Environmental influences on the pace of brain development.

Childhood socio-economic status (SES), a measure of the availability of material and social resources, is one of the strongest predictors of lifelong well-being. Here we review evidence that experiences associated with childhood SES affect not only the outcome but also the pace of brain development. We argue that higher childhood SES is associated with protracted structural brain development and a prolonged trajectory of functional network segregation, ultimately leading to more efficient cortical networks in adulthood. We hypothesize that greater exposure to chronic stress accelerates brain maturation, whereas greater access to novel positive experiences decelerates maturation. We discuss the impact of variation in the pace of brain development on plasticity and learning. We provide a generative theoretical framework to catalyse future basic science and translational research on environmental influences on brain development.

The association between adverse childhood experiences and alterations in brain volume and cortical thickness in adults with alcohol use disorder.

BACKGROUND: Previous studies have established a connection between adverse childhood experiences (ACE) and alcohol use disorder (AUD), both of which are associated with alterations in grey matter volume (GMV) and cortical thickness (CT). The current study aimed to assess the neurobiological impact of ACE specifically in the context of AUD, as well as the role of maltreatment type (i.e., abuse or neglect) and timing. METHODS: Structural MRI data were collected from 35 adults with AUD (mean age: 40; 31% female) and 28 healthy controls (mean age: 36; 61% female). ACE were assessed retrospectively using the Childhood Trauma Questionnaire, and the Maltreatment and Abuse Chronology interview. Global and regional GMV and CT were estimated using voxel- and surface-based morphometry. RESULTS: Relative to the healthy controls, the AUD group had significantly reduced CT in the left inferior frontal gyrus, left circular sulcus of the insula and subcentral gyrus and sulci (cluster C1), and in the central sulcus and precentral gyrus (cluster C2). Within the AUD group, a reduction of CT in cluster C1 was significantly associated with higher severity of ACE and AUD. Type and timing analyses revealed a significant association between higher levels of abuse at ages 13 to 15 and reduced CT in cluster C1 within the AUD group. CONCLUSIONS: In adults with AUD, abuse experienced during early adolescence is associated with reduced CT in regions involved in inhibitory control, indicating the potential relevance of cognitive pathways in the association between ACE and AUD. Longitudinal studies are needed to confirm and expand upon current findings.

Childhood and adulthood trauma exposure: Associations with perinatal mental health and psychotherapy response.

Trauma exposure is strongly linked to maternal posttraumatic stress disorder (PTSD) and depressive symptoms during the perinatal period; however, childhood trauma exposure is often assessed without accounting for adult exposure. This study tested the unique impacts of childhood and adulthood trauma exposure on PTSD and depressive symptoms among pregnant women (N = 107, 82.9% Latina) enrolled in a nonrandomized intervention study. Regression analyses at baseline showed positive associations between trauma exposure and PTSD symptoms irrespective of trauma timing, childhood: B = 1.62, t(91) = 2.11, p = .038; adulthood: B = 2.92, t(91) = 3.04, p = .003. However only adulthood trauma exposure, B = 1.28, t(94) = 2.94, p = .004, was positively associated with depressive symptoms. Mixed-effects analyses of variance revealed interaction effects of time and adulthood trauma exposure, indicating that women with high degrees of adulthood trauma exposure had higher baseline levels of PTSD, F(1, 76.4) = 6.45, p = .013, and depressive symptoms, F(1, 87.2) = 4.88, p = .030, but showed a more precipitous decrease posttreatment than women with lower levels of adulthood trauma exposure. These findings support the clinical relevance of assessing both childhood and adulthood trauma exposure during the perinatal period given their impacts on baseline symptoms and psychotherapy response.

Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

The development and evaluation of a virtual, asynchronous, trauma-focused treatment program for adult survivors of childhood interpersonal trauma.

BACKGROUND: The long-term mental and physical health implications of childhood interpersonal trauma on adult survivors is immense, however, there is a lack of available trauma-focused treatment services that are widely accessible. This study, utilizing a user-centered design process, sought feedback on the initial design and development of a novel, self-paced psychoeducation and skills-based treatment intervention for this population. AIMS: To explore the views and perspectives of adult survivors of childhood interpersonal trauma on the first two modules of an asynchronous trauma-focused treatment program. METHODS: Fourteen participants from our outpatient hospital service who completed the modules consented to provide feedback on their user experience. A thematic analysis of the three focus groups was conducted. RESULTS: Four major themes emerged from the focus groups: (1) technology utilization, (2) module content, (3) asynchronous delivery, and (4) opportunity for interactivity. Participants noted the convenience of the platform and the use of multimedia content to increase engagement and did not find the modules to be emotionally overwhelming. CONCLUSIONS: Our research findings suggest that an asynchronous virtual intervention for childhood interpersonal trauma survivors may be a safe and acceptable way to provide a stabilization-focused intervention on a wider scale.

