Connectome-wide structure-function coupling models implicate polysynaptic alterations in autism.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms.

Age-related topographic map of magnetic resonance diffusion metrics in neonatal brains.

Accelerated maturation of brain parenchyma close to term-equivalent age leads to rapid changes in diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) metrics of neonatal brains, which can complicate the evaluation and interpretation of these scans. In this study, we characterized the topography of age-related evolution of diffusion metrics in neonatal brains. We included 565 neonates who had MRI between 0 and 3 months of age, with no structural or signal abnormality-including 162 who had DTI scans. We analyzed the age-related changes of apparent diffusion coefficient (ADC) values throughout brain and DTI metrics (fractional anisotropy [FA] and mean diffusivity [MD]) along white matter (WM) tracts. Rate of change in ADC, FA, and MD values across 5 mm cubic voxels was calculated. There was significant reduction of ADC and MD values and increase of FA with increasing gestational age (GA) throughout neonates' brain, with the highest temporal rates in subcortical WM, corticospinal tract, cerebellar WM, and vermis. GA at birth had significant effect on ADC values in convexity cortex and corpus callosum as well as FA/MD values in corpus callosum, after correcting for GA at scan. We developed online interactive atlases depicting age-specific normative values of ADC (ages 34-46 weeks), and FA/MD (35-41 weeks). Our results show a rapid decrease in diffusivity metrics of cerebral/cerebellar WM and vermis in the first few weeks of neonatal age, likely attributable to myelination. In addition, prematurity and low GA at birth may result in lasting delay in corpus callosum myelination and cerebral cortex cellularity.

Impact of postnatal weight gain on brain white matter maturation in very preterm infants.

BACKGROUND AND PURPOSE: Very preterm infants (VPIs, <32 weeks gestational age at birth) are prone to long-term neurological deficits. While the effects of birth weight and postnatal growth on VPIs' neurological outcome are well established, the neurobiological mechanism behind these associations remains elusive. In this study, we utilized diffusion tensor imaging (DTI) to characterize how birth weight and postnatal weight gain influence VPIs' white matter (WM) maturation. METHODS: We included VPIs with complete birth and postnatal weight data in their health record, and DTI scan as part of their predischarge Magnetic Resonance Imaging (MRI). We conducted voxel-wise general linear model and tract-based regression analyses to explore the impact of birth weight and postnatal weight gain on WM maturation. RESULTS: We included 91 VPIs in our analysis. After controlling for gestational age at birth and time between birth and scan, higher birth weight Z-scores were associated with DTI markers of more mature WM tracts, most prominently in the corpus callosum and sagittal striatum. The postnatal weight Z-score changes over the first 4 weeks of life were also associated with increased maturity in these WM tracts, when controlling for gestational age at birth, birth weight Z-score, and time between birth and scan. CONCLUSIONS: In VPIs, birth weight and post-natal weight gain are associated with markers of brain WM maturation, particularly in the corpus callosum, which can be captured on discharge MRI. These neuroimaging metrics can serve as potential biomarkers for the early effects of nutritional interventions on VPIs' brain development.

Early brain microstructural development among preterm infants requiring caesarean section versus those delivered vaginally.

It is known that the rate of caesarean section (C-section) has been increasing among preterm births. However, the relationship between C-section and long-term neurological outcomes is unclear. In this study, we utilized diffusion tensor imaging (DTI) to characterize the association of delivery method with brain white matter (WM) microstructural integrity in preterm infants. We retrospectively analyzed the DTI scans and health records of preterm infants without neuroimaging abnormality on pre-discharge term-equivalent MRI. We applied both voxel-wise and tract-based analyses to evaluate the association between delivery method and DTI metrics across WM tracts while controlling for numerous covariates. We included 68 preterm infants in this study (23 delivered vaginally, 45 delivered via C-section). Voxel-wise and tract-based analyses revealed significantly lower fractional anisotropy values and significantly higher diffusivity values across major WM tracts in preterm infants delivered via C-section when compared to those delivered vaginally. These results may be partially, but not entirely, mediated by lower birth weight among infants delivered by C-section. Nevertheless, these infants may be at risk for delayed neurodevelopment and could benefit from close neurological follow up for early intervention and mitigation of adverse long-term outcomes.

Early brain microstructural development among preterm infants requiring caesarean section versus those delivered vaginally.

