Subcortical Brain Volumes Research Articles

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

The interplay of genetic and environmental factors on the morphology of the limbic cortex and hippocampal subfields: Insights from an MRI twin study

IntroductionThe limbic system and the hippocampus are complex brain structures with key roles in memory, emotions, sexual stimulation and learning, with subregion abnormalities associated with a range of disorders and psychopathologies. Our study aimed to explore the heritability of specific subfield structures within the limbic system and hippocampus first in a Caucasian twin sample with volBrain pipeline. Materials and Methods59 healthy adult Caucasian twin pairs from the Hungarian Twin Registry without any history of previous neurodegenerative or cerebrovascular diseases underwent brain MRI on a 3.0 T scanner (43 monozygotic, MZ and 16 dizygotic, DZ pairs, with a median age of 50±+27 years). The volBrain automated volumetry pipeline was used to calculate the subcortical and general brain volumes from three-dimensional T1-weighted images. Based on age- and sex-adjusted MZ and DZ intra-pair correlations, the univariate ACE model was applied to calculate additive genetic, shared and unshared environmental influences. ResultsAdjusting for age and sex, moderate to strong heritability (A: 59.7 to 73.1 %) was found for most limbic cortex volumes, except for the volumes of entorhinal area and posterior cingulate gyrus where common environmental contribution was detected (C: 56.6 % and 65.0 %, respectively). A substantial heritability (A: 67.0 to 79.4 %) was estimated for the overall hippocampus and most subfield volumes, except for the CA2-CA3 region which was determinated by common environmental factors (C: 45.7 %). Unique environmental variance was a minor to moderate contributor across all variables (E: 20.6 to 54.3 %). ConclusionsAlbeit most limbic cortex, overall hippocampus and most subfield volumes are under substantial genetic influence in healthy adult twins, the volumes of entorhinal area, posterior cingulate gyrus and the CA2-CA3 region of the hippocampus are influenced common environmental factors. The findings underline the importance of unique environmental factors which may play a role in the prevention of disorders related to limbic cortex and hippocampus.

Altered Subcortical Brain Volume and Cortical Thickness Related to Insulin Resistance in Type 2 Diabetes Mellitus.

The objective of this study is to examine the alterations in subcortical brain volume and cortical thickness among individuals diagnosed with Type 2 diabetes mellitus (T2DM) through the application of morphometry techniques and, additionally, to investigate the potential association between these modifications and insulin resistance (IR). The present cross-sectional study comprised a total of 121 participants (n=48 with healthy controls [HCs] and n=73 with T2DM) who were recruited and underwent a battery of cognitive testing and structural magnetic resonance imaging (MRI). FreeSurfer was used to process the MRI data. Analysis of covariance compared discrepancies in cortical thickness and subcortical brain volume between T2DM and HCs, adjusting for the potential confounding effects of gender, age, education, and body mass index (BMI). Exploratory partial correlations investigated links between IR and brain structure in T2DM participants. Compared with HCs, individuals with T2DM demonstrated a cortical thickness decrease in the right caudal middle frontal gyrus, right pars opercularis, left precentral gyrus, and bilateral superior frontal gyrus. Furthermore, this study for T2DM found that the severity of IR was inversely related to the volume of the left putamen and left hippocampus, as well as the thickness of the left pars orbitalis, left pericalcarine, right entorhinal area, and right rostral anterior cingulate gyrus. The evidence for structural brain changes in T2DM was observed, and alterations in cortical thickness were concentrated in the frontal lobes. Correlations between IR and frontal cortical thinning may serve as a potential neuroimaging marker of T2DM and lead to various diabetes-related brain complications.

Subcortical Change and Neurohabilitation Treatment Adherence Effects in Extremely Preterm Children.

