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Fredric Schiffer,1,2 Alaptagin Khan,1,2 Kyoko Ohashi,1,2 Laura C Hernandez Garcia,1,2 Carl M Anderson,1,2 Lisa D Nickerson,1,3 Martin H Teicher1,2 1Department of Psychiatry, Harvard Medical School, Boston, MA, USA; 2Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA; 3McLean Imaging Center, McLean Hospital, Belmont, MA, USACorrespondence: Fredric Schiffer, Developmental Biopsychiatry Research Program, McLean Hospital, Belmont, MA, USA, Tel +1 617 855 2970, Fax +1 617 855 3712, Email fschiffer@mclean.harvard.eduPurpose: Conventional theories of hemispheric emotional valence (HEV) postulate fixed hemispheric differences in emotional processing. Schiffer’s dual brain psychology proposes that there are prominent individual differences with a substantial subset showing a reversed laterality pattern. He further proposed that hemispheric differences were more akin to differences in personality than in emotional processing. This theory is supported by findings that unilateral treatments, such as transcranial magnetic stimulation, are effective if they accurately target individual differences in laterality. The aim of this paper was to assess if a computer test of hemispheric emotional valence (CTHEV) could effectively identify individual differences in HEV and to ascertain if these individual differences were associated with underlying differences in brain structure and connectivity.Patients and Methods: The CTHEV was administered to 50 (18 male/32 female) right-handed participants, aged 18– 19 years, enrolled in a study assessing the neurobiological effects of childhood maltreatment. Based on a literature review, we determined whether CTHEV correlated with lateralized volumes of the nucleus accumbens, amygdala, hippocampus, and subgenual anterior cingulate as well as volume of the corpus callosum.Results: CTHEV scores correlated with laterality indices of the nucleus accumbens (p = 0.00016), amygdala (p = 0.0138) and hippocampus (p = 0.031). A positive left hemispheric valence was associated with a larger left-sided nucleus accumbens and hippocampus and a smaller left amygdala. We identified four eigenvector network centrality DTI measures that predict CTHEV, most notably the left amygdala, and found that CTHEV results correlated with total and segment-specific corpus callosal volumes.Conclusion: Individual differences in HEV can be readily assessed by computer test and correlate with differences in brain structure and connectivity that could provide a mechanistic understanding. These findings provide further support for a revised understanding of HEV and provide a tool that could be used to guide lateralized brain treatments.Keywords: cerebral laterality, brain structure, personality, Dual-Brain Psychology, corpus callosum

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Adverse Childhood Experience (ACE) has detrimental impacts on neural development, especially hippocampal morphometry. Mindfulness-Based Interventions (MBI) has been shown to induce adaptive hippocampal changes especially at the subiculum. The present study aims to investigate the effects of MBI on subiculum volumes among ACE survivors, as well as the effects on episodic memory as a probe into hippocampal functionality., Methods: We analyzed anatomical MRI data and performance indices from an episodic memory task called the Mnemonic Similarity Task (MST) collected from a randomized controlled longitudinal study that compared an 8-week MBI ( N = 20) to an active control condition of Stress Management Education (SME) ( N = 19). FreeSurfer 6.0 was used for automated hippocampal subfield segmentation and volumetric estimation., Results: Significant group differences were observed with the volumetric changes of the right whole hippocampus and right subiculum. Only the MBI group showed improved pattern separation capability from MST, which was associated with stress reduction and right subiculum volumetric changes., Limitations: Modest sample size. MST task was performed outside of MRI., Conclusions: These findings suggest beneficial effects of MBI for hippocampal volumes and episodic memory, while highlighting the importance of the subiculum for MBI-induced neural and cognitive changes. The subiculum's known role in inhibitory control was interpreted as a potential mechanism for it to exhibit MBI-induced volumetric changes, which sheds light on the potential neural underpinnings of mindfulness meditation for reducing stress reactivity among ACE survivors., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DJ and SWL are practitioners of mindfulness meditation.

Childhood maltreatment is a risk factor for psychopathologies, and influences brain development at specific periods, particularly during early childhood and adolescence. This narrative review addresses phenotypic alterations in sensory systems associated with specific types of childhood maltreatment exposure, periods of vulnerability to the neurobiological effects of maltreatment, and the relationships between childhood maltreatment and brain structure, function, connectivity, and network architecture; psychopathology; and resilience. It also addresses neurobiological alterations associated with maternal communication and attachment disturbances, and uses laboratory-based measures during infancy and case-control studies to elucidate neurobiological alterations in reactive attachment disorders in children with maltreatment histories. Moreover, we review studies on the acute effects of oxytocin on reactive attachment disorder and maltreatment and methylation of oxytocin regulatory genes. Epigenetic changes may play a critical role in initiating or producing the atypical structural and functional brain alterations associated with childhood maltreatment. However, these changes could be reversed through psychological and pharmacological interventions, and by anticipating or preventing the emergence of brain alterations and subsequent psychopathological risks., (© 2024. The Author(s).)

Objective: Nonsuicidal self-injury (NSSI) is common in adolescence. Rumination is a key risk factor and often co-occurs with depressive symptoms. This is the first study to examine the joint longitudinal trajectories of rumination and depressive symptoms as predictors of NSSI, and the adverse experiences associated with these trajectories., Method: A community sample of 1,835 adolescents (55.9% male participants, 12.3 ± 0.5 years of age) completed questionnaires to assess adverse childhood experiences, rumination, depressive symptoms, and NSSI. Assessments were made 4 times over 18 months., Results: A parallel process growth mixture model showed that youth with high trajectories of rumination but low trajectories of depression had moderately increased odds of NSSI (2.43-fold, 95% CI 1.53-3.91) compared with adolescents with low trajectories of both rumination and depression. Odds ratios (ORs) in adolescents with low trajectories of rumination but increasing or high trajectories of depression were similarly elevated, suggesting that high trajectories of rumination or depression were risk factors in isolation. However, odds were 10.06-fold greater (95% CI 5.68-18.02) when high trajectories of rumination occurred in tandem with high trajectories of depression. Multinomial logistic regression showed that male sex (OR 10.54, 95% CI 5.66-19.63), peer victimization (OR 2.25, 95% CI 1.72-2.96), and parental alienation (OR 1.94, 95% CI 1.46-2.57) were key determinants of membership in the highest risk group., Conclusion: Risk for NSSI is markedly increased in adolescents with high longitudinal trajectories of depression and rumination. Reducing exposure to peer victimization, cyber victimization, emotional abuse, parental alienation, and interparental conflict may reduce risk., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Childhood maltreatment is one of the most important preventable risk factors for a wide variety of psychiatric disorders. Further, when psychiatric disorders emerge in maltreated individuals they typically do so at younger ages, with greater severity, more psychiatric comorbid conditions, and poorer response to established treatments, resulting in a more pernicious course with an increased risk for suicide. Practitioners treating children, adolescents, and young adults with psychiatric disorders will likely encounter the highest prevalence of clients with early-onset maltreatment-associated psychiatric disorders. These may be some of their most challenging cases., Method: In this report, we explore key validated alterations in brain structure, function, and connectivity associated with exposure to childhood maltreatment as potential mechanisms behind their patients' clinical presentations., Results: We then summarize key behavioral presentations likely associated with neurobiological alterations and propose a toolkit of established trauma and skills-based strategies that may help diminish symptoms and foster recovery. We also discuss how some of these alterations may serve as latent vulnerability factors for the possible development of future psychopathology., Conclusions: Research on the neurobiological consequences of childhood adversity provides a vastly enriched biopsychosocial understanding of the developmental origins of health and pathology that will hopefully lead to fundamental advances in clinical psychology and psychiatry., (© 2023 Association for Child and Adolescent Mental Health.)

