Elizabeth B Hutchinson

Interests

Teaching

MRI methods, Neuroscience

Research

Magnetic Resonance Imaging, Pre-clinical rodent and ferret models, Traumatic, Brain Injury, Epilepsy, Diffusion MRI

Courses

Scholarly Contributions

Journals/Publications

• Bonaventura, J., Morara, K., Carlson, R., Comrie, C., Twer, A., Hutchinson, E., & Sawyer, T. W. (2024). Evaluating backscattering polarized light imaging microstructural mapping capabilities through neural tissue and analogous phantom imaging. Journal of biomedical optics, 29(5), 052914.
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  Knowledge of fiber microstructure and orientation in the brain is critical for many applications. Polarized light imaging (PLI) has been shown to have potential for better understanding neural fiber microstructure and directionality due to the anisotropy in myelin sheaths surrounding nerve fibers of the brain. Continuing to advance backscattering based PLI systems could provide a valuable avenue for neural imaging.
• Comrie, C. J., Carlson, R., Ahsan, Z., Moshkriz, A., Sawyer, T. W., Intorcia, A. J., Serrano, G. E., Beach, T. G., & Hutchinson, E. B. (2024). Identification of diffusion, kurtosis, and propagator MRI markers of Alzheimer’s disease pathology in post-mortem human tissue. Imaging Neuroscience, 2, 1--19.
• Berry, D. B., Galinsky, V. L., Hutchinson, E. B., Galons, J. P., Ward, S. R., & Frank, L. R. (2023). Double pulsed field gradient diffusion MRI to assess skeletal muscle microstructure. Magnetic Resonance in Medicine, 90(4), 1582-1593. doi:10.1002/mrm.29751
• Berry, D. B., Galinsky, V. L., Hutchinson, E. B., Galons, J. P., Ward, S. R., & Frank, L. R. (2023). Double pulsed field gradient diffusion MRI to assess skeletal muscle microstructure. Magnetic resonance in medicine, 90(4), 1582-1593.
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  Preliminary study to determine whether double pulsed field gradient (PFG) diffusion MRI is sensitive to key features of muscle microstructure related to function.
• Bonaventura, J., Morara, K., Carlson, R., Comrie, C., Twer, A., Hutchinson, E., & Sawyer, T. W. (2023). Evaluating backscattering polarized light imaging microstructural mapping capabilities through neural tissue and analogous phantom imaging. Journal of Biomedical Optics, 29(05). doi:10.1117/1.jbo.29.5.052914
• Gangolli, M., Pajevic, S., Kim, J. H., Hutchinson, E. B., Benjamini, D., & Basser, P. J. (2023). Correspondence of mean apparent propagator MRI metrics with phosphorylated tau and astrogliosis in chronic traumatic encephalopathy. Brain Communications, 5(5). doi:10.1093/braincomms/fcad253
• Kamali, A., Dieckhaus, L. A., Peters, E. C., Preszler, C. A., Witte, R. S., Pires, P. W., Hutchinson, E. B., & Laksari, K. (2023). Ultrasound, photoacoustic, and magnetic resonance imaging to study hyperacute pathophysiology of traumatic and vascular brain injury. Journal of Neuroimaging, 33(4), 534-546. doi:10.1111/jon.13115
• , A. K., , L. D., , E. C., , C. A., , R. S., , P. W., , E. B., & , K. L. (2022). Hyperacute pathophysiology of traumatic and vascular brain injury captured by ultrasound, photoacoustic, and magnetic resonance imaging.
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  Cerebrovascular dynamics and pathomechanisms that evolve in the minutes andhours following traumatic vascular injury in the brain remain largely unknown.We investigated the pathophysiology evolution within the first three hoursafter closed-head traumatic brain injury (TBI) and subarachnoid hemorrhage(SAH), two common traumatic vascular injuries, in mice. We took a multi-modalimaging approach using photoacoustic, color Doppler, and magnetic resonanceimaging (MRI) in mice. Brain oxygenation (%sO2) and velocity-weighted volume ofblood flow (VVF) values significantly decreased from baseline to fifteenminutes after both TBI and SAH. TBI resulted in 19.2% and 41.0% ipsilateral%sO2 and VVF reductions 15 minutes post injury while SAH resulted in 43.9% %sO2and 85.0% VVF reduction ipsilaterally (p
• Hutchinson, E. B., Pierpaoli, C., Dardzinski, B. J., Juliano, S. L., Schwerin, S. C., King, S. G., Shunmugavel, A., Korotcov, A., Bosomtwi, A., Knutsen, A. K., Johnson, H. R., & Romero-Lozano, A. (2022). Translationally Relevant Magnetic Resonance Imaging Markers in a Ferret Model of Closed Head Injury. Frontiers in Neuroscience. doi:10.3389/fnins.2021.779533
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  Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.
• Hutchinson, E. B., Romero-Lozano, A., Johnson, H. R., Knutsen, A. K., Bosomtwi, A., Korotcov, A., Shunmugavel, A., King, S. G., Schwerin, S. C., Juliano, S. L., Dardzinski, B. J., & Pierpaoli, C. (2021). Translationally Relevant Magnetic Resonance Imaging Markers in a Ferret Model of Closed Head Injury. Frontiers in neuroscience, 15, 779533.
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  Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.
• Hutchinson, E., Osting, S., Rutecki, P., & Sutula, T. (2021). Diffusion Tensor Orientation as a Microstructural MRI Marker of Mossy Fiber Sprouting After TBI in Rats. Journal of neuropathology and experimental neurology.