Extremely preterm birth entails an increased risk for multimorbidity and the prevalence of developmental deficits because this risk is negatively correlated to the number of gestation weeks. This work evaluated subcortical volume changes in children born extremely preterm who received Katona neurohabilitation, as well as the effects of subcortical volume and treatment adherence on their three-year-old neurodevelopment outcomes. Fifteen extremely preterm-born participants were treated from two months to two years old and followed up until past three years of age. The participants received Katona neurohabilitation, which provides vestibular and proprioceptive stimulation and promotes movement integration through the early, intensive practice of human-specific elementary movements. Subcortical brain volumes from magnetic resonance images were obtained at the beginning and after treatment. Also, treatment adherence to Katona neurohabilitation and neurodevelopment outcomes were measured. The results showed that absolute subcortical volumes increased after treatment; however, when adjusted by intracranial volume, these volumes decreased. Subcortical function inhibition allows cortical control and increased connectivity, which may explain decreased adjusted volume. Regression analyses showed that after-treatment hippocampal volumes had a discrete predictive value. However, treatment adherence showed a clear effect on mental and psychomotor neurodevelopment. Thus, the effectiveness of Katona neurohabilitation is constrained by treatment adherence.

Investigating the genetic relationship of intracranial and subcortical brain volumes with depression and other psychiatric disorders

Abstract Depression is one of the most common mental health disorders worldwide, yet its neurobiological mechanisms remain poorly understood. Structural brain differences in subcortical limbic regions are thought to be implicated in the pathology of depression. We leveraged genome-wide association studies (GWAS) summary-level data to explore the molecular pathways underlying the relationship between genetic risk for depression and intracranial and subcortical brain volumes measured via magnetic resonance imaging. At the whole-genome level, we identified a negative genetic correlation (rG) between depression and the volume of the ventral diencephalon (rG = -0.08), which remained significant after adjusting for multiple testing. We observed nominal (P < 0.05) positive genetic correlations between depression and the volumes of the caudate nucleus (rG = 0.06) and the putamen (rG = 0.06), while hippocampal volume displayed a negative genetic correlation (rG = -0.06) with depression. Pairwise GWAS analyses uncovered 104 genome segments with genetic variants influencing the aetiology of depression and at least one brain volume at the local genetic level. Gene association analyses of these genomic segments suggest putative links with dopamine neurotransmission, mesocorticolimbic functional connectivity, GABAergic transmission, and the insulin signalling pathway. Sensitivity analyses showed that the volume of the ventral diencephalon is also negatively correlated with bipolar disorder and schizophrenia; however, most of the genes associated with depression and brain volumes are specific for depression and do not replicate when investigating bipolar disorder or schizophrenia with brain volumes. We observed negative phenotypic correlations between depression and intracranial and subcortical brain volumes. Overall, our findings contribute to our understanding of the neurobiology of depression and suggest that, besides the known role of the hippocampus, other subcortical structures might also play essential roles in the aetiology of depression.

Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. We performed GWAS meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and, for the first time, the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signalling and brain ageing-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and ADHD. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases.

Hippocampal hub failure is linked to long-term memory impairment in anti-NMDA-receptor encephalitis: insights from structural connectome graph theoretical network analysis

BackgroundAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis.MethodsStructural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome.ResultsPatients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p = 0.049; right: p = 0.013) and increased node strength of right precuneus (p = 0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p = 0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p = 0.021). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001).ConclusionsFocal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis.

Shared Genetic Architecture Among Gastrointestinal Diseases, Schizophrenia, and Brain Subcortical Volumes.

The gut-brain axis plays important roles in both gastrointestinal diseases (GI diseases) and schizophrenia (SCZ). Moreover, both GI diseases and SCZ exhibit notable abnormalities in brain subcortical volumes. However, the genetic mechanisms underlying the comorbidity of these diseases and the shared alterations in brain subcortical volumes remain unclear. Using the genome-wide association studies data of SCZ, 14 brain subcortical volumes, and 8 GI diseases, the global polygenic overlap and local genetic correlations were identified, as well as the shared genetic variants among those phenotypes. Furthermore, we conducted multi-trait colocalization analyses to bolster our findings. Functional annotations, cell-type enrichment, and protein-protein interaction (PPI) analyses were carried out to reveal the critical etiology and pathology mechanisms. The global polygenic overlap and local genetic correlations informed the close relationships between SCZ and both GI diseases and brain subcortical volumes. Moreover, 84 unique lead-shared variants were identified. The associated genes were linked to vital biological processes within the immune system. Additionally, significant correlations were observed with key immune cells and the PPI analysis identified several histone-associated hub genes. These findings highlighted the pivotal roles played by the immune system for both SCZ and GI diseases, along with the shared alterations in brain subcortical volumes. These findings revealed the shared genetic architecture contributing to SCZ and GI diseases, as well as their shared alterations in brain subcortical volumes. These insights have substantial implications for the concurrent development of intervention and therapy targets for these diseases.

