Sex hormones as correlates of oxidative stress in the adult brain.

Oxidative stress, an imbalance between the production of reactive oxygen species and available antioxidant capacity, is implicated in multiple psychiatric disorders and neurodegenerative conditions. Peripheral and preclinical studies suggest oxidative stress differs by biological sex and covaries with estrogens. However, limited knowledge exists on the effect of circulating sex hormones on oxidative stress in the brain in humans in vivo. We aimed to examine the relationship of circulating estrogen with regional concentrations of brain glutathione (GSH) as a marker of oxidative stress. GSH was measured using magnetic resonance spectroscopy (MRS) at 7 Tesla in the dorsal anterior cingulate cortex (ACC), ventromedial prefrontal cortex (VMPFC), and left dorsolateral prefrontal cortex (DLPFC) in 34 individuals (18 females and 16 males). We observed an inverse correlation of estradiol with DLPFC GSH, as well as a trend inverse correlation of estrone with DLPFC GSH, in the combined sample of males and females and in females only. No significant sex differences were observed for GSH levels in the brain. Our study provides evidence of diminished DLPFC GSH in females with higher estradiol, suggesting circulating sex hormones may be important factors to consider in future studies examining brain GSH levels related to psychiatric and other disorders.

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.

Perceived Stress, Cortical GABA, and Functional Connectivity Correlates: A Hypothesis-Generating Preliminary Study.

Stress exposures and dysregulated responses to stress are implicated in psychiatric disorders of mood, anxiety, and cognition. Perceived stress, an individual's appraisal of experienced stress and ability for coping, relates to dysregulated functioning in resting state brain networks. Alterations in GABAergic function may underlie perceived stress-related functional dysregulation in resting state networks but this has not yet been explored. Therefore, the current study examined the association of perceived stress, via the Perceived Stress Scale (PSS), with prefrontal GABA levels and corresponding resting state functional connectivity (RSFC) alterations. Twelve women and five men, ages 35-61, participated. MR spectroscopy was used to measure brain GABA levels in the anterior cingulate cortex (ACC), left dorsolateral prefrontal cortex (DLPFC), and ventromedial prefrontal cortex (VMPFC). Resting state functional scans acquired at 3 Tesla were used to measure RSFC within and between the default mode (DMN), salience (SN), and central executive networks (CEN), hippocampus and amygdala. We observed significant negative correlations between total PSS scores and left DLPFC GABA levels (r = -0.62, p = 0.023). However, PSS scores were not significantly correlated with RSFC measures (all p > 0.148). These preliminary results support a relationship between perceived stress and GABAergic functioning in DLPFC, a core node of the CEN, an intrinsic network thought to underlie goal-directed attentional processes. Our findings extend previous work suggesting that functioning in the CEN is related to perceived stress and may inform treatment strategies to improve outcomes in stress-related conditions.

Age moderates the relationship between affective response inhibition and bipolar disorder in adults.

BACKGROUND: Patients with bipolar disorder (BD) often have impairments in neurocognition, including affective processing and affective response inhibition. While studies suggest that cognitive control in general may decline with age in BD, less is known about age-related changes in response inhibition to emotionally salient information. METHODS: 258 participants with BD and 54 healthy controls, ages 18-70, completed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Affective Go/No-Go task to assess affective response inhibition to positive and negative valenced stimuli. We examined the relationship between BD and affective response inhibition (number of commission and omission errors and reaction time), as well as a potential moderating effect of age, using mixed effects linear regression models. RESULTS: The BD group made more omission and commission errors overall than the control group (p < 0.018). We observed a significant 3-way group-by-age-by-valence interaction for reaction time (p = 0.006). Within BD, a slower reaction time to negative than positive stimuli was found in middle and older age groups (p < 0.012), but not in the younger age group. No significant moderating effect of age was observed within the control group. CONCLUSIONS: These cross-sectional findings indicate that compared with healthy controls, individuals with BD display differential and age-related effects in inhibition to emotionally salient information that is valence-dependent. The observed pattern of a switch in bias from negative to positive stimuli with age in BD may aid in our understanding of the progression of neurocognitive changes with aging in BD, as well as inform targeted treatments for cognitive symptoms.

Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years.

[Figure: see text].

Childhood vascular phenotypes have differing associations with prenatal and postnatal growth.

OBJECTIVE: In children aged 8--9 years, we examined the associations of linear and abdominal circumference growth during critical stages of prenatal and postnatal development with six vascular measurements commonly used as early markers of atherosclerosis and later cardiovascular disease (CVD) risk. METHODS: In 724 children from the UK Southampton Women's Survey mother--offspring cohort, offspring length/height and abdominal circumference measurements were collected at 10 ages between 11 weeks' gestation and age 8--9 years. Using residual growth modelling and linear regression, we examined the independent associations between growth and detailed vascular measures made at 8--9 years. RESULTS: Postnatal linear and abdominal circumference growth were associated with higher childhood SBP and carotid--femoral pulse wave velocity, whereas prenatal growth was not. For example, 1SD faster abdominal circumference gain between ages 3 and 6 years was associated with 2.27 [95% confidence interval (CI): 1.56--2.98] mmHg higher SBP. In contrast, faster abdominal circumference gain before 19 weeks' gestation was associated with greater carotid intima--media thickness [0.009 mm (0.004--0.015) per 1SD larger 19-week abdominal circumference), whereas later growth was not. We found no strong associations between prenatal or postnatal growth and DBP or measures of endothelial function. CONCLUSION: Higher postnatal linear growth and adiposity gain are related to higher SBP and carotid--femoral pulse wave velocity in childhood. In contrast, faster growth in early gestation is associated with greater childhood carotid intima--media thickness, perhaps resulting from subtle changes in vascular structure that reflect physiological adaptations rather than subclinical atherosclerosis.

A 7 Tesla Amygdalar-Hippocampal Shape Analysis of Lithium Response in Bipolar Disorder.

Research to discover clinically useful predictors of lithium response in patients with bipolar disorder has largely found them to be elusive. We demonstrate here that detailed neuroimaging may have the potential to fill this important gap in mood disorder therapeutics. Lithium treatment and bipolar disorder have both been shown to affect anatomy of the hippocampi and amygdalae but there is no consensus on the nature of their effects. We aimed to investigate structural surface anatomy changes in amygdala and hippocampus correlated with treatment response in bipolar disorder. Patients with bipolar disorder (N = 14) underwent lithium treatment, were classified by response status at acute and long-term time points, and scanned with 7 Tesla structural MRI. Large Deformation Diffeomorphic Metric Mapping was applied to detect local differences in hippocampal and amygdalar anatomy between lithium responders and non-responders. Anatomy was also compared to 21 healthy comparison participants. A patch of the ventral surface of the left hippocampus was found to be significantly atrophied in non-responders as compared to responders at the acute time point and was associated at a trend-level with long-term response status. We did not detect an association between response status and surface anatomy of the right hippocampus or amygdala. To the best of our knowledge, this is the first shape analysis of hippocampus and amygdala in bipolar disorder using 7 Tesla MRI. These results can inform future work investigating possible neuroimaging predictors of lithium response in bipolar disorder.

Hypothalamic-pituitary-adrenal axis, subjective, and thermal stress responses in midlife women with vasomotor symptoms.

