A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Alterations in neural circuits underlying emotion regulation following child maltreatment: a mechanism underlying trauma-related psychopathology.

BACKGROUND: Disruptions in neural circuits underlying emotion regulation (ER) may be a mechanism linking child maltreatment with psychopathology. We examined the associations of maltreatment with neural responses during passive viewing of negative emotional stimuli and attempts to modulate emotional responses. We investigated whether the influence of maltreatment on neural activation during ER differed across development and whether alterations in brain function mediated the association between maltreatment and a latent general psychopathology ('p') factor. METHODS: Youth aged 8-16 years with (n = 79) and without (n = 72) exposure to maltreatment completed an ER task assessing neural responses during passive viewing of negative and neutral images and effortful attempts to regulate emotional responses to negative stimuli. P-factor scores were defined by a bi-factor model encompassing internalizing and externalizing psychopathology. RESULTS: Maltreated youth had greater activation in left amygdala and salience processing regions and reduced activation in multiple regions involved in cognitive control (bilateral superior frontal gyrus, middle frontal gyrus, and dorsal anterior cingulate cortex) when viewing negative v. neutral images than youth without maltreatment exposure. Reduced neural recruitment in cognitive control regions mediated the association of maltreatment with p-factor in whole-brain analysis. Maltreated youth exhibited increasing recruitment with age in ventrolateral prefrontal cortex during reappraisal while control participants exhibited decreasing recruitment with age. Findings were similar after adjusting for co-occurring neglect. CONCLUSIONS: Child maltreatment influences the development of regions associated with salience processing and cognitive control during ER in ways that contribute to psychopathology.

Executive function as a mechanism linking socioeconomic status to internalizing and externalizing psychopathology in children and adolescents.

INTRODUCTION: The association between low socioeconomic status (SES) in childhood and increased risk for psychopathology is well established, but the mechanisms explaining this relationship are poorly understood. Here, we investigate the potential role of difficulties in executive functioning (EF) as a mechanism linking childhood and adolescent SES with externalizing and internalizing psychopathology. METHODS: We examined whether difficulties with EF mediated the association between SES and externalizing and internalizing psychopathology in two cross-sectional samples of children and adolescents (Study 1: N = 94, ages 6-18, 51.1% male; Study 2: N = 259, ages 8-16, 54.1% male) from diverse SES backgrounds in the United States. EF was measured through behavioral tasks and parent-reported behavioral regulation (BR). RESULTS: In both samples, children and adolescents from lower SES families were more likely to experience both externalizing and internalizing psychopathology than youth from more advantaged backgrounds and exhibited greater EF difficulties - they had lower performance on a task measuring inhibitory control and lower parent-rated BR. Reduced inhibitory control and BR, in turn, were associated with higher externalizing and internalizing psychopathology. In Study 1, difficulties with BR mediated the association of low-SES with both externalizing and internalizing psychopathology. In Study 2, low inhibitory control mediated the association between low-SES and externalizing psychopathology. These findings largely persisted after adjusting for exposure to violence, a form of adversity that is common in children from low-SES backgrounds. CONCLUSIONS: These findings suggest that reduced EF may be an underlying mechanism through which low-SES confers risk for psychopathology in children and adolescents.

Reduced hippocampal and amygdala volume as a mechanism underlying stress sensitization to depression following childhood trauma.

BACKGROUND: Stressful life events are more likely to trigger depression among individuals exposed to childhood adversity. However, the mechanisms underlying this stress sensitization remain largely unknown. Any such mechanism must be altered by childhood adversity and interact with recent stressful life events, magnifying their association with depression. AIM: This study investigated whether reduced hippocampal and amygdala volume are potential mechanisms underlying stress sensitization following childhood violence exposure. METHOD: A sample of 149 youth (aged 8-17 years), with (N = 75) and without (N = 74) exposure to physical abuse, sexual abuse, or domestic violence participated. Participants completed a structural MRI scan and assessments of depression. Approximately 2 years later, stressful life events were assessed along with depression symptoms in 120 participants (57 violence exposed). RESULTS: Childhood violence exposure was associated with smaller hippocampal and amygdala volume. Stressful life events occurring during the follow-up period predicted worsening depression over time, and this association was magnified among those with smaller hippocampal and amygdala volumes. Significant moderated mediation models revealed the indirect effects of violence exposure on increasing depression over time through hippocampal and amygdala volumes, particularly among youths who experienced more stressful life events. CONCLUSIONS: These results provide evidence for reduced hippocampal and amygdala volume as potential mechanisms of stress sensitization to depression following exposure to violence. More broadly, these patterns suggest that hippocampal and amygdala-mediated emotional and cognitive processes may confer vulnerability to stressful life events among children who have experienced violence.