Adolescents who experience potentially traumatic experiences (PTEs) have an increased risk of psychopathology. PTEs often co-occur and may form interrelated patterns of exposure. This study investigated underlying classes of PTE exposure among Norwegian adolescent participants in the youth@hordaland study, and whether such classes were associated with contact with child and adolescent mental health services (CAMHS) and psychiatric diagnoses. The data stem from the population-based youth@hordaland study conducted in 2012 which was linked to the Norwegian Patient Registry (NPR, n = 8845). Exposure to PTEs was assessed by adolescent self-report whereas psychiatric disorders (Axis 1) were derived from the NPR. Latent Class Analysis was used to identify distinct classes of PTE exposure-patterns in the data. Logistic regression analyses were performed to investigate associations between classes of PTEs and contact with CAMHS and psychiatric diagnoses. Three classes of PTE exposure were identified based on model fit indices and theoretical considerations. Compared with participants in the low trauma class (88% of participants), those in the Situational-(6%) and Interpersonal trauma class (6%) had higher odds-ratios (ORs) for contact with CAMHS (OR = 2.27 (95% CI [1.78, 2.87])) and (OR = 3.26 (95% CI [2.61, 4.04])) respectively, and for being diagnosed with a psychiatric disorder in CAMHS (ORs ranged from 2.19 - 10.4) after adjusting for sex and parental education. There were more participants diagnosed with ADHD within the Interpersonal trauma class compared to the Situational trauma class when adjusting for sex and parental education (OR = 2.22 (95% CI [1.17, 4.40])). Three relatively homogeneous PTE classes, consisting of distinct patterns of trauma exposure were associated with a higher odds of contact with CAMHS and of being diagnosed with a psychiatric disorder in CAMHS. The study highlights the co-occurrence of PTEs and their impact across the diagnostic spectrum., (© 2024. The Author(s).)

Exposure to potentially traumatic experiences (PTEs) is common among children and adolescents and associated with an increased risk of psychiatric diagnoses. This study aimed to ascertain how the number of PTEs differed across adolescent psychiatric diagnoses. Data on PTE exposure were derived from the youth@hordaland survey, and Axis 1 data were from the linked Norwegian National Patient Registry (NPR). Among 10,257 total adolescents, 9,555 (age range: 16-19 years, 53.9% female) consented to register linkage, 8,845 of whom were included in the analyses. Having contact with Child and Adolescent Mental Health Services (CAMHS) predicted more PTEs (estimated marginal mean [EMM] = 1.04, SE = 0.05) and exposure to two or more PTEs compared to having no CAMHS contact (EMM = 0.60) after adjusting for age, ethnicity, sex, and parental education. Adolescents diagnosed with attention-deficit/hyperactivity disorder, depression, trauma-related disorders, conduct disorder, and anxiety experienced significantly more PTEs (EMMs = 0.90-1.63) than those with no CAMHS contact (EMM = 0.57, SE = 0.01). All diagnostic categories except psychosis, autism spectrum disorders, and eating disorders had a significantly higher rate of PTEs compared with adolescents with no CAMHS contact. The study highlights the potential role of exposure to multiple PTEs as a transdiagnostic risk factor, although the level of risk varies between diagnoses., (© 2023 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Background: Adverse Childhood Experience (ACE) has been shown to have detrimental impact on amygdala structure. Prior research found that adaptive psychological changes after Mindfulness-Based Interventions (MBI) were associated with amygdala volumetric changes. The present study aims to further investigate whether such effects also occur among ACE survivors and whether the effects are unique to MBI., Methods: A total of 64 young adult childhood adversity survivors were randomized to an eight-week MBI or Stress Management Education (SME) as an active control condition. Anatomical MRI and questionnaires on mindfulness, stress and psychological health were collected at baseline and post-intervention. Due to subject dropout, the final sample included 39 subjects (MBI:20, SME:19)., Results: Both groups showed increased mindfulness levels, reduced stress, and improved psychological symptoms (depression, anxiety, and somatization), with no significant group by time interaction effect. There was no significant group difference on amygdala volumetric changes. Within the MBI group, childhood maltreatment severity was a significant mediator between changes of mindfulness levels and right amygdala volumetric changes. Across pooled sample of both groups, childhood maltreatment was a significant moderator for the effect of trait anxiety level changes on left amygdala volumetric changes., Limitations: Modest sample size, relatively low retention rates, suboptimal monitoring of home practice., Conclusions: MBI did not demonstrate overall better clinical effects than SME. Psychological-change-dependent amygdala volumetric change was not specific to MBI. Childhood maltreatment severity modulated the relationships between adaptive psychological changes and amygdala volumetric changes., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DJ and SWL are practitioners of mindfulness meditation.