Sleep Quality, Sleep-Related Experiences, and Dissociation in Adult Survivors of Childhood Trauma.

OBJECTIVES: Exposure to traumatic stress in childhood increases the risk of sleep disturbances. Preliminary evidence suggests that the relationship between childhood trauma and sleep may depend on trauma chronicity. Additionally, little is known about the relationship between sleep and dissociation, a common symptom in post-traumatic stress disorder. This study examined sleep quality, sleep-related experiences, and dissociation in survivors of childhood trauma with different trauma chronicity. METHOD: Nine-hundred-and-fourteen community-dwelling adults completed an online survey. They were divided into three groups: no childhood trauma, short-term childhood trauma, and chronic childhood trauma. RESULTS: We found that survivors of chronic childhood trauma had poorer sleep quality than survivors of short-term childhood trauma and individuals without a history of childhood trauma, controlling for age, number of trauma types experienced, psychological distress, and PTSD symptoms. The relationship between dissociation and sleep quality was moderated by trauma chronicity such that dissociation was associated with better sleep quality only in the chronic trauma group. Dissociation was positively associated with sleep-related experiences regardless of trauma exposure and trauma chronicity. CONCLUSION: Our findings highlighted the differential impact of acute and chronic traumatic stress on sleep, and suggested that the relationship between dissociation and sleep could depend on trauma chronicity.

Cumulative childhood trauma and complex psychiatric symptoms in pregnant women and expecting men.

BACKGROUND: Women and men having been exposed to childhood trauma would be at high risk of various mental health symptoms while awaiting a child. This study aimed to evaluate the association between cumulative childhood trauma and the accumulation of symptoms belonging to different psychiatric problems in pregnant women and expecting men. METHODS: We first examined prevalence rates of childhood trauma across our samples of 2853 pregnant women and 561 expecting men from the community. Second, we evaluated the association between cumulative childhood trauma and symptom complexity (i.e., the simultaneous presentation of symptoms belonging to multiple psychiatric problems) using subsamples of 1779 pregnant women and 118 expecting men. Participants completed self-reported measures of trauma (Childhood Trauma Questionnaire) and psychiatric symptoms (PTSD Checklist for DSM-5; Kessler Psychological Distress Scale; State-Trait Anger Expression Inventory-2; Self and Interpersonal Functioning Scale). RESULTS: Trauma was more frequent in pregnant women than in expecting men and in participants reporting sociodemographic risk factors than in those not reporting any. A dose-response relationship was observed between the number of different traumas reported by pregnant women and expecting men and the complexity of their psychiatric symptoms, even when controlling for the variance explained by other risk factors. Women having been exposed to cumulative childhood trauma were 4.95 times more at risk of presenting comorbid psychiatric problems during pregnancy than non-exposed women. CONCLUSIONS: Childhood trauma is frequent in the general population of pregnant women and expecting men and is associated with symptom complexity during the antenatal period. These findings call for delivering and evaluating innovative trauma-informed antenatal programs to support mental health and adaptation to parenthood in adults having been exposed to childhood trauma.

Maternal adverse childhood experiences and their association with preterm birth: secondary analysis of data from universal health visiting.