The Role of Visual Association Cortex in Associative Memory Formation across Development.

Associative learning underlies the formation of new episodic memories. Associative memory improves across development, and this age-related improvement is supported by the development of the hippocampus and pFC. Recent work, however, additionally suggests a role for visual association cortex in the formation of associative memories. This study investigated the role of category-preferential visual processing regions in associative memory across development using a paired associate learning task in a sample of 56 youths (age 6-19 years). Participants were asked to bind an emotional face with an object while undergoing fMRI scanning. Outside the scanner, participants completed a memory test. We first investigated age-related changes in neural recruitment and found linear age-related increases in activation in lateral occipital cortex and fusiform gyrus, which are involved in visual processing of objects and faces, respectively. Furthermore, greater activation in these visual processing regions was associated with better subsequent memory for pairs over and above the effect of age and of hippocampal and pFC activation on performance. Recruitment of these visual processing regions mediated the association between age and memory performance, over and above the effects of hippocampal activation. Taken together, these findings extend the existing literature to suggest that greater recruitment of category-preferential visual processing regions during encoding of associative memories is a neural mechanism explaining improved memory across development.

Dimensions of childhood adversity have distinct associations with neural systems underlying executive functioning.

Childhood adversity is associated with increased risk for psychopathology. Neurodevelopmental pathways underlying this risk remain poorly understood. A recent conceptual model posits that childhood adversity can be deconstructed into at least two underlying dimensions, deprivation and threat, that are associated with distinct neurocognitive consequences. This model argues that deprivation (i.e., a lack of cognitive stimulation and learning opportunities) is associated with poor executive function (EF), whereas threat is not. We examine this hypothesis in two studies measuring EF at multiple levels: performance on EF tasks, neural recruitment during EF, and problems with EF in daily life. In Study 1, deprivation (low parental education and child neglect) was associated with greater parent-reported problems with EF in adolescents (N = 169; 13-17 years) after adjustment for levels of threat (community violence and abuse), which were unrelated to EF. In Study 2, low parental education was associated with poor working memory (WM) performance and inefficient neural recruitment in the parietal and prefrontal cortex during high WM load among adolescents (N = 51, 13-20 years) after adjusting for abuse, which was unrelated to WM task performance and neural recruitment during WM. These findings constitute strong preliminary evidence for a novel model of the neurodevelopmental consequences of childhood adversity.

Childhood abuse and reduced cortical thickness in brain regions involved in emotional processing.

BACKGROUND: Alterations in gray matter development represent a potential pathway through which childhood abuse is associated with psychopathology. Several prior studies find reduced volume and thickness of prefrontal (PFC) and temporal cortex regions in abused compared with nonabused adolescents, although most prior research is based on adults and volume-based measures. This study tests the hypothesis that child abuse, independent of parental education, predicts reduced cortical thickness in prefrontal and temporal cortices as well as reduced gray mater volume (GMV) in subcortical regions during adolescence. METHODS: Structural MRI scans were obtained from 21 adolescents exposed to physical and/or sexual abuse and 37 nonabused adolescents (ages 13-20). Abuse was operationalized using dichotomous and continuous measures. We examined associations between abuse and brain structure in several a priori-defined regions, controlling for parental education, age, sex, race, and total brain volume for subcortical GMV. Significance was evaluated at p < .05 with a false discovery rate correction. RESULTS: Child abuse exposure and severity were associated with reduced thickness in ventromedial prefrontal cortex (PFC), right lateral orbitofrontal cortex, right inferior frontal gyrus, bilateral parahippocampal gyrus (PHG), left temporal pole, and bilateral inferior, right middle, and right superior temporal gyri. Neither abuse measure predicted cortical surface area or subcortical GMV. Bilateral PHG thickness was inversely related to externalizing symptoms. CONCLUSIONS: Child abuse, an experience characterized by a high degree of threat, is associated with reduced cortical thickness in ventromedial and ventrolateral PFC and medial and lateral temporal cortex in adolescence. Reduced PHG thickness may be a mediator linking abuse with externalizing psychopathology, although prospective research is needed to evaluate this possibility.

Childhood trauma and brain structure in children and adolescents.