Childhood maltreatment is a leading risk factor for psychopathology, though it is unclear why some develop risk averse disorders, such as anxiety and depression, and others risk-taking disorders including substance abuse. A critical question is whether the consequences of maltreatment depend on the number of different types of maltreatment experienced at any time during childhood or whether there are sensitive periods when exposure to particular types of maltreatment at specific ages exert maximal effects. Retrospective information on severity of exposure to ten types of maltreatment during each year of childhood was collected using the Maltreatment and Abuse Chronology of Exposure scale. Artificial Intelligence predictive analytics were used to delineate the most important type/time risk factors. BOLD activation fMRI response to threatening versus neutral facial images was assessed in key components of the threat detection system (i.e., amygdala, hippocampus, anterior cingulate, inferior frontal gyrus and ventromedial and dorsomedial prefrontal cortices) in 202 healthy, unmedicated, participants (84 M/118 F, 23.2 ± 1.7 years old). Emotional maltreatment during teenage years was associated with hyperactive response to threat whereas early childhood exposure, primarily to witnessing violence and peer physical bullying, was associated with an opposite pattern of greater activation to neutral than fearful faces in all regions. These findings strongly suggest that corticolimbic regions have two different sensitive period windows of enhanced plasticity when maltreatment can exert opposite effects on function. Maltreatment needs to be viewed from a developmental perspective in order to fully comprehend its enduring neurobiological and clinical consequences., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Adolescents typically sleep too little and feel drowsy during morning classes. We assessed whether morning use of an LED bright light device could increase alertness in school students. Twenty-six (8M/18F) healthy, unmedicated participants, ages 13-18 years, (mean 17.1±1.4) were recruited following screenings to exclude psychopathology. Baseline assessments were made of actigraph-assessed sleep, attention, math solving ability, electroencephalography and structural and functional MRI (N = 10-11, pre-post). Participants nonrandomly received 3-4 weeks of bright light therapy (BLT) for 30 minutes each morning and used blue light blocking glasses for 2 hours before bedtime. BLT devices were modified to surreptitiously record degree of use so that the hypothesis tested was whether there was a significant relationship between degree of use and outcome. They were used 57±18% (range 23%-90%) of recommended time. There was a significant association between degree of use and: (1) increased beta spectral power in frontal EEG leads (primary measure); (2) greater post-test improvement in math performance and reduction in errors of omission on attention test; (3) reduced day-to-day variability in bed times, sleep onset, and sleep duration during school days; (4) increased dentate gyrus volume and (5) enhanced frontal connectivity with temporal, occipital and cerebellar regions during Go/No-Go task performance. BLT was associated with improvement in sleep cycle consistency, arousal, attention and functional connectivity, but not sleep onset or duration (primary measures). Although this was an open study, it suggests that use of bright morning light and blue light blocking glasses before bed may benefit adolescents experiencing daytime sleepiness. Clinical trial registration: Clinicaltrials.gov ID-NCT05383690., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Teicher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Distinct neural effects of threat versus deprivation emerge by childhood, but little data are available in infancy. Withdrawn versus negative parenting may represent dimensionalized indices of early deprivation versus early threat, but no studies have assessed neural correlates of withdrawn versus negative parenting in infancy. The objective of this study was to separately assess the links of maternal withdrawal and maternal negative/inappropriate interaction with infant gray matter volume (GMV), white matter volume (WMV), amygdala, and hippocampal volume. Participants included 57 mother-infant dyads. Withdrawn and negative/inappropriate aspects of maternal behavior were coded from the Still-Face Paradigm at four months infant age. Between 4 and 24 months (M age = 12.28 months, SD = 5.99), during natural sleep, infants completed an MRI using a 3.0 T Siemens scanner. GMV, WMV, amygdala, and hippocampal volumes were extracted via automated segmentation. Diffusion weighted imaging volumetric data were also generated for major white matter tracts. Maternal withdrawal was associated with lower infant GMV. Negative/inappropriate interaction was associated with lower overall WMV. Age did not moderate these effects. Maternal withdrawal was further associated with reduced right hippocampal volume at older ages. Exploratory analyses of white matter tracts found that negative/inappropriate maternal behavior was specifically associated with reduced volume in the ventral language network. Results suggest that quality of day-to-day parenting is related to infant brain volumes during the first two years of life, with distinct aspects of interaction associated with distinct neural effects., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Exposure to potentially traumatic experiences (PTEs) is common among children and adolescents, but relatively little is known about the epidemiology of trauma and trauma-related psychopathology in children and youth. The present cross- sectional epidemiological study aimed to explore factors that is associated with posttraumatic stress symptoms (PTSS) in children., Method: Data stem from the Bergen Child Study, a series of cross-sectional multi-phase surveys of children born between 1993 and 1995 in Bergen, Norway. The sample used is from the second wave of the Bergen Child Study (BCS) conducted in 2006, a two-phase study. The study entailed a detailed psychiatric evaluation using the Development and well-being assessment (DAWBA). The DAWBA was administered to parents or caregivers and covered diagnostic areas, child and family background, and child strengths. A total of 2043 parents participated., Results: Out of the total sample, parents reported that 4.8% children had experienced PTEs at some point in their lives. The findings revealed current PTSS in 30.9% of children exposed to PTE, which was 1.5% of the total sample. None of the parents reported PTSS in their children over the threshold for diagnosing posttraumatic stress disorder (PTSD). The most common PTSS cluster was arousal reactivity (90.0%), followed by negative cognitions and mood (80%). The least frequent symptom cluster was intrusions (63.3%) and avoidance (60%). Children with PTSS were reported to live in families with significantly more family stressors (p = 0.001, d = 0.8) and had utilized significantly more sources for help relative to those without PTSS (p = 0.001, d = 0.75)., Conclusion: The present population study on children revealed a lower prevalence rate of PTEs and PTSD than previous studies. It provided findings in the field of trauma on parent- reported PTSS and PTSD symptom clusters not restricted to the clinical level of PTSD. Lastly, it highlighted how family-life stressors and support differed between those who had PTSS and those with no PTSS., (© 2023. The Author(s).)

Deficits in executive functions (EFs) are theorized to play an important role in causing functional impairment and associated psychopathology in individuals with ADHD. The objective of this study was to examine the role of EFs and ADHD symptoms as longitudinal predictors of psychopathology symptoms in individuals with ADHD and typically developing individuals. We assessed individuals with and without ADHD (N = 135) with neuropsychological tests of EFs and scales of ADHD symptoms and psychopathology symptoms at baseline (T1; M age = 11.59, 57.8% boys), 2-year follow-up (T2; M age = 13.63, 97% retention), and 10-year follow-up (M age = 21.18, 75% retention). Baseline EFs predicted psychopathology symptoms at the 2- and the 10-year follow-up, explaining 17% and 12% of the variance, respectively. Baseline EFs predicted both internalizing and externalizing symptoms, and the predictive value of EFs on psychopathology symptoms at 10-year follow-up was accounted for by cognitive flexibility. Baseline ADHD symptoms were a significant predictor of all symptom domains at all time points. Thus, childhood EFs, in particular cognitive flexibility, can predict psychopathology symptoms in emerging adulthood beyond the effect of ADHD symptoms. This supports dominating theories of ADHD stating that executive dysfunction contributes to the observed phenotype, including associated psychopathology symptoms, and suggests that EFs are important targets of interventional efforts., (© 2022. The Author(s).)

Adverse childhood experiences, including child maltreatment (CM), are relevant environmental risk factors for bipolar disorder (BD). However, little is known about the interaction of the type, duration and frequency of abuse with the timing of abuse in BD. The aim of this study was to investigate the different patterns of childhood trauma (frequency, type and chronology) between BD patients and healthy controls (HCs) and to identify BD-sensitive periods of exposure to CM that could influence functioning outcomes. The Maltreatment and Abuse Chronology Exposure (MACE) scale was used to evaluate the importance of the type and timing of maltreatment in a sample of 60 patients diagnosed with euthymic BD. Additionally, 76 HCs were recruited for comparison. All participants were of European-Caucasian origin and were assessed in the 2016-2019 period. To identify the variables that maximally differentiated the type and timing of exposure to CM between the BD and HC groups, a linear mixed effects model and random forest (RF) analyses were applied. We showed that multiplicity and severity, nonverbal emotional abuse, witnessing interparental violence and emotional neglect were the main factors associated with BD. In addition, regarding the occurrence of maltreatment in BD patients, we identified two sensitive periods with a principal peak at the age of 6 and a secondary peak at the age of 11. Functionality at the assessment time was associated with CM in adolescence for both HC and BD participants. Although the sample size and retrospective nature of the MACE instrument were the main limitations of our study, we were unable to explore the role of variables such as sex or socioeconomic status. We concluded that the multiplicity and sensitivity of CM exposure, mainly of the emotional type, during middle childhood are important risk factors for BD, at least in the European-Caucasian cultural setting.

