher diffusivity and higher rCBF values in ASD compared with TD participants. Conclusions: Reduced neuronal density (reduced NAA) likely underlies abnormalities in DTI indices of white matter microstructure in ASD, which in turn are major determinants of elevated blood flow. Together, these findings suggest the presence of reduced axonal density and axonal pathology in ASD white matter. Greater pathology in turn accounts for more severe symptoms, lower intellectual ability, and reduced global efficiency for measures of white matter connectivity in ASD. [ABSTRACT FROM AUTHOR]

Background: Risk for childhood psychopathology is complex and multifactorial, implicating direct and interacting effects of familial and environmental factors. The role of environmental neurotoxicants in psychiatric risk is of growing concern, including polycyclic aromatic hydrocarbons (PAH), common in air pollution. Prenatal PAH exposure is linked to adverse physical, behavioral, and cognitive outcomes as well as increasing psychiatric risk. It is unclear whether environmental exposures, like PAH, magnify the effects of exposure to early life stress (ELS), a critical risk factor for psychopathology. The current work aimed to test potential interactions between prenatal PAH exposure and psychosocial/socioeconomic stress on psychiatric symptoms in school‐age children. Methods: Data were from the Columbia Center for Children's Environmental Health Mothers and Newborns longitudinal birth cohort study. Prenatal PAH exposure was ascertained though air monitoring during pregnancy and maternal PAH‐DNA adducts at delivery. Mothers reported on ELS (child age 5) and on child psychiatric symptoms across childhood (child age 5, 7, 9, and 11) using the Child Behavior Checklist (CBCL). Results: Significant prenatal airborne PAH × ELS interactions (FDR‐corrected) predicted CBCL Attention (β = 0.22, t(307) = 3.47, p <.001, pfdr =.003) and Thought Problems T‐scores (β = 0.21, t(307) = 3.29, p =.001, pfdr =.004) at age 11 (n = 319). Relative to those with lower exposure, children with higher prenatal PAH exposure exhibited stronger positive associations between ELS and CBCL Attention and Thought Problem T‐scores. This interaction was also significant examining convergent ADHD measures (Conners, DuPaul) and examining maternal PAH‐DNA adducts (β = 0.29, t(261) = 2.48, p =.01; n = 273). A three‐way interaction with assessment wave indicated that the PAH × ELS interaction on Attention Problems was stronger later in development (β = 0.03, t(1,601) = 2.19, p =.03; n = 477). Conclusions: Prenatal exposure to PAH, a common neurotoxicant in air pollution, may magnify or sustain the effects of early life psychosocial/socioeconomic stress on psychiatric outcomes later in child development. This work highlights the critical role of air pollution exposure on child mental health. [ABSTRACT FROM AUTHOR]

Background: The prenatal period is a period of vulnerability during which neurotoxic exposures exert persistent changes in brain development and behavior. Polybrominated diphenyl ethers (PBDEs), used as flame retardants in commercial products, are known to be developmental neurotoxicants. PBDEs were phased out of use in the United States a decade ago, but exposure remains widespread due to their release from existing products and biopersistence. Despite consistent animal and epidemiological evidence of developmental neurotoxicity, the neural substrates linking prenatal PBDE serum concentrations to impaired neurodevelopment are poorly understood. Methods: In the present study, we used resting state functional magnetic resonance imaging (fMRI) to examine associations between prenatal PBDE concentrations measured in maternal serum and intrinsic functional network organization (i.e., global and local efficiency; estimated using a graph‐theoretical approach) in 5‐year‐old children (n = 34). We explored whether PBDE serum concentrations were associated with executive functioning (EF) assessed using a parent‐report questionnaire (BRIEF‐P) (n = 106) and whether changes in intrinsic functional network organization linked the association between prenatal PBDE serum concentrations and EF problems. Results: Children with higher prenatal PBDE serum concentrations showed: (a) increased global efficiency of brain areas involved in visual attention (e.g., inferior occipital gyrus) (β's = .01, FDR‐corrected p's ≤ .05); (b) more reported EF problems (β's = .001, FDR‐corrected p's ≤ .05). Higher global efficiency of brain areas involved in visual attention was associated with more EF problems (β's = .01, FDR‐corrected p's < .05). Conclusions: Intrinsic functional network organization of visual attention brain areas linked prenatal PBDE concentrations to EF problems in childhood. Visual attention may contribute to the development of higher‐order cognitive functions, such as EF, which could be explored in future studies. [ABSTRACT FROM AUTHOR]

Precision medicine and biomarker development have become the prevailing paradigm for mental health research. Despite its conceptual elegance and dominance as a research framework, precision medicine has a very limited track record of demonstrable success thus far for mental illnesses, due in varying degrees to the complexity of both the brain and the pathophysiology of mental illnesses, which limits our ability to develop, replicate, and validate biomarkers for use in enhancing clinical care for mental illnesses, especially in high‐risk and complex clinical populations. Research and funding priorities should integrate biomarker development and precision medicine interventions that target the robust behavioral, environmental, and social determinants that we know are important for population‐based mental health. [ABSTRACT FROM AUTHOR]

