Smaller Amygdala Volumes Research Articles

Amygdala volume and depression symptoms in young adolescents who use cannabis

IntroductionBoth cannabis use and depressive symptomology increase in prevalence throughout adolescence. Concurrently, the brain is undergoing neurodevelopment in important limbic regions, such as the amygdala. Prior research indicates the amygdala may also be related to cannabis use and depressive symptoms. We aimed to investigate the effects of adolescent cannabis use on amygdala volumes as well as the interaction of cannabis use and amygdala morphometry on depressive symptoms in youth. MethodTwo-hundred-twenty-four participants (ages 12–15), balanced by sex assigned at birth, were selected from a sub-sample of the Adolescent Brain Cognitive Development (ABCD) Study based on hair toxicology and self-report measures of cannabis use. Participants positive for cannabinoids in hair and/or self-reported cannabis use were demographically matched to youth with no self-reported or confirmed cannabis use. The guardians of these youth reported depression symptoms on the Child Behavioral Checklist. Linear mixed effect models were run investigating cannabis use group on amygdala volumes bilaterally, controlling for whole brain volume and random effects of scanner type. Additional analyses examined cannabis group status and bilateral amygdala volume on depression symptoms. ResultsCannabis use was not significantly associated with amygdala volume but was associated with increased depressive symptoms (p<0.01). Cannabis group interacted with amygdala volume, such that individuals with smaller volumes had increased depressive symptoms within the cannabis group (p’s<0.01–0.02). ConclusionAberrations in amygdala volume based on cannabis use were not found in early adolescence; however, more depressive symptoms were related to cannabis group. Youth who use cannabis and have smaller amygdala volumes were at increased risk for depressive symptomology, suggesting potential neurovulnerabilities to cannabis use.

Associations between early trajectories of amygdala development and later school-age anxiety in two longitudinal samples

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6–12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In the IBIS sample, children with higher anxiety showed accelerated amygdala growth from 6 to 24 months. ASD diagnosis and ASD familial likelihood were not significant predictors. In the EBDS sample, amygdala growth from birth to 24 months was associated with anxiety. More anxious children had smaller amygdala volume and slower rates of amygdala growth. We explore reasons for the contrasting results between high-familial likelihood for ASD and TD samples, grounding results in the broader literature of variable associations between early amygdala volume and later anxiety. Results have the potential to identify mechanisms linking early amygdala growth to later anxiety in certain groups.

Maternal perinatal depression and child brain structure at 2-3 years in a South African birth cohort study

Maternal perinatal depression is associated with risk of adverse child developmental outcomes and differences in offspring brain structure. Evidence from low- and middle-income countries is lacking as is an investigation of antenatal, postnatal, and persistent depression in the same sample. In a South African birth cohort, we investigated the effect of antenatal and postpartum maternal depressive symptoms on offspring brain structure at 2–3 years of age. Magnetic resonance imaging was performed, extracting cortical thickness and surface areas in frontal cortex regions of interest and subcortical volumes using FreeSurfer software. Maternal depressive symptoms were measured using the Edinburgh Postpartum Depression Scale and the Beck Depression Inventory II antenatally and at 6–10 weeks, 6 months, 12 months, and 18 months postpartum and analyzed dichotomously and continuously. Linear regressions were used controlling for child age, sex, intracranial volume, maternal education, age, smoking, alcohol use and HIV. 146 children were included with 38 (37%) exposed to depressive symptoms antenatally and 44 (35%) exposed postnatally. Of these, 16 (13%) were exposed to both. Postpartum, but not antenatal, depressive symptoms were associated with smaller amygdala volumes in children (B = −74.73, p = 0.01). Persistent maternal depressive symptoms across pregnancy and postpartum were also independently associated with smaller amygdala volumes (B = −78.61, p = 0.047). Differences in amygdala volumes among children exposed to postnatal as well as persistent maternal depressive symptomatology underscore the importance of identifying women at-risk for depression during the entire perinatal period.