The aim of this open study was to delineate domains of benefit and effect size measures to design an appropriately powered randomized control trial to assess the efficacy of Brain Balance @ exercises and Interactive Metronome @ training (BB/IM) on ADHD symptoms in children. Participants underwent an extensive 15-week, 5 time per week, at-home training program. Results were assessed in 16 youths with ADHD (14M/2F, 10.8±1.7 years) who completed the program and compared to 8 typically developing controls (4M/F4, 11.0±1.8 years). BB/IM was associated with a significant reduction of 8.3 and 8.2 points on the Conner's Parent Rating Scale - Revised and the ADHD Rating Scale - IV. BB/IM was not associated with improvement on the Quotient ADHD System but with rate-dependent effects on hyperactivity and attention that were similar to previously reported effects of low dose methylphenidate. Both therapeutic and rate-dependent effects were observed on the Tower of London. The study provides information that could be used to design a randomized control trial, which is required for proof of efficacy. A key limitation is that 59% of the 39 enrolled participants with ADHD dropped out of the study and a new study should include multiple ratings during the course of treatment., Competing Interests: Declaration of Competing Interest Dr. Teicher was provided with travel and accommodation to present at a Brain Balance Center annual meeting but did not receive an honorarium. He has received de minimis consulting fees from Brain Balance and Interactive Metronome. Dr. Teicher developed the Quotient ADHD System that was licensed to BioBehavioral Diagnostics/Pearson and received royalties for its use in accordance with conflict of interest policies at Harvard Medical School and Partners Health Care. Quotient ceased being licensed on January 1, 2019. None of the other authors have any declarations of interest to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Posttraumatic stress disorder (PTSD) is a heritable (h 2  = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10 -8 ). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further., (© 2022. The Author(s).)

Background: Childhood adversity has been found to impact stress and brain reward systems but it is unclear whether interactions between these systems might explain resilient vs. non-resilient trajectories following childhood sexual abuse (CSA). To address this gap, we adopted a multimodal approach in which cortisol reactivity to an acute stressor was assessed in conjunction with behavioral and neural measures of reward responsiveness in females with major depressive disorder (MDD) or no psychiatric disorders (i.e., resilient) who experienced CSA compared to females with and without MDD who did not experience abuse., Methods: Latent Class Mixed Modelling (LCMM) identified classes of adults ( n  = 62; M Age  = 26.48, SD = 5.68) characterized by distinct cortisol trajectories in response to a combined social evaluative cold pressor task. Classes were examined for their history of CSA and resilience as well as behavioral and neural measures of reward responsiveness using 128-channel electroencephalography (event-related potentials and source localization analysis)., Results: LCMM analysis identified two distinct classes of individuals with increased ( Responders ) or blunted ( Non-Responders ) cortisol reactivity to an acute stressor. Unlike Responders, Non-Responders did not modulate reward responses throughout the stress manipulation. No differences emerged between Responders and Non-Responders in terms of CSA or resilience. However, exploratory results showed that blunted cortisol response and non-modulation of reward responses emerged for those who experienced CSA at a younger age., Conclusions: Co-occurring blunted stress and reward reactivity emerged irrespective of adults' experience of CSA or resilience. However, preliminary findings showed that CSA ending during peripubertal development was associated with blunted cortisol and reward responsiveness. Future research needs to replicate findings in larger samples and could investigate if increasing reward responsiveness during critical times of neurodevelopment could normalize stress reactivity to future stressors and thus promote resilience., Competing Interests: Over the past 3 years, Dr. Pizzagalli has received consulting fees from 10.13039/100005306Albright Stonebridge Group, 10.13039/100001003Boehringer Ingelheim, Compass Pathways, Concert Pharmaceuticals, Engrail Therapeutics, 10.13039/100014593Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, and 10.13039/100007723Takeda Pharmaceuticals; honoraria from the Psychonomic Society and American Psychological Society (for editorial work) and Alkermes, and research funding from 10.13039/100000025NIMH, 10.13039/100001068Dana Foundation, 10.13039/100000874Brain and Behavior Research Foundation, Millennium Pharmaceuticals. In addition, he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (former BlackThorn Therapeutics), and Neuroscience Software. Dr. Pizzagalli has a financial interest in Neumora Therapeutics (former BlackThorn Therapeutics), which has licensed the copyright to the Probabilistic Reward Task through Harvard University. Dr. Pizzagalli's interests were reviewed and are managed by McLean Hospital and Massachusetts General Brigham in accordance with their conflict-of-interest policies. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors report no financial relationships with commercial interest., (© 2022 The Authors.)

Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs)., Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms., Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program., Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Corpus callosum (CC) abnormalities have been observed in several psychiatric disorders. Maltreatment has also been associated with marked differences in CC anatomy and microstructure, though rarely controlled for in psychiatric neuroimaging studies. The aim of this study was to identify type and timing of maltreatment associated with alterations in CC microstructure and to ascertain if they differ by sex. T1 and diffusion-weighted MRIs were obtained from 345 (135 M/210 F) healthy 18-25-year-olds. The Maltreatment and Abuse Chronology of Exposure scale provided retrospective data on exposure to ten types of maltreatment across each year of childhood. AI predictive analytics were used to identify the most significant type and time risk factors. The most striking maltreatment-associated alterations in males were in axial diffusivity and were most specifically associated with exposure to emotional abuse or neglect during segment-specific sensitive periods. In contrast, maltreatment was associated with marked alteration in radial diffusivity and fractional anisotropy in females and was most specifically associated with early physical neglect during one common sensitive period involving all segments except the splenium. Overall sex differences, controlling for maltreatment, brain size, and sociodemographic factors were limited to the genu with greater fractional anisotropy in males and radial diffusivity in females. These findings suggest that maltreatment may target myelinization in females and axonal development in males and that these sex differences need to be taken into account in studies seeking to delineate the contribution of CC abnormalities and interhemispheric communication to psychiatric disorders., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Childhood maltreatment is the most important preventable risk factor for psychiatric disorders. Maltreated individuals typically develop psychiatric disorders at an earlier age, have a more pernicious course, more comorbidities, greater symptom severity, and respond less favorably to treatments than non-maltreated individuals with the same primary DSM-5 diagnosis. Furthermore, maltreated individuals have alterations in stress-susceptible brain regions, hypothalamic-pituitary-adrenal response, and inflammatory marker levels not discernible in their non-maltreated counterparts. Hence, maltreated and non-maltreated individuals with the same primary DSM-5 diagnoses appear to be clinically and neurobiologically distinct. The failure to embody this distinction in DSM-5 has interfered with our ability to discover novel treatments, to recommend currently available treatments most likely to be efficacious, and has been a largely unrecognized confound that has thwarted our ability to identify the biological basis for major psychiatric disorders. Incorporating this distinction into DSM will help transform this sign and symptom-based classification system to a more etiologically informed nosology. We discuss several diagnostic alternatives and recommend the inclusion of a Developmental Trauma Disorder diagnosis for severely dysregulated individuals, of all ages, with numerous comorbidities, who experienced interpersonal victimization and disruptions in attachment, such as emotional maltreatment or neglect. For less severely affected maltreated individuals, we suggest using conventional diagnostic categories, such as major depression, but with an essential modifier indicating a history of childhood maltreatment, or early life stress, to delineate the ecophenotypic variant. Implementing this strategy should improve our ability to effectively diagnose and treat individuals with psychiatric disorders and to accelerate discovery., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Childhood maltreatment represents a form of trauma capable of altering fundamental neurobiological properties and negatively impacting neurodevelopmental processes. An outcome of childhood maltreatment is the emergence of psychopathology, which might become evident during childhood or adolescence, but might also project into adulthood. In this Review, we propose a biobehavioural framework in which childhood maltreatment and the associated aberrant neurobiological mechanisms and behavioural processes additionally lead to the onset of altered pain processing and, ultimately, the existence of pain syndromes. Considering that subpopulations of maltreated children show preserved function and minimal psychiatric or pain symptoms, compensatory mechanisms-perhaps instilled by robust psychosocial support systems-are also discussed. We present validated tools and experimental methods that could facilitate better comprehension of the interactions between childhood maltreatment, psychopathology, and pain. Such tools and approaches can in parallel be implemented to monitor abnormal pain-related processes and potentially guide early intervention strategies in cases of childhood maltreatment., Competing Interests: Declaration of interests JG-H has received consulting fees from Alkermes Biopharmaceuticals and Sunovion Pharmaceuticals, and serves on the scientific advisory board for Mightier by Neuromotion Labs. JU has received consulting fees from Orion Corporation. MC, MHT, HvdH, DO, and AKS declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Early life stress (ELS) and major depressive disorder (MDD) share neural network abnormalities. However, it is unclear how ELS and MDD may separately and/or jointly relate to brain networks, and whether neural differences exist between depressed individuals with vs without ELS. Moreover, prior work evaluated static versus dynamic network properties, a critical gap considering brain networks show changes in coordinated activity over time. Seventy-one unmedicated females with and without childhood sexual abuse (CSA) histories and/or MDD completed a resting state scan and a stress task in which cortisol and affective ratings were collected. Recurring functional network co-activation patterns (CAPs) were examined and time in CAP (number of times each CAP is expressed) and transition frequencies (transitioning between different CAPs) were computed. The effects of MDD and CSA on CAP metrics were examined and CAP metrics were correlated with depression and stress-related variables. Results showed that MDD, but not CSA, related to CAP metrics. Specifically, individuals with MDD (N = 35) relative to HCs (N = 36), spent more time in a posterior default mode (DMN)-frontoparietal network (FPN) CAP and transitioned more frequently between posterior DMN-FPN and prototypical DMN CAPs. Across groups, more time spent in a posterior DMN-FPN CAP and greater DMN-FPN and prototypical DMN CAP transition frequencies were linked to higher rumination. Imbalances between the DMN and the FPN appear central to MDD and might contribute to MDD-related cognitive dysfunction, including rumination. Unexpectedly, CSA did not modulate such dysfunctions, a finding that needs to be replicated by future studies with larger sample sizes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Over the past 3 years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, the Dana Foundation, Millennium Pharmaceuticals, and NIMH; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. All other authors have no conflicts of interest or relevant disclosures., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Childhood maltreatment affects approximately 25% of the world's population. Importantly, the children of mothers who have been maltreated are at increased risk of behavioral problems. Thus, one important priority is to identify child neurobiological processes associated with maternal childhood maltreatment (MCM) that might contribute to such intergenerational transmission. This study assessed the impact of MCM on infant gray and white matter volumes and infant amygdala and hippocampal volumes during the first 2 years of life., Methods: Fifty-seven mothers with 4-month-old infants were assessed for MCM, using both the brief Adverse Childhood Experiences screening questionnaire and the more detailed Maltreatment and Abuse Chronology of Exposure scale. A total of 58% had experienced childhood maltreatment. Between 4 and 24 months (age in months: mean = 12.28, SD = 5.99), under natural sleep, infants completed a magnetic resonance imaging scan using a 3T Siemens scanner. Total brain volume, gray matter volume, white matter volume, and amygdala and hippocampal volumes were extracted via automated segmentation., Results: MCM on the Adverse Childhood Experiences and Maltreatment and Abuse Chronology of Exposure scales were associated with lower infant total brain volume and gray matter volume, with no moderation by infant age. However, infant age moderated the association between MCM and right amygdala volume, such that MCM was associated with lower volume at older ages., Conclusions: MCM is associated with alterations in infant brain volumes, calling for further identification of the prenatal and postnatal mechanisms contributing to such intergenerational transmission. Furthermore, the brief Adverse Childhood Experiences questionnaire predicted these alterations, suggesting the potential utility of early screening for infant risk., (© 2021 The Authors.)

Background: The opioid epidemic is a global tragedy even with current treatments, and a novel, safe, and effective treatment would be welcomed. We report here our findings from our second randomized controlled trial to evaluate unilateral transcranial photobiomodulation as a treatment for opioid use disorder. Methods: We enrolled 39 participants with active opioid cravings at 2 sites, 19 received the active treatment which consisted of a 4-min twice weekly (every 3 or 4 days) application of a light-emitting diode at 810 nm with an irradiance of 250 mW/cm 2 and a fluence of 60 J/cm 2 to the forehead over either the left or right dorsolateral prefrontal cortex with a fluence to the brain of 2.1 J/cm 2 . Twenty participants received a sham treatment with the same device with foil over the bulb. The side of the treatment was based on Dual-Brain Psychology, which posits that one hemisphere is more affected by past maltreatments and is more prone to anxiety and drug cravings that the other hemisphere. We treated the hemisphere with the more positive hemispheric emotional valence (HEV) by 2 tests for HEV. Results: Our primary outcome was changes in pre-treatment opioid craving scale (OCS) minus baseline, and we found using a mixed model that the active group had a highly significant treatment * time benefit over the sham group, p < 0.0001, effect size at the last follow-up of 1.5. The active treatment benefited those not on buprenorphine as well as those not on it. The TimeLine Follow Back measure of opioid use was significantly better in the actively treated group, p = 0.0001, with an effect size of 0.45. We observed no adverse effects. Conclusion: Active unilateral transcranial photobiomodulation to the brain hemisphere with the better HEV was better than sham in the reduction of opioid cravings and opioid use to a very significant degree in a RCT of 39 participants at 2 independent sites. In the active group those on buprenorphine and those not on it both had improvements in cravings over the study. No adverse responses were reported in either group. ClinicalTrials.gov Identifier: NCT04340622., Competing Interests: FS is the Founder of MindLight, LLC, which intends further research and commercialization of the methods and device described in the paper. The author has been issued 2 US patents which cover the method of unilateral tPBM to a positive hemisphere as described in this study: U.S. Patent No. 8303636, Methods for treating psychiatric disorders using light energy. Issued 11/06/2012, and U.S. Patent No. 8574279, Methods for treating psychiatric disorders using light energy. Issued 11/05/2013. He has filed on December 5, 2019 a US patent application, #16/703,937, Method and Apparatus for Determining Hemispheric Emotional Valence, and on August 3, 2020, he filed a US provisional patent application #63060177, Enhanced Treatment of Brain Disorders Utilizing Coordinated Negative Suppressive Stimulation and Related Devices Designed to Achieve Treatment. EF and WS were employed by MindLight, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schiffer, Khan, Bolger, Flynn, Seltzer and Teicher.)