Research on automatic processes in fear has emphasized the provocation of fear responses rather than their attenuation. We have previously shown that the repeated presentation of feared images without conscious awareness via backward masking reduces avoidance of a live tarantula in spider-phobic participants. Herein we investigated the neural basis for these adaptive effects of masked exposure. 21 spider-phobic and 21 control participants, identified by a psychiatric interview, fear questionnaire, and approaching a live tarantula, viewed stimuli in each of three conditions: (1) very brief exposure (VBE) to masked images of spiders, severely limited awareness; (2) clearly visible exposure (CVE) to spiders, full awareness; and (3) masked images of flowers (control), severely limited awareness. Only VBE to masked spiders generated neural activity more strongly in phobic than in control participants, within subcortical fear, attention, higher-order language, and vision systems. Moreover, VBE activated regions that support fear processing in phobic participants without causing them to experience fear consciously. Counter-intuitively, CVE to the same spiders generated stronger neural activity in control rather than phobic participants within these and other systems. CVE deactivated regions supporting fear regulation and caused phobic participants to experience fear. CVE-induced activations also correlated with measures of explicit fear ratings, whereas VBE-induced activations correlated with measures of implicit fear (color-naming interference of spider words). These multiple dissociations between the effects of VBE and CVE to spiders suggest that limiting awareness of exposure to phobic stimuli through visual masking paradoxically facilitates their processing, while simultaneously minimizing the experience of fear. Hum Brain Mapp 38:2466-2481, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective To study resting cerebral blood flow in children and adults with developmental stuttering. Methods We acquired pulsed arterial spin labeling magnetic resonance imaging data in 26 participants with stuttering and 36 healthy, fluent controls. While covarying for age, sex, and IQ, we compared perfusion values voxel-wise across diagnostic groups and assessed correlations of perfusion with stuttering severity within the stuttering group and with measures of motor speed in both groups. Results We detected lower regional Cerebral Blood Flow (rCBF) at rest in the stuttering group compared with healthy controls in Broca's area bilaterally and the superior frontal gyrus. rCBF values in Broca's area bilaterally correlated inversely with the severity of stuttering and extended posteriorly into other portions of the language loop. We also found increased rCBF in cerebellar nuclei and parietal cortex in the stuttering group compared with healthy controls. Findings were unchanged in child-only analyses and when excluding participants with comorbid illnesses or those taking medication. Conclusions rCBF is reduced in Broca's region in persons who stutter. More severe stuttering is associated with even greater reductions in rCBF to Broca's region, additive to the underlying putative trait reduction in rCBF relative to control values. Moreover, a greater abnormality in rCBF in the posterior language loop is associated with more severe symptoms, suggesting that a common pathophysiology throughout the language loop likely contributes to stuttering severity. Hum Brain Mapp 38:1865-1874, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background 22q11.2 deletion syndrome (22q11 DS) is a genetic disorder that greatly increases risk of developing schizophrenia. We previously characterized cerebral surface morphology trajectories from late childhood to mid adolescence in a cohort of youth with 22q11 DS. Herein, we extend the study period into early adulthood, and describe further the trajectories associated with severe psychiatric symptoms in this cohort. Methods Participants included 76 youth with 22q11 DS and 30 unaffected siblings, assessed at three timepoints, during which high resolution, anatomic magnetic resonance images were acquired. High-dimensional, nonlinear warping algorithms were applied to images in order to derive characteristics of cerebral surface morphology for each participant at each timepoint. Repeated-measures, linear regressions using a mixed model were conducted, while covarying for age and sex. Results Alterations in cerebral surface morphology during late adolescence/early adulthood in individuals with 22q11 DS were observed in the lateral frontal, orbitofrontal, temporal, parietal, occipital, and cerebellar regions. An Age x Diagnosis interaction revealed that relative to unaffected siblings, individuals with 22q11 DS showed age-related surface protrusions in the prefrontal cortex (which remained stable or increased during early adulthood), and surface indentations in posterior regions (which seemed to level off during late adolescence). Symptoms of psychosis were associated with a trajectory of surface indentations in the orbitofrontal and parietal regions. Conclusions These results advance our understanding of cerebral maturation in individuals with 22q11 DS, and provide clinically relevant information about the psychiatric phenotype associated with the longitudinal trajectory of cortical surface morphology in youth with this genetic syndrome. [ABSTRACT FROM AUTHOR]

Meta‐analyses have consistently shown a wide variety of psychotherapeutic and pharmacological interventions to yield similar effect sizes, suggesting the possibility that those interventions share common factors that account for the vast majority of variance in clinical outcomes. Although mediation analyses are needed to know definitively whether factors common or specific to the interventions are responsible for clinical improvement, a large number of association studies suggest that a common set of characteristics representing the ways in which clinicians relate to their patients, and not the technical expertise of clinicians or the therapeutic modality in which they work, account for the majority of therapeutic change across all medical disciplines and cultures. These characteristics include clinician empathy, warmth, and genuineness, a capacity to maintain a positive regard for the patient in moments of vulnerability, and an ability to establish a strong therapeutic alliance and clinical narrative through which the patient understands their suffering and is challenged to change through health‐promoting activities. These common factors are amenable to study to improve our knowledge of precisely how they produce clinical change. They can be taught across all medical disciplines, in order to deepen the shared understanding, interpersonal attunement, and alliance between clinicians and their patients, which together constitute the true science and art of healing. [ABSTRACT FROM AUTHOR]

Adults with autism spectrum disorder (ASD) may describe other individuals differently compared with typical adults. In this study, we first asked participants to describe closely related individuals such as parents and close friends with 10 positive and 10 negative characteristics. We then used standard natural language processing methods to digitize and visualize these descriptions. The complex patterns of these descriptive sentences exhibited a difference in semantic space between individuals with ASD and control participants. Machine learning algorithms were able to automatically detect and discriminate between these two groups. Furthermore, we showed that these descriptive sentences from adults with ASD exhibited fewer connections as defined by word-word co-occurrences in descriptions, and these connections in words formed a less 'small-world' like network. Autism Res 2016, 9: 846-853. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background We evaluated the influence of prenatal exposure to widespread urban air pollutants on the development of self-regulation and social competence in a longitudinal prospective cohort of children born to nonsmoking minority women in New York City. Methods Air pollutant exposure was estimated categorically by level of polycyclic aromatic hydrocarbon ( PAH)- DNA adducts in maternal blood collected at delivery, providing a biomarker of maternal exposure to PAH over a 2- to 3-month period. Deficient emotional self-regulation (DESR) was defined as moderate elevations on three specific scales of the child behavior checklist (anxious/depressed, aggressive behavior, and attention problems). We used generalized estimating equations to assess the influence of prenatal exposure to PAH on DESR in children at 3-5, 7, 9, and 11 years of age, adjusted for gender and race/ethnicity. Next, we assessed the association of prenatal exposure to PAH with social competence, as measured by the social responsiveness scale ( SRS), the association of impaired self-regulation with social competence, and whether impairment in self-regulation mediated the association of prenatal exposure to PAH with social competence. Results We detected a significant interaction (at p = .05) of exposure with time, in which the developmental trajectory of self-regulatory capacity was delayed in the exposed children. Multiple linear regression revealed a positive association between presence of PAH- DNA adducts and problems with social competence ( p < .04), level of dysregulation and problems with social competence ( p < .0001), and evidence that self-regulation mediates the association of prenatal exposure to PAH with social competence ( p < .0007). Conclusions These data suggest that prenatal exposure to PAH produces long-lasting effects on self-regulatory capacities across early and middle childhood, and that these deficits point to emerging social problems with real-world consequences for high-risk adolescent behaviors in this minority urban cohort. [ABSTRACT FROM AUTHOR]