Excessive Crying, Behavior Problems, and Amygdala Volume: A Study From Infancy to Adolescence

Excessive crying in infancy has been associated with increased risk of later behavioral problems. To identify individuals at risk for behavioral problems and to understand the mechanisms underlying excessive crying and irritability in infancy, research into the neurobiology of excessive crying is needed. We examined whether excessive crying and irritability in infancy are associated with behavioral problems and amygdala volume among children and adolescents. This study included 4,751 singleton children from the prospective population-based Generation R Study cohort, born in the Netherlands in 2002 to 2006. Excessive crying (>3 hours on at least 1 day/wk) and irritability (Mother and Baby Scales questionnaire) were parent-rated at 3 months. Amygdala volume was measured at 10 years using magnetic resonance imaging, and internalizing and externalizing were parent-rated at 1.5, 3, 6, 10, and 14 years and self-rated at 14 years. Covariates included child age, sex, national origin, gestational age, and maternal age, psychopathology score, parity, education, relationship status, and family income. Children who cried excessively in infancy had higher parent-rated internalizing (effect estimate= 0.20 SD-units, 95% CI= 0.14, 0.27) and externalizing (0.17 SD-units, 95% CI= 0.10, 0.24) throughout childhood (linear mixed models), and smaller amygdala volume at 10 years (-0.19 SD-units, 95% CI=-0.32,-0.06) (linear regression model). The pattern of associations for both behavioral problems and amygdala volume was similar for irritability. Excessive crying and irritability in infancy may reflect an early vulnerability to behavioral problems and may be linked with neurobiological differences in the development of the amygdala.

Poverty from fetal life onward and child brain morphology

Poverty is a risk factor for impaired child development, an association possibly mediated by brain morphology. Previous studies lacked prospective poverty assessments during pregnancy and did not stratify by majority/minority status. We investigated the association of household poverty from fetal life forward with brain morphological differences at age 10 years, in 2166 mother–child dyads. Overall, the results showed no associations between any poverty exposure early in life and brain volumes. However, there was the evidence of timing effects: children exposed to poverty in utero had smaller amygdala volumes (B = − 0.18, 95%CI − 0.30; − 0.07, pFDR-adjusted = 0.009). There were also differences in associations by majority/minority status (cerebral white matter: p for interaction = 0.04). Dutch children exposed to childhood poverty showed smaller cerebral white matter volumes than their control (B = − 0.26, 95%CI − 0.45; − 0.06, pFDR-adjusted = 0.035). This association was not observed in the minority population (B = − 0.05, 95%CI − 0.23; 0.12, pFDR-adjusted = 0.542). The smaller cerebral white matter volume mediated the association between childhood poverty and poorer school performance in Dutch children. Our findings point to the importance of poverty exposure in the fetal period and suggest different mechanisms and vulnerabilities across majority/minority groups.

Neurostructural associations with traumatic experiences during child- and adulthood

Adverse experiences can lead to severe mental health problems, such as posttraumatic stress disorder (PTSD), throughout the lifespan. In individuals with PTSD, both global and local brain volume reductions have been reported—especially in the amygdala and hippocampus—while the literature on childhood maltreatment suggests a strong dependency on the timing of adverse events. In the present study, we pooled data from two studies to contrast the effects of reported trauma exposure during neurodevelopmentally sensitive periods in early life with trauma exposure during adulthood. A total of 155 women were allocated into one of six age-matched groups according to the timing of traumatization (childhood vs adulthood) and psychopathology (PTSD vs trauma-exposed healthy vs trauma-naïve healthy). Volumes of the amygdala and hippocampus were compared between these groups. Six additional exploratory regions of interest (ROI) were included based on a recent meta-analysis. Amygdala volume was strongly dependent on the timing of traumatization: Smaller amygdala volumes were observed in participants with childhood trauma and PTSD compared to the healthy control groups. In contrast, larger amygdala volumes were observed in both groups with trauma exposure during adulthood compared to the trauma-naïve control group. Hippocampal volume comparisons revealed no statistically significant differences, although the descriptive pattern was similar to that found for the amygdala. The remaining exploratory ROIs showed significant group effects, but no timing effects. The timing might be an important moderator for adversity effects on amygdala volume, potentially reflecting neurodevelopmental factors. Albeit confounded by characteristics like trauma type and multiplicity, these findings pertain to typical childhood and adulthood trauma as often observed in clinical practice and speak against a simple association between traumatic stress and amygdala volume.