Purpose of Review: Survivors of childhood maltreatment are at high risk for developing complex psychiatric disorders. Traditional treatments, including psychopharmacology, tend to be less efficacious for this population. This scoping review aimed to discuss existing empirical studies on the effects of mindfulness-based interventions for adult childhood trauma survivors, as well as the documented clinical challenges and adaptations for this population., Recent Findings: We reviewed 17 research articles that measured the effects of mindfulness-based interventions for adults with childhood maltreatment histories. These studies showed that mindfulness-based interventions can be beneficial for childhood maltreatment survivors to alleviate psychological symptoms including stress, anxiety, recurrent depression, substance use, and post-traumatic stress. Studies had a wide range of methodological quality and reported a broad range of effect sizes. The wide variety of outcome measures and control conditions made it difficult to compare across studies., Summary: Mindfulness-based interventions can be beneficial for addressing psychopathology among adults with childhood maltreatment histories, although some adaptations can be necessary to address possible challenges this population are likely to encounter. More research is needed to specifically evaluate the clinical effects among childhood maltreatment survivors and to directly compare the effects among those with and without childhood maltreatment histories.

The amygdala morphometry is highly sensitive to stress and is implicated in various psychopathologies that are common among individuals with childhood maltreatment histories. This pilot study investigated bilateral amygdala volumetric changes among 15 young adults with childhood maltreatment histories undergoing an eight-week mindfulness intervention compared to 19 matched participants in a waitlist control group. Results indicated significant cross-individual variability in amygdala volumetric changes after the intervention, which resulted in no significant group by time interaction effect. Degree and direction of changes in right amygdala volume correlated with baseline volumes, with larger than average right amygdala showing an increase in volume and smaller amygdala a decrease. Increasing right amygdala volume was also associated with higher intervention compliance, and a greater increase in self-compassion. Increasing left amygdala volume was associated with more reduction in perceived stress, rejection sensitivity and interpersonal distress. Findings from the present study highlight the importance of investigating individual variability and its contributing factors in future studies on neural responses of mindfulness interventions, as well as the distinct responses of the left and right amygdala., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The ability to resist adverse outcomes, or demonstrate resilience after exposure to trauma is a thriving field of study. Yet ongoing debate persists regarding definitions of resilience, generalizability of the extant literature, neurobiological correlates, and a consensus research agenda. Objectives: To address these pressing questions, Drs. Christy Denckla and Karestan Koenen (co-chairs) convened a multidisciplinary panel including Drs. Dante Cicchetti, Laura Kubzansky, Soraya Seedat, Martin Teicher, and David Williams at the 2019 annual meeting of the International Society for Traumatic Stress Studies (ISTSS). Questions included (1) how have definitions of resilience evolved, (2) what are the best approaches to capture the complexity of resilience processes, and (3) what are the most important areas for future research? Methods: The proceedings of this panel are summarized in this report, and prominent themes are synthesized and integrated. Results: While different definitions emerged, all shared a focus on conceptualizing resilience at multiple levels, from the biological to the social structural level, a focus on the dynamic nature of resilience, and a move away from conceptualizing resilience as only an individual trait. Critical areas for future research included 1) focused efforts to improve assessment that has international and cross-cultural validity, 2) developing within-study designs that employ more intensive phenotyping strategies, 3) examining outcomes across multiple levels and domains, and 4) integrating conceptualizations of resilience from the individual-level to the larger social context at the population health level. Conclusion: Increasingly sophisticated and nuanced conceptual frameworks, coupled with research leveraging advances in genetics, molecular biology, increased computational capacity, and larger, more diverse datasets suggest that the next decade of research could bring significant breakthroughs., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Childhood maltreatment has long lasting impacts on neural development of the hippocampus, which is important for learning and memory. The present study aimed to assess the effects of a mindfulness based intervention on hippocampal morphometry and episodic memory in this population. We administered MRI, psychological questionnaires and an episodic memory task to 21 participants (5 males) before and after a mindfulness-based behavioral intervention, compared to 21 participants (7 males) on the waiting list. Changes in Gray Matter Volume (GMV) in bilateral hippocampi were analyzed with Voxel-Based Morphometry (VBM). One cluster was identified in the right hippocampus with a group by time interaction effect that consisted of 130 contiguous voxels but fell short of significance with full FDR correction (p = 0.077). GMV in this cluster increased by 0.76% in the mindfulness group and decreased by 0.78% in the control group. Within the mindfulness group, changes in hippocampal GMV were negatively associated with changes in perceived stress and depression severity and positively associated with enhancement in performance accuracy on the episodic memory task. Findings from this pilot study suggest that a mindfulness-based intervention may lead to an increase in partial hippocampal GMV with associated symptom reduction and improvement in episodic memory., Competing Interests: Declarations of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Individuals with a childhood maltreatment history tend to have various psychological symptoms and impaired social functioning. This study aimed to investigate the related therapeutic effects of a mindfulness-based intervention in this population., Methods: We analyzed self-report questionnaire scores of the Mindful Attention Awareness Scale (MAAS), Non-Attachment Scale (NAS), Adult Rejection Sensitivity Questionnaire (A-RSQ), Interpersonal Reactivity Index (IRI), PTSD CheckList (PCL), and Anxiety Sensitivity Index (ASI), from 16 (3 males) young adults (age range 22-29) with mild to moderate childhood maltreatment, compared to 18 matched participants (6 males) on a waiting list, during both pre- and post-intervention/waiting periods. Analyses were conducted with linear mixed effects models, partial correlation analyses and t -tests., Results: There were group by time interaction effects with the scores of MAAS, NAS, PCL, IRI-Fantasy, and A-RSQ ( p < .05). The mindfulness group had significant increase in MAAS (17.325%) and NAS (8.957%) scores, as well as reduction in PCL (15.599%) and A-RSQ (23.189%) scores ( p < .05). Changes in non-attachment, but not mindfulness, had significant contributions to the score changes of PCL (16.375%), ASI (36.244%), IRI-Personal Distress (24.141%), IRI-Empathic Concern (16.830%), and A-RSQ (10.826%) ( p < .05). The number of intervention sessions attended was correlated with score changes of NAS ( r = .955, p < .001), and ASI ( r = -.887, p < .001), suggesting a dose-dependent effect., Conclusions: Findings from this pilot study suggest that the mindfulness-based intervention improved mindfulness, non-attachment and empathy, which contributed to reduced interpersonal distress, rejection sensitivity and other psychological symptoms., Competing Interests: Disclosures All authors declare no conflict of interest.

Childhood maltreatment is associated with increased risk for psychiatric and substance use disorders. However, some maltreated individuals appear resilient to these consequences while manifesting the same array of brain changes as maltreated individuals with psychopathology. Hence, a critical issue has been to identify compensatory brain alterations in these resilient individuals. We recently reported that maltreatment is associated with a more vulnerable structural brain network architecture. Resilient individuals have this same vulnerability but appeared to be able to effectively compensate due to reduced nodal efficiency (ability of a node to influence the global network) in 9 specific brain regions that moderate the relationship between maltreatment and psychopathology. Following up we now report that network vulnerability increases progressively during late adolescence to plateau at about 21 years of age, which may help to explain age of onset of psychopathology. Further, we found that network vulnerability was most significantly affected by parental verbal abuse between 16-18 years of age and number of types of maltreatment during childhood. Asymptomatic individuals with no history of psychopathology had more prominent alterations in nodal efficiency than asymptomatic individuals with prior history, who specifically showed reduced nodal efficiency in right amygdala and right subcallosal gyrus. Experiencing inadequate financial sufficiency during childhood increased risk of susceptibility versus resilience by 2.98-fold (95% CI 1.49-5.97, p = 0.002) after adjusting for differences in exposure to maltreatment. Interestingly, adequate-to-higher financial sufficiency appeared to be protective and was associated with reduced nodal efficiency in the right postcentral gyrus and subcallosal gyrus 'resilience' nodes.

