Faculty Bibliography

Morphological change of anatomy over time has been of great interest for tracking disease progression, aging, and growth. Shape regression methods have shown great success to model the shape changes over time to create a smooth and representative shape trajectory of sparsely scanned medical images. Shape changes modeled by shape regression methods can be affected by pose changes of shapes caused by neighboring anatomies. Such pose changes can cause informative local shape changes to be obscured and neglected in longitudinal shape analysis. In this paper, we propose a method that estimates a continuous trajectory of medial surfaces with correspondence over time to track longitudinal pose changes and local thickness changes separately. A spatiotemporally continuous medial surface trajectory is estimated by integrating velocity fields from a series of continuous medial representations individually estimated for each shape in a continuous 3D shape trajectory. The proposed method enables straightforward analysis on continuous local thickness changes and pose changes of a continuous multi-object shape trajectory. Longitudinal shape analysis which makes use of correspondence and temporal coherence of the estimated continuous medial surface trajectory is demonstrated with experiments on synthetic examples and real anatomical shape complexes

BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life. METHODS: This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion. RESULTS: Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity. CONCLUSIONS: These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior.

BACKGROUND: We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS: A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS: Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohen's d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS: This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

Many problems in medicine are inherently dynamic processes which include the aspect of change over time, such as childhood development, aging, and disease progression. From medical images, numerous geometric structures can be extracted with various representations, such as landmarks, point clouds, curves, and surfaces. Different sources of geometry may characterize different aspects of the anatomy, such as fiber tracts from DTI and subcortical shapes from structural MRI, and therefore require a modeling scheme which can include various shape representations in any combination. In this paper, we present a geodesic regression model in the large deformation (LDDMM) framework applicable to multi-object complexes in a variety of shape representations. Our model decouples the deformation parameters from the specific shape representations, allowing the complexity of the model to reflect the nature of the shape changes, rather than the sampling of the data. As a consequence, the sparse representation of diffeomorphic flow allows for the straightforward embedding of a variety of geometry in different combinations, which all contribute towards the estimation of a single deformation of the ambient space. Additionally, the sparse representation along with the geodesic constraint results in a compact statistical model of shape change by a small number of parameters defined by the user. Experimental validation on multi-object complexes demonstrate robust model estimation across a variety of parameter settings. We further demonstrate the utility of our method to support the analysis of derived shape features, such as volume, and explore shape model extrapolation. Our method is freely available in the software package deformetrica which can be downloaded at www.deformetrica.org.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.

Imaging is a crucial tool in medicine and biomedical research. Magnetic resonance imaging (MRI), computational tomography (CT), proton emission tomography (PET), and ultrasound are routinely used not only to diagnose disease but also to plan and guide surgical interventions, track disease progression, measure the response of the body to treatment, and understand how genetic and environmental factors relate to anatomical and functional phenotypes.

Purpose: To image and analyze individual RPE melanosomes (M), lipofuscin (LF), and melanolipofuscin (MLF) granules using high-resolution structured illumination microscopy (hrSIM) and confocal multispectral laser scanning microscopy (cmLSM). Methods: Human donor RPE-flatmounts (n=35; normal macular status: 9<51yrs, 9>80yrs; age-related macular degeneration (AMD): 17) were scanned apical to basal through RPE cells at the fovea, perifovea, and near periphery using hrSIM (Zeiss Elyra.S1; ex488 nm; em>510 nm; 100 nm step size) and cmLSM (Zeiss LSM780; ex488 nm; em 490-695 nm; 390 nm step size; 8.9 nm spectral channel width). The hrSIM and lower-resolution cmLSM images were co-registered by linear 3D registration and choice of mutual information as the image match criterion (PMID16545965). This results in a 1:1 mapping between the single channel hrSIM and multichannel cmLSM data. Individual granules were segmented from the hrSIM data by expert-guided 3D level-set segmentation. Via the hrSIM-cmLSM mapping, the spectra of individual granules can be extracted for quantitative analysis. M, LF, MLF granules/cell were also counted using a custom FIJI plugin. Results: HrSIM imaging and segmentation enables clear delineation and identification of M, LF, and MLF granules (Fig. A,B). Individual granules can be tracked in the z-direction, and size, shape, dimensions, and intracellular position can be monitored. Each cell contains several hundred granules. A cushion of M localizes apically, while LF/MLF prefer basolateral accumulation. Software-assisted mapping of corresponding z-sections (hrSIM/cmLSM) for spectral characterization (Fig. C,D) demonstrates spectral variability among granules. Conclusions: With the combination of hrSIM and cmLSM imaging, individual autofluorescent RPE granules can be identified, localized in three-dimensions, and spectrally analyzed. The examination of spectral characteristics and changes related to intracellular and tissue localization, age, and disease status, on an individual granule basis, might reveal LF/MLF metabolism, and help elucidate LF's role in human RPE physiology. Ongoing studies are examining RPE granule properties in aging and AMD

Modeling subject-specific shape change is one of the most important challenges in longitudinal shape analysis of disease progression. Whereas anatomical change over time can be a function of normal aging; anatomy can also be impacted by disease related degeneration. Shape changes to anatomy may also be affected by external structural changes from neighboring structures, which may cause non-linear pose variations. In this paper, we propose a framework to analyze disease related shape changes by coupling extrinsic modeling of the ambient anatomical space via spatiotemporal deformations with intrinsic shape properties from medial surface analysis. We compare intrinsic shape properties of a subject-specific shape trajectory to a normative 4D shape atlas representing normal aging to separately quantify shape changes related to disease. The spatiotemporal shape modeling establishes inter/intra subject anatomical correspondence, which in turn enables comparisons between subjects and the 4D shape atlas, and also quantitative analysis of disease related shape change. The medial surface analysis captures intrinsic shape properties related to local patterns of deformation. The proposed framework simultaneously models extrinsic longitudinal shape changes in the ambient anatomical space, as well as intrinsic shape properties to give localized measurements of degeneration. Six high risk subjects and six controls are randomly sampled from a Huntington's disease image database for quantitative and qualitative comparison.

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

The association between developmental trajectories of language-related white matter fiber pathways from 6 to 24 months of age and individual differences in language production at 24 months of age was investigated. The splenium of the corpus callosum, a fiber pathway projecting through the posterior hub of the default mode network to occipital visual areas, was examined as well as pathways implicated in language function in the mature brain, including the arcuate fasciculi, uncinate fasciculi, and inferior longitudinal fasciculi. The hypothesis that the development of neural circuitry supporting domain-general orienting skills would relate to later language performance was tested in a large sample of typically developing infants. The present study included 77 infants with diffusion weighted MRI scans at 6, 12 and 24 months and language assessment at 24 months. The rate of change in splenium development varied significantly as a function of language production, such that children with greater change in fractional anisotropy (FA) from 6 to 24 months produced more words at 24 months. Contrary to findings from older children and adults, significant associations between language production and FA in the arcuate, uncinate, or left inferior longitudinal fasciculi were not observed. The current study highlights the importance of tracing brain development trajectories from infancy to fully elucidate emerging brain-behavior associations while also emphasizing the role of the splenium as a key node in the structural network that supports the acquisition of spoken language.