OBJECTIVE: Dysregulated responses to experimental stress paradigms may indicate exposure to chronic stress. Vasomotor symptoms (VMS) are linked with diminished quality of life and psychological stress, but induced stress responsivity has received limited investigation. We examined whether women with and without VMS differ in their evoked hypothalamic-pituitary-adrenal axis, subjective, hemodynamic, and thermal stress responses. METHODS: A total of 37 midlife women (27 VMS+; 10 VMS-) completed 2 experimental stress paradigms: (1) Montreal Imaging Stress Task (MIST; computerized social-evaluative stressor) and (2) Quantitative Sensory Testing (QST; thermal stress task). Responses on a five-domain (range 0-50) Visual Analog Scale, salivary cortisol (hypothalamic-pituitary-adrenal axis), and hemodynamic indices (blood pressure, heart rate) were measured before and after each task to compare within-person change between groups. Thermal sensitivity was assessed on the QST. RESULTS: On the MIST, the VMS+ group showed a smaller cortisol release (0.01 vs 0.07 µg/dL; P = 0.046; corresponding to 54% vs 83% increases), and subjective stress response (21.2- vs 31.1-point Visual Analog Scale increase, P = 0.05; corresponding to 2427% vs 2863% increases) but no hemodynamic difference, compared to the VMS- group. The QST did not provoke stress responses via cortisol release or subjective report, but the VMS+ group tended to perceive heat at a higher temperature (38.5°C vs 36.4°C, P = 0.08). CONCLUSIONS: Women with VMS exhibited both diminished cortisol and subjective stress responses to the MIST, and reduced thermal sensitivity on QST compared to women without VMS. Dysregulated stress responsivity provides preliminary evidence suggesting that VMS may represent a chronic stress condition.

Hemorrhage Control Training Promotes Resilience-Associated Traits in Medical Students.

OBJECTIVE: Given rising rates of physician burnout, the potential for clinical skills training programs to develop and reinforce resilience-associated traits in medical students warrants investigation. The primary objective of this study was to examine the impact of a hemorrhage control training program on resilience-associated traits (role-clarity, self-efficacy, and empowerment) in medical students. A secondary objective was to examine the differential impact of additional hands-on skills training. DESIGN: This was a prospective study of medical students participating in an established hemorrhage control training program, utilizing pre-, mid-, and post-training questionnaires. The program included both an in-person lecture and hands-on skills training. Primary endpoints were self-reported increases in role clarity (when the hemorrhage control skills would and would not be applicable), self-efficacy (confidence in ability to use the skill), and empowerment (to act in a situation where the skill was needed). SETTING: Harvard Medical School, Boston, Massachusetts. PARTICIPANTS: One hundred and twenty-six Harvard Medical School students participated. RESULTS: There was a significant increase at each stage of training in self-reported role clarity about when to apply hemorrhage control skills (p < 0.01) and when not to apply them (p < 0.01); confidence in application of the skill (p < 0.01); as well as empowerment to apply the skill when appropriate (p < 0.01). CONCLUSIONS: Hemorrhage control training, a first response-related clinical skills program, is a promising domain for development and reinforcement of resilience-associated traits in medical students, particularly when the program includes hands-on skills training. Providing experiential learning opportunities that are designed not only for skills-specific outcomes, but also to reinforce such resilience-associated traits as role-clarity, self-efficacy, and empowerment provides an essential integrated perspective.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics.

BACKGROUND: Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. RESULTS: Two of these rules-one associated with eating disorder and the other with anxiety-remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. CONCLUSION: Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.

Childhood Fat and Lean Mass: Differing Relations to Vascular Structure and Function at Age 8 to 9 Years