Individuals with autism spectrum disorders (ASD) often have difficulty recognizing and interpreting facial expressions of emotion, which may impair their ability to navigate and communicate successfully in their social, interpersonal environments. Characterizing specific differences between individuals with ASD and their typically developing (TD) counterparts in the neural activity subserving their experience of emotional faces may provide distinct targets for ASD interventions. Thus we used functional magnetic resonance imaging (fMRI) and a parametric experimental design to identify brain regions in which neural activity correlated with ratings of arousal and valence for a broad range of emotional faces. Participants (51 ASD, 84 TD) were group-matched by age, sex, IQ, race, and socioeconomic status. Using task-related change in blood-oxygen-level-dependent (BOLD) fMRI signal as a measure, and covarying for age, sex, FSIQ, and ADOS scores, we detected significant differences across diagnostic groups in the neural activity subserving the dimension of arousal but not valence. BOLD-signal in TD participants correlated inversely with ratings of arousal in regions associated primarily with attentional functions, whereas BOLD-signal in ASD participants correlated positively with arousal ratings in regions commonly associated with impulse control and default-mode activity. Only minor differences were detected between groups in the BOLD signal correlates of valence ratings. Our findings provide unique insight into the emotional experiences of individuals with ASD. Although behavioral responses to face-stimuli were comparable across diagnostic groups, the corresponding neural activity for our ASD and TD groups differed dramatically. The near absence of group differences for valence correlates and the presence of strong group differences for arousal correlates suggest that individuals with ASD are not atypical in all aspects of emotion-processing. Studying these similarities and differences may help us to understand the origins of divergent interpersonal emotional experience in persons with ASD. Hum Brain Mapp 37:443-461, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The paucity of major scientific breakthroughs leading to new or improved treatments, and the inability to identify valid and reproducible biomarkers that improve clinical management, has produced a crisis in confidence in the validity of our pathogenic theories and the reproducibility of our research findings. This crisis in turn has driven changes in standards for research methodologies and prompted calls for the creation of open‐access data repositories and the preregistration of research hypotheses. Although we should embrace the creation of repositories and registries, and the promise for greater statistical power, reproducibility, and generalizability of research findings they afford, we should also recognize that they alone are no substitute for sound design in minimizing study confounds, and they are no guarantor of faith in the validity of our pathogenic theories, findings, and biomarkers. One way, and maybe the only sure way, of knowing that we have a valid understanding of brain processes and disease mechanisms in human studies is by experimentally manipulating variables and predicting its effects on outcome measures and biomarkers. [ABSTRACT FROM AUTHOR]

In developing new ways of classifying mental disorders, RDoC is developing a new nosology, a new way of dividing nature at its seams. Given the NIMH influence on research agendas across the world, this scientific agenda will have important consequences for researchers and clinicians worldwide. Defining discrete neural systems and the behavioral and cognitive functions they subserve is scientifically important. Understanding how these systems relate to clinical problems, patient suffering, and improved treatments has immense potential practical value for clinical care worldwide. This Editorial places the RDoC framework in context and then sets out a series of conceptual, empirical, and developmental challenges for RDoC. Together these challenges suggest that RDoC is premature as a nosology and, as currently implemented, risks being reified and overly rigid in its application. [ABSTRACT FROM AUTHOR]

Fetal alcohol spectrum disorders (FASD) are characterized by a range of neurodevelopmental deficits that result from prenatal exposure to alcohol. These can include cognitive, behavioural, and neurological impairment, as well as structural and functional brain damage. Eyeblink conditioning (EBC) is among the most sensitive endpoints affected in FASD. The cerebellar peduncles, large bundles of myelinated nerve fibers that connect the cerebellum to the brainstem, constitute the principal white matter element of the EBC circuit. Diffusion tensor imaging (DTI) is used to assess white matter integrity in fibre pathways linking brain regions. DTI scans of 54 children with FASD and 23 healthy controls, mean age 10.1 ± 1.0 years, from the Cape Town Longitudinal Cohort were processed using voxelwise group comparisons. Prenatal alcohol exposure was related to lower fractional anisotropy (FA) bilaterally in the superior cerebellar peduncles and higher mean diffusivity (MD) in the left middle peduncle, effects that remained significant after controlling for potential confounding variables. Lower FA and higher MD in these regions were associated with poorer EBC performance. Moreover, effects of alcohol exposure on EBC decreased significantly after inclusion of these DTI measures in regression models, suggesting that these white matter deficits partially mediate the relation of prenatal alcohol exposure to EBC. The associations of greater alcohol consumption with these DTI measures are largely attributable to greater radial diffusivity, possibly indicating poorer myelination. Thus, these data suggest that fetal alcohol-related deficits in EBC are attributable, in part, to poorer myelination in key regions of the cerebellar peduncles. Hum Brain Mapp 36:2470-2482, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement-learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial-by-trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning. Hum Brain Mapp 36:793-803, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Proton magnetic resonance spectroscopic imaging (1H MRSI) has been used for the in vivo measurement of intramyocellular lipids (IMCLs) in human calf muscle for almost two decades, but the low spectral resolution between extramyocellular lipids (EMCLs) and IMCLs, partially caused by the magnetic field inhomogeneity, has hindered the accuracy of spectral fitting. The purpose of this paper was to enhance the spectral resolution of 1H MRSI data from human calf muscle using the SPREAD (spectral resolution amelioration by deconvolution) technique and to assess the influence of improved spectral resolution on the accuracy of spectral fitting and on in vivo measurement of IMCLs. We acquired MRI and 1H MRSI data from calf muscles of three healthy volunteers. We reconstructed spectral lineshapes of the 1H MRSI data based on field maps and used the lineshapes to deconvolve the measured MRS spectra, thereby eliminating the line broadening caused by field inhomogeneities and improving the spectral resolution of the 1H MRSI data. We employed Monte Carlo (MC) simulations with 200 noise realizations to measure the variations of spectral fitting parameters and used an F-test to evaluate the significance of the differences of the variations between the spectra before SPREAD and after SPREAD. We also used Cramer-Rao lower bounds (CRLBs) to assess the improvements of spectral fitting after SPREAD. The use of SPREAD enhanced the separation between EMCL and IMCL peaks in 1H MRSI spectra from human calf muscle. MC simulations and F-tests showed that the use of SPREAD significantly reduced the standard deviations of the estimated IMCL peak areas ( p < 10−8), and the CRLBs were strongly reduced (by ~37%). Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Knowledge of the role of brain maturation in the development of cognitive abilities derives primarily from studies of school-age children to adults. Little is known about the morphological features of the neonatal brain that support the subsequent development of abilities in early childhood, when maturation of the brain and these abilities are the most dynamic. The goal of our study was to determine whether brain morphology during the neonatal period supports early cognitive development through 2 years of age. We correlated morphological features of the cerebral surface assessed using deformation-based measures (surface distances) of high-resolution MRI scans for 33 healthy neonates, scanned between the first to sixth week of postmenstrual life, with subsequent measures of their motor, language, and cognitive abilities at ages 6, 12, 18, and 24 months. We found that morphological features of the cerebral surface of the frontal, mesial prefrontal, temporal, and occipital regions correlated with subsequent motor scores, posterior parietal regions correlated with subsequent language scores, and temporal and occipital regions correlated with subsequent cognitive scores. Measures of the anterior and middle portions of the cingulate gyrus correlated with scores across all three domains of ability. Most of the significant findings were inverse correlations located bilaterally in the brain. The inverse correlations may suggest either that a more protracted morphological maturation or smaller local volumes of neonatal brain tissue supports better performance on measures of subsequent motor, language, and cognitive abilities throughout the first 2 years of postnatal life. The correlations of morphological measures of the cingulate with measures of performance across all domains of ability suggest that the cingulate supports a broad range of skills in infancy and early childhood, similar to its functions in older children and adults. Hum Brain Mapp 35:4459-4474, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Extensive evidence indicates that mammalian memory is organized into multiple brains systems, including a 'cognitive' memory system that depends on the hippocampus and a stimulus-response 'habit' memory system that depends on the dorsolateral striatum. Dorsal striatal-dependent habit memory may in part influence the development and expression of some human psychopathologies, particularly those characterized by strong habit-like behavioral features. The present review considers this hypothesis as it pertains to psychopathologies that typically emerge during childhood and adolescence. These disorders include Tourette syndrome, attention-deficit/hyperactivity disorder, obsessive--compulsive disorder, eating disorders, and autism spectrum disorders. Human and nonhuman animal research shows that the typical development of memory systems comprises the early maturation of striatal-dependent habit memory and the relatively late maturation of hippocampal-dependent cognitive memory. We speculate that the differing rates of development of these memory systems may in part contribute to the early emergence of habit-like symptoms in childhood and adolescence. In addition, abnormalities in hippocampal and striatal brain regions have been observed consistently in youth with these disorders, suggesting that the aberrant development of memory systems may also contribute to the emergence of habit-like symptoms as core pathological features of these illnesses. Considering these disorders within the context of multiple memory systems may help elucidate the pathogenesis of habit-like symptoms in childhood and adolescence, and lead to novel treatments that lessen the habit-like behavioral features of these disorders. [ABSTRACT FROM AUTHOR]