Brain and Ventricle Volume Alterations in Idiopathic Normal Pressure Hydrocephalus Determined by Artificial Intelligence-Based MRI Volumetry.

The aim of this study was to employ artificial intelligence (AI)-based magnetic resonance imaging (MRI) brain volumetry to potentially distinguish between idiopathic normal pressure hydrocephalus (iNPH), Alzheimer's disease (AD), and age- and sex-matched healthy controls (CG) by evaluating cortical, subcortical, and ventricular volumes. Additionally, correlations between the measured brain and ventricle volumes and two established semi-quantitative radiologic markers for iNPH were examined. An IRB-approved retrospective analysis was conducted on 123 age- and sex-matched subjects (41 iNPH, 41 AD, and 41 controls), with all of the iNPH patients undergoing routine clinical brain MRI prior to ventriculoperitoneal shunt implantation. Automated AI-based determination of different cortical and subcortical brain and ventricular volumes in mL, as well as calculation of population-based normalized percentiles according to an embedded database, was performed; the CE-certified software mdbrain v4.4.1 or above was used with a standardized T1-weighted 3D magnetization-prepared rapid gradient echo (MPRAGE) sequence. Measured brain volumes and percentiles were analyzed for between-group differences and correlated with semi-quantitative measurements of the Evans' index and corpus callosal angle: iNPH patients exhibited ventricular enlargement and changes in gray and white matter compared to AD patients and controls, with the most significant differences observed in total ventricular volume (+67%) and the lateral (+68%), third (+38%), and fourth (+31%) ventricles compared to controls. Global ventriculomegaly and marked white matter reduction with concomitant preservation of gray matter compared to AD and CG were characteristic of iNPH, whereas global and frontoparietally accentuated gray matter reductions were characteristic of AD. Evans' index and corpus callosal angle differed significantly between the three groups and moderately correlated with the lateral ventricular volumes in iNPH patients [Evans' index (r > 0.83, p ≤ 0.001), corpus callosal angle (r < -0.74, p ≤ 0.001)]. AI-based MRI volumetry in iNPH patients revealed global ventricular enlargement and focal brain atrophy, which, in contrast to healthy controls and AD patients, primarily involved the supratentorial white matter and was marked temporomesially and in the midbrain, while largely preserving gray matter. Integrating AI volumetry in conjunction with traditional radiologic measures could enhance iNPH identification and differentiation, potentially improving patient management and therapy response assessment.

Subcortical Brain Volumes and Neurocognitive Function in Children With Perinatal HIV Exposure: A Population-Based Cohort Study in South Africa.

Children who are HIV-exposed and uninfected (HEU) are at risk for early neurodevelopmental impairment. Smaller basal ganglia nuclei have been reported in neonates who are HEU compared to HIV-unexposed (HU); however, neuroimaging studies outside infancy are scarce. We examined subcortical brain structures and associations with neurocognition in children who are HEU. This neuroimaging study was nested within the Drakenstein Child Health Study birth cohort in South Africa. We compared (T1-weighted) magnetic resonance imaging-derived subcortical brain volumes between children who were HEU (n = 70) and HU (n = 92) at age 2-3 years using linear regression. Brain volumes were correlated with neurodevelopmental outcomes measured with the Bayley Scales of Infant and Toddler Development III. Compared to HU children, on average children who were HEU had 3% lower subcortical grey matter volumes. Analyses of individual structures found smaller volume of the putamen nucleus in the basal ganglia (-5% difference, P = .016) and the hippocampus (-3% difference, P = .044), which held on adjustment for potential confounders (P < .05). Maternal viremia and lower CD4 count in pregnancy were associated with smaller child putamen volumes. Children who were HEU had lower language scores than HU; putamen and hippocampus volumes were positively correlated with language outcomes. Overall, children who are HEU had a pattern of smaller subcortical volumes in the basal ganglia and hippocampal regions compared to HU children, which correlated with language function. Findings suggest that optimizing maternal perinatal HIV care is important for child brain development. Further studies are needed to investigate underlying mechanisms and long-term outcomes.

Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study

BackgroundRecent studies have associated immune abnormalities with dementia. IL-6 is a crucial cytokine in inflammatory responses, and recent evidence has linked elevated IL-6 levels to changes in brain structure and cognitive decline. However, the connection between IL-6 levels, cognition, brain volumes, and dementia risk requires exploration in large prospective cohorts. MethodsThis study utilized a longitudinal cohort from the UK Biobank to analyze the correlation between IL-6 expression levels, cognitive performance, and cortical and subcortical brain volumes through linear regression. Additionally, we assessed the association between IL-6 levels and long-term dementia risk using Cox regression analysis. We also used one-sample Mendelian randomization to analyze the impact of genetic predisposition of dementia on elevated IL-6 levels. ResultsA total of 50,864 participants were included in this study, with 1,391 new cases of all-cause dementia identified. Higher plasma IL-6 levels are associated with cortical and subcortical atrophy in regions such as the fusiform, thalamus proper, hippocampus, and larger ventricle volumes. IL-6 levels are negatively associated with cognitive performance in pair matching, numeric memory, prospective memory, and reaction time tests. Furthermore, elevated IL-6 levels are linked to a 23–35 % increased risk of all-cause dementia over an average follow-up period of 13.2 years. The one-sample Mendelian randomization analysis did not show associations between the genetic predisposition of dementia and elevated IL-6 levels. ConclusionsIncreased IL-6 levels are associated with worse cognition, brain atrophy, and a heightened risk of all-cause dementia. Our study highlights the need to focus on the role of peripheral IL-6 levels in managing brain health and dementia risk.

The effects of psychotherapy for anhedonia on subcortical brain volumes measured with ultra-high field MRI

BackgroundAnhedonia is a transdiagnostic symptom often resistant to treatment. The identification of biomarkers sensitive to anhedonia treatment will aid in the evaluation of novel anhedonia interventions. MethodsThis is an exploratory analysis of changes in subcortical brain volumes accompanying psychotherapy in a transdiagnostic anhedonic sample using ultra-high field (7-Tesla) MRI. Outpatients with clinically impairing anhedonia (n = 116) received Behavioral Activation Treatment for Anhedonia, a novel psychotherapy, or Mindfulness-Based Cognitive Therapy (ClinicalTrials.gov Identifiers NCT02874534 and NCT04036136). Subcortical brain volumes were estimated via the MultisegPipeline, and regions of interest were the amygdala, caudate nucleus, hippocampus, pallidum, putamen, and thalamus. Bivariate mixed effects models estimated pre-treatment relations between anhedonia severity and subcortical brain volumes, change over time in subcortical brain volumes, and associations between changes in subcortical brain volumes and changes in anhedonia symptoms. ResultsAs reported previously (Cernasov et al., 2023), both forms of psychotherapy resulted in equivalent and significant reductions in anhedonia symptoms. Pre-treatment anhedonia severity and subcortical brain volumes were not related. No changes in subcortical brain volumes were observed over the course of treatment. Additionally, no relations were observed between changes in subcortical brain volumes and changes in anhedonia severity over the course of treatment. LimitationsThis trial included a modest sample size and did not have a waitlist-control condition or a non-anhedonic comparison group. ConclusionsIn this exploratory analysis, psychotherapy for anhedonia was not accompanied by changes in subcortical brain volumes, suggesting that subcortical brain volumes may not be a candidate biomarker sensitive to response to psychotherapy.