Objective- Childhood body mass index (BMI) has been related to vascular structure and function. However, little is known about the differing contributions of fat and lean mass to this relationship. Our objectives were to relate the fat and lean mass (bone excluded) components of BMI (fat mass index and lean mass index; mass [kg]/height [m]2) to vascular measures in prepubertal children. Approach and Results- In the UK Southampton Women's Survey mother-offspring cohort, 983 children had dual x-ray absorptiometry and vascular measurements at 8 to 9 years. Using linear regression analyses, we found that most vascular measures were related to BMI, but fat and lean mass contributed differently. Systolic blood pressure was positively associated with both fat mass index (ß=0.91 [95% CI, 0.52-1.30] mm Hg) and lean mass index (ß=2.16 [95% CI, 1.47-2.85] mm Hg), whereas pulse rate was positively associated with fat mass index (ß=0.93 [95% CI, 0.48-1.38] b/min) but negatively associated with lean mass index (ß=-1.79 [95% CI, -2.59 to -0.99] b/min). The positive relation between BMI and carotid intima-media thickness was mainly due to a positive association with lean mass index (ß=0.013 [95% CI, 0.008-0.019] mm). Carotid-femoral pulse wave velocity, but not carotid-radial pulse wave velocity, was positively associated with fat mass index (ß=0.06 [95% CI, 0.03-0.09] m/s). For systolic blood pressure, carotid-femoral pulse wave velocity and reactive hyperemia significant interactions indicated that the association with fat mass depended on the amount of lean mass. Conclusions- In prepubertal children, differences in vascular structure and function in relation to BMI probably represent combinations of adverse effects of fat mass, adaptive effects of body size, and relatively protective effects of lean mass.

DNA methylation and sex-specific expression of FKBP5 as correlates of one-month bedtime cortisol levels in healthy individuals.

Chronic exposure to cortisol is associated with cardiovascular, metabolic, and psychiatric disorders. Although cortisol can be readily measured from peripheral sources such as blood, urine, or saliva, multiple samplings spanning several days to weeks are necessary to reliably assess chronic cortisol exposure levels (referred to as cortisol load). Although cortisol levels in hair have been proposed as a measure of cortisol load, measurement is cumbersome and many people are not candidates due to short hair length and use of hair dyes. To date, there are no blood biomarkers that capture cortisol load. To identify a blood biomarker capable of integrating one-month cortisol exposure levels, 75 healthy participants provided 30+ days of awakening and bedtime saliva cortisol and completed psychosocial measures of anxiety, depression, and stress. Mean daily awakening and bedtime cortisol levels were then compared to CpG methylation levels, gene expression, and genotypes of the stress response gene FKBP5 obtained from blood drawn on the last day of the study. We found a correlation between FKBP5 methylation levels and mean 30+day awakening and bedtime cortisol levels (|r|≥0.32, p ≤ 0.006). We also observed a sex-specific correlation between bedtime cortisol levels and FKBP5 mRNA expression in female participants (r = 0.42, p = 0.005). Dividing the 30-day sampling period into four weekly bins showed that the correlations for both methylation and expression were not being driven by cortisol levels in the week preceding the blood draw. We also identified a female-specific association between FKBP5 mRNA expression and scores on the Beck Anxiety Inventory (r = 0.37, p = 0.013) and Beck Depression Inventory-II (r = 0.32, p = 0.033). Finally, DNA was genotyped at four SNPs, and variation in rs4713902 was shown to have an effect on FKBP5 expression under a codominant model (f = 3.41, p = 0.048) for females only. Our results suggest that blood FKBP5 DNA methylation and mRNA expression levels may be a useful marker for determining general or sex-specific 30-day cortisol load and justifies genome-wide approaches that can potentially identify additional cortisol markers with broader clinical utility.

Southampton PRegnancy Intervention for the Next Generation (SPRING): protocol for a randomised controlled trial.