Background: The widespread use of Magnetic Resonance Imaging (MRI) in the study of child- and adult-onset developmental psychopathologies has generated many investigations that have measured brain structure and function in vivo throughout development, often generating great excitement over our ability to visualize the living, developing brain using the attractive, even seductive images that these studies produce. Often lost in this excitement is the recognition that brain imaging generally, and MRI in particular, is simply a technology, one that does not fundamentally differ from any other technology, be it a blood test, a genotyping assay, a biochemical assay, or behavioral test. No technology alone can generate valid scientific findings. Rather, it is only technology coupled with a strong experimental design that can generate valid and reproducible findings that lead to new insights into the mechanisms of disease and therapeutic response. Methods: In this review we discuss selected studies to illustrate the most common and important limitations of MRI study designs as most commonly implemented thus far, as well as the misunderstanding that the interpretations of findings from those studies can create for our theories of developmental psychopathologies. Results: Common limitations of MRI study designs are in large part responsible thus far for the generally poor reproducibility of findings across studies, poor generalizability to the larger population, failure to identify developmental trajectories, inability to distinguish causes from effects of illness, and poor ability to infer causal mechanisms in most MRI studies of developmental psychopathologies. For each of these limitations in study design and the difficulties they entail for the interpretation of findings, we discuss various approaches that numerous laboratories are now taking to address those difficulties, which have in common the yoking of brain imaging technologies to studies with inherently stronger designs that permit more valid and more powerful causal inferences. Those study designs include epidemiological, longitudinal, high-risk, clinical trials, and multimodal imaging studies. Conclusions: We highlight several studies that have yoked brain imaging technologies to these stronger designs to illustrate how doing so can aid our understanding of disease mechanisms and in the foreseeable future can improve clinical diagnosis, prevention, and treatment planning for developmental psychopathologies. [ABSTRACT FROM AUTHOR]

Cortico-striato-thalamo-cortical (CSTC) loops project from the cortex to the striatum, then from the striatum to the thalamus via the globus pallidus, and finally from the thalamus back to the cortex again. These loops have been implicated in Obsessive-Compulsive Disorder (OCD) with particular focus on the limbic CSTC loop, which encompasses the orbitofrontal and anterior cingulate cortices, as well as the ventral striatum. Resting state functional-connectivity MRI (rs-fcMRI) studies, which examine temporal correlations in neural activity across brain regions at rest, have examined CSTC loop connectivity in patients with OCD and suggest hyperconnectivity within these loops in medicated adults with OCD. We used rs-fcMRI to examine functional connectivity within CSTC loops in unmedicated adults with OCD ( n = 23) versus healthy controls (HCs) ( n = 20). Contrary to prior rs-fcMRI studies in OCD patients on medications that report hyperconnectivity in the limbic CSTC loop, we found that compared with HCs, unmedicated OCD participants had reduced connectivity within the limbic CSTC loop. Exploratory analyses revealed that reduced connectivity within the limbic CSTC loop correlated with OCD symptom severity in the OCD group. Our finding of limbic loop hypoconnectivity in unmedicted OCD patients highlights the potential confounding effects of antidepressants on connectivity measures and the value of future examinations of the effects of pharmacological and/or behavioral treatments on limbic CSTC loop connectivity. Hum Brain Mapp 35:2852-2860, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Potential sources of multisensory influences on low-level sensory cortices include direct projections from sensory cortices of different modalities, as well as more indirect feedback inputs from higher order multisensory cortical regions. These multiple architectures may be functionally complementary, but the exact roles and inter-relationships of the circuits are unknown. Using a fully balanced context manipulation, we tested the hypotheses that: (1) feedforward and lateral pathways subserve speed functions, such as detecting peripheral stimuli. Multisensory integration effects in this context are predicted in peripheral fields of low-level sensory cortices. (2) Slower feedback pathways underpin accuracy functions, such as object discrimination. Integration effects in this context are predicted in higher-order association cortices and central/foveal fields of low-level sensory cortex. We used functional magnetic resonance imaging to compare the effects of central versus peripheral stimulation on audiovisual integration, while varying speed and accuracy requirements for behavioral responses. We found that interactions of task demands and stimulus eccentricity in low-level sensory cortices are more complex than would be predicted by a simple dichotomy such as our hypothesized peripheral/speed and foveal/accuracy functions. Additionally, our findings point to individual differences in integration that may be related to skills and strategy. Overall, our findings suggest that instead of using fixed, specialized pathways, the exact circuits and mechanisms that are used for low-level multisensory integration are much more flexible and contingent upon both individual and contextual factors than previously assumed. Hum Brain Mapp 35:2394-2411, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo 1H magnetic resonance spectroscopy ( MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region. Methods MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa. Results Increased maternal alcohol consumption around time of conception was associated with lower N-Acetylaspartate ( NAA) levels in the deep nuclei ( r = −0.33, p < 0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites ( r = −0.37, p < 0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception ( r = 0.35, p < 0.01) and during pregnancy ( r = 0.38, p < 0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders. Conclusions The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission. [ABSTRACT FROM AUTHOR]