Sex versus gender associations with brain structure

In contrast to sex (a biological distinction), little is known about the associations between gender (a societal construct) and brain structure in the general population. In response to this knowledge gap, we examined the associations of sex vs. gender with FreeSurfer-generated cortical thickness and proportion-adjusted subcortical brain volume regions-of-interest (ROIs) in healthy adults (n = 88) screened for general medical conditions, mental illness, substance abuse, and intracranial pathologies. Gender role endorsement was assessed using the well-established and validated Bem Sex Role Inventory. For our main objectives, we calculated a continuum score as a composite measure of gender. For our secondary objectives, we examined sex-specific associations of the masculine vs. feminine gender role endorsement domains with brain structural outcomes. We found that female sex, independent of continuum scores, was associated with larger proportion-adjusted volumes for the basal ganglia, hippocampus, and ventral diencephalon. Higher continuum scores, independent of sex, were associated with thicker cortical thickness for the left and right superior frontal cortex, caudal and rostral middle frontal cortex, and right pars orbitalis. Female sex and higher continuum scores were independently associated with larger corpus callosum volumes. Post-hoc testing showed sex-specific associations between higher femininity scores and thicker prefrontal cortical thickness for the ROIs in females, but not in males. In conclusion, sex and gender showed semi-independent associations with brain structure in a general population sample. Our research supports the disaggregation of sex and gender to provide a more nuanced perspective on brain structural differences between men and women.

T2* Mapping of Placental Oxygenation to Estimate Fetal Cortical and Subcortical Maturation

This cohort study investigates the association between T2* mapping of placental oxygenation and cortical and subcortical fetal brain volumes in typically developing fetuses scanned longitudinally in the third trimester.

A causal relationship between gut microbiota and subcortical brain structures contributes to the microbiota-gut-brain axis: a Mendelian randomization study.

A correlation between gut microbiota and brain structure, referring to as a component of the gut-brain axis, has been observed in observational studies. However, the causality of this relationship and its specific bacterial taxa remains uncertain. To reveal the causal effects of gut microbiota on subcortical brain volume, we applied Mendelian randomization (MR) studies in this study. Genome-wide association study data were obtained from the MiBioGen Consortium (n = 18,340) and the Enhancing Neuro Imaging Genetics through Meta-Analysis Consortium (n = 13,170). The primary estimate was obtained utilizing the inverse-variance weighted, while heterogeneity and pleiotropy were assessed using the Cochrane Q statistic, MR Pleiotropy RESidual Sum and Outlier, and MR-Egger intercept. Our findings provide strong evidence that a higher abundance of the genus Parasutterella is causally correlated with a decrease in intracranial volume (β = -30,921.33, 95% CI -46,671.78 to -15,170.88, P = 1.19 × 10-4), and the genus FamilyXIIIUCG001 is associated with a decrease in thalamus volume (β = -141.96, 95% CI: -214.81 to -69.12, P = 1.0× 10-4). This MR study offers novel perspectives on the intricate interplay between the gut microbiota and subcortical brain volume, thereby lending some support to the existence of the microbiota-gut-brain axis.

Polygenic scores of subcortical brain volumes as possible modulators of treatment response in depression

A significant proportion of patients with major depressive disorder (MDD) do not experience remission after one or more pharmacological treatments. Research has explored brain structural measures, particularly hippocampal volume, as potential predictors of treatment response, as well as genetic factors.This study investigated the association of polygenic scores (PGSs) for seven subcortical brain volumes (including the hippocampus, nucleus accumbens, amygdala, and caudate nucleus) with treatment non-response and non-remission in MDD.Patients with MDD were recruited in the context of five clinical studies, including a total of 3637 individuals. PGSs were estimated using a Bayesian framework and continuous shrinkage priors (PRS-CS-auto) after standard genotype quality control and imputation. Logistic regressions were performed between PGSs and non-response or non-remission in each sample, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, using a random-effect model.No association was significant in the meta-analysis after Bonferroni correction. The top finding was found for the caudate volume PGS and non-remission (OR = 1.09, 95% CI = 1.01–1.19, p = 0.036), with no evidence of heterogeneity. Leave-one-out sensitivity analyses showed that this result was influenced by the two largest samples in the meta-analysis.This result should be considered as preliminary as it did not reach the Bonferroni-adjusted significance threshold. Future studies with greater statistical power may enhance the predictive performance of PGSs and contribute to the identification of polygenic predictors of treatment outcomes in MDD, contributing to precision psychiatry.