Parkinson's disease (PD) is a neurodegenerative disorder associated with loss of striatal dopamine, secondary to degeneration of midbrain dopamine (mDA) neurons in the substantia nigra, rendering cell transplantation a promising therapeutic strategy. To establish human induced pluripotent stem cell-based (hiPSC-based) autologous cell therapy, we report a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, we developed a method to more efficiently generate clinical-grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, we established a "spotting"-based in vitro differentiation methodology to generate functional and healthy mDA cells in a scalable manner. Third, we developed a chemical method that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restores motor function and reinnervates host brain, while showing no evidence of tumor formation or redistribution of the implanted cells. We propose that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h 2 snp ), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n = 124,000) and a replication sample from the Psychiatric Genomics Consortium-posttraumatic stress disorder group (PGC-PTSD) (n = 26,290). h 2 snp for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression. PRS was calculated using PRSice and mtCOJO was used to perform conditional analysis. Two genome-wide significant loci associated with childhood maltreatment (rs142346759, p = 4.35 × 10 -8 , FOXP1; rs10262462, p = 3.24 × 10 -8 , FOXP2) were identified in the discovery dataset but were not replicated in PGC-PTSD. h 2 snp for childhood maltreatment was ~6% and the PRS derived from the UKBB was significantly predictive of childhood maltreatment in PGC-PTSD (r 2  = 0.0025; p = 1.8 × 10 -15 ). The most significant genetic correlation of childhood maltreatment was with depressive symptoms (r g  = 0.70, p = 4.65 × 10 -40 ), although we show evidence that our top hits may be specific to childhood maltreatment. This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment. Speculatively, FOXP genes might influence externalizing traits and so be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with a range of phenotypes, may ultimately be useful in in developing targeted treatment and prevention strategies.

The hippocampus plays an important role in stress regulation and has been the focus of research regarding the effects of early life stress on brain development. Much of this research has focused on severe forms of early adversity, particularly maltreatment. However, a handful of studies are now examining the effects of more subtle variations in quality of early caregiving on hippocampal development. In addition, both early caregiving and hippocampal volumes have been linked to psychopathology, particularly borderline personality disorder (BPD) and its associated features, such as suicidality. In the context of a 30-year longitudinal study, we assessed associations between maternal withdrawal in infancy, hippocampal volume, and BPD features in adulthood. Hippocampal volume was assessed among 18 adults (29.33 ± 0.49 years) assessed for caregiving quality at 18 months (M =18.55 months, SD = 1.21 months) and followed longitudinally to age 29. Left hippocampal volume in adulthood was associated with maternal withdrawal in infancy, but not by other components of disrupted parenting. Other risk factors, including maternal psychosocial risk and severity of maltreatment in childhood, were not significantly related to left hippocampal volume. Left hippocampal volume was further associated with increased BPD features and suicidality/self-injury. In addition, left hippocampal volume partially mediated the association between early maternal withdrawal and later suicidality/self-injury. Results point to the importance of quality of early care for hippocampal development and suggest that the first two years of life may be an early sensitive period during which intervention could have important consequences for long-term psychological functioning into adulthood., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Child maltreatment (CM) is the most important preventable risk factor for psychopathology and there is a pressing need to understand how CM gets 'under the skin' to markedly increase risk in some individuals as well as a comparable effort to identify factors associated with better than expected outcomes in other individuals. This special issue of Child Maltreatment provides a series of sophisticated studies on the neurobiological impact of CM, of which we have chosen 4 articles to comment on.The articles by Oshri et al., and Peveril, Sheridan, Busso & McLaughlin are amygdala centric and provide important new information on the impact of CM on the morphology and functional connectivity of this highly stress susceptible structure. The article by Demers et al., presents data from a longitudinal study that illustrates the potentially disruptive effects of CM on the association between maternal relationship quality, frontal cortical development and symptomatology. Finally, the De Bellis et al., study addresses the pressing question, which we have labeled the 'ecophenotype hypothesis', that postulates that maltreated and non-maltreated individuals with the same primary DSM diagnosis are clinically and neurobiologically distinct, and provides new evidence for a specific prefrontal cortical neurobiological abnormality in the maltreated subtype.

Background: Individuals who were maltreated during childhood are faced with increased risks for developing various psychological symptoms that are particularly resistant to traditional treatments. This pilot study investigated the effects of a mindfulness based behavioral intervention for young adults with a childhood maltreatment history., Methods: This study looked at self-report psychological questionnaires from 20 subjects (5 males) before and after a mindfulness-based behavioral intervention, compared to 18 subjects (6 males) in the waiting list control group (age range 22-29); all subjects experienced mild-to-moderate childhood maltreatment. We analyzed changes in stress, anxiety, depression, mindfulness and self-compassion related to the intervention with linear mixed effects models; we also analyzed the relationships among questionnaire score changes with partial correlation analyses and mediation analysis., Results: Linear mixed effects model analyses revealed significant group by time interaction on stress ( p < 0.01), anxiety ( p < 0.05), and self-compassion ( p < 0.01), with the mindfulness group having significant reduction in stress and anxiety ( p < 0.01), and significant increase in mindfulness ( p < 0.05) and self-compassion ( p < 0.001). Partial correlation analyses showed that among all subjects from both groups, changes in mindfulness positively correlated with changes in self-compassion ( r = 0.578, p = 0.001), which negatively correlated with changes in depression ( r = -0.374, p = 0.05) and anxiety ( r = -0.395, p < 0.05). Changes in self-compassion mediated, in part, the relationship between changes in mindfulness and changes in anxiety (average causal mediation effect = -4.721, p < 0.05). We observed a dose-dependent effect of the treatment, i.e., the number of intervention sessions attended were negatively correlated with changes in stress ( r = -0.674, p < 0.01), anxiety ( r = -0.580, p < 0.01), and depression ( r = -0.544, p < 0.05), after controlling for the individual differences in childhood maltreatment severity., Conclusion: Our results suggest that, to some extent, the mindfulness-based intervention can be helpful for improving self-compassion and psychological health among young adults with a childhood maltreatment history., Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02447744., (Copyright © 2019 Joss, Khan, Lazar and Teicher.)