It is known that the rate of caesarean section (C-section) has been increasing among preterm births. However, the relationship between C-section and long-term neurological outcomes is unclear. In this study, we utilized diffusion tensor imaging (DTI) to characterize the association of delivery method with brain white matter (WM) microstructural integrity in preterm infants. We retrospectively analyzed the DTI scans and health records of preterm infants without neuroimaging abnormality on pre-discharge term-equivalent MRI. We applied both voxel-wise and tract-based analyses to evaluate the association between delivery method and DTI metrics across WM tracts while controlling for numerous covariates. We included 68 preterm infants in this study (23 delivered vaginally, 45 delivered via C-section). Voxel-wise and tract-based analyses revealed significantly lower fractional anisotropy values and significantly higher diffusivity values across major WM tracts in preterm infants delivered via C-section when compared to those delivered vaginally. These results may be partially, but not entirely, mediated by lower birth weight among infants delivered by C-section. Nevertheless, these infants may be at risk for delayed neurodevelopment and could benefit from close neurological follow up for early intervention and mitigation of adverse long-term outcomes.

Association of Body Mass Index and Waist Circumference With Imaging Metrics of Brain Integrity and Functional Connectivity in Children Aged 9 to 10 Years in the US, 2016-2018.

Importance: Aside from widely known cardiovascular implications, higher weight in children may have negative associations with brain microstructure and neurodevelopment. Objective: To evaluate the association of body mass index (BMI) and waist circumference with imaging metrics that approximate brain health. Design, Setting, and Participants: This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) study to examine the association of BMI and waist circumference with multimodal neuroimaging metrics of brain health in cross-sectional and longitudinal analyses over 2 years. From 2016 to 2018, the multicenter ABCD study recruited more than 11 000 demographically representative children aged 9 to 10 years in the US. Children without any history of neurodevelopmental or psychiatric disorders were included in this study, and a subsample of children who completed 2-year follow-up (34%) was included for longitudinal analysis. Exposures: Children's weight, height, waist circumference, age, sex, race and ethnicity, socioeconomic status, handedness, puberty status, and magnetic resonance imaging scanner device were retrieved and included in the analysis. Main Outcomes and Measures: Association of preadolescents' BMI z scores and waist circumference with neuroimaging indicators of brain health: cortical morphometry, resting-state functional connectivity, and white matter microstructure and cytostructure. Results: A total of 4576 children (2208 [48.3%] female) at a mean (SD) age of 10.0 years (7.6 months) were included in the baseline cross-sectional analysis. There were 609 (13.3%) Black, 925 (20.2%) Hispanic, and 2565 (56.1%) White participants. Of those, 1567 had complete 2-year clinical and imaging information at a mean (SD) age of 12.0 years (7.7 months). In cross-sectional analyses at both time points, higher BMI and waist circumference were associated with lower microstructural integrity and neurite density, most pronounced in the corpus callosum (fractional anisotropy for BMI and waist circumference at baseline and second year: P < .001; neurite density for BMI at baseline: P < .001; neurite density for waist circumference at baseline: P = .09; neurite density for BMI at second year: P = .002; neurite density for waist circumference at second year: P = .05), reduced functional connectivity in reward- and control-related networks (eg, within the salience network for BMI and waist circumference at baseline and second year: P < .002), and thinner brain cortex (eg, for the right rostral middle frontal for BMI and waist circumference at baseline and second year: P < .001). In longitudinal analysis, higher baseline BMI was most strongly associated with decelerated interval development of the prefrontal cortex (left rostral middle frontal: P = .003) and microstructure and cytostructure of the corpus callosum (fractional anisotropy: P = .01; neurite density: P = .02). Conclusions and Relevance: In this cross-sectional study, higher BMI and waist circumference among children aged 9 to 10 years were associated with imaging metrics of poorer brain structure and connectivity as well as hindered interval development. Future follow-up data from the ABCD study can reveal long-term neurocognitive implications of excess childhood weight. Imaging metrics that had the strongest association with BMI and waist circumference in this population-level analysis may serve as target biomarkers of brain integrity in future treatment trials of childhood obesity.

Autism spectrum disorder-specific changes in white matter connectome edge density based on functionally defined nodes.

