Subcortical Gray Matter Volume Research Articles

1328-P: Impact of Early Childhood-Onset Type 1 Diabetes on Brain Structural Trajectories (CLARiFY Study)

Although childhood-onset of Type 1 diabetes (T1D) is associated with alterations in structural brain development, the influence of T1D over time remains poorly understood. We aimed to compare the trajectories of brain structure change in a sample of children with T1D to age-matched children without T1D. We recruited children presenting to a tertiary hospital in Australia between 1990 - 1992 into this prospective cohort study (Cognition and Longitudinal Assessment of Risk Factors over 30 Years (CLARiFY) Study). Brain magnetic resonance imaging (MRI) was performed at two time points, approximately 20 years apart. We examined for between-group differences in normalized brain volumes and cortical thickness (CT) across time using linear mixed models. A total of 127 images were available at timepoint 1 (77 with T1D, mean age=20 years, 43% female) and 68 at timepoint 2 (36 with T1D, mean age=37 years, 49% female). At timepoint 1, those with T1D had lower subcortical gray matter volume than those without T1D (p=0.01) but the remaining measures were similar. Across time, those with T1D had greater decline in cortical thickness (β=-2280, p=0.03) than those without T1D, with trajectories in other measures being similar (Table). In conclusion, these preliminary findings suggest that childhood-onset T1D is associated with lower subcortical gray matter and altered development of cortical gray matter over time. Disclosure O.Gbadeyan: None. C.Moran: None. A.Brown: None. S.A.Sakowski: None. V.Srikanth: None. F.Cameron: None. E.A.Northam: None. E.L.Feldman: None. R.Beare: None. Funding National Institutes of Health (R01DK129320)

Morphological abnormalities in youth with bipolar disorder and their relationship to clinical characteristics

ObjectivesTo characterize the neuroanatomy of BD in youth and its correlation to clinical characteristics. MethodsThe current study includes a sample of 105 unmedicated youth with first-episode BD, aged between 10.1 and 17.9 years, and 61 healthy comparison adolescents, aged between 10.1 and 17.7 years, who were matched for age, race, sex, socioeconomic status, intelligence quotient (IQ), and education level. T1-weighted magnetic resonance imaging (MRI) images were obtained using a 4 T MRI scanner. Freesurfer (V6.0) was used to preprocess and parcellate the structural data, and 68 cortical and 12 subcortical regions were considered for statistical comparisons. The relationship between morphological deficits and clinical and demographic characteristics were evaluated using linear models. ResultsCompared with healthy youth, youth with BD had decreased cortical thickness in frontal, parietal, and anterior cingulate regions. These youth also showed decreased gray matter volumes in 6 of the 12 subcortical regions examined including thalamus, putamen, amygdala and caudate. In further subgroup analyses, we found that youth with BD with comorbid attention-deficit hyperactivity disorder (ADHD) or with psychotic symptoms had more significant deficits in subcortical gray matter volume. LimitationsWe cannot provide information about the course of structural changes and impact of treatment and illness progression. ConclusionsOur findings indicate that youth with BD have significant neurostructural deficits in both cortical and subcortical regions mainly located in the regions related to emotion processing and regulation. Variability in clinical characteristics and comorbidities may contribute to the severity of anatomic alterations in this disorder.

Intrauterine exposure to chorioamnionitis and neuroanatomical alterations at term-equivalent age in preterm infants.

Infants born to mothers with chorioamnionitis (CAM) are at increased risk of developing adverse neurodevelopmental disorders in later life. However, clinical magnetic resonance imaging (MRI) studies examining brain injuries and neuroanatomical alterations attributed to CAM have yielded inconsistent results. We aimed to determine whether exposure to histological CAM in utero leads to brain injuries and alterations in the neuroanatomy of preterm infants using 3.0- Tesla MRI at term-equivalent age. A total of 58 preterm infants born before 34weeks of gestation at Nagoya University Hospital between 2010 and 2018 were eligible for this study (CAM group, n = 21; non-CAM group, n = 37). Brain injuries and abnormalities were assessed using the Kidokoro Global Brain Abnormality Scoring system. Gray matter, white matter, and subcortical gray matter (thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens) volumes were evaluated using segmentation tools (SPM12 and Infant FreeSurfer). The Kidokoro scores for each category and severity in the CAM group were comparable to those observed in the non-CAM group. White matter volume was significantly smaller in the CAM group after adjusting for covariates (postmenstrual age at MRI, infant sex, and gestational age) (p = 0.007), whereas gray matter volume was not significantly different. Multiple linear regression analyses revealed significantly smaller volumes in the bilateral pallidums (right, p = 0.045; left, p = 0.038) and nucleus accumbens (right, p = 0.030; left, p = 0.004) after adjusting for covariates. Preterm infants born to mothers with histological CAM showed smaller volumes in white matter, pallidum, and nucleus accumbens at term-equivalent age.