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  Diffusion tensor imaging (DTI) metrics are highly sensitive to microstructural brain alterations and are potentially useful imaging biomarkers for underlying neuropathologic changes after experimental and human traumatic brain injury (TBI). As potential imaging biomarkers require direct correlation with neuropathologic alterations for validation and interpretation, this study systematically examined neuropathologic abnormalities underlying alterations in DTI metrics in the hippocampus and cortex following controlled cortical impact (CCI) in rats. Ex vivo DTI metrics were directly compared with a comprehensive histologic battery for neurodegeneration, microgliosis, astrocytosis, and mossy fiber sprouting by Timm histochemistry at carefully matched locations immediately, 48 hours, and 4 weeks after injury. DTI abnormalities corresponded to spatially overlapping but temporally distinct neuropathologic alterations representing an aggregate measure of dynamic tissue damage and reorganization. Prominent DTI alterations of were observed for both the immediate and acute intervals after injury and associated with neurodegeneration and inflammation. In the chronic period, diffusion tensor orientation in the hilus of the dentate gyrus became prominently abnormal and was identified as a reliable structural biomarker for mossy fiber sprouting after CCI in rats, suggesting potential application as a biomarker to follow secondary progression in experimental and human TBI.
• Kishimoto, A. O., Kishimoto, Y., Shi, X., Hutchinson, E. B., Zhang, H., Shi, Y., Oliveira, G., Li, L., Welham, N. V., & Rowland, I. J. (2021). High-resolution magnetic resonance and mass spectrometry imaging of the human larynx. Journal of anatomy, 239(3), 545-556.
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  High-resolution, noninvasive and nondestructive imaging of the subepithelial structures of the larynx would enhance microanatomic tissue assessment and clinical decision making; similarly, in situ molecular profiling of laryngeal tissue would enhance biomarker discovery and pathology readout. Towards these goals, we assessed the capabilities of high-resolution magnetic resonance imaging (MRI) and matrix-assisted laser desorption/ionisation-mass spectrometry (MALDI-MS) imaging of rarely reported paediatric and adult cadaveric larynges that contained pathologies. The donors were a 13-month-old male, a 10-year-old female with an infraglottic mucus retention cyst and a 74-year-old female with advanced polypoid degeneration and a mucus retention cyst. MR and molecular imaging data were corroborated using whole-organ histology. Our MR protocols imaged the larynges at 45-117 μm in-plane resolution and capably resolved microanatomic structures that have not been previously reported radiographically-such as the vocal fold superficial lamina propria, vocal ligament and macula flavae; age-related tissue features-such as intramuscular fat deposition and cartilage ossification; and the lesions. Diffusion tensor imaging characterised differences in water diffusivity, primary tissue fibre orientation, and fractional anisotropy between the intrinsic laryngeal muscles, mucosae and lesions. MALDI-MS imaging revealed peptide signatures and putative protein assignments for the polypoid degeneration lesion and the N-glycan constituents of one mucus retention cyst. These imaging approaches have immediate application in experimental research and, with ongoing technology development, potential for future clinical application.
• Kishimoto, A. O., Kishimoto, Y., Shi, X., Hutchinson, E. B., Zhang, H., Shi, Y., Oliveira, G., Li, L., Welham, N. V., & Rowland, I. J. (2021). High‐resolution magnetic resonance and mass spectrometry imaging of the human larynx. Journal of Anatomy, 239(3), 545-556. doi:10.1111/joa.13451
• Schwerin, S. C., Chatterjee, M., Hutchinson, E. B., Djankpa, F. T., Armstrong, R. C., McCabe, J. T., Perl, D. P., & Juliano, S. L. (2021). Expression of GFAP and Tau Following Blast Exposure in the Cerebral Cortex of Ferrets. Journal of neuropathology and experimental neurology, 80(2), 112-128.
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  Blast exposures are a hallmark of contemporary military conflicts. We need improved preclinical models of blast traumatic brain injury for translation of pharmaceutical and therapeutic protocols. Compared with rodents, the ferret brain is larger, has substantial sulci, gyri, a higher white to gray matter ratio, and the hippocampus in a ventral position; these attributes facilitate comparison with the human brain. In this study, ferrets received compressed air shock waves and subsequent evaluation of glia and forms of tau following survival of up to 12 weeks. Immunohistochemistry and Western blot demonstrated altered distributions of astrogliosis and tau expression after blast exposure. Many aspects of the astrogliosis corresponded to human pathology: increased subpial reactivity, gliosis at gray-white matter interfaces, and extensive outlining of blood vessels. MRI analysis showed numerous hypointensities occurring in the 12-week survival animals, appearing to correspond to luminal expansions of blood vessels. Changes in forms of tau, including phosphorylated tau, and the isoforms 3R and 4R were noted using immunohistochemistry and Western blot in specific regions of the cerebral cortex. Of particular interest were the 3R and 4R isoforms, which modified their ratio after blast. Our data strongly support the ferret as an animal model with highly translational features to study blast injury.
• Benjamini, D., Hutchinson, E. B., Komlosh, M. E., Comrie, C. J., Schwerin, S. C., Zhang, G., Pierpaoli, C., & Basser, P. J. (2020). Direct and specific assessment of axonal injury and spinal cord microenvironments using diffusion correlation imaging. NeuroImage, 221, 117195.
