Faculty Bibliography

Resting state functional magnetic resonance imaging (rs-fMRI) in infants enables important studies of functional brain organization early in human development. However, rs-fMRI in infants has universally been obtained during sleep to reduce participant motion artifact, raising the question of whether differences in functional organization between awake adults and sleeping infants that are commonly attributed to development may instead derive, at least in part, from sleep. This question is especially important as rs-fMRI differences in adult wake vs. sleep are well documented. To investigate this question, we compared functional connectivity and BOLD signal propagation patterns in 6, 12, and 24 month old sleeping infants with patterns in adult wakefulness and non-REM sleep. We find that important functional connectivity features seen during infant sleep closely resemble those seen during adult sleep, including reduced default mode network functional connectivity. However, we also find differences between infant and adult sleep, especially in thalamic BOLD signal propagation patterns. These findings highlight the importance of considering sleep state when drawing developmental inferences in infant rs-fMRI.

Glaucoma, a progressive and degenerative disease of the optic nerve, is the second leading cause of blindness worldwide. Mechanical deformation of the lamina cribrosa (LC) under high intraocular pressure (IOP) can lead to axonal death of optic nerve fibers. To explore the effect of pressure on the LC, we utilize an experimental setup where longitudinal 3D optical coherence tomography (OCT) images are acquired at different levels of IOP administered via a well-controlled external force. Structural changes are measured via image deformations which map all observed images simultaneously into a common coordinate space. These deformations encode local patterns of structural and volume change across the image sequence, resulting in quantification of the spatiotemporal deformation pattern of the LC due to variation of pressure. We also describe a 3D segmentation algorithm to restrict our deformation analysis separately to the beams or pores of the LC. A single case study demonstrates the potential of the proposed methodology for non-invasive in-vivo analysis of LC dynamics in individual subjects

BACKGROUND: Restricted and repetitive behaviors are defining features of autism spectrum disorder (ASD). Under revised diagnostic criteria for ASD, this behavioral domain now includes atypical responses to sensory stimuli. To date, little is known about the neural circuitry underlying these features of ASD early in life. METHODS: Longitudinal diffusion tensor imaging data were collected from 217 infants at high familial risk for ASD. Forty-four of these infants were diagnosed with ASD at age 2. Targeted cortical, cerebellar, and striatal white matter pathways were defined and measured at ages 6, 12, and 24 months. Dependent variables included the Repetitive Behavior Scale-Revised and the Sensory Experiences Questionnaire. RESULTS: Among children diagnosed with ASD, repetitive behaviors and sensory response patterns were strongly correlated, even when accounting for developmental level or social impairment. Longitudinal analyses indicated that the genu and cerebellar pathways were significantly associated with both repetitive behaviors and sensory responsiveness but not social deficits. At age 6 months, fractional anisotropy in the genu significantly predicted repetitive behaviors and sensory responsiveness at age 2. Cerebellar pathways significantly predicted later sensory responsiveness. Exploratory analyses suggested a possible disordinal interaction based on diagnostic status for the association between fractional anisotropy and repetitive behavior. CONCLUSIONS: Our findings suggest that restricted and repetitive behaviors contributing to a diagnosis of ASD at age 2 years are associated with structural properties of callosal and cerebellar white matter pathways measured during infancy and toddlerhood. We further identified that repetitive behaviors and unusual sensory response patterns co-occur and share common brain-behavior relationships. These results were strikingly specific given the absence of association between targeted pathways and social deficits.

The increased number of challenges for comparative evaluation of biomedical image analysis procedures clearly reflects a need for unbiased assessment of the state-of-the-art methodological advances. Moreover, the ultimate translation of novel image analysis procedures to the clinic requires rigorous validation and evaluation of alternative schemes, a task that is best outsourced to the international research community. We commonly see an increase of the number of metrics to be used in parallel, reflecting alternative ways to measure similarity. Since different measures come with different scales and distributions, these are often normalized or converted into an individual rank ordering, leaving the problem of combining the set of multiple rankings into a final score. Proposed solutions are averaging or accumulation of rankings, raising the question if different metrics are to be treated the same or if all metrics would be needed to assess closeness to truth. We address this issue with a data-driven method for automatic estimation of weights for a set of metrics based on unsupervised rank aggregation. Our method requires no normalization procedures and makes no assumptions about metric distributions. We explore the sensitivity of metrics to small changes in input data with an iterative perturbation scheme, to prioritize the contribution of the most robust metrics in the overall ranking. We show on real anatomical data that our weighting scheme can dramatically change the ranking