Genetic and Environmental Contributions to Subcortical Gray Matter Microstructure and Volume in the Developing Brain

Using baseline (ages 9–10) and two-year follow-up (ages 11–12) data from monozygotic and dizygotic twins enrolled in the longitudinal Adolescent Brain Cognitive DevelopmentSM Study, we investigated the genetic and environmental contributions to microstructure and volume of nine subcortical gray matter regions. Microstructure was assessed using diffusion MRI data analyzed using restriction spectrum imaging (RSI) and diffusion tensor imaging (DTI) models. The highest heritability estimates (estimate [95% confidence interval]) for microstructure were found using the RSI model in the pallidum (baseline: 0.859 [0.818, 0.889], follow-up: 0.835 [0.787, 0.871]), putamen (baseline: 0.859 [0.819, 0.889], follow-up: 0.874 [0.838, 0.902]), and thalamus (baseline: 0.855 [0.814, 0.887], follow-up: 0.819 [0.769, 0.857]). For volumes the corresponding regions were the caudate (baseline: 0.831 [0.688, 0.992], follow-up: 0.848 [0.701, 1.011]) and putamen (baseline: 0.906 [0.875, 0.914], follow-up: 0.906 [0.885, 0.923]). The subcortical regions displayed high genetic stability (rA = 0.743–1.000) across time and exhibited unique environmental correlations (rE = 0.194–0.610). Individual differences in both gray matter microstructure and volumes can be largely explained by additive genetic effects in this sample.

Brain structural co-development is associated with internalizing symptoms two years later in the ABCD cohort.

About 1/3 of youth spend more than four hours/day engaged in screen media activity (SMA). This investigation utilized longitudinal brain imaging and mediation analyses to examine relationships among SMA, brain patterns, and internalizing problems. Data from Adolescent Brain Cognitive Development (ABCD) participants with baseline and two-year follow-up structural imaging data that passed quality control (N = 5,166; 2,385 girls) were analyzed. Joint and Individual Variation Explained (JIVE) identified a brain co-development pattern among 221 brain features (i.e., differences in surface area, thickness, or cortical and subcortical gray-matter volume between baseline and two-year-follow-up data). Generalized linear mixed-effect models investigated associations between baseline SMA, structural co-development and internalizing and externalizing psychopathology at two-year follow-up. SMA at baseline was related to internalizing psychopathology at year 2 (β=0.020,SE=0.008,P=0.014) and a structural co-development pattern (β=0.015,SE=0.007,P=0.029), where the co-development pattern suggested that rates of change in gray-matter volumes of the brainstem, gray-matter volumes and/or cortical thickness measures of bilateral superior frontal, rostral middle frontal, inferior parietal, and inferior temporal regions were more similar than those in other regions. This component partially mediated the relationship between baseline SMA and future internalizing problems (indirect effect = 0.020, P-value = 0.043, proportion mediated: 2.24%). Greater youth engagement in SMA at ages 9-10 years statistically predicted higher levels of internalizing two years later. This association was mediated by cortical-brainstem circuitry, albeit with relatively small effect sizes. The findings may help delineate processes contributing to internalizing behaviors and assist in identifying individuals at greater risk for such problems.

Telomere length and brain imaging phenotypes in UK Biobank.

Telomeres form protective caps at the ends of chromosomes, and their attrition is a marker of biological aging. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. The mechanism underlying this risk is unclear, and may involve brain structure and function. However, the relationship between telomere length and neuroimaging markers is poorly characterized. Here we show that leucocyte telomere length (LTL) is associated with multi-modal MRI phenotypes in 31,661 UK Biobank participants. Longer LTL is associated with: i) larger global and subcortical grey matter volumes including the hippocampus, ii) lower T1-weighted grey-white tissue contrast in sensory cortices, iii) white-matter microstructure measures in corpus callosum and association fibres, iv) lower volume of white matter hyperintensities, and v) lower basal ganglia iron. Longer LTL was protective against certain related clinical manifestations, namely all-cause dementia (HR 0.93, 95% CI: 0.91-0.96), but not stroke or Parkinson's disease. LTL is associated with multiple MRI endophenotypes of neurodegenerative disease, suggesting a pathway by which longer LTL may confer protective against dementia.

Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

ObjectiveaaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. MethodsaaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. ResultsaaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. ConclusionaaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

Gray matter volume and pain tolerance in a general population: the Tromsø study.

As pain is processed by an extensive network of brain regions, the structural status of the brain may affect pain perception. We aimed to study the association between gray matter volume (GMV) and pain sensitivity in a general population. We used data from 1522 participants in the seventh wave of the Tromsø study, who had completed the cold pressor test (3°C, maximum time 120 seconds), undergone magnetic resonance imaging (MRI) of the brain, and had complete information on covariates. Cox proportional hazards regression models were fitted with time to hand withdrawal from cold exposure as outcome. Gray matter volume was the independent variable, and analyses were adjusted for intracranial volume, age, sex, education level, and cardiovascular risk factors. Additional adjustment was made for chronic pain and depression in subsamples with available information on the respective item. FreeSurfer was used to estimate vertexwise cortical and subcortical gray matter volumes from the T1-weighted MR image. Post hoc analyses were performed on cortical and subcortical volume estimates. Standardized total GMV was associated with risk of hand withdrawal (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.71-0.93). The effect remained significant after additional adjustment for chronic pain (HR 0.84, 95% CI 0.72-0.97) or depression (HR 0.82, 95% CI 0.71-0.94). In post hoc analyses, positive associations between standardized GMV and pain tolerance were seen in most brain regions, with larger effect sizes in regions previously shown to be associated with pain. In conclusion, our findings indicate that larger GMV is associated with longer pain tolerance in the general population.

Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort.

Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.

Associations Between Thinner Retinal Neuronal Layers and Suboptimal Brain Structural Integrity in a Middle-Aged Cohort.

The retina has potential as a biomarker of brain health and Alzheimer's disease (AD) because it is the only part of the central nervous system which can be easily imaged and has advantages over brain imaging technologies. Few studies have compared retinal and brain measurements in a middle-aged sample. The objective of our study was to investigate whether retinal neuronal measurements were associated with structural brain measurements in a middle-aged population-based cohort. Participants were members of the Dunedin Multidisciplinary Health and Development Study (n=1037; a longitudinal cohort followed from birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently at age 45, when 94% of the living Study members participated). Retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured by optical coherence tomography (OCT). Brain age gap estimate (brainAGE), cortical surface area, cortical thickness, subcortical grey matter volumes, white matter hyperintensities, were measured by magnetic resonance imaging (MRI). Participants with both MRI and OCT data were included in the analysis (RNFL n=828, female n=413 [49.9%], male n=415 [50.1%]; GC-IPL n=825, female n=413 [50.1%], male n=412 [49.9%]). Thinner retinal neuronal layers were associated with older brain age, smaller cortical surface area, thinner average cortex, smaller subcortical grey matter volumes, and increased volume of white matter hyperintensities. These findings provide evidence that the retinal neuronal layers reflect differences in midlife structural brain integrity consistent with increased risk for later AD, supporting the proposition that the retina may be an early biomarker of brain health.

Functional and structural alterations as diagnostic imaging markers for depression in de novo Parkinson's disease.

Depression in Parkinson's disease (PD) is identified and diagnosed with behavioral observations and neuropsychological measurements. Due to the large overlaps of depression and PD symptoms in clinical manifestations, it is challenging for neurologists to distinguish and diagnose depression in PD (DPD) in the early clinical stage of PD. The advancement in magnetic resonance imaging (MRI) technology provides potential clinical utility in the diagnosis of DPD. This study aimed to explore the alterations of functional and structural MRI in DPD to produce neuroimaging markers in discriminating DPD from non-depressed PD (NDPD) and healthy controls (HC). We recruited 20 DPD, 37 NDPD, and 41 HC matched in age, gender, and education years. The patients' diagnosis with PD was de novo. The differences in regional homogeneity (ReHo), voxel-wise degree centrality (DC), cortical thickness, cortical gray matter (GM) volumes, and subcortical GM volumes among these groups were detected, and the relationship between altered indicators and depression was analyzed. Moreover, the receiver operating characteristic (ROC) analysis was performed to assess the diagnostic efficacy of altered indicators for DPD. Compared to NDPD and HC, DPD showed significantly increased ReHo in left dorsolateral superior frontal gyrus (DSFG) and DC in left inferior temporal gyrus (ITG), and decreased GM volumes in left temporal lobe and right Amygdala. Among these altered indicators, ReHo value in left DSFG and DC values in left ITG and left DSFG were significantly correlated with the severity of depression in PD patients. Comparing DPD and NDPD, the ROC analysis revealed a better area under the curve value for the combination of ReHo value in left DSFG and DC value in left ITG, followed by each independent indicator. However, the difference is not statistically significant. This study demonstrates that both functional and structural impairments are present in DPD. Among them, ReHo value of left DSFG and DC value of left ITG are equally well suited for the diagnosis and differential diagnosis of DPD, with a combination of them being slightly preferable. The multimodal MRI technique represents a promising approach for the classification of subjects with PD.

