Faculty Bibliography

Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss. Recent advances in MRI hardware and biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. Using ultra-strong gradient MRI, this study quantifies cortical neurite and soma microstructure in typically developing youth. Across domain-specific networks, cortical neurite signal fraction, attributed to neuronal and glial processes, increases with age. The apparent soma radius, attributed to the apparent radius of glial and neuronal cell bodies, decreases with age. Analyses of two independent post-mortem datasets reveal that genes increasing in expression through adolescence are significantly enriched in cortical oligodendrocytes and Layer 5-6 neurons. In our study, we show spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes, suggesting that ongoing cortical myelination processes drive adolescent cortical development.

With increasing numbers of magnetic resonance imaging (MRI) datasets becoming publicly available, researchers and clinicians alike have turned to automated methods of segmentation to enable population-level analyses of these data. Although prior research has evaluated the extent to which automated methods recapitulate "gold standard" manual segmentation methods in the human brain, such an evaluation has not yet been carried out for segmentation of MRIs of the macaque brain. Macaques offer the important opportunity to bridge gaps between microanatomical studies using invasive methods like tract tracing, neural recordings, and high-resolution histology and non-invasive macroanatomical studies using methods like MRI. As such, it is important to evaluate whether automated tools derive data of sufficient quality from macaque MRIs to bridge these gaps. We tested the relationship between automated registration-based segmentation using an open source and actively maintained NHP imaging analysis pipeline (AFNI) and gold standard manual segmentation of 4 structures (2 cortical: anterior cingulate cortex and insula; 2 subcortical: amygdala and caudate) across 37 rhesus macaques (Macaca mulatta). We identified some variability in the strength of correlation between automated and manual segmentations across neural regions and differences in relationships with demographic variables like age and sex between the two techniques.

The hippocampus is a structure in the medial temporal lobe which serves multiple cognitive functions. While important, the development of the hippocampus in the formative period of childhood and adolescence has not been extensively investigated, with most contemporary research focusing on macrostructural measures of volume. Thus, there has been little research on the development of the micron-scale structures (i.e., microstructure) of the hippocampus, which engender its cognitive functions. The current study examined age-related changes of hippocampal microstructure using diffusion MRI data acquired with an ultra-strong gradient (300 mT/m) MRI scanner in a sample of children and adolescents (N=88; 8-19 years). Surface-based hippocampal modelling was combined with established microstructural approaches, such as Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion Density Imaging (NODDI), and a more advanced gray matter diffusion model Soma And Neurite Density Imaging (SANDI). No significant changes in macrostructural measures (volume, gyrification, and thickness) were found between 8-19 years, while significant changes in microstructure measures related to neurites (from NODDI and SANDI), soma (from SANDI), and mean diffusivity (from DTI) were found. In particular, there was a significant increase across age in neurite MR signal fraction and a significant decrease in extracellular MR signal fraction and mean diffusivity across the hippocampal subfields and long-axis. A significant negative correlation between age and MR apparent soma radius was found in the subiculum and CA1 throughout the anterior and body of the hippocampus. Further surface-based analyses uncovered variability in age-related microstructural changes between the subfields and long-axis, which may reflect ostensible developmental differences along these two axes. Finally, correlation of hippocampal surfaces representing age-related changes of microstructure with maps derived from histology allowed for postulation of the potential underlying microstructure that diffusion changes across age may be capturing. Overall, distinct neurite and soma developmental profiles in the human hippocampus during late childhood and adolescence are reported for the first time.

Neuroanatomical changes to the cortex during adolescence have been well documented using MRI, revealing ongoing cortical thinning and volume loss with age. However, the underlying cellular mechanisms remain elusive with conventional neuroimaging. Recent advances in MRI hardware and new biophysical models of tissue informed by diffusion MRI data hold promise for identifying the cellular changes driving these morphological observations. This study used ultra-strong gradient MRI to obtain high-resolution, in vivo estimates of cortical neurite and soma microstructure in sample of typically developing children and adolescents. Cortical neurite signal fraction, attributed to neuronal and glial processes, increased with age (mean R² _fneurite=.53, p<3.3e-11, 11.91% increase over age), while apparent soma radius decreased (mean R² _Rsoma=.48, p<4.4e-10, 1% decrease over age) across domain-specific networks. To complement these findings, developmental patterns of cortical gene expression in two independent post-mortem databases were analysed. This revealed increased expression of genes expressed in oligodendrocytes, and excitatory neurons, alongside a relative decrease in expression of genes expressed in astrocyte, microglia and endothelial cell-types. Age-related genes were significantly enriched in cortical oligodendrocytes, oligodendrocyte progenitors and Layer 5-6 neurons (p_FDR<.001) and prominently expressed in adolescence and young adulthood. The spatial and temporal alignment of oligodendrocyte cell-type gene expression with neurite and soma microstructural changes suggest that ongoing cortical myelination processes contribute to adolescent cortical development. These findings highlight the role of intra-cortical myelination in cortical maturation during adolescence and into adulthood.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