Differing imaging modalities provide unique channels of information to probe differing aspects of the brain's structural or functional organization. In combination, differing modalities provide complementary and mutually informative data about tissue organization that is more than their sum. We acquired and spatially coregistered data in four MRI modalities-anatomical MRI, functional MRI, diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS)-from 20 healthy adults to understand how interindividual variability in measures from one modality account for variability in measures from other modalities at each voxel of the brain. We detected significant correlations of local volumes with the magnitude of functional activation, suggesting that underlying variation in local volumes contributes to individual variability in functional activation. We also detected significant inverse correlations of NAA (a putative measure of neuronal density and viability) with volumes of white matter in the frontal cortex, with DTI-based measures of tissue organization within the superior longitudinal fasciculus, and with the magnitude of functional activation and default-mode activity during simple visual and motor tasks, indicating that substantial variance in local volumes, white matter organization, and functional activation derives from an underlying variability in the number or density of neurons in those regions. Many of these imaging measures correlated with measures of intellectual ability within differing brain tissues and differing neural systems, demonstrating that the neural determinants of intellectual capacity involve numerous and disparate features of brain tissue organization, a conclusion that could be made with confidence only when imaging the same individuals with multiple MRI modalities. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim The role of feedback processing in decision-making has been assessed in psychiatric patients using the Iowa Gambling Task ( IGT). Although impaired performance on the IGT has been documented extensively in schizophrenia patients, the neuropsychological mechanisms underlying the performance deficits have not yet been elucidated. Therefore, the aim of this study was to investigate the neuropsychological origins of impaired decision-making in schizophrenia patients using various versions of the IGT. Methods Thirty chronic schizophrenia patients and 33 healthy subjects underwent computerized versions of the IGT, the Variant Gambling Task ( VGT), and the Shuffled Gambling Task ( SGT) to assess the contributions of motivational balance and reversal learning on IGT performance. In addition, performance on the Wisconsin Card- Sorting Test ( WCST) was assessed. Results The schizophrenia patients exhibited deficits on the IGT and SGT, particularly in later trials. No significant group difference was detected on the VGT due to the improved performance of schizophrenia patients in the earlier trials. Performance on the gambling tasks in the schizophrenia group did not correlate with performance on the WCST or with the severity of clinical symptoms. Conclusion Deficits in motivational balance, but not reversal learning, play a dominant role in the impaired decision-making of patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single-spikes and phasic bursts that encode information for certain types of reward-related learning and behavior. Non-linear dynamical analysis has previously demonstrated the presence of a non-linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non-linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non-linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter-spike interval data recorded in vivo from bursting and non-bursting DA neurons in the chloral hydrate-anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non-linear determinism in their firing patterns, whereas non-bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter-burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane-anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate-anesthetized rats. These results strongly indicate that bursting activity is the main source of low-dimensional, non-linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons. [ABSTRACT FROM AUTHOR]

Studies have found abnormalities of resting EEG measures of hemispheric activity in depressive disorders. Similar EEG findings and a prominent thinning of the cortical mantle have been reported for persons at risk for depression. The correspondence between EEG alpha power and magnetic resonance imaging (MRI) measures of cortical thickness was examined in a multigenerational study of individuals at risk for depression. Seventy-five participants underwent resting EEG and approximately 5 years later underwent MRI scanning. High-risk participants ( n = 37) were biological descendants of probands having major depression and low-risk participants ( n = 38) were descendants of individuals without a history of depression. EEG alpha power was interpolated across the surface of a template brain and coregistered with measures of cortical thickness. Voxel-wise correlations of cortical thickness and alpha power were computed while covarying for age and gender. The high-risk group, when compared to the low-risk group, showed greater alpha asymmetry in an eyes-closed condition, with relatively less activity over right parietal cortex. Alpha power correlated inversely with cortical thickness, particularly over the right posterior region, indicating that EEG evidence of reduced cortical activity was associated with increased cortical thinning. This is the first report of widespread correlation of EEG alpha activity with MRI measures of cortical thickness. Although both EEG and MRI measures are associated with risk for depression, we did not detect evidence that cortical thickness mediated the alpha asymmetry findings. Thus, alpha asymmetry, alone or in combination with MRI, may be a marker of vulnerability for a familial form of depression. Hum Brain Mapp, 2011. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Brain morphometry in recent decades has increased our understanding of the neural bases of psychiatric disorders by localizing anatomical disturbances to specific nuclei and subnuclei of the brain. At least some of these disturbances precede the overt expression of clinical symptoms and possibly are endophenotypes that could be used to diagnose an individual accurately as having a specific psychiatric disorder. More accurate diagnoses could significantly reduce the emotional and financial burden of disease by aiding clinicians in implementing appropriate treatments earlier and in tailoring treatment to the individual needs. Several methods, especially those based on machine learning, have been proposed that use anatomical brain measures and gold-standard diagnoses of participants to learn decision rules that classify a person automatically as having one disorder rather than another. We review the general principles and procedures for machine learning, particularly as applied to diagnostic classification, and then review the procedures that have thus far attempted to diagnose psychiatric illnesses automatically using anatomical measures of the brain. We discuss the strengths and limitations of extant procedures and note that the sensitivity and specificity of these procedures in their most successful implementations have approximated 90%. Although these methods have not yet been applied within clinical settings, they provide strong evidence that individual patients can be diagnosed accurately using the spatial pattern of disturbances across the brain. [ABSTRACT FROM AUTHOR]

Aim The aim of this article is to review neuroimaging studies of autism spectrum disorders (ASD) that examine declarative, socio-emotional, and procedural learning and memory systems. Method We conducted a search of PubMed from 1996 to 2010 using the terms 'autism,''learning,''memory,' and 'neuroimaging.' We limited our review to studies correlating learning and memory function with neuroimaging features of the brain. Results The early literature supports the following preliminary hypotheses: (1) abnormalities of hippocampal subregions may contribute to autistic deficits in episodic and relational memory; (2) disturbances to an amygdala-based network (which may include the fusiform gyrus, superior temporal cortex, and mirror neuron system) may contribute to autistic deficits in socio-emotional learning and memory; and (3) abnormalities of the striatum may contribute to developmental dyspraxia in individuals with ASD. Interpretation Characterizing the disturbances to learning and memory systems in ASD can inform our understanding of the neural bases of autistic behaviors and the phenotypic heterogeneity of ASD. [ABSTRACT FROM AUTHOR]