BACKGROUND: Being born before full gestation can have short-term and life-long health implications, yet it remains difficult to determine the risk of preterm birth among expectant mothers. Across different health settings, increasing attention is given to the health and behavioural consequences of adverse childhood experiences (ACEs) such as child abuse or neglect, or exposure to harmful household environments (e.g. in which caregivers abuse alcohol), and the potential value of understanding these hidden harms when supporting individuals and families. A large international evidence base describes the association between childhood adversity and early years outcomes for mothers and children. However, the relationship between maternal ACEs and preterm birth has received far less attention. METHODS: Secondary analysis was carried out on anonymised cross-sectional data from health visiting services in south and west Wales that had previously captured information on mothers' ACEs during routine contacts. Demographic data and information on mothers' health were extracted from the Healthy Child Wales Programme. RESULTS: Half of all mothers sampled had experienced at least one ACE, with a history of ACEs more common among younger, white British mothers and those residing in deprived areas. Preterm birth was significantly independently associated with retrospective reports of childhood sexual abuse (adjusted odds ratio [AOR] = 3.83, 95% confidence interval [CI] = 1.19-12.32, p = 0.025), neglect (AOR = 7.60, 95%CI = 1.81-31.97, p = 0.006) and overall ACE exposure (AOR = 2.67, 95%CI = 1.14-6.23, p = 0.024), with one in ten mothers (10.0%) who experienced ≥4 ACEs having preterm birth. Sub-analyses revealed a more pronounced relationship among mothers with no known chronic health conditions, with those with ≥4 ACEs and no known chronic condition four times more likely to give birth preterm (AOR = 3.89, 95%CI = 1.40-10.80, p = 0.009). CONCLUSIONS: Findings highlight the importance of the entire maternal experience. The experience of childhood adversity can have a lasting impact into and beyond the prenatal period, potentially increasing the risk of preterm birth, even among otherwise healthy women. Increasing our understanding of the potential perinatal outcomes associated with ACEs can help to inform how maternity services and partners offer trauma-sensitive support to mitigate some of the risks of early parturition, as well as target intergenerational cycles of adversity and poor health.

Emotion regulation deficits mediate childhood sexual abuse effects on stress sensitization and depression outcomes.

Child sexual abuse (CSA) is a notable risk factor for depressive disorders. Though multiply determined, increased sensitivity to stress (stress sensitization) and difficulty managing distress (emotion regulation) may reflect two pathways by which CSA confers depression risk. However, it remains unclear whether stress sensitization and emotion regulation deficits contribute to depression risk independently or in a sequential manner. That is, the frequent use of maladaptive emotion regulation responses and insufficient use of those that attenuate distress (adaptive emotion regulation) may lead to stress sensitization. We tested competing models of CSA, stress sensitization, and emotion regulation to predict depression symptoms and depressive affects in daily life among adults with and without histories of CSA. Results supported a sequential mediation: CSA predicted greater maladaptive repertoires that, in turn, exacerbated the effects of stress on depression symptoms. Maladaptive responses also exacerbated the effects of daily life stress on contemporaneous negative affect (NA) levels and their increase over time. Independent of stress sensitization, emotion regulation deficits also mediated CSA effects on both depressive outcomes, though the effect of maladaptive strategies was specific to NA, and adaptive responses to positive affect. Our findings suggest that emotion regulation deficits and stress sensitization play key intervening roles between CSA and risk for depression.

Selective enhancement of fear learning and resistance to extinction in a mouse model of acute early life trauma.

Early life stress (ELS) experiences can cause changes in cognitive and affective functioning. This study examined the persistent effects of a single traumatic event in infancy on several adult behavioral outcomes in male and female C57BL/6J mice. Mice received 15 footshocks in infancy and were tested for stress-enhanced fear learning, extinction learning, discrimination and reversal learning, and novel object recognition. Infant trauma potentiated fear learning in adulthood and produced resistance to extinction but did not influence other behaviors, suggesting restricted effects of infant trauma on behaviors reliant on cortico-amygdala circuitry.

Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study.

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population-based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4-fold risk compared to that expected (95% confidence interval [CI]: 3.7-4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0-17.4; SHR = 5.4; 95% CI: 4.5-6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4-4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life-style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case-control study to comprehensively determine risk-factors for CVD.

The Long-Term Impact of Adversity in Adolescence on Health in Middle and Older Adulthood: A Natural Experiment From the Chinese Send-Down Movement.

The 1950s-1970s Chinese send-down movement can be treated as a natural experiment to study the impact of adolescent exposure on subsequent health. This paper used data from the China Family Panel Studies 2010 to evaluate the long-term impact of the Chinese send-down movement on individual health later in life. Drawing from the life-course perspective, results from difference-in-differences models suggested that the send-down experience had a significant impact on worse self-rated health; the pathways from structural equation models showed that subsequent achievements-age of marriage and educational attainment-had mediating effects linking the send-down experience to worse self-rated health and better mental health, respectively. Taken together, our results highlight the roles of the send-down experience and post-send-down characteristics in shaping health outcomes later in life.