In response to a growing interest in refining brain connectivity assessments, this study focuses on integrating white matter fiber-specific microstructural properties into structural connectomes. Spanning ages 8-19 years in a developmental sample, it explores age-related patterns of microstructure-informed network properties at both local and global scales. First, the diffusion-weighted signal fraction associated with each tractography-reconstructed streamline was constructed. Subsequently, the convex optimization modeling for microstructure-informed tractography (COMMIT) approach was employed to generate microstructure-informed connectomes from diffusion MRI data. To complete the investigation, network characteristics within eight functionally defined networks (visual, somatomotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, and subcortical networks) were evaluated. The findings underscore a consistent increase in global efficiency across child and adolescent development within the visual, somatomotor, and default mode networks (p < 0.005). Additionally, mean strength exhibits an upward trend in the somatomotor and visual networks (p < 0.001). Notably, nodes within the dorsal and ventral visual pathways manifest substantial age-dependent changes in local efficiency, aligning with existing evidence of extended maturation in these pathways. The outcomes strongly support the notion of a prolonged developmental trajectory for visual association cortices. This study contributes valuable insights into the nuanced dynamics of microstructure-informed brain connectivity throughout different developmental stages.

22q11.2 deletion syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia and autism spectrum disorders, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterization of white matter microstructure in participants with 22q11.2DS (12-15 years) and those undergoing typical development (8-18 years) using a customized magnetic resonance imaging scanner which is sensitive to axonal morphology. A rich array of diffusion MRI metrics are extracted to present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences in individuals with 22q11.2DS. A recent, large-scale consortium study of 22q11.2DS identified higher diffusion anisotropy and reduced overall diffusion mobility of water as hallmark microstructural alterations of white matter in individuals across a wide age range (6-52 years). We observed similar findings across the white matter tracts included in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that abnormal microstructural connectivity in 22q11.2DS may be mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo white matter phenotype of 22q11.2DS, and promote the continued investigation of shared features in neurodevelopmental and psychiatric disorders.

White matter microstructural development in late childhood and adolescence is driven predominantly by increasing axon density and myelin thickness. Ex vivo studies suggest that the increase in axon diameter drives developmental increases in axon density observed with pubertal onset. In this cross-sectional study, 50 typically developing participants aged 8-18 years were scanned using an ultra-strong gradient magnetic resonance imaging scanner. Microstructural properties, including apparent axon diameter $({d}_a)$, myelin content, and g-ratio, were estimated in regions of the corpus callosum. We observed age-related differences in ${d}_a$, myelin content, and g-ratio. In early puberty, males had larger ${d}_a$ in the splenium and lower myelin content in the genu and body of the corpus callosum, compared with females. Overall, this work provides novel insights into developmental, pubertal, and cognitive correlates of individual differences in apparent axon diameter and myelin content in the developing human brain.

Facial expression and body posture recognition have protracted developmental trajectories. Interactions between face and body perception, such as the influence of body posture on facial expression perception, also change with development. While the brain regions underpinning face and body processing are well-defined, little is known about how white-matter tracts linking these regions relate to perceptual development. Here, we obtained complementary diffusion magnetic resonance imaging (MRI) measures (fractional anisotropy [FA], spherical mean Ṧ_μ ), and a quantitative MRI myelin-proxy measure (R1), within white-matter tracts of face- and body-selective networks in children and adolescents and related these to perceptual development. In tracts linking occipital and fusiform face areas, facial expression perception was predicted by age-related maturation, as measured by Ṧ_μ and R1, as well as age-independent individual differences in microstructure, captured by FA and R1. Tract microstructure measures linking posterior superior temporal sulcus body region with anterior temporal lobe (ATL) were related to the influence of body on facial expression perception, supporting ATL as a site of face and body network convergence. Overall, our results highlight age-dependent and age-independent constraints that white-matter microstructure poses on perceptual abilities during development and the importance of complementary microstructural measures in linking brain structure and behaviour.