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Background: Childhood adversities and traumatic events have each been associated with hypothalamus-pituitary-adrenal (HPA) axis dysregulation and trauma-related symptoms in adulthood. Hair cortisol concentration (HCC) reflects cumulative cortisol levels over the course of months and is discussed as a potential marker between trauma-induced neuroendocrine dysfunction and trauma-related symptoms. The present study examines this hypothetical link by delineating the impact of exposure to categories of abuse and neglect during development and lifetime traumatic experiences on HCC and trauma-related symptoms., Methods: The Maltreatment and Abuse Chronology Exposure (MACE) scale, Life Events Checklist, and predictive analytics were used to evaluate the importance of type and timing of maltreatment and trauma load on HCC in inpatients (n = 183) with different psychiatric diagnoses. Additionally, a comparison group of n = 75 controls were recruited from the community. The extent to which the relationship between trauma load and trauma-related symptoms was influenced by childhood adversities and HCC was determined by analysis of variance., Results: Early neglect, in particular neglect at 3 years, emerged as the most important predictor of adult HCC. Post-hoc explanatory analysis showed that patients with high neglect at age 3 had lower HCC compared to patients with low neglect at age 3 and controls. Patients with high neglect at age 3 and low cortisol reported increased trauma-related symptoms upon trauma exposure., Conclusion: Results strengthen evidence that inadequate care and neglect during critical periods alter HPA axis biology towards enduring reduction in cortisol, the latter being associated with augmented trauma-related symptoms upon trauma exposure. If validated by longitudinal assessments these cross-sectional findings suggest biological mechanisms of childhood adversities into psychopathology in adulthood., (Copyright © 2019. Published by Elsevier Ltd.)

Importance: Abnormalities in amygdala response to threatening faces have been observed in anxiety disorders, autism, bipolar disorder, depression, posttraumatic stress disorder, and schizophrenia. Abnormally hyperactive and hypoactive responses have typically been associated with anxiety and inhibition vs risk taking and inappropriate social behaviors. Maltreatment is a major risk factor for most of these disorders and is associated with abnormal amygdala function., Objective: To identify the type and age of exposure to childhood maltreatment that are associated with hyperactive and hypoactive amygdala responses in young adulthood., Design, Setting, and Participants: Data collection for this retrospective cohort study took place from November 8, 2010, to August 23, 2012. Data analyses were conducted from September 20, 2012, to June 27, 2018. Participants were recruited from the urban and suburban Boston vicinity without diagnostic restrictions based on exposure history., Exposures: The Maltreatment and Abuse Chronology of Exposure (MACE) scale was used to retrospectively assess type and age of exposure to childhood maltreatment., Main Outcomes and Measures: Activation and pattern information functional magnetic resonance imaging were used to assess bilateral amygdala response to angry and fearful faces vs neutral faces or shapes, and sensitive exposure periods were identified using cross-validated artificial intelligence predictive analytics (50 averaged randomized iterations with training on 63.3% and testing on 36.7% of the sample)., Results: Of the 202 participants (mean [SD] age, 23.2 [1.7] years; 118 [58.4%] female), 52 (25.7%) reported no exposure to maltreatment and 150 (74.3%) reported exposure to 1 or more maltreatment types. Eight participants (15.1%) with a MACE score of 0 and 51 (34.2%) with a MACE score of 1 or higher had a history of major depression (odds ratio, 2.40; 95% CI, 1.05-6.06; P = .03); 8 unexposed participants (15.1%) and 46 with MACE scores of 1 or higher (30.9%) had a history of 1 or more anxiety disorders (odds ratio, 2.45; 95% CI, 1.03-6.50; P = .03). Retrospective self-report of physical maltreatment between 3 and 6 years of age and peer emotional abuse at 13 and 15 years were associated with amygdala activation to emotional faces vs shapes. Early exposure was associated with blunted response (β = -0.17, P < .001), whereas later exposure was associated with augmented response (β = 0.16, P < .001). Prepubertal vs postpubertal maltreatment was associated with an opposite response on the voxelwise response pattern in clustering stimuli of the same type (eg, mean [SD] emotional ellipse areas for physical maltreatment at age 4 years vs nonverbal emotional abuse at 13 years: 1.41 [1.05] vs 0.25 [0.10], P < .001) and in distinguishing between stimuli of different types (eg, mean [SD] emotional vs neutral faces distance for peer emotional abuse at age 6 years vs 13 years: 1.89 [0.75] vs 0.80 [0.39], P < .001)., Conclusions and Relevance: The findings suggest that prepubertal vs postpubertal developmental differences in the association between maltreatment and amygdala response to threatening or salient stimuli exist. Understanding the role of adversity in different sensitive exposure periods and the potential adaptive significance of attenuated vs enhanced amygdala response may help explain why maltreatment may be a risk factor for many different disorders and foster creation of targeted interventions to preempt the emergence of psychopathology in at-risk youths.

Background: Childhood maltreatment is a major risk factor for psychopathology. However, some maltreated individuals appear remarkably resilient to the psychiatric effects while manifesting the same array of brain abnormalities as maltreated individuals with psychopathology. Hence, a critical aim is to identify compensatory brain alterations that enable resilient individuals to maintain mental well-being despite alterations in stress-susceptible regions., Methods: Network models were constructed from diffusion tensor imaging and tractography in physically healthy unmedicated 18- to 25-year-old participants (N = 342, n = 192 maltreated) to develop network-based explanatory models., Results: First, we determined that susceptible and resilient individuals had the same alterations in global fiber stream network architecture using two different definitions of resilience: 1) no lifetime history of Axis I or II disorders, and 2) no clinically significant symptoms of anxiety, depression, anger-hostility, or somatization. Second, we confirmed an a priori hypothesis that right amygdala nodal efficiency was lower in asymptomatic resilient than in susceptible participants or control subjects. Third, we identified eight other nodes with reduced nodal efficiency in resilient individuals and showed that nodal efficiency moderated the relationship between maltreatment and psychopathology. Fourth, we found that models based on global network architecture and nodal efficiency could delineate group membership (control, susceptible, resilient) with 75%, 82%, and 80% cross-validated accuracy., Conclusions: Together these findings suggest that sparse fiber networks with increased small-worldness following maltreatment render individuals vulnerable to psychopathology if abnormalities occur in specific nodes, but that decreased ability of certain nodes to propagate information throughout the network mitigates the effects and leads to resilience., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Trauma and adverse childhood experiences (ACE) occur more often in mental illness, including psychosis, than in the general population. Individuals with psychosis (cases) report a higher number and severity (dose) of adversities than healthy controls. While a dose-dependent increase of adversities has been related to more severe psychopathology, the role of type and timing is still insufficiently understood on the exacerbation of positive and negative psychotic symptoms. Moreover, dissociative symptoms were examined as potential mediator between adversities and severity of psychotic symptoms., Methods: Exposure to adversities were assessed by interviews in n=180 cases and n=70 controls. In cases, symptom severities were obtained for psychotic symptoms and dissociation. Conditioned random forest regression determined the importance of type and timing of ACE for positive and negative symptom severity, and mediator analyses evaluated the role of dissociative symptoms in the relationship between adversities and psychotic symptoms., Results: Cases experienced substantially more abuse and neglect than controls. Adversities were related in a dose-dependent manner to psychotic disorder. An array of adversities was associated with more severe positive symptoms, while the conditioned random forest regression depicted neglect at age 10 as the most important predictor. Dissociative symptoms mediated the small relation of trauma load in childhood and positive symptoms., Conclusion: The role of trauma and ACE on psychotic symptoms can be specified by neglect during frontocortical development in the exacerbation of positive symptoms. The mediating role of dissociation is restricted to the relation of childhood trauma and positive symptoms., (Copyright © 2017 Elsevier B.V. All rights reserved.)