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  We describe a practical two-dimensional (2D) diffusion MRI framework to deliver specificity and improve sensitivity to axonal injury in the spinal cord. This approach provides intravoxel distributions of correlations of water mobilities in orthogonal directions, revealing sub-voxel diffusion components. Here we use it to investigate water diffusivities along axial and radial orientations within spinal cord specimens with confirmed, tract-specific axonal injury. First, we show using transmission electron microscopy and immunohistochemistry that tract-specific axonal beading occurs following Wallerian degeneration in the cortico-spinal tract as direct sequelae to closed head injury. We demonstrate that although some voxel-averaged diffusion tensor imaging (DTI) metrics are sensitive to this axonal injury, they are non-specific, i.e., they do not reveal an underlying biophysical mechanism of injury. Then we employ 2D diffusion correlation imaging (DCI) to improve discrimination of different water microenvironments by measuring and mapping the joint water mobility distributions perpendicular and parallel to the spinal cord axis. We determine six distinct diffusion spectral components that differ according to their microscopic anisotropy and mobility. We show that at the injury site a highly anisotropic diffusion component completely disappears and instead becomes more isotropic. Based on these findings, an injury-specific MR image of the spinal cord was generated, and a radiological-pathological correlation with histological silver staining % area was performed. The resulting strong and significant correlation (r=0.70,p 
• Engle, E. C., Erazo, M., Frempong, T., Hao, K., Jabs, E. W., Naidich, T. P., Rucker, J. C., Webb, B. D., Zhang, Z., Andrews, C., Barry, B. J., DiGioia, S. A., Engle, E., Hunter, D. G., MacKinnon, S. E., Robson, C., Rose, M., Biesecker, B. B., Bonnycastle, L. L., , Brewer, C. C., et al. (2020). Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry. Brain Communications, 2(1). doi:10.1093/braincomms/fcaa014
• Hutchinson, E. B., Basser, P. J., Pierpaoli, C., Zhang, G., Schwerin, S. C., Comrie, C. J., Komlosh, M. E., & Benjamini, D. (2020). Direct and specific assessment of axonal injury and spinal cord microenvironments using diffusion correlation imaging. bioRxiv. doi:10.1101/2020.05.04.074856
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  Abstract We describe a practical two-dimensional (2D) diffusion MRI framework to deliver specificity and improve sensitivity to axonal injury in the spinal cord. This approach provides intravoxel distributions of correlations of water mobilities in orthogonal directions, revealing sub-voxel diffusion components. Here we use it to investigate water diffusivities along axial and radial orientations within spinal cord specimens with confirmed, tract-specific axonal injury. First, we show using transmission electron microscopy and immunohistochemistry that tract-specific axonal beading occurs following Wallerian degeneration in the cortico-spinal tract as direct sequelae to closed head injury. We demonstrate that although some voxel-averaged diffusion tensor imaging (DTI) metrics are sensitive to this axonal injury, they are non-specific, i.e., they do not reveal an underlying biophysical mechanism of injury. Then we employ 2D diffusion correlation imaging (DCI) to improve discrimination of different water microenvironments by measuring and mapping the joint water mobility distributions perpendicular and parallel to the spinal cord axis. We determine six distinct diffusion spectral components that differ according to their microscopic anisotropy and mobility. We show that at the injury site a highly anisotropic diffusion component completely disappears and instead becomes more isotropic. Based on these findings, an injury-specific MR image of the spinal cord was generated, and a radiological-pathological correlation with histological silver staining % area was performed. The resulting strong and significant correlation ( r = 0.70, p < 0.0001) indicates the high specificity with which DCI detects injury-induced tissue alterations. We predict that the ability to selectively image microstructural changes following axonal injury in the spinal cord can be useful in clinical and research applications by enabling specific detection and increased sensitivity to injury-induced microstructural alterations. These results also encourage us to translate DCI to higher spatial dimensions to enable assessment of traumatic axonal injury, and possibly other diseases and disorders in the brain.
• Sadeghi, N., Hutchinson, E., Van Ryzin, C., FitzGibbon, E. J., Butman, J. A., Webb, B. D., Facio, F., Brooks, B. P., Collins, F. S., Jabs, E. W., Engle, E. C., Manoli, I., Pierpaoli, C., & , M. S. (2020). Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry. Brain communications, 2(1), fcaa014.
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  In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome ( = 21), other congenital facial weakness disorders ( = 9) and healthy controls ( = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.
• Sadeghi, N., Hutchinson, E., Van, R. C., FitzGibbon, E. J., Butman, J. A., Webb, B. D., Facio, F., Brooks, B. P., Collins, F. S., Jabs, E. W., & others, . (2020). Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry. Brain Communications.
• Han, T. U., Root, J., Reyes, L. D., Huchinson, E. B., Hoffmann, J. D., Lee, W. S., Barnes, T. D., & Drayna, D. (2019). Human stuttering mutations engineered into mice cause vocalization deficits and astrocyte pathology in the corpus callosum. Proceedings of the National Academy of Sciences of the United States of America, 116(35), 17515-17524.
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  Stuttering is a common neurodevelopmental disorder that has been associated with mutations in genes involved in intracellular trafficking. However, the cellular mechanisms leading to stuttering remain unknown. Engineering a mutation in -acetylglucosamine-1-phosphate transferase subunits α and β (GNPTAB) found in humans who stutter into the mouse gene resulted in deficits in the flow of ultrasonic vocalizations similar to speech deficits of humans who stutter. Here we show that other human stuttering mutations introduced into this mouse gene, Ser321Gly and Ala455Ser, produce the same vocalization deficit in 8-day-old pup isolation calls and do not affect other nonvocal behaviors. Immunohistochemistry showed a marked decrease in staining of astrocytes, particularly in the corpus callosum of the Ser321Gly homozygote mice compared to wild-type littermates, while the staining of cerebellar Purkinje cells, oligodendrocytes, microglial cells, and dopaminergic neurons was not significantly different. Diffusion tensor imaging also detected deficits in the corpus callosum of the Ser321Gly mice. Using a range of cell type-specific Cre-drivers and a conditional knockout line, we found that only astrocyte-specific -deficient mice displayed a similar vocalization deficit. These data suggest that vocalization defects in mice carrying human stuttering mutations in derive from abnormalities in astrocytes, particularly in the corpus callosum, and provide support for hypotheses that focus on deficits in interhemispheric communication in stuttering.
• Hutchinson, E. B., Chatterjee, M., Reyes, L., Djankpa, F. T., Valiant, W. G., Dardzinski, B., Mattapallil, J. J., Pierpaoli, C., & Juliano, S. L. (2019). The effect of Zika virus infection in the ferret. The Journal of comparative neurology, 527(10), 1706-1719.