Increased Resting-State Functional Connectivity as a Compensatory Mechanism for Reduced Brain Volume in Prediabetes and Type 2 Diabetes.

To investigate the contribution of alterations in brain structure and function to cognitive function and their interactions in individuals with diabetes and patients with type 2 diabetes mellitus (T2DM). This population-based study included 2,483 participants who underwent structural MRI (n = 569 with normal glucose metabolism [NGM], n = 1,353 with prediabetes, and n = 561 with T2DM) and cognitive testing. Of these, 2145 participants also underwent functional MRI (n = 496 NGM, n = 1,170 prediabetes, and n = 479 T2DM). Multivariate linear regression models were used to assess the association of brain volume and functional connectivity with cognition, as well as the association of brain volume and functional connectivity. Compared with NGM participants, those with T2DM had lower brain volume in a wide range of brain regions and stronger functional connectivity between the bilateral thalamus and brain functional network (visual network and default mode network), and those with prediabetes had lower brain volume in specific local regions (subcortical gray matter volume and subcortical subregions [bilateral thalamus, bilateral nucleus accumbens, and right putamen]) and stronger functional connectivity between the right thalamus and visual network. Cognition was associated with greater right thalamus volume and lower functional connectivity between the right thalamus and visual network. Functional connectivity between the right thalamus and visual network was associated with lower right thalamus volume. Cognition was associated with greater brain volume and lower functional connectivity in T2DM. Increased functional connectivity may indicate a compensatory mechanism for reduced brain volume that begins in the prediabetic phase.

Brain development after intrauterine exposure to lithium: A magnetic resonance imaging study in school-age children.

Lithium is often continued during pregnancy to reduce the risk of perinatal mood episodes for women with bipolar disorder. However, little is known about the effect of intrauterine lithium exposure on brain development. The aim of this study was to investigate brain structure in children after intrauterine exposure to lithium. Participants were offspring, aged 8-14 years, of women with a diagnosis of bipolar spectrum disorder. In total, 63 children participated in the study: 30 with and 33 without intrauterine exposure to lithium. Global brain volume outcomes and white matter integrity were assessed using structural MRI and diffusion tensor imaging, respectively. Primary outcomes were total brain, cortical and subcortical gray matter, cortical white matter, lateral ventricles, cerebellum, hippocampus and amygdala volumes, cortical thickness, cortical surface area and global fractional anisotropy, and mean diffusivity. To assess how our data compared to the general population, global brain volumes were compared to data from the Generation R study (N=3243). In our primary analyses, we found no statistically significant associations between intrauterine exposure to lithium and structural brain measures. There was a non-significant trend toward reduced subcortical gray matter volume. Compared to the general population, lithium-exposed children showed reduced subcortical gray and cortical white matter volumes. We found no differences in brain structure between lithium-exposed and non-lithium-exposed children aged 8-14 years following correction for multiple testing. While a rare population to study, future and likely multi-site studies with larger datasets are required to validate and extend these initial findings.

Classifying Alzheimer's disease and frontotemporal dementia using machine learning with cross-sectional and longitudinal magnetic resonance imaging data.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are common causes of dementia with partly overlapping, symptoms and brain signatures. There is a need to establish an accurate diagnosis and to obtain markers for disease tracking. We combined unsupervised and supervised machine learning to discriminate between AD and FTD using brain magnetic resonance imaging (MRI). We included baseline 3T-T1 MRI data from 339 subjects: 99 healthy controls (CTR), 153AD and 87 FTD patients; and 2-year follow-up data from 114 subjects. We obtained subcortical gray matter volumes and cortical thickness measures using FreeSurfer. We used dimensionality reduction to obtain a single feature that was later used in a support vector machine for classification. Discrimination patterns were obtained with the contribution of each region to the single feature. Our algorithm differentiated CTR versus AD and CTR versus FTD at the cross-sectional level with 83.3% and 82.1% of accuracy. These increased up to 90.0% and 88.0% with longitudinal data. When we studied the classification between AD versus FTD we obtained an accuracy of 63.3% at the cross-sectional level and 75.0% for longitudinal data. The AD versus FTD versus CTR classification has reached an accuracy of 60.7%, and 71.3% for cross-sectional and longitudinal data respectively. Disease discrimination brain maps are in concordance with previous results obtained with classical approaches. By using a single feature, we were capable to classify CTR, AD, and FTD with good accuracy, considering the inherent overlap between diseases. Importantly, the algorithm can be used with cross-sectional and longitudinal data.