Adverse Childhood Experiences and Rate of Memory Decline From Mid to Later Life: Evidence From the English Longitudinal Study of Ageing.

Evidence on the role of early-life adversity in later-life memory decline is conflicting. We investigated the relationships between adverse childhood experiences (ACEs) and memory performance and rate of decline over a 10-year follow-up among middle-aged and older adults in England. Data were from biennial interviews with 5,223 participants aged 54 years or older in the population-representative English Longitudinal Study of Ageing from 2006/2007 to 2016/2017. We examined self-reports of 9 ACEs prior to age 16 years that related to abuse, household dysfunction, and separation from family. Memory was assessed at each time point as immediate and delayed recall of 10 words. Using linear mixed-effects models with person-specific random intercepts and slopes and adjusted for baseline age, participants' baseline age squared, sex, ethnicity, and childhood socioeconomic factors, we observed that most individual and cumulative ACE exposures had null to weakly negative associations with memory function and rate of decline over the 10-year follow-up. Having lived in residential or foster care was associated with lower baseline memory (adjusted ß = -0.124 standard deviation units; 95% confidence interval: -0.273, -0.025) but not memory decline. Our findings suggest potential long-term impacts of residential or foster care on memory and highlight the need for accurate and detailed exposure measures when studying ACEs in relation to later-life cognitive outcomes.

Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.

Effects of childhood adversity on the volumes of the amygdala subnuclei and hippocampal subfields in individuals with major depressive disorder.

Background: Reductions in total hippocampus volume have frequently been reported in MRI studies in major depressive disorder (MDD), but reports of differences in total amygdala volume have been inconsistent. Childhood maltreatment is an important risk factor for MDD in adulthood and may affect the volume of the hippocampus and amygdala. In the present study, we examined associations between the volumes of the amygdala subnuclei and hippocampal subfields and history of childhood maltreatment in participants with MDD. Methods: We recruited 35 patients who met the DSM-IV criteria for MDD and 35 healthy controls. We acquired MRI data sets on a 4.7 T Varian Inova scanner. We manually delineated the amygdala subnuclei (lateral, basal and accessory basal nuclei, and the cortical and centromedial groups) and hippocampal subfields (cornu ammonis, subiculum and dentate gyrus) using reliable volumetric methods. We assessed childhood maltreatment using the Childhood Trauma Questionnaire in participants with MDD. Results: In participants with MDD, a history of childhood maltreatment had significant negative associations with volume in the right amygdala, anterior hippocampus and total cornu ammonis subfield bilaterally. For volumes of the amygdala subnuclei, such effects were limited to the basal, accessory basal and cortical subnuclei in the right hemisphere, but they did not survive correction for multiple comparisons. We did not find significant effects of MDD or antidepressant treatment on volumes of the amygdala subnuclei. Limitations: Our study was a cross-sectional study. Conclusion: Our results provide evidence of negative associations between history of childhood maltreatment and volumes of medial temporal lobe structures in participants with MDD. This may help to identify potential mechanisms by which maltreatment leads to clinical impacts.

Childhhood Trauma in Schizophrenia Spectrum Disorders: Dissociative, Psychotic Symptoms, and Suicide Behavior.

Current evidence suggests a high prevalence of childhood trauma (CT) among adult patients diagnosed with schizophrenia spectrum disorders. Exposure to CT might lead to clinical differences eventually observed in these patients. We present a cross-sectional study with 54 patients with schizophrenia spectrum disorder (schizophrenia and schizoaffective disorder). We obtained sociodemographic data, as well as data on CT, dissociation, suicide history, and intensity of positive and negative psychotic symptoms. More than 75% of the patients reported a history of CT. We observed a link between CT and suicidal behavior. Patients showed high rates of dissociation. Dissociative experiences were related to CT, both in terms of intensity of trauma and number of traumas experienced. All CT forms except emotional neglect showed direct correlations with dissociative experiences. We found no correlation between intensity of CT and intensity of positive psychotic symptoms, yet we observed a moderate inverse correlation with negative psychotic symptoms.

Gambling Disorder and Childhood Trauma: A Complex Association.