Introduction: Autism spectrum disorder (ASD) is associated with both functional and microstructural connectome disruptions. We deployed a novel methodology using functionally defined nodes to guide white matter (WM) tractography and identify ASD-related microstructural connectome changes across the lifespan. Methods: We used diffusion tensor imaging and clinical data from four studies in the national database for autism research (NDAR) including 155 infants, 102 toddlers, 230 adolescents, and 96 young adults - of whom 264 (45%) were diagnosed with ASD. We applied cortical nodes from a prior fMRI study identifying regions related to symptom severity scores and used these seeds to construct WM fiber tracts as connectome Edge Density (ED) maps. Resulting ED maps were assessed for between-group differences using voxel-wise and tract-based analysis. We then examined the association of ASD diagnosis with ED driven from functional nodes generated from different sensitivity thresholds. Results: In ED derived from functionally guided tractography, we identified ASD-related changes in infants (pFDR ≤ 0.001-0.483). Overall, more wide-spread ASD-related differences were detectable in ED based on functional nodes with positive symptom correlation than negative correlation to ASD, and stricter thresholds for functional nodes resulted in stronger correlation with ASD among infants (z = -6.413 to 6.666, pFDR ≤ 0.001-0.968). Voxel-wise analysis revealed wide-spread ED reductions in central WM tracts of toddlers, adolescents, and adults. Discussion: We detected early changes of aberrant WM development in infants developing ASD when generating microstructural connectome ED map with cortical nodes defined by functional imaging. These were not evident when applying structurally defined nodes, suggesting that functionally guided DTI-based tractography can help identify early ASD-related WM disruptions between cortical regions exhibiting abnormal connectivity patterns later in life. Furthermore, our results suggest a benefit of involving functionally informed nodes in diffusion imaging-based probabilistic tractography, and underline that different age cohorts can benefit from age- and brain development-adapted image processing protocols.

An Online Calculator for Estimating Breast Implant Volume from Imaging.

Breast implant surgery remains one of the most common surgical procedures performed in the United States. Implant exchange can be complicated by unavailability of medical records or implant identification cards. Using chest imaging of 154 breast implants, an algorithm for estimating breast implant volume was generated. Based on four simple measurements and patient body mass index, a free, online calculator was created with a mean error of volume estimate of less than 1 cm3 and a SD of 44 cm3. In instances where a surgeon does not have implant records available but has chest imaging, this online tool can be used to obtain a relatively accurate estimate of implant volume.

Age-dependent white matter microstructural disintegrity in autism spectrum disorder.

There has been increasing evidence of White Matter (WM) microstructural disintegrity and connectome disruption in Autism Spectrum Disorder (ASD). We evaluated the effects of age on WM microstructure by examining Diffusion Tensor Imaging (DTI) metrics and connectome Edge Density (ED) in a large dataset of ASD and control patients from different age cohorts. N = 583 subjects from four studies from the National Database of Autism Research were included, representing four different age groups: (1) A Longitudinal MRI Study of Infants at Risk of Autism [infants, median age: 7 (interquartile range 1) months, n = 155], (2) Biomarkers of Autism at 12 months [toddlers, 32 (11)m, n = 102], (3) Multimodal Developmental Neurogenetics of Females with ASD [adolescents, 13.1 (5.3) years, n = 230], (4) Atypical Late Neurodevelopment in Autism [young adults, 19.1 (10.7)y, n = 96]. For each subject, we created Fractional Anisotropy (FA), Mean- (MD), Radial- (RD), and Axial Diffusivity (AD) maps as well as ED maps. We performed voxel-wise and tract-based analyses to assess the effects of age, ASD diagnosis and sex on DTI metrics and connectome ED. We also optimized, trained, tested, and validated different combinations of machine learning classifiers and dimensionality reduction algorithms for prediction of ASD diagnoses based on tract-based DTI and ED metrics. There is an age-dependent increase in FA and a decline in MD and RD across WM tracts in all four age cohorts, as well as an ED increase in toddlers and adolescents. After correction for age and sex, we found an ASD-related decrease in FA and ED only in adolescents and young adults, but not in infants or toddlers. While DTI abnormalities were mostly limited to the corpus callosum, connectomes showed a more widespread ASD-related decrease in ED. Finally, the best performing machine-leaning classification model achieved an area under the receiver operating curve of 0.70 in an independent validation cohort. Our results suggest that ASD-related WM microstructural disintegrity becomes evident in adolescents and young adults-but not in infants and toddlers. The ASD-related decrease in ED demonstrates a more widespread involvement of the connectome than DTI metrics, with the most striking differences being localized in the corpus callosum.