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

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

Sexual Orientation and Neuroanatomy: An MRI Study of Gray Matter Differences in Homosexual, Bisexual, and Heterosexual Women and Men

In this study, we attempted to replicate past work focusing on differences in neuroanatomical structures between heterosexual and homosexual men and women. We also performed the first analyses of sexual orientation and neuroanatomy to include bisexual men and women. Sex differences in raw subcortical volumes were consistent with past work and a broader literature on sex differences, showing larger raw subcortical volumes in male groups than female groups. However, we did not confirm past findings showing larger raw volumes in heterosexual than in homosexual men in the left thalamus or right thalamus. Additionally, we did not confirm past findings showing thicker cortices in heterosexual men than in homosexual men in visual/occipital areas (right cuneus, right lingual gyrus, right pericalcarine cortex) or a frontal area (right pars triangularis). Exploratory whole-brain analyses revealed several areas of difference between women that may be of interest for future confirmatory research. Bisexual women had smaller volumes in a region of the olfactory tubercule than heterosexual women as well as a thicker right anterior insula region than homosexual women. Homosexual women had smaller volumes in regions of the inferior parietal lobule (IPL) than both heterosexual women and bisexual women. The functional relevance of these brain areas in terms of understanding female sexual orientation is unclear. However, based on these areas, future work may wish to consider the potential social, emotional, attentional, interoceptive, or general reward-related characteristics that may differentiate women with different attraction patterns. In contrast to previous work, no differences were found between groups of men (heterosexual, bisexual, or homosexual) in any of our analyses. Finally, in terms of whole-brain analyses of sex differences, heterosexual women had both thicker cortices and larger (relative to the whole brain) gray matter volume than heterosexual men in the superior frontal gyrus, in contrast to large-scale studies of sex difference. Although statistically significant at a stringent threshold (FWE-corrected), our whole-brain findings should be interpreted and generalized with caution. The heterogeneity of patterns across analyses of sexual orientation and brain structure (and even across studies of sex/gender and brain structure) suggests that findings may potentially depend upon particular sample characteristics, and potentially Type 1 error due to the testing of many different brain areas.

Multi-Racial Normative Data for Lobar and Subcortical Brain Volumes in Old Age: Korean and Caucasian Norms May Be Incompatible With Each Other†

Brain aging is becoming an increasingly important topic, and the norms of brain structures are essential for diagnosing neurodegenerative diseases. However, previous studies of the aging brain have mostly focused on Caucasians, not East Asians. The aim of this paper was to examine ethnic differences in the aging process of brain structures or to determine to what extent ethnicity affects the normative values of lobar and subcortical volumes in clinically normal elderly and the diagnosis in multi-racial patients with Alzheimer's disease (AD). Lobar and subcortical volumes were measured using FreeSurfer from MRI data of 1,686 normal Koreans (age range 59–89) and 851 Caucasian, non-Hispanic subjects in the ADNI and OASIS datasets. The regression models were designed to predict brain volumes, including ethnicity, age, sex, intracranial volume (ICV), magnetic field strength (MFS), and MRI scanner manufacturers as independent variables. Ethnicity had a significant effect for all lobar (|β| &gt; 0.20, p &lt; 0.001) and subcortical regions (|β| &gt; 0.08, p &lt; 0.001) except left pallidus and bilateral ventricles. To demonstrate the validity of the z-score for AD diagnosis, 420 patients and 420 normal controls were selected evenly from the Korean and Caucasian datasets. The four validation groups divided by race and diagnosis were matched on age and sex using a propensity score matching. We analyzed whether and to what extent the ethnicity adjustment improved the diagnostic power of the logistic regression model that was built using the only z-scores of six regions: bilateral temporal cortices, hippocampi, and amygdalae. The performance of the classifier after ethnicity adjustment was significantly improved compared with the classifier before ethnicity adjustment (ΔAUC = 0.10, D = 7.80, p &lt; 0.001; AUC comparison test using bootstrap). Korean AD dementia patients may not be classified by Caucasian norms of brain volumes because the brain regions vulnerable to AD dementia are bigger in normal Korean elderly peoples. Therefore, ethnicity is an essential factor in establishing normative data for regional volumes in brain aging and applying it to the diagnosis of neurodegenerative diseases.