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  Although initial observations of infections with the Zika virus describe a mild illness, more recent reports show that infections by Zika result in neurotropism. In 2015, substantial congenital malformations were observed, with numerous infants born with microcephaly in Brazil. To study the underlying mechanism and effects of the disease, it is critical to find suitable animal models. Rodents lack an immune system parallel to humans and also have lissencephalic brains, which are likely to react differently to infections. As the smallest gyrencephalic mammal, ferrets may provide an important animal model to study the Zika virus, as their brains share many characteristics with humans. To evaluate the prospect of using ferrets to study Zika virus infection, we injected seven pregnant jills with the PR strain subcutaneously on gestational day 21, corresponding to the initiation of corticogenesis. These injections resulted in mixed effects. Two animals died of apparent infection, and all kits were resorbed in another animal that did not die. The other four animals remained pregnant until gestational day 40, when the kits were delivered by caesarian section. We evaluated the animals using CT, MRI, diffusion tensor imaging, and immunohistochemistry. The kits displayed a number of features compatible with an infection that impacted both the brain and skull. The outcomes, however, were variable and differed within and across litters, which ranged from the absence of observable abnormalities to prominent changes, suggesting differential vulnerability of kits to infection by the Zika virus or to subsequent mechanisms of neurodevelopmental disruption.
• Komlosh, M. E., Benjamini, D., Williamson, N. W., Horkay, F., Hutchinson, E. B., & Basser, P. J. (2019). A novel MRI phantom to study interstitial fluid transport in the glymphatic system. Magnetic resonance imaging, 56, 181-186.
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  The glymphatic system is a recently discovered transport system, mediated by cerebral spinal fluid (CSF), that clears metabolic and cellular waste products in the brain. This system's function in the brain is analogous to that of the lymphatic system in the rest of the mammalian body. It is hypothesized that CSF clears harmful chemicals from the brain by flowing through interstitial spaces in the brain during sleep. While there is growing recognition of the critical role the glymphatic system plays in maintaining normal brain health and in explaining pathology, there are few noninvasive imaging methods that measure and characterize the efficacy of glymphatic transport in vivo. In this study we designed, constructed, and tested a glymphatic transport magnetic resonance imaging (MRI) flow phantom, which combines regions that mimic CSF-filled ventricles and brain interstitial space. We tested high- and low-q space diffusion MRI and diffusion tensor imaging (DTI) acquisitions to determine if they could detect, measure, and map interstitial glymphatic flows. The results suggest that, under certain flow conditions, diffusion-weighted MRI can detect the enhanced mixing that occurs during glymphatic clearance.
• Avram, A. V., Sarlls, J. E., Hutchinson, E., & Basser, P. J. (2018). Efficient experimental designs for isotropic generalized diffusion tensor MRI (IGDTI). Magnetic resonance in medicine, 79(1), 180-194.
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  We propose a new generalized diffusion tensor imaging (GDTI) experimental design and analysis framework for efficiently measuring orientationally averaged diffusion-weighted images (DWIs), which remove bulk signal modulations attributed to diffusion anisotropy and quantify isotropic higher-order diffusion tensors (HOT). We illustrate how this framework accelerates the clinical measurement of rotation-invariant tissue microstructural parameters derived from HOT, such as the HOT-Trace and the mean t-kurtosis.
• Hutchinson, E. B., Basser, P. J., Sarlls, J. E., & Avram, A. V. (2018). Efficient experimental designs for isotropic generalized diffusion tensor MRI (IGDTI). Magnetic Resonance in Medicine. doi:10.1002/mrm.26656
• Hutchinson, E. B., Pierpaoli, C., Bassi, M. T., Modi, P., Nayak, A., Irfanoglu, M. O., Thomas, C., D'Angelo, M. G., Arrigoni, F., & Sadeghi, N. (2018). Tensor‐based morphometry using scalar and directional information of diffusion tensor MRI data (DTBM): Application to hereditary spastic paraplegia. Human Brain Mapping. doi:10.1002/hbm.24278
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  Tensor-based morphometry (TBM) performed using T1-weighted images (T1WIs) is a well-established method for analyzing local morphological changes occurring in the brain due to normal aging and disease. However, in white matter regions that appear homogeneous on T1WIs, T1W-TBM may be inadequate for detecting changes that affect specific pathways. In these regions, diffusion tensor MRI (DTI) can identify white matter pathways on the basis of their different anisotropy and orientation. In this study, we propose performing TBM using deformation fields constructed using all scalar and directional information provided by the diffusion tensor (DTBM) with the goal of increasing sensitivity in detecting morphological abnormalities of specific white matter pathways. Previously, mostly fractional anisotropy (FA) has been used to drive registration in diffusion MRI-based TBM (FA-TBM). However, FA does not have the directional information that the tensors contain, therefore, the registration based on tensors provides better alignment of brain structures and better localization of volume change. We compare our DTBM method to both T1W-TBM and FA-TBM in investigating differences in brain morphology between patients with complicated hereditary spastic paraplegia of type 11 (SPG11) and a group of healthy controls. Effect size maps of T1W-TBM of SPG11 patients showed diffuse atrophy of white matter. However, DTBM indicated that atrophy was more localized, predominantly affecting several long-range pathways. The results of our study suggest that DTBM could be a powerful tool for detecting morphological changes of specific white matter pathways in normal brain development and aging, as well as in degenerative disorders.
• Hutchinson, E. B., Schwerin, S. C., Avram, A. V., Juliano, S. L., & Pierpaoli, C. (2018). Diffusion MRI and the detection of alterations following traumatic brain injury. Journal of neuroscience research, 96(4), 612-625.
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  This article provides a review of brain tissue alterations that may be detectable using diffusion magnetic resonance imaging MRI (dMRI) approaches and an overview and perspective on the modern dMRI toolkits for characterizing alterations that follow traumatic brain injury (TBI). Noninvasive imaging is a cornerstone of clinical treatment of TBI and has become increasingly used for preclinical and basic research studies. In particular, quantitative MRI methods have the potential to distinguish and evaluate the complex collection of neurobiological responses to TBI arising from pathology, neuroprotection, and recovery. dMRI provides unique information about the physical environment in tissue and can be used to probe physiological, architectural, and microstructural features. Although well-established approaches such as diffusion tensor imaging are known to be highly sensitive to changes in the tissue environment, more advanced dMRI techniques have been developed that may offer increased specificity or new information for describing abnormalities. These tools are promising, but incompletely understood in the context of TBI. Furthermore, model dependencies and relative limitations may impact the implementation of these approaches and the interpretation of abnormalities in their metrics. The objective of this paper is to present a basic review and comparison across dMRI methods as they pertain to the detection of the most commonly observed tissue and cellular alterations following TBI.