Subcortical brain structure and APOE genotype: An analysis of 43,000 participants from the UK Biobank

AbstractBackgroundCarriers of the ε4 allele of the apolipoprotein (APOE) gene are at higher risk for developing Alzheimer’s disease (AD). In individuals with mild cognitive impairment or AD, the ε4 allele is associated with lower hippocampal and amygdala volumes. How ε4 affects brain structure in healthy individuals before AD symptom onset is less clear. APOE ε2 allele carriers may show slower rates of hippocampal volume loss, suggesting protection against AD. In this large‐scale analysis, we plot normative regional brain volume trajectories in adults (45‐82 years) and map regional subcortical volume differences between APOE genotypes.MethodWe used FreeSurfer 7.1 to segment average left and right accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus and lateral ventricle volumes from T1‐weighted brain MRI (N=43,000). Comparisons between APOE genotypes (ε2ε2, n=257; ε2ε3, n=5,479; ε3ε3, n=26,016; ε3ε4, n=10,263; ε4ε4, n=985) were made using linear mixed effect models, correcting for population structure, age, sex, and intracranial volume (ICV) as fixed effects, and site as a random effect. Results were adjusted for multiple comparisons (FDR q&lt;0.05). Nomograms were derived by adjusting subcortical volumes for population structure, ICV, and site then fitting normative quantile regression models based on the standardized residuals for each region stratified by genotype.ResultNomograms showed similar age‐related trajectories for all APOE genotypes, with smaller gray matter volume and larger ventricle volumes with increasing age. Significantly smaller amygdala and hippocampal volumes were found in ε4ε4 compared to ε3ε4, ε3ε3, and ε2ε3 carriers, and smaller amygdala volumes in ε2ε2 versus ε3ε3 carriers. Smaller accumbens volumes were found in ε4ε4 carriers versus ε2ε3 and ε3ε3, and in ε3ε4 versus ε3ε3 and ε2ε3. Smaller thalamus volumes were found in ε3ε4 versus ε2ε3 and ε3ε3, ε4ε4 carriers had smaller volumes versus ε2ε3 and ε3ε3, and ε2ε2 carriers had smaller volumes versus ε2ε3 and ε3ε3.ConclusionIn this large sample of generally healthy individuals, APOE ε4 allele carriers exhibited lower subcortical volumes compared to those with more neutral AD genetic risk background (ε3ε3). Carriers of ε2ε2 had smaller thalamus and amygdala volumes compared to ε3ε3, suggesting differential effects of AD genetic risk across brain structures known to play a role in AD pathophysiology.

Childhood trauma and brain structure in children and adolescents

The dimensional model of adversity proposes that experiences of threat and deprivation have distinct neurodevelopmental consequences. We examined these dimensions, separately and jointly, with brain structure in a sample of 149 youth aged 8–17—half recruited based on exposure to threat-related experiences. We predicted that greater threat would be uniquely associated with reduced cortical thickness and surface area in brain regions associated with salience processing including ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), and insula, and that deprivation experiences would be uniquely associated with reductions in cortical thickness and surface area in frontoparietal areas associated with cognitive control. As predicted, greater threat was associated with thinner cortex in a network including areas involved in salience processing (anterior insula, vmPFC), and smaller amygdala volume (particularly in younger participants), after controlling for deprivation. Contrary to our hypotheses, threat was also associated with thinning in the frontoparietal control network. However, these associations were reduced following control for deprivation. No associations were found between deprivation and brain structure. This examination of deprivation and threat concurrently in the same sample provided further evidence that threat-related experiences influence the structure of the developing brain independent of deprivation.