Structural and Functional Brain Changes in Acute Takotsubo Syndrome

BackgroundTakotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress. ObjectivesThe mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation. MethodsTwenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox. ResultsThere was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05). ConclusionsThe authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients’ rehabilitation.

Atrophy in subcortical gray matter in adult patients with moyamoya disease

BackgroundAcute cerebrovascular accidents, long-term hypoperfusion, and/or remote neuronal degeneration may lead to structural alterations in patients with moyamoya disease (MMD). This study sought to comprehensively investigate the distribution characteristics of subcortical gray matter volume and their correlations with angiographic changes in the intracranial artery in patients with MMD. MethodOne hundred forty-two patients with MMD and 142 age- and sex-matched healthy controls underwent 3-dimensional high-resolution structural magnetic resonance imaging. Volumes of subcortical gray matter and subregions of the hippocampus and amygdala were calculated, and the degree of stenosis/occlusion of intracranial arteries in patients with MMD was evaluated on MR angiography.ResultsVolume reductions in the thalamus, caudate, putamen, hippocampus, amygdala, pallidum, and nucleus accumbens were found in patients with MMD. Hippocampal subfields and amygdala subnuclei in patients with MMD showed distinct vulnerability, and morphological alterations in specific subregions were more obvious than in the whole hippocampus/amygdala. Volume loss in several subcortical areas was related to disease duration and intracranial arterial changes.ConclusionsOur findings revealed structural alteration patterns of subcortical gray matter in MMD. The specific atrophy in subregions of the hippocampus and the amygdala suggested potential cognitive and affective impairments in MMD, which warrants further investigation. Chronic cerebral hemodynamic alterations in MMD may play a pivotal role in morphological changes in subcortical areas.

Thalamic structure and anastomosis in different hemispheres of moyamoya disease.

The progression of the asymptomatic hemisphere of moyamoya disease (MMD) is largely unknown. In this study, we investigated the differences in subcortical gray matter structure and angiographic features between asymptomatic and symptomatic hemispheres in patients with MMD. We retrospectively reviewed patients with MMD in consecutive cases in our center. We compared subcortical gray matter volume and three types of collaterals (lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis) between symptomatic and asymptomatic hemispheres. Symptomatic hemispheres were classified as ischemic hemisphere (i-hemisphere) and hemorrhagic hemisphere (h-hemisphere). Asymptomatic hemispheres were classified as contralateral asymptomatic hemisphere of i-hemisphere (ai-hemisphere), contralateral asymptomatic hemisphere of h-hemisphere (ah-hemisphere), bilateral asymptomatic hemispheres in asymptomatic group (aa-hemisphere). A total of 117 MMD patients were reviewed, and 49 of them met the inclusion criteria, with 98 hemispheres being analyzed. The thalamic volume was found to differ significantly between the i- and ai-hemispheres (P = 0.010), between the i- and ah-hemispheres (P = 0.004), as well as between the h- and ai-hemispheres (P = 0.002), between the h- and ah-hemispheres (P < 0.001). There was a higher incidence of thalamic anastomosis in the ai-hemispheres than i-hemispheres (31.3% vs. 6.3%, P = 0.070), and in the ah-hemispheres than h-hemispheres (29.6% vs. 11.1%, P = 0.088). Additionally, the hemispheres with thalamic anastomosis had a significantly greater volume than those without thalamic anastomosis (P = 0.024). Univariate and multivariate logistic regression analysis showed that thalamic volume was closely associated with thalamic anastomosis. The thalamic volume and the incidence of thalamic anastomosis increase in asymptomatic hemispheres and decrease in symptomatic hemispheres. Combining these two characteristics may be helpful in assessing the risk of stroke in the asymptomatic hemispheres of MMD as well as understanding the pathological evolution of the disease.

Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10–5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10–22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Neural correlates of verbal fluency revealed by longitudinal T1, T2 and FLAIR imaging in stroke

Diffusion-weighted imaging has been widely used in the research on post-stroke verbal fluency but acquiring diffusion data is not always clinically feasible. Achieving comparable reliability for detecting brain variables associated with verbal fluency impairments, based on more readily available anatomical, non-diffusion images (T1, T2 and FLAIR), enables clinical practitioners to have complementary neurophysiological information at hand to facilitate diagnosis and treatment of language impairment. Meanwhile, although the predominant focus in the stroke recovery literature has been on cortical contributions to verbal fluency, it remains unclear how subcortical regions and white matter disconnection are related to verbal fluency. Our study thus utilized anatomical scans of ischaemic stroke survivors (n = 121) to identify longitudinal relationships between subcortical volume, white matter tract disconnection, and verbal fluency performance at 3- and 12-months post-stroke. Subcortical grey matter volume was derived from FreeSurfer. We used an indirect probabilistic approach to quantify white matter disconnection in terms of disconnection severity, the proportion of lesioned voxel volume to the total volume of a tract, and disconnection probability, the probability of the overlap between the stroke lesion and a tract. These disconnection variables of each subject were identified based on the disconnectome map of the BCBToolkit. Using a linear mixed multiple regression method with 5-fold cross-validations, we correlated the semantic and phonemic fluency scores with longitudinal measurements of subcortical grey matter volume and 22 bilateral white matter tracts, while controlling for demographic variables (age, sex, handedness and education), total brain volume, lesion volume, and cortical thickness. The results showed that the right subcortical grey matter volume was positively correlated with phonemic fluency averaged over 3 months and 12 months. The finding generalized well on the test data. The disconnection probability of left superior longitudinal fasciculus II and left posterior arcuate fasciculus was negatively associated with semantic fluency only on the training data, but the result aligned with our previous study using diffusion scans in the same clinical population. In sum, our results presented evidence that routinely acquired anatomical scans can serve as a reliable source for deriving neural variables of post-stroke verbal fluency performance. The use of this method might provide an ecologically valid and more readily implementable analysis tool.

Polygenic risk scores and brain structures both contribute to externalizing behavior in childhood - A study in the Adolescent Brain and Cognitive Development (ABCD) cohort

IntroductionExternalizing behaviors are defined as behaviors violating social norms and can be harmful to self and others. Predicting the escalation of externalizing behaviors in children would allow for early interventions to prevent the occurrence of antisocial and criminal acts. Externalizing behaviors are heritable traits, and have been associated with structures of the brain. Brain structure, in turn, is also influenced by genetics. Here, we investigated the association of genetic and brain structural variation with externalizing behaviors in late childhood, and we assessed potential mediating effects. MethodsData was collected for 11,878 children aged 9–10 years old from the Adolescent Brain Cognitive Development (ABCD) cohort. We extracted data on externalizing behaviors measured by the parent-reported Child Behavior Checklist (CBCL), brain volumes and white matter integrity measured by magnetic resonance imaging (MRI), and polygenic risk scores (PRS) for (i) antisocial behaviors, (ii) attention-deficit/hyperactivity disorder comorbid with disruptive behavior disorder (ADHD ​+ ​DBD), (iii) irritability, and (iv) traits related to self-regulation & addiction. We examined the associations between brain structures, PRS, and externalizing behavior, and to what extent brain structures mediate the association between PRS and externalizing behavior. Phenotypic associations between brain structures and externalizing behaviors were validated in an independent cohort of 150 adolescents aged 12–21 years enriched for individuals with antisocial behavior. ResultsIncreasing levels of externalizing behaviors were associated with reduced total brain and focal gray matter volumes, but not with white matter integrity. These results could not be validated in the independent cohort, except for a good correlation of several effect sizes between the cohorts. Higher PRS for externalizing behaviors were associated with lower cortical gray matter volume, larger subcortical gray matter volume, larger white matter volume, and reduced global white matter fractional anisotropy. Genetic and brain structural variation, combined with sociodemographic factors, explained up to 7% of variation in externalizing behaviors in late childhood; brain structures and PRS each explained up to ∼0.5% of variation. A multivariate model with all sociodemographic factors, brain structures and PRS combined explained up to 11.9% (+5%). Total cortical gray matter volume mediated the association between PRS for ADHD ​+ ​DBD and externalizing behavior in late childhood. However, a large proportion of individual variation in externalizing behavior remained unidentified (∼90%). Brain function and interaction effects with the environment are surmised as potential sources of additional variation.