Sex Differences in the Brain's White Matter Microstructure during Development assessed using Advanced Diffusion MRI Models.

Typical sex differences in white matter (WM) microstructure during development are incompletely understood. Here we evaluated sex differences in WM microstructure during typical brain development using a sample of neurotypical individuals across a wide developmental age (N=239, aged 5-22 years). We used the conventional diffusion-weighted MRI (dMRI) model, diffusion tensor imaging (DTI), and two advanced dMRI models, the tensor distribution function (TDF) and neurite orientation dispersion density imaging (NODDI) to assess WM microstructure. WM microstructure exhibited significant, regionally consistent sex differences across the brain during typical development. Additionally, the TDF model was most sensitive in detecting sex differences. These findings highlight the importance of considering sex in neurodevelopmental research and underscore the value of the advanced TDF model.

White matter microstructure shows sex differences in late childhood: Evidence from 6797 children.

Sex differences in white matter microstructure have been robustly demonstrated in the adult brain using both conventional and advanced diffusion-weighted magnetic resonance imaging approaches. However, sex differences in white matter microstructure prior to adulthood remain poorly understood; previous developmental work focused on conventional microstructure metrics and yielded mixed results. Here, we rigorously characterized sex differences in white matter microstructure among over 6000 children from the Adolescent Brain Cognitive Development study who were between 9 and 10 years old. Microstructure was quantified using both the conventional model-diffusion tensor imaging (DTI)-and an advanced model, restriction spectrum imaging (RSI). DTI metrics included fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). RSI metrics included normalized isotropic, directional, and total intracellular diffusion (N0, ND, NT). We found significant and replicable sex differences in DTI or RSI microstructure metrics in every white matter region examined across the brain. Sex differences in FA were regionally specific. Across white matter regions, boys exhibited greater MD, AD, and RD than girls, on average. Girls displayed increased N0, ND, and NT compared to boys, on average, suggesting greater cell and neurite density in girls. Together, these robust and replicable findings provide an important foundation for understanding sex differences in health and disease.

Age and sex effects on advanced white matter microstructure measures in 15,628 older adults: A UK biobank study.

A comprehensive characterization of the brain's white matter is critical for improving our understanding of healthy and diseased aging. Here we used diffusion-weighted magnetic resonance imaging (dMRI) to estimate age and sex effects on white matter microstructure in a cross-sectional sample of 15,628 adults aged 45-80 years old (47.6% male, 52.4% female). Microstructure was assessed using the following four models: a conventional single-shell model, diffusion tensor imaging (DTI); a more advanced single-shell model, the tensor distribution function (TDF); an advanced multi-shell model, neurite orientation dispersion and density imaging (NODDI); and another advanced multi-shell model, mean apparent propagator MRI (MAPMRI). Age was modeled using a data-driven statistical approach, and normative centile curves were created to provide sex-stratified white matter reference charts. Participant age and sex substantially impacted many aspects of white matter microstructure across the brain, with the advanced dMRI models TDF and NODDI detecting such effects the most sensitively. These findings and the normative reference curves provide an important foundation for the study of healthy and diseased brain aging.

Striatal morphology and neurocognitive dysfunction in Huntington disease: The IMAGE-HD study.

We aimed to investigate the relationship between striatal morphology in Huntington disease (HD) and measures of motor and cognitive dysfunction. MRI scans, from the IMAGE-HD study, were obtained from 36 individuals with pre-symptomatic HD (pre-HD), 37 with early symptomatic HD (symp-HD), and 36 healthy matched controls. The neostriatum was manually segmented and a surface-based parametric mapping protocol derived two pointwise shape measures: thickness and surface dilation ratio. Significant shape differences were detected between all groups. Negative associations were detected between lower thickness and surface area shape measure and CAG repeats, disease burden score, and UHDRS total motor score. In symp-HD, UPSIT scores were correlated with higher thickness in left caudate tail and surface dilation ratio in left posterior putamen; Stroop scores were positively correlated with the thickness of left putamen head and body. Self-paced tapping (slow) was correlated with higher thickness and surface dilation ratio in the right caudate in symp-HD and with bilateral putamen in pre-HD. Self-paced tapping (fast) was correlated with higher surface dilation ratio in the right anterior putamen in symp-HD. Shape changes correlated with functional measures subserved by corticostriatal circuits, suggesting that the neostriatum is a potentially useful structural basis for characterisation of endophenotypes of HD.

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.

Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.

IMPORTANCE: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

A longitudinal study of the long-term consequences of drinking during pregnancy: heavy in utero alcohol exposure disrupts the normal processes of brain development.

Exposure to alcohol in utero can cause birth defects, including face and brain abnormalities, and is the most common preventable cause of intellectual disabilities. Here we use structural magnetic resonance imaging to measure cortical volume change longitudinally in a cohort of human children and youth with prenatal alcohol exposure (PAE) and a group of unexposed control subjects, demonstrating that the normal processes of brain maturation are disrupted in individuals whose mothers drank heavily during pregnancy. Trajectories of cortical volume change within children and youth with PAE differed from those of unexposed control subjects in posterior brain regions, particularly in the parietal cortex. In these areas, control children appear to show a particularly plastic cortex with a prolonged pattern of cortical volume increases followed by equally vigorous volume loss during adolescence, while the alcohol-exposed participants showed primarily volume loss, demonstrating decreased plasticity. Furthermore, smaller volume changes between scans were associated with lower intelligence and worse facial morphology in both groups, and were related to the amount of PAE during each trimester of pregnancy in the exposed group. This demonstrates that measures of IQ and facial dysmorphology predict, to some degree, the structural brain development that occurs in subsequent years. These results are encouraging in that interventions aimed at altering "experience" over time may improve brain trajectories in individuals with heavy PAE and possibly other neurodevelopmental disorders.

Anatomic brain asymmetry in vervet monkeys.

Asymmetry is a prominent feature of human brains with important functional consequences. Many asymmetric traits show population bias, but little is known about the genetic and environmental sources contributing to inter-individual variance. Anatomic asymmetry has been observed in Old World monkeys, but the evidence for the direction and extent of asymmetry is equivocal and only one study has estimated the genetic contributions to inter-individual variance. In this study we characterize a range of qualitative and quantitative asymmetry measures in structural brain MRIs acquired from an extended pedigree of Old World vervet monkeys (n = 357), and implement variance component methods to estimate the proportion of trait variance attributable to genetic and environmental sources. Four of six asymmetry measures show pedigree-level bias and one of the traits has a significant heritability estimate of about 30%. We also found that environmental variables more significantly influence the width of the right compared to the left prefrontal lobe.