• Hutchinson, E. B., Schwerin, S. C., Radomski, K. L., Sadeghi, N., Komlosh, M. E., Irfanoglu, M. O., Juliano, S. L., & Pierpaoli, C. (2018). Detection and Distinction of Mild Brain Injury Effects in a Ferret Model Using Diffusion Tensor MRI (DTI) and DTI-Driven Tensor-Based Morphometry (D-TBM). Frontiers in neuroscience, 12, 573.
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  Mild traumatic brain injury (mTBI) is highly prevalent but lacks both research tools with adequate sensitivity to detect cellular alterations that accompany mild injury and pre-clinical models that are able to robustly mimic hallmark features of human TBI. To address these related challenges, high-resolution diffusion tensor MRI (DTI) analysis was performed in a model of mild TBI in the ferret - a species that, unlike rodents, share with humans a gyrencephalic cortex and high white matter (WM) volume. A set of DTI image analysis tools were optimized and implemented to explore key features of DTI alterations in adult male ferret brains ( = 26), evaluated 1 day to 16 weeks after mild controlled cortical impact (CCI). Using template-based ROI analysis, lesion overlay mapping and DTI-driven tensor-based morphometry (D-TBM) significant differences in DTI and morphometric values were found and their dependence on time after injury evaluated. These observations were also qualitatively compared with immunohistochemistry staining of neurons, astrocytes, and microglia in the same tissue. Focal DTI abnormalities including reduced cortical diffusivity were apparent in 12/13 injured brains with greatest lesion extent found acutely following CCI by ROI overlay maps and reduced WM FA in the chronic period was observed near to the CCI site (ANOVA for FA in focal WM: time after CCI = 0.046, brain hemisphere = 0.0012) often in regions without other prominent MRI abnormalities. Global abnormalities were also detected, especially for WM regions, which demonstrated reduced diffusivity (ANOVA for Trace: time after CCI = 0.007) and atrophy that appeared to become more extensive and bilateral with longer time after injury (ANOVA for D-TBM Log of the Jacobian values: time after CCI = 0.007). The findings of this study extend earlier work in rodent models especially by evaluation of focal WM abnormalities that are not influenced by partial volume effects in the ferret. There is also substantial overlap between DTI and morphometric findings in this model and those from human studies of mTBI implying that the combination of DTI tools with a human-similar model system can provide an advantageous and informative approach for mTBI research.
• Komlosh, M. E., Benjamini, D., Hutchinson, E. B., King, S., Haber, M., Avram, A. V., Holtzclaw, L. A., Desai, A., Pierpaoli, C., & Basser, P. J. (2018). Using double pulsed-field gradient MRI to study tissue microstructure in traumatic brain injury (TBI). Microporous and mesoporous materials : the official journal of the International Zeolite Association, 269, 156-159.
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  Double pulsed-field gradient (dPFG) MRI is proposed as a new sensitive tool to detect and characterize tissue microstructure following diffuse axonal injury. In this study dPFG MRI was used to estimate apparent mean axon diameter in a diffuse axonal injury animal model and in healthy fixed mouse brain. Histological analysis was used to verify the presence of the injury detected by MRI.
• Latremoliere, A., Cheng, L., Wu, C., Chew, S., Hutchinson, E. B., Sheridan, A., Alexandre, C., Latremoliere, F., Golidy, S., Omura, T., Huebner, E. A., Fan, Y., Whitman, M. C., Nguyen, E., Hermawan, C., Pierpaoli, C., Tischfield, M. A., Woolf, C. J., Engle, E. C., , Sheu, S. H., et al. (2018). Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration.. Cell reports, 24(7), 1865-1879.e9. doi:10.1016/j.celrep.2018.07.029
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  We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3-/- mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total β-tubulin levels in Tubb3-/- and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.
• Sadeghi, N., Arrigoni, F., D'Angelo, M. G., Thomas, C., Irfanoglu, M. O., Hutchinson, E. B., Nayak, A., Modi, P., Bassi, M. T., & Pierpaoli, C. (2018). Tensor-based morphometry using scalar and directional information of diffusion tensor MRI data (DTBM): Application to hereditary spastic paraplegia. Human brain mapping, 39(12), 4643-4651.
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  Tensor-based morphometry (TBM) performed using T1-weighted images (T1WIs) is a well-established method for analyzing local morphological changes occurring in the brain due to normal aging and disease. However, in white matter regions that appear homogeneous on T1WIs, T1W-TBM may be inadequate for detecting changes that affect specific pathways. In these regions, diffusion tensor MRI (DTI) can identify white matter pathways on the basis of their different anisotropy and orientation. In this study, we propose performing TBM using deformation fields constructed using all scalar and directional information provided by the diffusion tensor (DTBM) with the goal of increasing sensitivity in detecting morphological abnormalities of specific white matter pathways. Previously, mostly fractional anisotropy (FA) has been used to drive registration in diffusion MRI-based TBM (FA-TBM). However, FA does not have the directional information that the tensors contain, therefore, the registration based on tensors provides better alignment of brain structures and better localization of volume change. We compare our DTBM method to both T1W-TBM and FA-TBM in investigating differences in brain morphology between patients with complicated hereditary spastic paraplegia of type 11 (SPG11) and a group of healthy controls. Effect size maps of T1W-TBM of SPG11 patients showed diffuse atrophy of white matter. However, DTBM indicated that atrophy was more localized, predominantly affecting several long-range pathways. The results of our study suggest that DTBM could be a powerful tool for detecting morphological changes of specific white matter pathways in normal brain development and aging, as well as in degenerative disorders.
• Schwerin, S. C., Chatterjee, M., Imam-Fulani, A. O., Radomski, K. L., Hutchinson, E. B., Pierpaoli, C. M., & Juliano, S. L. (2018). Progression of histopathological and behavioral abnormalities following mild traumatic brain injury in the male ferret. Journal of neuroscience research, 96(4), 556-572.