The dimensional model of adversity proposes that experiences of threat and deprivation have distinct neurodevelopmental consequences. We examined these dimensions, separately and jointly, with brain structure in a sample of 149 youth aged 8-17-half recruited based on exposure to threat-related experiences. We predicted that greater threat would be uniquely associated with reduced cortical thickness and surface area in brain regions associated with salience processing including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and insula, and that deprivation experiences would be uniquely associated with reductions in cortical thickness and surface area in frontoparietal areas associated with cognitive control. As predicted, greater threat was associated with thinner cortex in a network including areas involved in salience processing (anterior insula, vmPFC), and smaller amygdala volume (particularly in younger participants), after controlling for deprivation. Contrary to our hypotheses, threat was also associated with thinning in the frontoparietal control network. However, these associations were reduced following control for deprivation. No associations were found between deprivation and brain structure. This examination of deprivation and threat concurrently in the same sample provided further evidence that threat-related experiences influence the structure of the developing brain independent of deprivation.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Socioeconomic status and child psychopathology in the United States: A meta-analysis of population-based studies.

Children raised in families with low socioeconomic status (SES) are more likely to exhibit symptoms of psychopathology. However, the strength of this association, the specific indices of SES most strongly associated with childhood psychopathology, and factors moderating the association are strikingly inconsistent across studies. We conducted a meta-analysis of 120 estimates of the association between family SES and child psychopathology in 13 population-representative cohorts of children studied in the US since 1980. Among 26,715 participants aged 3-19 years, we observed small to moderate associations of low family income (g = 0.19), low Hollingshead index (g = 0.21), low subjective SES (g = 0.24), low parental education (g = 0.25), poverty status (g = 0.25), and receipt of public assistance (g = 0.32) with higher levels of childhood psychopathology. Moderator testing revealed that receipt of public assistance showed an especially strong association with psychopathology and that SES was more strongly related to externalizing than internalizing psychopathology. Dispersion in our final, random effects, model suggested that the relation between SES and child psychopathology is likely to vary in different populations of children and in different communities. These findings highlight the need for additional research on the mechanisms of SES-related psychopathology risk in children in order to identify targets for potential intervention.

Trauma and posttraumatic stress disorder modulate polygenic predictors of hippocampal and amygdala volume.

The volume of subcortical structures represents a reliable, quantitative, and objective phenotype that captures genetic effects, environmental effects such as trauma, and disease effects such as posttraumatic stress disorder (PTSD). Trauma and PTSD represent potent exposures that may interact with genetic markers to influence brain structure and function. Genetic variants, associated with subcortical volumes in two large normative discovery samples, were used to compute polygenic scores (PGS) for the volume of seven subcortical structures. These were applied to a target sample enriched for childhood trauma and PTSD. Subcortical volume PGS from the discovery sample were strongly associated in our trauma/PTSD enriched sample (n = 7580) with respective subcortical volumes of the hippocampus (p = 1.10 × 10-20), thalamus (p = 7.46 × 10-10), caudate (p = 1.97 × 10-18), putamen (p = 1.7 × 10-12), and nucleus accumbens (p = 1.99 × 10-7). We found a significant association between the hippocampal volume PGS and hippocampal volume in control subjects from our sample, but was absent in individuals with PTSD (GxE; (beta = -0.10, p = 0.027)). This significant GxE (PGS × PTSD) relationship persisted (p < 1 × 10-19) in four out of five threshold peaks (0.024, 0.133, 0.487, 0.730, and 0.889) used to calculate hippocampal volume PGSs. We detected similar GxE (G × ChildTrauma) relationships in the amygdala for exposure to childhood trauma (rs4702973; p = 2.16 × 10-7) or PTSD (rs10861272; p = 1.78 × 10-6) in the CHST11 gene. The hippocampus and amygdala are pivotal brain structures in mediating PTSD symptomatology. Trauma exposure and PTSD modulate the effect of polygenic markers on hippocampal volume (GxE) and the amygdala volume PGS is associated with PTSD risk, which supports the role of amygdala volume as a risk factor for PTSD.

Dynamic associations between stressful life events and adolescent internalizing psychopathology in a multiwave longitudinal study.