Beyond the Buzz: Cortical and subcortical brain changes in patients with pulsatile tinnitus

Pulsatile tinnitus (PT) can be a debilitating condition characterized by rhythmic, heartbeat-synchronous sounds, which can severely impact patients’ quality of life. Understanding the neuroanatomical changes in PT patients may provide critical insights into the impacts of this condition. This study aimed to investigate potential differences in cortical and subcortical brain volume between adults with PT and age-matched controls (60 to 70 years of age). A retrospective, cross-sectional analysis of imaging and medical records was conducted, with data collected from January 2015 to December 2021. The study was conducted in a tertiary referral center with a specialized tinnitus clinic. A total of 135 adults diagnosed with PT and 135 age-matched controls were included. All participants were screened for PT and relevant medical history, with consecutive sampling used for selection. Cortical and subcortical brain volume differences between PT patients and controls were measured using Freesurfer. PT patients (n = 79, after exclusion of patients with inadequate imaging data) exhibited significant decreases in cortical thickness in the anterior cingulate and entorhinal cortex, and decreased volume in the left putamen, compared to age-matched controls (n = 135). PT patients also demonstrated significant increased volume in frontal and occipital lobe structures, the cerebellum, hippocampi, and ventral pallidum. In conclusion, our findings suggest that individuals with PT may have structural differences in brain regions related to auditory processing, and depression, which provides additional evidence of the psychiatric sequalae of PT. These findings demonstrate that there are neuroanatomical alterations in patients with PT, emphasizing the value in evaluating and treating this disease to prevent these neuroanatomical differences from developing.

SHARED AND DISTINCT ASSOCIATIONS OF MANUAL DEXTERITY AND GROSS MOTOR FUNCTION WITH BRAIN ATROPHY

Abstract Poor motor function is associated with brain volume and cognitive impairment. Less is known about the associations among motor domains and brain atrophy and whether associations are affected by cerebrovascular burden and/or physical activity. We analyzed data from 726 Baltimore Longitudinal Study of Aging participants (mean age 70.6±10.1 years, 56%women, 27%Black), 525 of whom had repeat MRI scans over 5.0±2.1 years. Two motor domains were operationalized as latent variables. Manual dexterity using the Purdue Pegboard and gross motor function using grip strength and comprehensive physical performance testing. Associations between the latent variables and cortical and subcortical brain volumes of interest were examined using latent growth curve modeling, adjusted for demographics, white matter hyperintensities, and physical activity. Both higher manual dexterity and gross motor function were cross-sectionally associated with smaller ventricular volume and greater white matter volumes in the frontal, parietal, and temporal lobes (all p&amp;lt;.05). Higher manual dexterity was also cross-sectionally associated with greater parietal gray matter ( =0.14;95%CI:0.05,0.23), hippocampal ( =0.10;95%CI:0.01,0.20), postcentral gyrus ( =0.11;95%CI:0.01,0.20), and occipital white matter ( =0.10;95%CI:0.01,0.21) volumes, and better gross motor function with greater temporal gray matter volume ( =0.16;95%CI:0.05,0.26). Longitudinally, higher manual dexterity and gross motor function were associated with lower temporal white matter and occipital gray matter atrophy (all p&amp;lt;0.05). Greater manual dexterity was also associated with a slower rate of ventricular enlargement ( =-0.17;95%CI:-0.29,-0.05) and less atrophy of occipital white matter ( =0.39;95%CI:0.04,0.71). Among cognitively normal middle- and older-aged adults, manual dexterity and gross motor function exhibited shared as well as distinct associations with brain atrophy over time.

