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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

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.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.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.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.

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.

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.

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.

Childhood adversity is commonly measured via retrospective self-report on the Adverse Childhood Experiences (ACE) questionnaire and the Childhood Trauma Questionnaire (CTQ). To facilitate comparison of studies and data employing these measures, we employed a variety of approaches to equate CTQ and ACE questionnaire responses pertaining to emotional, physical, and sexual abuse, as well as emotional and physical neglect. The accuracy, sensitivity, and specificity of these approaches suggest moderate to strong levels of questionnaire correspondence in a sample of middle-class young adults living in the United States (N=471; 273 female; mean age=23 years, SD=1.7 years) across maltreatment types, except for physical neglect (which exhibited poorer and more variable correspondence across approaches). Results in a validation sample (N=64; 43 female; mean age=19.1, SD=0.5) did not suggest model overfitting. We also provide an interactive web-based tool to examine questionnaire correspondence across approaches.

Adolescents typically sleep too little and feel drowsy during morning classes. We assessed whether early 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 (LiteBook Edge™) for 30 minutes each morning and used blue light blocking glasses for 2 hours before bedtime. LiteBooks™ 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. LiteBooks™ 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) earlier rise times on non-school days and reduced day-to-day variability in rise times; (4) increased dentate gyrus volume and (5) enhanced frontal connectivity with temporal, occipital and cerebellar regions during Go/No-Go task performance. Degree of bright light therapy use 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.

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

Childhood maltreatment is associated with an 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 and 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 the right amygdala and right subcallosal gyrus. Experiencing inadequate financial sufficiency during childhood increased the 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.

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.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry 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. publishersversion published

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). Posttraumatic stress disorder (PTSD) is a heritable (h2 = 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. publishersversion published

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

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.

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.

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.

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.

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., HIGHLIGHTS: • The field of psychological resilience is characterized by ongoing debate over definitions, generalizability, and a research agenda.•Evolving definitions share a focus on conceptualizing resilience at multiple levels, a focus on dynamic processes, and moving away from individual trait conceptualizations.• Future research recommendations include improving assessment cross-culturally, employing within-study designs, and examining outcomes at multiple levels and domains.

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.

Objective Reduced hippocampal volume and alterations in white matter tracts have been frequently reported in adults having the history of emotional maltreatment. We investigated whether these structural change occur in adolescents with previous verbal abuse (VA) experiences. Methods Hippocampal subfield volume and white matter structural connectivity measures were assessed in 31 first year male high school students with various degrees of exposure to parental and peer VA. Results The high VA group showed significant volume reduction in the left cornu ammonis (CA) 1 and left subiculum compared to the low VA group (p＜0.05). Volumes of left hippocampal subfields CA1 and subiculum were negatively correlated with previous VA experiences (p＜0.05). Increased mean diffusivity (MD) of the splenium of the corpus callosum was related to high VA score across all subjects (p＜0.05). There was an inverse relationship between volume of the CA1 and subiculum and MD of the splenium (p＜0.05). Conclusion Exposure to parental and peer VA may affect development of the left hippocampal subfields and the splenium of corpus callosum. These structural alterations can be discernible during adolescence.

Reactive attachment disorder (RAD) is a severe social functioning disorder associated with early childhood maltreatment where the child displays emotionally withdrawn/inhibited behaviors toward caregivers. Brain regions develop at different rates and regions undergoing rapid change may be particularly vulnerable during these times to stressors or adverse experiences. The aim of this study was to investigate the effect of type and timing of childhood adversities on structural alterations in regional gray matter (GM) volume in maltreated children with RAD. High-resolution magnetic resonance imaging datasets were obtained for children and adolescents with RAD (n = 21; mean age = 12.76 years) and typically developing (TD) control subjects (n = 22; mean age = 12.95 years). Structural images were analyzed using a whole-brain voxel-based morphometry approach and the type and timing of maltreatment, which may be more strongly associated with structural alterations, was assessed using random forest regression with conditional inference trees. Our findings revealed that there is a potential sensitive period between 5 and 7 years of age for GM volume reduction of the left primary visual cortex (BA17) due to maltreatment. We also found that the number of types of maltreatment had the most significant effect on GM volume reduction and that the second most significant variable was exposure to neglect. The present study provides the first evidence showing that type and timing of maltreatment have an important role in inducing structural abnormalities in children and adolescents with RAD., Highlights • We studied the effect of maltreatment type and timing on brain structure in RAD. • There was a sensitive period for GM volume reduction in the visual cortex. • The clinical symptoms of RAD showed the same sensitive period. • The number of types of maltreatment had significant effects on GM volume reduction. • Neglect was common and could be acting as a basis for the effects of maltreatment.

BackgroundExposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood.MethodsSeventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge.ResultsHigher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood.ConclusionsThreat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

Background: The majority of seasonal affective disorder (SAD) studies have evaluated the use of light or selective serotonin reuptake inhibitors (SSRI). The purpose of the present study was to evaluate bupropion sustained-released (SR), a non-SSRI antidepressant, for the treatment of SAD.

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., Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

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.

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 reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. 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 working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35×10−8,FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24×10−8,FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be ∼6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65×10−40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment.FOXPgenes could influence traits such as depression and thereby 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 various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

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