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  White matter damage is an important consequence of traumatic brain injury (TBI) in humans. Unlike rodents, ferrets have a substantial amount of white matter and a gyrencephalic brain; therefore, they may represent an ideal small mammal model to study human-pertinent consequences of TBI. Here we report immunohistochemical and behavioral results after a controlled cortical impact (CCI) injury to the sensorimotor cortex of adult male ferrets. We assessed inflammation in the neocortex and white matter, and behavior at 1 day post injury and 1, 4, and 16 weeks post injury (WPI). CCI in the ferret produced inflammation that originated in the neocortex near the site of the injury and progressed deep into the white matter with time. The density of microglia and astrocytes increased in the neocortex near the injury, peaking at 4WPI and remaining elevated at 16WPI. Microglial morphology in the neocortex was significantly altered in the first 4 weeks, but showed a return toward normal at 16 weeks. Clusters of microglial cells in the white matter persisted until 16WPI. We assessed motor and cognitive behavior using the open field, novel object recognition, T-maze, and gait tests. A transient deficit in memory occurred at 4WPI, with a reduction of rearing and motor ability at 12 and 16WPI. Behavioral impairments coincide with features of the inflammatory changes in the neocortex revealed by immunohistochemistry. The ferret represents an important animal model to explore ongoing damage in the white matter and cerebral cortex after TBI.
• Haber, M., Hutchinson, E. B., Sadeghi, N., Cheng, W. H., Namjoshi, D., Cripton, P., Irfanoglu, M. O., Wellington, C., Diaz-Arrastia, R., & Pierpaoli, C. (2017). Defining an Analytic Framework to Evaluate Quantitative MRI Markers of Traumatic Axonal Injury: Preliminary Results in a Mouse Closed Head Injury Model. eNeuro, 4(5).
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  Diffuse axonal injury (DAI) is a hallmark of traumatic brain injury (TBI) pathology. Recently, the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) was developed to generate an experimental model of DAI in a mouse. The characterization of DAI using diffusion tensor magnetic resonance imaging (MRI; diffusion tensor imaging, DTI) may provide a useful set of outcome measures for preclinical and clinical studies. The objective of this study was to identify the complex neurobiological underpinnings of DTI features following DAI using a comprehensive and quantitative evaluation of DTI and histopathology in the CHIMERA mouse model. A consistent neuroanatomical pattern of pathology in specific white matter tracts was identified across DTI maps and photomicrographs of histology. These observations were confirmed by voxelwise and regional analysis of DTI maps, demonstrating reduced fractional anisotropy (FA) in distinct regions such as the optic tract. Similar regions were identified by quantitative histology and exhibited axonal damage as well as robust gliosis. Additional analysis using a machine-learning algorithm was performed to identify regions and metrics important for injury classification in a manner free from potential user bias. This analysis found that diffusion metrics were able to identify injured brains almost with the same degree of accuracy as the histology metrics. Good agreement between regions detected as abnormal by histology and MRI was also found. The findings of this work elucidate the complexity of cellular changes that give rise to imaging abnormalities and provide a comprehensive and quantitative evaluation of the relative importance of DTI and histological measures to detect brain injury.
• Hutchinson, E. B., Avram, A. V., Irfanoglu, M. O., Koay, C. G., Barnett, A. S., Komlosh, M. E., Özarslan, E., Schwerin, S. C., Juliano, S. L., & Pierpaoli, C. (2017). Analysis of the effects of noise, DWI sampling, and value of assumed parameters in diffusion MRI models. Magnetic resonance in medicine, 78(5), 1767-1780.
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  This study was a systematic evaluation across different and prominent diffusion MRI models to better understand the ways in which scalar metrics are influenced by experimental factors, including experimental design (diffusion-weighted imaging [DWI] sampling) and noise.
• Hutchinson, E. B., Basser, P. J., Pierpaoli, C., Desai, A., Holtzclaw, L. A., Avram, A. V., Haber, M., King, S., Benjamini, D., & Komlosh, M. E. (2017). Using double pulsed-field gradient MRI to study tissue microstructure in traumatic brain injury (TBI). Microporous and Mesoporous Materials. doi:10.1016/j.micromeso.2017.05.030
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  Double pulsed-field gradient (dPFG) MRI is proposed as a new sensitive tool to detect and characterize tissue microstructure following diffuse axonal injury. In this study dPFG MRI was used to estimate apparent mean axon diameter in a diffuse axonal injury animal model and in healthy fixed mouse brain. Histological analysis was used to verify the presence of the injury detected by MRI.
• Hutchinson, E. B., Pierpaoli, C., Juliano, S. L., Schwerin, S. C., Özarslan, E., Komlosh, M. E., Barnett, A. S., Koay, C. G., Irfanoglu, M. O., & Avram, A. V. (2017). Analysis of the effects of noise, DWI sampling, and value of assumed parameters in diffusion MRI models. Magnetic Resonance in Medicine. doi:10.1002/mrm.26575
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  This study was a systematic evaluation across different and prominent diffusion MRI models to better understand the ways in which scalar metrics are influenced by experimental factors, including experimental design (diffusion-weighted imaging [DWI] sampling) and noise.Four diffusion MRI models-diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator MRI (MAP-MRI), and neurite orientation dispersion and density imaging (NODDI)-were evaluated by comparing maps and histogram values of the scalar metrics generated using DWI datasets obtained in fixed mouse brain with different noise levels and DWI sampling complexity. Additionally, models were fit with different input parameters or constraints to examine the consequences of model fitting procedures.Experimental factors affected all models and metrics to varying degrees. Model complexity influenced sensitivity to DWI sampling and noise, especially for metrics reporting non-Gaussian information. DKI metrics were highly susceptible to noise and experimental design. The influence of fixed parameter selection for the NODDI model was found to be considerable, as was the impact of initial tensor fitting in the MAP-MRI model.Across DTI, DKI, MAP-MRI, and NODDI, a wide range of dependence on experimental factors was observed that elucidate principles and practical implications for advanced diffusion MRI. Magn Reson Med 78:1767-1780, 2017. © 2017 International Society for Magnetic Resonance in Medicine.