Associations between stressful life events (SLEs) and internalizing psychopathology are complex and bidirectional, involving interactions among stressors across development to predict psychopathology (i.e., stress sensitization) and psychopathology predicting greater exposure to SLEs (i.e., stress generation). Although stress sensitization and generation theoretical models inherently focus on within-person effects, most previous research has compared average levels of stress and psychopathology across individuals in a sample (i.e., between-person effects). The present study addressed this gap by investigating stress sensitization and stress generation effects in a multiwave, prospective study of SLEs and adolescent depression and anxiety symptoms. Depression, anxiety, and SLE exposure were assessed every 3 months for 2 years (8 waves of data) in a sample of adolescents (n = 382, aged 11 to 15 at baseline). Multilevel modeling revealed within-person stress sensitization effects such that the association between within-person increases in SLEs and depression, but not anxiety, symptoms were stronger among adolescents who experienced higher average levels of SLEs across 2 years. We also observed within-person stress generation effects, such that adolescents reported a greater number of dependent-interpersonal SLEs during time periods after experiencing higher levels of depression at the previous wave than was typical for them. Although no within-person stress generation effects emerged for anxiety, higher overall levels of anxiety predicted greater exposure to dependent-interpersonal SLEs. Our findings extend prior work by demonstrating stress sensitization in predicting depression following normative forms of SLEs and stress generation effects for both depression and anxiety using a multilevel modeling approach. Clinical implications include an individualized approach to interventions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Atypical Prefrontal-Amygdala Circuitry Following Childhood Exposure to Abuse: Links With Adolescent Psychopathology.

Adverse childhood experiences have been associated with more negative coupling between the ventromedial prefrontal cortex (vmPFC) and amygdala, a brain network involved in emotion regulation in both children and adults. This pattern may be particularly likely to emerge in individuals exposed to threatening experiences during childhood (e.g., exposure to child abuse), although this has not been examined in prior research. We collected functional magnetic resonance imaging data on 57 adolescents during an emotion regulation task. Greater negative functional connectivity between vmPFC and amygdala occurred during viewing of negative compared to neutral images. This vmPFC-amygdala task-related functional connectivity was more negative in adolescents exposed to physical, sexual, or emotional abuse than those without a history of maltreatment and was associated with abuse severity. This pattern of more negative functional connectivity was associated with higher levels of externalizing psychopathology concurrently and 2 years later. Greater negative connectivity in the vmPFC-amygdala network during passive viewing of negative images may reflect disengagement of regulatory responses from vmPFC in situations eliciting strong amygdala reactivity, potentially due to stronger appraisals of threat in children exposed to early threatening environments. This pattern may be adaptive in the short term but place adolescents at higher risk of psychopathology later in life.

Altered development of hippocampus-dependent associative learning following early-life adversity.

Little is known about how childhood adversity influences the development of learning and memory and underlying neural circuits. We examined whether violence exposure in childhood influenced hippocampus-dependent associative learning and whether differences: a) were broad or specific to threat cues, and b) exhibited developmental variation. Children (n = 59; 8-19 years, 24 violence-exposed) completed an associative learning task with angry, happy, and neutral faces paired with objects during fMRI scanning. Outside the scanner, participants completed an associative memory test for face-object pairings. Violence-exposed children exhibited broad associative memory difficulties that became more pronounced with age, along with reduced recruitment of the hippocampus and atypical recruitment of fronto-parietal regions during encoding. Violence-exposed children also showed selective disruption of associative memory for threat cues regardless of age, along with reduced recruitment of the intraparietal sulcus (IPS) during encoding in the presence of threat. Broad associative learning difficulties may be a functional consequence of the toxic effects of early-life stress on hippocampal and fronto-parietal cortical development. Difficulties in the presence of threat cues may result from enhanced threat processing that disrupts encoding and short-term storage of associative information in the IPS. These associative learning difficulties may contribute to poor life outcomes following childhood violence exposure.

Structural covariance network centrality in maltreated youth with posttraumatic stress disorder.

Childhood maltreatment is associated with posttraumatic stress disorder (PTSD) and elevated rates of adolescent and adult psychopathology including major depression, bipolar disorder, substance use disorders, and other medical comorbidities. Gray matter volume changes have been found in maltreated youth with (versus without) PTSD. However, little is known about the alterations of brain structural covariance network topology derived from cortical thickness in maltreated youth with PTSD. High-resolution T1-weighted magnetic resonance imaging scans were from demographically matched maltreated youth with PTSD (N = 24), without PTSD (N = 64), and non-maltreated healthy controls (n = 67). Cortical thickness data from 148 cortical regions was entered into interregional partial correlation analyses across participants. The supra-threshold correlations constituted connections in a structural brain network derived from four types of centrality measures (degree, betweenness, closeness, and eigenvector) estimated network topology and the importance of nodes. Between-group differences were determined by permutation testing. Maltreated youth with PTSD exhibited larger centrality in left anterior cingulate cortex than the other two groups, suggesting cortical network topology specific to maltreated youth with PTSD. Moreover, maltreated youth with versus without PTSD showed smaller centrality in right orbitofrontal cortex, suggesting that this may represent a vulnerability factor to PTSD following maltreatment. Longitudinal follow-up of the present results will help characterize the role that altered centrality plays in vulnerability and resilience to PTSD following childhood maltreatment.