Impaired ability to smile in Alzheimer’s disease is associated with reduced brain volume of nucleus accumbens and pallidum, revealed by artificial intelligence

AbstractBackgroundPatients tend to lose the ability to smile during the clinical course of dementia. However, details of such impairment remain obscure presumably due to difficulty of quantifying facial expression. Feature extraction is now automated as a result of recent developments in artificial intelligence (AI). The authors applied a model to quantify impaired smile expression in patients with Alzheimer disease (AD). The relationship between the expression of a smile and subcortical volumes was also investigated.MethodThis study included 280 and 190 participants with AD and with normal cognition (NC), respectively. The faces of the participants were photographed as they smiled or maintained a neutral expression. Subcortical brain volume was assessed in 210 and 90 of those with AD and NC, respectively, using MRI and the FSL‐FIRST algorithm. Datasets of the photographs were prepared with combinations of smiling and neutral expression in NC and AD, smiling in AD and NC, and neutral expression in AD and NC, then binary discrimination proceeded using the VGG‐Face convolutional neural network (CNN).ResultThe accuracy of discriminating a smile from a neutral expression was of 92.3% in NC, and 61.2% in AD, indicating that a considerable proportion of patients with AD have difficulties forming a natural smile. 48.5% of smile AD were classified as negative in NC dataset. The smile/neutral‐NC scores for AD were robustly associated with the volume of the bilateral nucleus accumbens (right, r = 0.51, p = 2.59 × 10−15; left, r = 0.493, p = 2.89 × 10−14) and the bilateral pallidum (right, r = 0.266, p = 0.0000981; left, r = 0.256, p = 0.000174). The accuracy of discriminating between AD and NC was 95.2% with smile and 90.1% with a neutral expression, respectively (p = 0.0045). The neutral‐AD/NC score inversely correlated with the results of the MMSE (p = 1.62 × 10−7), but not with smile/neutral‐NC or smile‐AD/NC scores.ConclusionThe ability to form smile was impaired in AD and associated with nucleus accumbens and pallidum shrinkage. Such impairment enhanced the accuracy of facial discrimination between AD and NC, whereas a neutral expression was associated with cognitive function.

Bridging the Brain‐Age Gap: Quantifying regional contributions using Shapley‐Owen values

AbstractBackgroundThe concept of brain age gap (BAG) is increasingly being used to express the deviation of brain from the normative trajectory. However, each brain region is subject to independent aging transformations due to differences in neurobiological processes. So, reducing high‐dimensional imaging features down to a single number for simultaneously evaluating brain health, capacity, and residual lifespan is an error‐prone task. Furthermore, brain age is observed to be correlated with chronological age. Therefore, there is need for a systematic empirical evaluation of BAG to understand contributions of different regions when considering BAG as a potential aging biomarker for age‐related neuroanatomical abnormalities. Although methods such as saliency maps have been proposed, there is need for a model‐agnostic technique that quantifies consistent feature contributions across various predictive models.MethodWe used morphological features estimated by Freesurfer from T1w (OASIS3 dataset) to train predictive models for BAG. The bias‐correction was performed using two strategies (i.e., scale‐down and scale up) on each of linear regression and XGBoost models as shown in Figure 1. We present feature importance for top‐10 features (based on median feature importance scores) across 100 bootstrap runs (Figures 2 and 3 respectively), along with correlations with chronological age. We use Shapley‐Owen feature attribution technique as a way of assigning importance to features.ResultAs shown in Figures 2 and 3, we found sub‐cortical, anterior cingulate, and ventricle volumes among the most relevant features. We also observe that SHAP determines an almost identical set of most relevant features for predicting corrected BAG irrespective of the predictive model (linear regression or XGboost) or the bias‐correction approach. Furthermore, we found the results to be consistent with prior literature e.g., subcortical brain volumes esp. gray matter. We also empirically observe that bias‐correction mitigates dependence on chronological age.ConclusionWe present a systematic empirical evaluation to identify the most relevant morphological features for predicting corrected BAG using SHAP. A consistent overlap of most relevant features irrespective of predictive model and the bias‐correction approach provides evidence for the robustness of using Shapley‐Owen values in explaining the contribution of morphological features for predicting corrected BAG.