• Hutchinson, E. B., Schwerin, S. C., Radomski, K. L., Sadeghi, N., Jenkins, J., Komlosh, M. E., Irfanoglu, M. O., Juliano, S. L., & Pierpaoli, C. (2017). Population based MRI and DTI templates of the adult ferret brain and tools for voxelwise analysis. NeuroImage, 152, 575-589.
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  Non-invasive imaging has the potential to play a crucial role in the characterization and translation of experimental animal models to investigate human brain development and disorders, especially when employed to study animal models that more accurately represent features of human neuroanatomy. The purpose of this study was to build and make available MRI and DTI templates and analysis tools for the ferret brain as the ferret is a well-suited species for pre-clinical MRI studies with folded cortical surface, relatively high white matter volume and body dimensions that allow imaging with pre-clinical MRI scanners. Four ferret brain templates were built in this study - in-vivo MRI and DTI and ex-vivo MRI and DTI - using brain images across many ferrets and region of interest (ROI) masks corresponding to established ferret neuroanatomy were generated by semi-automatic and manual segmentation. The templates and ROI masks were used to create a web-based ferret brain viewing software for browsing the MRI and DTI volumes with annotations based on the ROI masks. A second objective of this study was to provide a careful description of the imaging methods used for acquisition, processing, registration and template building and to demonstrate several voxelwise analysis methods including Jacobian analysis of morphometry differences between the female and male brain and bias-free identification of DTI abnormalities in an injured ferret brain. The templates, tools and methodological optimization presented in this study are intended to advance non-invasive imaging approaches for human-similar animal species that will enable the use of pre-clinical MRI studies for understanding and treating brain disorders.
• Schwerin, S. C., Hutchinson, E. B., Radomski, K. L., Ngalula, K. P., Pierpaoli, C. M., & Juliano, S. L. (2017). Establishing the ferret as a gyrencephalic animal model of traumatic brain injury: Optimization of controlled cortical impact procedures. Journal of neuroscience methods, 285, 82-96.
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  Although rodent TBI studies provide valuable information regarding the effects of injury and recovery, an animal model with neuroanatomical characteristics closer to humans may provide a more meaningful basis for clinical translation. The ferret has a high white/gray matter ratio, gyrencephalic neocortex, and ventral hippocampal location. Furthermore, ferrets are amenable to behavioral training, have a body size compatible with pre-clinical MRI, and are cost-effective.
• Avram, A. V., Sarlls, J. E., Barnett, A. S., Özarslan, E., Thomas, C., Irfanoglu, M. O., Hutchinson, E., Pierpaoli, C., & Basser, P. J. (2016). Clinical feasibility of using mean apparent propagator (MAP) MRI to characterize brain tissue microstructure. NeuroImage, 127, 422-434.
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  Diffusion tensor imaging (DTI) is the most widely used method for characterizing noninvasively structural and architectural features of brain tissues. However, the assumption of a Gaussian spin displacement distribution intrinsic to DTI weakens its ability to describe intricate tissue microanatomy. Consequently, the biological interpretation of microstructural parameters, such as fractional anisotropy or mean diffusivity, is often equivocal. We evaluate the clinical feasibility of assessing brain tissue microstructure with mean apparent propagator (MAP) MRI, a powerful analytical framework that efficiently measures the probability density function (PDF) of spin displacements and quantifies useful metrics of this PDF indicative of diffusion in complex microstructure (e.g., restrictions, multiple compartments). Rotation invariant and scalar parameters computed from the MAP show consistent variation across neuroanatomical brain regions and increased ability to differentiate tissues with distinct structural and architectural features compared with DTI-derived parameters. The return-to-origin probability (RTOP) appears to reflect cellularity and restrictions better than MD, while the non-Gaussianity (NG) measures diffusion heterogeneity by comprehensively quantifying the deviation between the spin displacement PDF and its Gaussian approximation. Both RTOP and NG can be decomposed in the local anatomical frame for reference determined by the orientation of the diffusion tensor and reveal additional information complementary to DTI. The propagator anisotropy (PA) shows high tissue contrast even in deep brain nuclei and cortical gray matter and is more uniform in white matter than the FA, which drops significantly in regions containing crossing fibers. Orientational profiles of the propagator computed analytically from the MAP MRI series coefficients allow separation of different fiber populations in regions of crossing white matter pathways, which in turn improves our ability to perform whole-brain fiber tractography. Reconstructions from subsampled data sets suggest that MAP MRI parameters can be computed from a relatively small number of DWIs acquired with high b-value and good signal-to-noise ratio in clinically achievable scan durations of less than 10min. The neuroanatomical consistency across healthy subjects and reproducibility in test-retest experiments of MAP MRI microstructural parameters further substantiate the robustness and clinical feasibility of this technique. The MAP MRI metrics could potentially provide more sensitive clinical biomarkers with increased pathophysiological specificity compared to microstructural measures derived using conventional diffusion MRI techniques.
• Hutchinson, E. B., Pierpaoli, C., Thomas, C., Sadeghi, N., Jenkins, J., Nayak, A., & Irfanoglu, M. O. (2016). DR-TAMAS: Diffeomorphic Registration for Tensor Accurate Alignment of Anatomical Structures. NeuroImage. doi:10.1016/j.neuroimage.2016.02.066
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  In this work, we propose DR-TAMAS (Diffeomorphic Registration for Tensor Accurate alignMent of Anatomical Structures), a novel framework for intersubject registration of Diffusion Tensor Imaging (DTI) data sets. This framework is optimized for brain data and its main goal is to achieve an accurate alignment of all brain structures, including white matter (WM), gray matter (GM), and spaces containing cerebrospinal fluid (CSF). Currently most DTI-based spatial normalization algorithms emphasize alignment of anisotropic structures. While some diffusion-derived metrics, such as diffusion anisotropy and tensor eigenvector orientation, are highly informative for proper alignment of WM, other tensor metrics such as the trace or mean diffusivity (MD) are fundamental for a proper alignment of GM and CSF boundaries. Moreover, it is desirable to include information from structural MRI data, e.g., T1-weighted or T2-weighted images, which are usually available together with the diffusion data. The fundamental property of DR-TAMAS is to achieve global anatomical accuracy by incorporating in its cost function the most informative metrics locally. Another important feature of DR-TAMAS is a symmetric time-varying velocity-based transformation model, which enables it to account for potentially large anatomical variability in healthy subjects and patients. The performance of DR-TAMAS is evaluated with several data sets and compared with other widely-used diffeomorphic image registration techniques employing both full tensor information and/or DTI-derived scalar maps. Our results show that the proposed method has excellent overall performance in the entire brain, while being equivalent to the best existing methods in WM.