Background: Prenatal alcohol exposure is related to a wide range of neurocognitive effects. Eyeblink conditioning (EBC), which involves temporal pairing of a conditioned with an unconditioned stimulus, has been shown to be a potential biomarker of fetal alcohol exposure. A growing body of evidence suggests that white matter may be a specific target of alcohol teratogenesis, and the neural circuitry underlying EBC is known to involve the cerebellar peduncles. Diffusion tensor imaging (DTI) is a magnetic resonance imaging (MRI) technique that has proven useful for assessing central nervous system white matter integrity. This study used DTI to examine the degree to which the fetal alcohol-related deficit in EBC may be mediated by structural impairment in the cerebellar peduncles. Methods: Thirteen children with fetal alcohol spectrum disorder (FASD) and 12 matched controls were scanned using DTI and structural MRI sequences. The DTI data were processed using a voxelwise technique, and the structural data were used for volumetric analyses. Prenatal alcohol exposure group and EBC performance were examined in relation to brain volumes and outputs from the DTI analysis. Results: Fractional anisotropy (FA) and perpendicular diffusivity group differences between alcohol-exposed and nonexposed children were identified in the left middle cerebellar peduncle. Alcohol exposure correlated with lower FA and greater perpendicular diffusivity in this region, and these correlations remained significant even after controlling for total brain and cerebellar volumes. Conversely, trace conditioning performance was related to higher FA and lower perpendicular diffusivity in the left middle peduncle. The effect of prenatal alcohol exposure on trace conditioning was partially mediated by lower FA in this region. Conclusions: This study extends recent findings that have used DTI to reveal microstructural deficits in white matter in children with FASD. This is the first DTI study to demonstrate mediation of a fetal alcohol-related effect on neuropsychological function by deficits in white matter integrity. [ABSTRACT FROM AUTHOR]

Background: Half of pediatric-onset OCD cases remit by adulthood. Studies have demonstrated that initial response to pharmacotherapy, age of onset, prominent hoarding symptoms, and the presence of comorbid tic disorders are associated with long-term outcome. Our goal was to examine the association between childhood performance on neuropsychological testing and persistence of OCD into adulthood. Methods: Twenty-four children with OCD were followed for an average of 7.5 years into early adulthood. Neuropsychological performance in childhood (<16 years) was measured. The battery included the Wechsler Intelligence Scale for Children (WISC-III), the Purdue pegboard test, the Rey-Osterreith Complex Figure Task (RCFT) and the Beery-Buktenica test of Visual Motor Integration (VMI). We hypothesized that deficits in fine-motor skills, visuospatial skills, and nonverbal memory as well as overall intelligence would be associated with adulthood outcome. We used a Cox proportional hazard model of survival analysis in which time to remission of OCD symptoms was the main outcome variable. Results: Poor childhood performance on the Purdue pegboard task and the block design subscale of WISC-III was associated with persistence of OCD symptoms into adulthood. IQ, VMI, and nonverbal memory performance did not predict significantly the persistence of OCD. Conclusions: These results suggest that visuospatial and fine-motor skill deficits are predictive of poor long-term outcome in pediatric-onset OCD. Future longitudinal studies are needed to chart the course of these deficits relative to the course of symptoms in OCD and to determine whether the association of these neuropsychiatric deficits with long-term outcome is specific to pediatric-onset OCD or generalizes to other psychiatric disorders. [ABSTRACT FROM AUTHOR]

Objective Neuroanatomical and functional imaging studies have identified the cerebellum as an integral component of motor and language control. Few studies, however, have investigated the role of the cerebellum in Tourette syndrome (TS), a condition defined by the presence of semi-involuntary movements and sounds. Methods Magnetic resonance imaging was conducted in 163 persons with TS and 147 control participants. Multivariate linear regression models were used to explore effects on cerebellar surface morphology and underlying volumes for the main diagnosis effects of TS as well as comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder. Additionally, the correlations of symptom severity with cerebellar morphology were also assessed. Results The TS group demonstrated reduced volumes of the cerebellar hemispheres bilaterally that derived primarily from reduced gray matter in crus I and lobules VI, VIIB, and VIIIA. These decreased regional volumes accompanied increasing tic symptom severity and motoric disinhibition as demonstrated by a finger tapping test. Males had reduced volumes of these same regions compared with females, irrespective of diagnosis. Comorbid OCD was associated with relative enlargement of these regions in proportion to the increasing severity of OCD symptoms. Interpretation The cerebellum is involved in the pathogenesis of TS and tic-related OCD. Baseline gender differences in cerebellar morphology may in part account for the more prevalent expression of TS in males. ANN NEUROL 2010;67:479-487 [ABSTRACT FROM AUTHOR]