Language Disorder in Progressive Supranuclear Palsy and Corticobasal Syndrome: Neural Correlates and Detection by the MLSE Screening Tool

Background: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) affect speech and language as well as motor functions. Clinical and neuropathological data indicate a close relationship between these two disorders and the non-fluent variant of primary progressive aphasia (nfvPPA). We use the recently developed Mini Linguistic State Examination tool (MLSE) to study speech and language disorders in patients with PSP, CBS, and nfvPPA, in combination with structural magnetic resonance imaging (MRI).Methods: Fifty-one patients (PSP N = 13, CBS N = 19, nfvPPA N = 19) and 30 age-matched controls completed the MLSE, the short form of the Boston Diagnostic Aphasia Examination (BDAE), and the Addenbrooke’s Cognitive Examination III. Thirty-eight patients and all controls underwent structural MRI at 3 Tesla, with T1 and T2-weighted images processed by surface-based and subcortical segmentation within FreeSurfer 6.0.0 to extract cortical thickness and subcortical volumes. Morphometric differences were compared between groups and correlated with the severity of speech and language impairment.Results: CBS and PSP patients showed impaired MLSE performance, compared to controls, with a similar language profile to nfvPPA, albeit less severe. All patient groups showed reduced cortical thickness in bilateral frontal regions and striatal volume. PSP and nfvPPA patients also showed reduced superior temporal cortical thickness, with additional thalamic and amygdalo-hippocampal volume reductions in nfvPPA. Multivariate analysis of brain-wide cortical thickness and subcortical volumes with MLSE domain scores revealed associations between performance on multiple speech and language domains with atrophy of left-lateralised fronto-temporal cortex, amygdala, hippocampus, putamen, and caudate.Conclusions: The effect of PSP and CBS on speech and language overlaps with nfvPPA. These three disorders cause a common anatomical pattern of atrophy in the left frontotemporal language network and striatum. The MLSE is a short clinical screening tool that can identify the language disorder of PSP and CBS, facilitating clinical management and patient access to future clinical trials.

Intrauterine Exposure to Vitamin B12 and Folate Imbalance and Brain Structure in Young Adults of the Pune Maternal Nutrition Study (PMNS) Birth Cohort

Objectives Intrauterine nutritional exposures to vitamin B12 and folate are known to influence neurodevelopment. We tested the hypothesis that intrauterine exposure to high folate in presence of low vitamin B12 is associated with poor neurodevelopmental outcomes in young adult offspring. Methods PMNS is a preconceptional birth cohort in its 24th year of follow up. We examined Intelligence Quotient (IQ) and obtained brain structural MPRAGE T1 sequence on a 3T MRI Scanner [participants selected based on exposure to maternal B12 at 18 wk pregnancy &lt;103 PM(Low maternal B12 group n = 97) and &gt;175 pM (high maternal B12 group, n = 93)]. Brain morphometric measurements (cortical volumes, thickness and subcortical volumes) were performed on Freesurfer software. Results The mean age of participants was 22.3 ± 0.5 years (n = 190, 96 boys). High maternal B12 group showed greater cortical thickness in temporal regions (P &lt; 0.001) and cortical thinning in frontal regions (P &lt; 0.01). Higher maternal folate (median Red Cell Folate at 28 wk pregnancy 420 ng/ml) was associated with greater frontal cortical volumes in the high maternal B12 group but cortical thinning in multiple temporal and parietal cortical areas in the low B12 group(P &lt; 0.05). There was a significant interaction between maternal B12 and folate status in relation to subcortical volumes. Exposure to higher maternal folate was associated with greater subcortical volume in high B12 group but lower volumes in low B12 group (P = 0.02, adjusted for age, education, gender and total intracranial volume). Higher IQ score was associated with larger subcortical brain volume (r = 0.34, P &lt; 0.001) in the offspring. Conclusions Intrauterine exposure to higher maternal folate in the presence of low vitamin B12 was associated with poorer cortical development in young adult offspring. Higher maternal folate with adequate B12 benefits subcortical brain development which reflects in higher IQ score. Optimizing maternal vitamin B12 and folate concentrations during pregnancy would benefit neurocognitive development in the offspring. Funding Sources DBT Wellcome India Alliance Clinical and Public Health Intermediate Fellowship.