Gambling disorder (GD) is classified as a behavioural addiction and has some phenotypic similarities with substance use disorders (SUDs). Childhood adversity and life stressors are associated with increased risk for SUDs in adulthood. However, there is limited research investigating the association between childhood trauma, stressors and behavioural addictions such as GD. In this case-control cross-sectional study, 31 adult patients with GD were compared to 31 matched healthy controls (HCs) in terms of exposure to early adversity using the Childhood Trauma Questionnaire (CTQ-SF). In addition, past 12-month stressful life event exposure was assessed using the Life Event Stress Scale (LESS) and investigated as a possible moderator of the relationship between childhood trauma and GD by means of a two-way analysis of variance (ANOVA). Logistic regression analyses were used to test if childhood trauma (CTQ-SF) and its subtypes were significant predictors of a diagnosis of GD. Severity of childhood trauma in general, and on all five subtypes, was significantly higher in GD patients compared to HCs. Childhood trauma was a significant predictor of a diagnosis of GD, with physical neglect being the single trauma subtype to significantly increase odds of GD in adulthood. Stressful life events moderated the relationship between childhood trauma and GD, i.e. childhood trauma was significantly higher in GD patients compared to HCs when LESS was low. The findings support a link between childhood trauma and GD, with current stress as a moderating variable, and may be useful for future individualized therapeutic strategies.

Health-Related Quality of Life in Young Adults Following Pediatric Arterial Ischemic Stroke.

Background and Purpose- Pediatric arterial ischemic stroke (AIS) is a rare disease leading to long-lasting neurological sequelae. Little is known about the long-term health-related quality of life (HRQoL) of these patients. The study aims to compare HRQoL in young adults who have had pediatric AIS with a healthy control group. Methods- A cross-sectional study compared self-rated HRQoL, depression, fatigability, and behavior in pediatric stroke survivors to healthy controls. Patients with a confirmed diagnosis of pediatric AIS who were ≥18 years at the time of recruitment and ≥2 years after acute AIS, as well as healthy controls ≥18 years matched for age, sex, and socioeconomic status were included. Primary outcome was HRQoL measured with the Short Form Health Survey. Results- Thirty-three patients (median [interquartile range] aged 22 years [20-26]; 22 males, 67%) and 71 controls (median [interquartile range] aged 23 years [21-25]; 41 males, 58%) were included. Overall, HRQoL, depression, or fatigability did not differ between the patients and the control group. Patients rated themselves lower on the disinhibition scale (P=0.049) and tended to rate themselves lower on the executive dysfunction scale (P=0.076). Patients with a poor outcome 24 months after AIS showed a clear trend toward impairment of executive functioning (P=0.056) and work/productivity in the stroke-specific QoL (P=0.05). Conclusions- Self-rated HRQoL, depression, and fatigability in adult pediatric stroke survivors are comparable to healthy adult peers. A poor outcome 24 months after acute stroke might affect work performance and executive functioning in adulthood.

Neighborhood effect and obesity in adult survivors of pediatric cancer: A report from the St. Jude lifetime cohort study.

Survivors of childhood cancer are at risk for obesity, a condition potentially modifiable if dietary intake and physical activity are optimized. These health behaviors are likely influenced by neighborhood of residence, a determinant of access to healthy, affordable food and safe and easy exercise opportunities. We examined associations between neighborhood level factors and obesity among survivors in the St. Jude Lifetime cohort and community comparison group members. Persons with residential addresses available for geocoding were eligible for analysis (n = 2,265, mean age 32.5 [SD 9.1] years, 46% female, 85% white). Survivors completed questionnaires regarding individual behaviors; percent body fat was assessed via dual X-ray absorptiometry (obesity: ≥25% males; ≥35% females); neighborhood effect was characterized using census tract of residence (e.g., neighborhood socioeconomic status [SES], rurality). Structural equation modeling was used to determine associations between neighborhood effect, physical activity, diet, smoking, treatment exposures and obesity. Obese survivors (n = 1,420, 62.7%) were more likely to live in neighborhoods with lower SES (RR: 1.23, 95% CI: 1.10-1.38) and rural areas (RR: 1.22, 95% CI: 1.07-1.39) compared to survivors with normal percent body fat. Resource-poor neighborhoods (standardized effect: 0.06, p < 0.001) and cranial radiation (0.16, p < 0.001) had direct effects on percent body fat. Associations between neighborhood of residence and percent body fat were increased (0.01, p = 0.04) among individuals with a poor diet. Neighborhoods where survivors reside as an adult is associated with obesity. Interventions targeting survivors should incorporate strategies that address environmental influences on obesity.

Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders.

BACKGROUND: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. METHODS: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach. RESULTS: Among the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. CONCLUSIONS: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.