Purpose To develop, implement, and evaluate a novel postprocessing method for enhancing the spectral resolution of in vivo MR spectroscopic imaging (MRSI) data. Materials and Methods Magnetic field inhomogeneity across the imaging volume was determined by acquiring MRI datasets with two differing echo times. The lineshapes of the MRSI spectra were derived from these field maps by simulating an MRSI scan of a virtual sample whose resonance frequencies varied according to the observed variations in the magnetic field. By deconvolving the lineshapes from the measured MRSI spectra, the linebroadening effects of the field inhomogeneities were reduced significantly. Results Both phantom and in vivo proton MRSI spectra exhibited significantly enhanced spectral resolutions and improved spectral lineshapes following application of our method. Quantitative studies on a phantom show that, on average, the full width at half maximum of water peaks was reduced 42%, the full width at tenth maximum was reduced 38%, and the asymmetries of the peaks were reduced 86%. Conclusion Our method reduces the linebroadening and lineshape distortions caused by magnetic field inhomogeneities. It substantially improves the spectral resolution and lineshape of MRSI data. J. Magn. Reson. Imaging 2009;29:1395-1405. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Objective: We aimed to study the neural processing of emotion-denoting words based on a circumplex model of affect, which posits that all emotions can be described as a linear combination of two neurophysiological dimensions, valence and arousal. Based on the circumplex model, we predicted a linear relationship between neural activity and incremental changes in these two affective dimensions. Methods: Using functional magnetic resonance imaging, we assessed in 10 subjects the correlations of BOLD (blood oxygen level dependent) signal with ratings of valence and arousal during the presentation of emotion-denoting words. Results: Valence ratings correlated positively with neural activity in the left insular cortex and inversely with neural activity in the right dorsolateral prefrontal and precuneus cortices. The absolute value of valence ratings (reflecting the positive and negative extremes of valence) correlated positively with neural activity in the left dorsolateral and medial prefrontal cortex (PFC), dorsal anterior cingulate cortex, posterior cingulate cortex, and right dorsal PFC, and inversely with neural activity in the left medial temporal cortex and right amygdala. Arousal ratings and neural activity correlated positively in the left parahippocampus and dorsal anterior cingulate cortex, and inversely in the left dorsolateral PFC and dorsal cerebellum. Conclusion: We found evidence for two neural networks subserving the affective dimensions of valence and arousal. These findings clarify inconsistencies from prior imaging studies of affect by suggesting that two underlying neurophysiological systems, valence and arousal, may subserve the processing of affective stimuli, consistent with the circumplex model of affect. Hum Brain Mapp, 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Purpose To optimize the homogeneity and efficiency of the B1 magnetic field of a four-ring birdcage head coil that is double-tuned at the Larmor frequencies of both 31P and 1H and optimized to acquire magnetic resonance spectroscopy (MRS) data at 3T for the study of infants. Materials and Methods We developed a finite difference time domain (FDTD) tool in-house to iteratively compute and seek the range of geometric and electromagnetic parameters of a dual-tuned, four-ring birdcage coil that would produce the desired resonance patterns, optimize homogeneity of the B1-field, and maximize efficiency of the coil. To demonstrate the validity of our computational results, we constructed three RF coils: one dual-tuned coil that was based on the calculated optimized parameters and two single-tuned coils that had dimensions similar to those of the dual-tuned coil, but tuned at the Larmor frequencies of both 31P and 1H, respectively. We then tested and compared the performances of the dual-tuned coil and single-tuned coils at both of these frequencies. Results We found that a dual-tuned, four-ring birdcage coil with a diameter of 180 mm, an inner birdcage length of 100-300 mm, and an outer birdcage length of 25-100 mm produces the desired resonance patterns. For the use of this coil with human infants, optimization of the homogeneity of the B1 field, combined with improved coil efficiency, yielded a dual-tuned birdcage coil with diameter of 180mm, an inner birdcage length of 150 mm, an outer birdcage length of 25 mm, and corresponding inner and outer capacitances of 17.2 pF and 7.6 pF, respectively. The experimental results from a constructed coil having the sameparameters with the modeled coil agreed well with the computational results from the modeled coil. This optimized design overcame the deficiencies of existing dual-tuned, four-ring birdcage coils. Conclusion The homogeneity and efficiency of the B1 field for 31P/1H dual-tuned, four-ring birdcage coils can be optimized well using our FDTD tool, especially at high static magnetic fields (B0). J. Magn. Reson. Imaging 2009;29:13-22. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Previous studies have investigated patterns of volumetric covariance (i.e. intercorrelation) among brain regions. Methodological issues, however, have limited the validity and generalizability of findings from these prior studies. Additionally, patterns of volumetric covariance have often been assumed to reflect the presence of structural networks, but this assumption has never been tested formally. We identified patterns of volumetric covariance, correlated these patterns with behavioral measures, and tested the hypothesis that the observed patterns of covariance reflect the presence of underlying networks. Specifically, we performed factor analysis on regional brain volumes of 99 healthy children and adults, and we correlated factor scores with scores on the Stroop Word-Color Interference Test. We identified four latent volumetric systems in each hemisphere: dorsal cortical, limbic, posterior, and basal ganglia. The positive correlation of the right posterior system with Stroop scores suggested that larger latent volumes are detrimental to inhibitory control. We also applied Structural Equation Modeling (SEM) to our dataset ( n = 107) to test whether a model based on the anatomical pathways within cortico-striatal-thalamic-cortical (CSTC) circuits accounts for the covariances observed in our sample. The degree to which SEM predicted volumetric covariance in the CSTC circuit depended on whether we controlled for age and whole brain volume in the analyses. Removing the effects of age worsened the fit of the model, pointing to a possible developmental component in establishing connections within CSTC circuits. These modeling techniques may prove useful in the future for the study of structural networks in disease populations. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The analysis of functional magnetic resonance imaging (fMRI) data is complicated by the presence of a mixture of many sources of signal and noise. Independent component analysis (ICA) can separate these mixtures into independent components, each of which contains maximal information from a single, independent source of signal, whether from noise or from a discrete physiological or neural system. ICA typically generates a large number of components for each subject imaged, however, and therefore it generates a vast number of components across all of the subjects imaged in an fMRI dataset. The practical implementation of ICA has been limited by the difficulty in discerning which of these many components are spurious and which are reproducible, either within or across individuals of the dataset. We have developed a novel clustering algorithm, termed 'Partner-Matching' (PM), which identifies automatically the independent components that are reproducible either within or between subjects. It identifies those components by clustering them according to robust measures of similarity in their spatial configurations either across different subjects of an fMRI dataset, within a single subject scanned across multiple scanning sessions, or within an individual subject scanned across multiple runs within a single scanning session. We demonstrate the face validity of our algorithm by applying it to the analysis of three fMRI datasets acquired in 13 healthy adults performing simple auditory, motor, and visual tasks. From among 50 independent components generated for each subject, our PM algorithm automatically identified, across all 13 subjects, components representing activity within auditory, motor, and visual cortices, respectively, as well as numerous other reproducible components outside of primary sensory and motor cortices, in functionally connected circuits that subserve higher-order cognitive functions, even in these simple tasks. Hum Brain Mapp, 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A developmental approach to the study of psychopathology can broaden understanding of a wide variety of complex psychological disorders. This article reviews research on Tourette's syndrome (TS), a developmental disorder characterized by unwanted motor and vocal tics. Over the past decade, knowledge of the neurobiology and pathophysiology of TS has progressed rapidly. The application of brain imaging techniques, primarily magnetic resonance imaging, to the study of Tourette's has increased knowledge of structural and functional deficits in brain areas associated with behavioral and psychological disturbances in the disorder. By reviewing some of this work, we will describe one way in which knowledge of brain function in TS has both informed and been informed by a developmental science approach. In particular, we will consider the extent to which the cognitive and emotional development of persons with TS may be affected by specific neurobiological characteristics of the disorder. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 50: 9–18, 2008. [ABSTRACT FROM AUTHOR]