Subcortical structures associated with childhood trauma and perceived stress in schizophrenia.

Childhood trauma influences the clinical features of schizophrenia. In this study, we examined how childhood trauma and perceived stress are associated with clinical manifestations and subcortical gray matter volumes (GMVs) in patients with schizophrenia. We recruited 127 patients with schizophrenia and 83 healthy controls for assessment of early childhood trauma, perceived stress, and clinical symptoms. With structural brain imaging, we identified the GMVs of subcortical structures and examined the relationships between childhood trauma, perceived stress, clinical symptoms, and subcortical GMVs. Compared to controls, patients with schizophrenia showed higher levels of childhood trauma and perceived stress. Patients with schizophrenia showed significantly smaller amygdala and hippocampus GMVs as well as total cortical GMVs than age-matched controls. Childhood trauma score was significantly correlated with the severity of clinical symptoms, depression, perceived stress, and amygdala GMVs. Perceived stress was significantly correlated with clinical symptoms, depression, and hippocampus and amygdala GMVs. Further, the association between childhood trauma (emotional neglect) and stress coping ability was mediated by right amygdala GMV in patients with schizophrenia. Patients with schizophrenia had more exposure to early-life trauma and poorer stress coping. Both childhood trauma and perceived stress were associated with smaller amygdala volumes. The relationship between early-life trauma and perceived stress was mediated by right amygdala GMV in patients with schizophrenia. These findings together suggest the long-term effects of childhood trauma on perceived stress and the subcortical volumetric correlates of the effects in schizophrenia.

Brain morphology predictors of alcohol, tobacco, and cannabis use in adolescence: A systematic review

In the last decade, extensive research has emerged on the predictive value of brain morphology for substance use initiation and related problems during adolescence. This systematic review provides an overview of longitudinal studies on pre-existing brain variations and later initiation of alcohol, tobacco, and cannabis use (N = 18). Adolescent structural neuroimaging studies that started before substance use initiation suggest that a smaller anterior cingulate cortex (ACC) volume, thicker or smaller superior frontal gyrus, and larger nucleus accumbens (NAcc) volume are associated with future alcohol use. Also, both smaller and larger orbitofrontal cortex (OFC) volumes were associated with future cannabis and combined alcohol/cannabis use. Smaller amygdala volumes were related to future daily tobacco smoking. These findings could point to specific vulnerabilities for adolescent substance use, as these brain areas are involved in cognitive control (ACC), reward (NAcc), motivation (OFC), and emotional memory (amygdala). However, the reported findings were inconsistent in directionality and laterality, and the largest study on alcohol use predictors reported null findings. Therefore, large population-based longitudinal studies should investigate the robustness and mechanisms of these associations. We suggested future research directions regarding sample selection, timing of baseline and follow-up measurements, and a harmonization approach of study methods.

Volumetric Assessment of Hippocampus and Subcortical Gray Matter Regions in Alzheimer Disease and Amnestic Mild Cognitive Impairment.

Quantitative MRI assessment methods have limited utility due to a lack of standardized methods and measures for Alzheimer disease (AD) and amnestic mild cognitive impairment (aMCI). To employ a relatively new and easy-to-use quantitative assessment method to reveal volumetric changes in subcortical gray matter (GM) regions, hippocampus, and global intracranial structures as well as the diagnostic performance and best thresholds of total hippocampal volumetry in individuals with AD and those with aMCI. A total of 74 individuals-37 with mild to moderate AD, 19 with aMCI, and 18 with normal cognition (NC)-underwent a 3T MRI. Fully automated segmentation and volumetric measurements were performed. The AD and aMCI groups had smaller volumes of amygdala, nucleus accumbens, and hippocampus compared with the NC group. These same two groups had significantly smaller total white matter volume than the NC group. The AD group had smaller total GM volume compared with the aMCI and NC groups. The thalamus in the AD group showed a subtle atrophy. There were no significant volumetric differences in the caudate nucleus, putamen, or globus pallidus between the groups. The amygdala and nucleus accumbens showed atrophy comparable to the hippocampal atrophy in both the AD and aMCI groups, which may contribute to cognitive impairment. Hippocampal volumetry is a reliable tool for differentiating between AD and NC groups but has substantially less power in differentiating between AD and aMCI groups. The loss of total GM volume differentiates AD from aMCI and NC.