PURPOSE: To elucidate the molecular pathogenesis of age-related macular degeneration (AMD) and interpretation of fundus autofluorescence imaging, the authors identified spectral autofluorescence characteristics of drusen and retinal pigment epithelium (RPE) in donor eyes with AMD. METHODS: Macular RPE/Bruch membrane flat mounts were prepared from 5 donor eyes with AMD. In 12 locations (1-3 per eye), hyperspectral autofluorescence images in 10-nm-wavelength steps were acquired at 2 excitation wavelengths (lambdaex 436, 480 nm). A nonnegative tensor factorization algorithm was used to recover 5 abundant emission spectra and their corresponding spatial localizations. RESULTS: At lambdaex 436 nm, the authors consistently localized a novel spectrum (SDr) with a peak emission near 510 nm in drusen and sub-RPE deposits. Abundant emission spectra seen previously (S0 in Bruch membrane and S1, S2, and S3 in RPE lipofuscin/melanolipofuscin, respectively) also appeared in AMD eyes, with the same shapes and peak wavelengths as in normal tissue. Lipofuscin/melanolipofuscin spectra localizations in AMD eyes varied widely in their overlap with drusen, ranging from none to complete. CONCLUSION: An emission spectrum peaking at approximately 510 nm (lambdaex 436 nm) appears to be sensitive and specific for drusen and sub-RPE deposits. One or more abundant spectra from RPE organelles exhibit characteristic relationships with drusen.

With the increasing use of efficient multimodal 3D imaging, clinicians are able to access longitudinal imaging to stage pathological diseases, to monitor the efficacy of therapeutic interventions, or to assess and quantify rehabilitation efforts. Analysis of such four-dimensional (4D) image data presenting pathologies, including disappearing and newly appearing lesions, represents a significant challenge due to the presence of complex spatio-temporal changes. Image analysis methods for such 4D image data have to include not only a concept for joint segmentation of 3D datasets to account for inherent correlations of subject-specific repeated scans but also a mechanism to account for large deformations and the destruction and formation of lesions (e.g., edema, bleeding) due to underlying physiological processes associated with damage, intervention, and recovery. In this paper, we propose a novel framework that provides a joint segmentation-registration framework to tackle the inherent problem of image registration in the presence of objects not present in all images of the time series. Our methodology models 4D changes in pathological anatomy across time and and also provides an explicit mapping of a healthy normative template to a subject's image data with pathologies. Since atlas-moderated segmentation methods cannot explain appearance and locality pathological structures that are not represented in the template atlas, the new framework provides different options for initialization via a supervised learning approach, iterative semisupervised active learning, and also transfer learning, which results in a fully automatic 4D segmentation method. We demonstrate the effectiveness of our novel approach with synthetic experiments and a 4D multimodal MRI dataset of severe traumatic brain injury (TBI), including validation via comparison to expert segmentations. However, the proposed methodology is generic in regard to different clinical applications requiring quantitative analysis of 4D imaging representing spatio-temporal changes of pathologies.

Clinical assessment routinely uses terms such as development, growth trajectory, degeneration, disease progression, recovery or prediction. This terminology inherently carries the aspect of dynamic processes, suggesting that single measurements in time and cross-sectional comparison may not sufficiently describe spatiotemporal changes. In view of medical imaging, such tasks encourage subject-specific longitudinal imaging. Whereas follow-up, monitoring and prediction are natural tasks in clinical diagnosis of disease progression and of assessment of therapeutic intervention, translation of methodologies for calculation of temporal profiles from longitudinal data to clinical routine still requires significant research and development efforts. Rapid advances in image acquisition technology with significantly reduced acquisition times and with increase of patient comfort favor repeated imaging over the observation period. In view of serial imaging ranging over multiple years, image acquisition faces the challenging issue of scanner standardization and calibration which is crucial for successful spatiotemporal analysis. Longitudinal 3D data, represented as 4D images, capture time-varying anatomy and function. Such data benefits from dedicated analysis methods and tools that make use of the inherent correlation and causality of repeated acquisitions of the same subject. Availability of such data spawned progress in the development of advanced 4D image analysis methodologies that carry the notion of linear and nonlinear regression, now applied to complex, high-dimensional data such as images, image-derived shapes and structures, or a combination thereof. This paper provides examples of recently developed analysis methodologies for 4D image data, primarily focusing on progress in areas of core expertise of the authors. These include spatiotemporal shape modeling and growth trajectories of white matter fiber tracts demonstrated with examples from ongoing longitudinal clinical neuroimaging studies such as analysis of early brain growth in subjects at risk for mental illness and neurodegeneration in Huntington's disease (HD). We will discuss broader aspects of current limitations and need for future research in view of data consistency and analysis methodologies.