Purpose: To introduce a framework that automatically identifies regions of anatomical abnormality within anatomical MR images and uses those regions in hypothesis-driven selection of seed points for fiber tracking with diffusion tensor (DT) imaging (DTI).Materials and Methods: Regions of interest (ROIs) are first extracted from MR images using an automated algorithm for volume-preserved warping (VPW) that identifies localized volumetric differences across groups. ROIs then serve as seed points for fiber tracking in coregistered DT images. Another algorithm automatically clusters and compares morphologies of detected fiber bundles. We tested our framework using datasets from a group of patients with Tourette's syndrome (TS) and normal controls.Results: Our framework automatically identified regions of localized volumetric differences across groups and then used those regions as seed points for fiber tracking. In our applied example, a comparison of fiber tracts in the two diagnostic groups showed that most fiber tracts failed to correspond across groups, suggesting that anatomical connectivity was severely disrupted in fiber bundles leading from regions of known anatomical abnormality.Conclusion: Our framework automatically detects volumetric abnormalities in anatomical MRIs to aid in generating a priori hypotheses concerning anatomical connectivity that then can be tested using DTI. Additionally, automation enhances the reliability of ROIs, fiber tracking, and fiber clustering. [ABSTRACT FROM AUTHOR]

Purpose: To correct eddy-current artifacts in diffusion tensor (DT) images without the need to obtain auxiliary scans for the sole purpose of correction.Materials and Methods: DT images are susceptible to distortions caused by eddy currents induced by large diffusion gradients. We propose a new postacquisition correction algorithm that does not require any auxiliary reference scans. It also avoids the problematic procedure of cross-correlating images with significantly different contrasts. A linear model is used to describe the dependence of distortion parameters (translation, scaling, and shear) on the diffusion gradients. The model is solved numerically to provide an individual correction for every diffusion-weighted (DW) image.Results: The assumptions of the linear model were successfully verified in a series of experiments on a silicon oil phantom. The correction obtained for this phantom was compared with correction obtained by a previously published method. The algorithm was then shown to markedly reduce eddy-current distortions in DT images from human subjects.Conclusion: The proposed algorithm can accurately correct eddy-current artifacts in DT images. Its principal advantages are that only images with comparable signals and contrasts are cross-correlated, and no additional scans are required. [ABSTRACT FROM AUTHOR]

We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of self-regulatory control across development in healthy individuals performing the Stroop interference task. Proper performance of the task requires the engagement of self-regulatory control to inhibit an automatized response (reading) in favor of another, less automatic response (color naming). Functional MRI scans were acquired from a sample of 70 healthy individuals ranging in age from 7 to 57 years. We measured task-related regional signal changes across the entire cerebrum and conducted correlation analyses to assess the associations of signal activation with age and with behavioral performance. The magnitude of fMRI signal change increased with age in the right inferolateral prefrontal cortex (Brodmann area [BA] 44/45) and right lenticular nucleus. Greater activation of the right inferolateral prefrontal cortex also accompanied better performance. Activity in the right frontostriatal systems increased with age and with better response inhibition, consistent with the known functions of frontostriatal circuits in self-regulatory control. Age-related deactivations in the mesial prefrontal cortex (BA 10), subgenual anterior cingulate cortex (BA 24), and posterior cingulate cortex (BA 31) likely represented the greater engagement of adults in self-monitoring and free associative thought processes during the easier baseline task, consistent with the improved performance on this task in adults compared with children. Although we cannot exclude the possibility that age-related changes in reading ability or in the strategies used to optimize task performance were responsible for our findings, the correlations of brain activation with performance suggest that changes in frontostriatal activity with age underlie the improvement in self-regulatory control that characterizes normal human development. Hum Brain Mapp, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Brain imaging studies have revealed anatomical anomalies in the brains of individuals with Tourette syndrome (TS). Prefrontal regions have been found to be larger and the corpus callosum (CC) area smaller in children and young adults with TS compared with healthy control subjects, and these anatomical features have been understood to reflect neural plasticity that helps to attenuate the severity of tics. Method: CC white matter connectivity, as measured by the Fractional Anisotropy (FA) index from diffusion tensor images, was assessed in 20 clinically well-defined boys with Tourette syndrome and 20 age- and gender-matched controls. Results: The hypothesis that children with TS would show reduced measures of connectivity in CC fibers was confirmed for all subregions of the CC. There was no significant interaction of TS and region. Reductions in FA in CC regions may reflect either fewer interhemispheric fibers or reduced axonal myelination. FA values did not correlate significantly with the severity of tic symptoms. Group differences in measures of connectivity did not seem to be attributable to the presence of comorbid ADHD or OCD, to medication exposure, or group differences in IQ. Conclusion: Our findings of a reduced interhemispheral white matter connectivity add to the understanding of neural connectivity and plasticity in the brains of children who have TS. [ABSTRACT FROM AUTHOR]

Objectives: Abnormalities in volumes of the amygdala have been reported previously in adolescents and adults with bipolar disorder (BD). Several studies have reported reduced volumes in adolescents with BD; however, both decreases and increases in volumes have been reported in adults with BD. Understanding of potential developmental contributions to these disturbances in morphology of the amygdala has been limited by the absence of longitudinal data in persons with BD. Here we use a within-subject longitudinal design to investigate whether amygdala volume abnormalities persist in adolescents and young adults with BD over a time interval of approximately 2 years. Methods: Participants included 18 adolescents and young adults: 10 participants with BD I and 8 healthy comparison participants. Amygdala volumes were measured on high-resolution magnetic resonance imaging scans acquired twice for each subject over intervals of approximately 2 years. Amygdala volumes were the dependent measures in a mixed-model statistical analysis to compare amygdala volumes between groups over time while covarying for total brain volume. Results: Amygdala volumes were significantly smaller in adolescents and young adults with BD compared with healthy participants (p = 0.018). The effect of time was not significant. Conclusions: Although the sample size is modest, this study provides preliminary evidence to support the presence of decreased amygdala volumes in adolescents and young adults with BD that persist during this developmental epoch. [ABSTRACT FROM AUTHOR]

The deficits of executive control of emotions and impulses of adult BD implicate involvement of a ventral prefrontal cortex (VPFC) neural system that subserves these functions that include the VPFC, as well as its subcortical connection sites of amygdala, striatum, and thalamus. Differences in the timing of major developmental changes in the structures within this neural system suggest that abnormalities in particular components of this neural system may emerge during critical developmental epochs during the course of the illness. Our recent neuroimaging data suggest that abnormalities in the subeortical components of VPFC neural systems may be evident by early adolescence in BD, whereas VPFC deficits progress over the course of adolescence and may be difficult to detect prior to late adolescence or early adulthood. This potential neurodevelopmental model for BD could have important implications for the recognition of early signs of the disorder and for age-specific treatment strategies. [ABSTRACT FROM AUTHOR]