Current methods and limitations for longitudinal fMRI analysis across development.

The human brain is remarkably plastic. The brain changes dramatically across development, with ongoing functional development continuing well into the third decade of life and substantial changes occurring again in older age. Dynamic changes in brain function are thought to underlie the innumerable changes in cognition, emotion, and behavior that occur across development. The brain also changes in response to experience, which raises important questions about how the environment influences the developing brain. Longitudinal functional magnetic resonance imaging (fMRI) studies are an essential means of understanding these developmental changes and their cognitive, emotional, and behavioral correlates. This paper provides an overview of common statistical models of longitudinal change applicable to developmental cognitive neuroscience, and a review of the functionality provided by major software packages for longitudinal fMRI analysis. We demonstrate that there are important developmental questions that cannot be answered using available software. We propose alternative approaches for addressing problems that are commonly faced in modeling developmental change with fMRI data.

Neural Correlates of Emotion Regulation and Adolescent Suicidal Ideation.

BACKGROUND: Research on the neural correlates associated with risk for suicidal ideation (SI) has been limited, particularly in one increasingly at-risk group-adolescents. Previous research with adolescents indicates that poor emotion regulation skills are linked with SI, but these studies have not previously examined neural activation in service of emotion regulation between those with and without SI histories. METHODS: Here we examine whether SI is associated with neural responses during an emotion regulation functional magnetic resonance imaging task in a group of adolescents (N = 49) 13 to 20 years of age (mean = 16.95). RESULTS: While there were no differences between youths with and without SI in self-reported emotional responses to negative pictures, youths with SI activated the dorsolateral prefrontal cortex more than youths without SI on trials in which they attempted to regulate their emotional responses compared with trials in which they passively viewed negative pictures. In contrast, during passive viewing of negative stimuli, youths with SI activated the dorsolateral prefrontal cortex, temporoparietal junction, and cerebellum less than same-age control subjects. CONCLUSIONS: These findings were robust to control subjects for depression and adversity exposure and are consistent with the idea that youths with SI have disrupted emotion regulation, potentially related to differences in recruitment of top-down control regions. In contrast, youths without SI activated regions implicated in emotion regulation even when not directed to effortfully control their emotional response. This is the first study to examine neural function during emotion regulation as a potential neural correlate of risk for SI in adolescents.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia.

BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.

Child Abuse, Neural Structure, and Adolescent Psychopathology: A Longitudinal Study.

OBJECTIVE: Child abuse exerts a deleterious impact on a broad array of mental health outcomes. However, the neurobiological mechanisms that mediate this association remain poorly characterized. Here, we use a longitudinal design to prospectively identify neural mediators of the association between child abuse and psychiatric disorders in a community sample of adolescents. METHOD: Structural magnetic resonance imaging (MRI) data and assessments of mental health were acquired for 51 adolescents (aged 13-20; M=16.96; SD=1.51), 19 of whom were exposed to physical or sexual abuse. Participants were assessed for abuse exposure (time 1), participated in MRI scanning and a diagnostic structured interview (time 2), and 2 years later were followed-up to assess psychopathology (time 3). We examined associations between child abuse and neural structure, and identified whether abuse-related differences in neural structure prospectively predicted psychiatric symptoms. RESULTS: Abuse was associated with reduced cortical thickness in medial and lateral prefrontal and temporal lobe regions. Thickness of the left and right parahippocampal gyrus predicted antisocial behavior symptoms, and thickness of the middle temporal gyrus predicted symptoms of generalized anxiety disorder. Thickness of the left parahippocampal gyrus mediated the longitudinal association of abuse with antisocial behavior. CONCLUSION: Child abuse is associated with widespread disruptions in cortical structure, and these disruptions are selectively associated with increased vulnerability to internalizing and externalizing psychopathology. Identifying predictive biomarkers of vulnerability following childhood maltreatment may uncover neurodevelopmental mechanisms linking environmental experience with the onset of psychopathology.