Real-time individual benefit from social interactions before and during the lockdown: the crucial role of personality, neurobiology and genes

Social integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood. We investigated the affective benefit from social interactions in a longitudinal birth cohort. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic (N = 70 participants; n~6800 observations) capturing the protective role of social interactions on well-being. Moreover, we used a multimethod approach to analyze ecological assessment data with individual risk and resilience factors, which are promising moderators in the relationship of social behavior, stress reactivity, and affective states (i.e., amygdala volume, neuroticism, polygenic risk for schizophrenia). Social contacts were linked to higher positive affect both during normal times and during the COVID-19-pandemic (beta coefficient = 0.1035), highlighting the beneficial role of social embedding. Interestingly, this relationship was differentially moderated by individual risk and resilience factors. In detail, participants with a larger left amygdala volume (beta coefficient = −0.0793) and higher neuroticism (beta coefficient = −0.0958) exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing an affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit (beta coefficient = −0.0528) from social interactions irrespective of the time point. Our results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a person’s neurobiology, personality, and genes under adverse circumstances.

Association between adverse childhood experiences and brain volumes among Japanese community-dwelling older people: Findings from the NEIGE study

BackgroundAdverse childhood experiences (ACEs) can affect later-life health outcomes via brain structural differences. However, there is no sufficient empirical evidence about whether brain morphological differences remain until old ages. ObjectiveWe examined the association between ACEs and brain volumes among older individuals. Participants and settingResidents aged 65–84 years in Tokamachi City, Japan, were randomly recruited, and 491 participants were included in the analysis. MethodsACEs were assessed with a self-reported questionnaire. The volumes of seven brain regions of interests were evaluated via structural magnetic resonance imaging. ResultsIn total, 143 (27.1%) participants experienced one ACE and 33 (6.7%) two or more ACEs. Participants with two or more ACEs had a larger anterior cingulate cortex volume (B = 0.346, 95% confidence interval [CI] = 0.04 to 0.66) and smaller hippocampal (B = −0.287, 95% CI = −0.58 to 0.001) and amygdala (B = −0.313, 95% CI = −0.59 to −0.03) volumes. Interestingly, we observed a distinct association between deprivation and threat. That is, deprivation was associated with a smaller amygdala volume (B = −0.164, 95% CI = −0.32 to −0.01) and threat with a larger anterior cingulate cortex volume (B = 0.401, 95% CI = 0.11 to 0.70). ConclusionsACEs were associated with the volumes of brain regions such as anterior cingulate cortex, hippocampus, and amygdala, which are responsible for emotion and self-regulation in older population. The effect of ACEs on the amygdala was commonly driven by deprivation experiences and that on the anterior cingulate cortex by threat.

TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer’s disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.

Internalizing-externalizing comorbidity and regional brain volumes in the ABCD study.

Despite nonoverlapping diagnostic criteria, internalizing and externalizing disorders show substantial comorbidity. This comorbidity is attributable, at least in part, to transdiagnostic neuroaffective mechanisms. Both unipolar depression and externalizing disorders are characterized by structural and functional compromises in the striatum and its projections to the anterior cingulate cortex (ACC) and other frontal regions. Smaller volumes and dampened reward responding in these regions are associated with anhedonia and irritability - mood states that cut across the internalizing and externalizing spectra. In contrast, smaller amygdala volumes and dampened amygdala function differentiate externalizing disorders from internalizing disorders. Little is known, however, about associations between internalizing-externalizing comorbidity and brain volumes in these regions, or whether such patterns differ by sex. Using a transdiagnostic, research domain criteria (RDoC)-informed approach, we evaluate associations between heterotypic (Internalizing × Externalizing) symptom interactions and striatal, amygdalar, and ACC volumes among participants in the Adolescent Brain Cognitive Development study (N = 6,971, mean age 9.9 years, 51.6% female). Heterotypic symptoms were associated with ACC volumes for both sexes, over and above the main effects of internalizing and externalizing alone. However, heterotypic comorbidity was associated with larger ACC volumes for girls, but with smaller ACC volumes for boys. These findings suggest a need for further studies and transdiagnostic assessment by sex.

Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk.

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

Sociability, but not spatial memory, is correlated with regional brain volume variation in the striped mouse Rhabdomys spp.

Local environmental conditions associated with different geographic areas may elicit variations in behavioural responses in animals, leading to concomitant differences in functional brain region volumes. We investigated the behavioural correlates of hippocampus and amygdala volumes in three sister taxa of the murid rodent genus Rhabdomys, occurring in different environments. We used a Barnes maze to test spatial memory, dyadic encounters to test social behaviour, and histological brain sections to calculate hippocampus and amygdala volumes. Arid-occurring R. pumilio made fewer errors and had shorter latencies in locating the escape tunnel compared to moist grassland-occurring R. d. dilectus and R. d. chakae in two probe trials, 48 and 96 h after the last learning trial. R. pumilio was more amicable than the R. dilectus subspecies in intra-specific dyadic encounters. R. pumilio had larger hippocampus and amygdala volumes than the other species. Smaller amygdala volumes were correlated with longer latencies in females for probe trial 1, but males showed similar latencies regardless of taxon. Higher amicability scores were correlated with larger amygdala volumes in all taxa. Higher amicability scores were correlated with larger hippocampus volumes in R. pumilio and R. d. chakae but smaller hippocampus volumes in R. d. dilectus. Correlative relationships between spatial memory and amygdala volume appeared 48 h, but not 96 h, after the last learning trial. Local environmental conditions may influence spatial navigation, but social correlates drive regional brain size within cryptic striped mouse taxa.

Chronic Pain Severity and Sociodemographics: An Evaluation of the Neurobiological Interface

Chronic pain is variably associated with brain structure. Phenotyping based on pain severity may address inconsistencies. Sociodemographic groups also differ in the experience of chronic pain severity. Whether differences by chronic pain severity and/or sociodemographic groups are indicated in pain-related areas of the brain is unknown. Relations between 2 measures of chronic pain severity and brain structure via T1-weighted MRI were investigated and sociodemographic group differences explored. The observational study included 142 community-dwelling (68 non-Hispanic Black [NHB] and 74 non-Hispanic White [NHW]) adults with/at risk for knee osteoarthritis. Relationships between chronic pain severity, sociodemographic groups, and a priori selected brain structures (postcentral gyrus, insula, medial orbitofrontal, anterior cingulate, rostral middle frontal gyrus, hippocampus, amygdala, thalamus) were explored. Chronic pain severity associated with cortical thickness. NHB participants reported lower sociodemographic protective factors and greater clinical pain compared to NHWs who reported higher sociodemographic protective factors and lower clinical pain. Greater chronic pain severity was associated with smaller amygdala volumes in the NHB group and larger amygdala volumes in the NHW group. Brain structure by chronic pain stage differed between and within sociodemographic groups. Overall, chronic pain severity and sociodemographic factors are associated with pain-related brain structures. Our findings highlight the importance of further investigating social and environmental contributions in the experience of chronic pain to unravel the complex array of factors contributing to disparities. PerspectiveThe study presents data demonstrating structural brain relationships with clinical pain severity, characteristic pain intensity and chronic pain stage, differ by sociodemographic groups. Findings yield insights into potential sources of previous inconsistent pain-brain relationships and highlights the need for future investigations to address social and environmental factors in chronic pain disparities research.

Association between body mass index and subcortical brain volumes in bipolar disorders\u2013ENIGMA study in 2735 individuals

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV

Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.