BACKGROUND: The nutritional status and health of mothers influence the growth and development of infants during pregnancy and postnatal life. Interventions that focus on improving the nutritional status and lifestyle of mothers have the potential to optimise the development of the fetus as well as improve the health of mothers themselves. Improving the diets of women of childbearing age is likely to require complex interventions that are delivered in a socially and culturally appropriate context. In this study we aim to test the efficacy of two interventions: behaviour change (Healthy Conversation Skills) and vitamin D supplementation, and to explore the efficacy of an intervention that combines both, in improving the diet quality and nutritional status of pregnant women. METHODS/DESIGN: Women attending the maternity hospital in Southampton are recruited at between 8 and 12 weeks gestation. They are randomised to one of four groups following a factorial design: Healthy Conversation Skills support plus vitamin D supplementation (1000 IU cholecalciferol) (n = 150); Healthy Conversation Skills support plus placebo (n = 150); usual care plus vitamin D supplementation (n = 150); usual care plus placebo (n = 150). Questionnaire data include parity, sunlight exposure, diet assessment allowing assessment of diet quality, cigarette and alcohol consumption, well-being, self-efficacy and food involvement. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH) vitamin D. Maternal diet quality and 25(OH) vitamin D are the primary outcomes. Secondary outcomes are women's level of self-efficacy at 34 weeks, pregnancy weight gain, women's self-efficacy and breastfeeding status at one month after birth and neonatal bone mineral content, assessed by DXA within the first 14 days after birth. DISCUSSION: This trial is evaluating two approaches to improving maternal diet: a behaviour change intervention and vitamin D supplementation. The factorial design of this trial has the advantage of enabling each intervention to be tested separately as well as allowing exploration of the synergistic effect of both interventions on women's diets and vitamin D levels. TRIAL REGISTRATION: ISRCTN07227232 . Registered on 13 September 2013.

Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the TSST than do women during the follicular phase of the menstrual cycle.

Morphometry of the amygdala in schizophrenia and psychotic bipolar disorder.

Volumetric studies suggest smaller amygdalae in subjects with schizophrenia (SZ) than with bipolar disorder (BP). We use morphometry to identify subregions of amygdala differentially affected in SZ and psychotic BP. Based on template centered population analysis, the shape of the amygdala in psychotic BP differs from SZ (pleft=0.044, pright=0.042). Using a high-field 7 T atlas, the bilateral basolateral, basomedial and centromedial subregions and the right lateral subregion were significantly atrophied in SZ compared to psychotic BP (p<0.02). These results suggest that change in shape of amygdala may represent a morphologic feature distinguishing SZ from psychotic BP.

Amygdalar atrophy in symptomatic Alzheimer's disease based on diffeomorphometry: the BIOCARD cohort.

This article examines the diffeomorphometry of magnetic resonance imaging-derived structural markers for the amygdala, in subjects with symptomatic Alzheimer's disease (AD). Using linear mixed-effects models we show differences between those with symptomatic AD and controls. Based on template centered population analysis, the distribution of statistically significant change is seen in both the volume and shape of the amygdala in subjects with symptomatic AD compared with controls. We find that high-dimensional vertex based markers are statistically more significantly discriminating (p < 0.00001) than lower-dimensional markers and volumes, consistent with comparable findings in presymptomatic AD. Using a high-field 7T atlas, significant atrophy was found to be centered in the basomedial and basolateral subregions, with no evidence of centromedial involvement.

Morphometric differences in planum temporale in schizophrenia and bipolar disorder revealed by statistical analysis of labeled cortical depth maps.

Differences in cortical thickness in the lateral temporal lobe, including the planum temporale (PT), have been reported in MRI studies of schizophrenia (SCZ) and bipolar disorder (BPD) patients. Most of these studies have used a single-valued global or local measure for thickness. However, additional and complementary information can be obtained by generating labeled cortical distance maps (LCDMs), which are distances of labeled gray matter (GM) voxels from the nearest point on the GM/white matter (WM) (inner) cortical surface. Statistical analyses of pooled and censored LCDM distances reveal subtle differences in PT between SCZ and BPD groups from data generated by Ratnanather et al. (Schizophrenia Research, http://dx.doi.org/10.1016/j.schres.2013.08.014). These results confirm that the left planum temporale (LPT) is more sensitive than the right PT in distinguishing between SCZ, BPD, and healthy controls. Also confirmed is a strong gender effect, with a thicker PT seen in males than in females. The differences between groups at smaller distances in the LPT revealed by pooled and censored LCDM analysis suggest that SCZ and BPD have different effects on the cortical mantle close to the GM/WM surface. This is consistent with reported subtle changes in the cortical mantle observed in post-mortem studies.