Biology subjects

Blumenthal, J. D.

Publications and source records attributed to Blumenthal, J. D..

5 recordsLinked to original sources

bioRxiv2020

Resting-state functional connectivity and psychopathology in Klinefelter syndrome (47, XXY)

Klinefelter syndrome (47, XXY; Henceforth: XXY syndrome) is a high impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first neuroimaging study to map resting-state functional connectivity (rsFC) changes in XXY syndrome and ask how these might relate to brain anatomy and psychopathology. We collected resting state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males. We implemented a brain-wide screen to identify regions with altered global rsFC in XXY vs. XY males, and then used seed-based analysis to decompose these alterations. We further compared rsFC changes with regional changes in brain volume from voxel-based morphometry and tested for correlations between rsFC and symptom variation within XXY syndrome. We found that XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC), associated with overconnectivity with diverse rsFC networks. Regional rsFC changes were partly coupled to regional volumetric changes in XXY syndrome. Within the precuneus, variation in DLPFC rsFC within XXY syndrome was correlated with the severity of psychopathology in XXY individuals. Our findings provide the first view of altered functional brain connectivity in XXY syndrome and delineate links between these alterations and those relating to both brain anatomy and psychopathology. Taken together, these insights advance biological understanding of XXY syndrome as a disorder in its own right, and as a model of genetic risk for psychopathology more broadly.

neuroscience↗

bioRxiv2019

Sex-Biased Trajectories of Amygdalo-Hippocampal Morphology Change Over Human Development

The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes - low vs. high areal expansion, and early vs. late growth deceleration. These results bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females and discover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence.\n\nSIGNIFICANCE STATEMENTThe amygdala and hippocampus are implicated in several developmentally-dynamic and sex-biased psychiatric disorders, but the spatiotemporal organization and sex-biased patterning of amygdalo-hippocampal maturation remains unclear in humans. Here, by integrating new methods for analysis of longitudinal neuroimaging data, we resolve the developmental milestones and spatial gradients that organize human amygdalo-hippocampal maturation. Each structures volume follows a tri-phasic, curvilinear growth trajectory which - for the amygdala - shows rapid male-female size divergence in mid-adolescence through delayed growth deceleration in males. Spatially fine-grained shape analyses localize these sex differences, and further reveal highly orchestrated shape changes across the amygdala and hippocampus that are organized by two topographical gradients. These data provide a new framework for understanding amygdalo-hippocampal organization in human development.

neuroscience↗

bioRxiv2019

Transcriptomic and Cellular Decoding of Regional Brain Vulnerability to Neurodevelopmental Disorders

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i) in vivo neuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorders anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this "transcriptional vulnerability model" by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

neuroscience↗

bioRxiv2018

Longitudinally Mapping Childhood Socioeconomic Status Associations with Cortical and Subcortical Morphology

Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with structural brain development is not yet well-characterized. Here, we analyzed 1243 longitudinally-acquired structural MRI scans from 623 youth to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were developmentally fixed rather than age-dependent. Surface-based shape analysis revealed that higher SES is associated with areal expansion of (i) lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and (ii) ventrolateral thalamic, and medial amygdalo-hippocampal sub-regions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Our findings clarify the spatiotemporal patterning of SES-related neuroanatomical variation and inform ongoing efforts to dissect the causal pathways underpinning observed associations between childhood SES and regional brain anatomy.

neuroscience↗

bioRxiv2017

Normative Brain Size Variation and the Remodeling of Brain Shape in Humans

Evolutionary and developmental increases in primate brain size have been accompanied by systematic shifts in the proportionality of different primate brain systems. However, it remains unknown if and how brain patterning varies across the more than 2-fold inter-individual variation in brain size that occurs amongst typically-developing humans. Using in vivo neuroimaging data from 2 independent cohorts totaling nearly 3000 individuals, we find that larger-brained humans show preferential areal expansion within specific fronto-parietal cortical networks (default mode, dorsal attentional) and related subcortical regions, at the expense of primary sensory/motor systems. This targeted areal expansion recapitulates cortical remodeling across evolution, manifests by early childhood and is linked to molecular signatures of heightened metabolic cost. Our results define a new organizing principle in human brain patterning which governs the highly-coordinated remodeling of human brain shape as a function of naturally-occurring variations in brain size.\n\nOne Sentence SummaryA hodologically and metabolically expensive brain network is preferentially expanded in larger-brained humans.

neuroscience↗