• Hutchinson, E. B., Schwerin, S. C., Radomski, K. L., Irfanoglu, M. O., Juliano, S. L., & Pierpaoli, C. M. (2016). Quantitative MRI and DTI Abnormalities During the Acute Period Following CCI in the Ferret. Shock (Augusta, Ga.), 46(3 Suppl 1), 167-76.
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  During the acute time period following traumatic brain injury (TBI), noninvasive brain imaging tools such as magnetic resonance imaging (MRI) can provide important information about the clinical and pathological features of the injury and may help predict long-term outcomes. In addition to standard imaging approaches, several quantitative MRI techniques including relaxometry and diffusion MRI have been identified as promising reporters of cellular alterations after TBI and may provide greater sensitivity and specificity for identifying brain abnormalities especially in mild TBI. However, for these imaging tools to be useful, it is crucial to define their relationship with the neurophysiological response to brain injury. Recently, a model of controlled cortical impact (CCI) has been developed in the ferret which has many advantages compared with rodent models (e.g., gyrencephalic cortex and high white matter volume). The objective of this study was to evaluate quantitative MRI metrics in the ferret CCI model, including T2 values and diffusion tensor imaging (DTI) metrics, during the acute time period. Longitudinal quantitative comparisons of in vivo MRI and DTI metrics were evaluated to identify abnormalities and characterize their spatial patterns in the ferret brain. Ex vivo MRI and DTI maps were then compared with histological staining for glial and neuronal abnormalities. The main findings of this article describe T2, diffusivity, and anisotropy markers of tissue change during the acute time period following mild TBI, and ex vivo analyses suggest that MRI and DTI markers are sensitive to subtle cellular alterations in this model. This was confirmed by comparison with immunohistochemistry, also showing altered markers in regions of MRI and DTI change.
• Irfanoglu, M. O., Nayak, A., Jenkins, J., Hutchinson, E. B., Sadeghi, N., Thomas, C. P., & Pierpaoli, C. (2016). DR-TAMAS: Diffeomorphic Registration for Tensor Accurate Alignment of Anatomical Structures. NeuroImage, 132, 439-454.
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  In this work, we propose DR-TAMAS (Diffeomorphic Registration for Tensor Accurate alignMent of Anatomical Structures), a novel framework for intersubject registration of Diffusion Tensor Imaging (DTI) data sets. This framework is optimized for brain data and its main goal is to achieve an accurate alignment of all brain structures, including white matter (WM), gray matter (GM), and spaces containing cerebrospinal fluid (CSF). Currently most DTI-based spatial normalization algorithms emphasize alignment of anisotropic structures. While some diffusion-derived metrics, such as diffusion anisotropy and tensor eigenvector orientation, are highly informative for proper alignment of WM, other tensor metrics such as the trace or mean diffusivity (MD) are fundamental for a proper alignment of GM and CSF boundaries. Moreover, it is desirable to include information from structural MRI data, e.g., T1-weighted or T2-weighted images, which are usually available together with the diffusion data. The fundamental property of DR-TAMAS is to achieve global anatomical accuracy by incorporating in its cost function the most informative metrics locally. Another important feature of DR-TAMAS is a symmetric time-varying velocity-based transformation model, which enables it to account for potentially large anatomical variability in healthy subjects and patients. The performance of DR-TAMAS is evaluated with several data sets and compared with other widely-used diffeomorphic image registration techniques employing both full tensor information and/or DTI-derived scalar maps. Our results show that the proposed method has excellent overall performance in the entire brain, while being equivalent to the best existing methods in WM.
• Irfanoglu, M. O., Modi, P., Nayak, A., Hutchinson, E. B., Sarlls, J., & Pierpaoli, C. (2015). DR-BUDDI (Diffeomorphic Registration for Blip-Up blip-Down Diffusion Imaging) method for correcting echo planar imaging distortions. NeuroImage, 106, 284-99.
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  We propose an echo planar imaging (EPI) distortion correction method (DR-BUDDI), specialized for diffusion MRI, which uses data acquired twice with reversed phase encoding directions, often referred to as blip-up blip-down acquisitions. DR-BUDDI can incorporate information from an undistorted structural MRI and also use diffusion-weighted images (DWI) to guide the registration, improving the quality of the registration in the presence of large deformations and in white matter regions. DR-BUDDI does not require the transformations for correcting blip-up and blip-down images to be the exact inverse of each other. Imposing the theoretical "blip-up blip-down distortion symmetry" may not be appropriate in the presence of common clinical scanning artifacts such as motion, ghosting, Gibbs ringing, vibrations, and low signal-to-noise. The performance of DR-BUDDI is evaluated with several data sets and compared to other existing blip-up blip-down correction approaches. The proposed method is robust and generally outperforms existing approaches. The inclusion of the DWIs in the correction process proves to be important to obtain a reliable correction of distortions in the brain stem. Methods that do not use DWIs may produce a visually appealing correction of the non-diffusion weighted images, but the directionally encoded color maps computed from the tensor reveal an abnormal anatomy of the white matter pathways.
• Sayin, U., Meyerand, M. E., Sutula, T. P., & Hutchinson, E. B. (2015). Age-dependent long-term structural and functional effects of early-life seizures: evidence for a hippocampal critical period influencing plasticity in adulthood.. Neuroscience, 288, 120-134. doi:10.1016/j.neuroscience.2014.12.017
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  Neural activity promotes circuit formation in developing systems and during critical periods permanently modifies circuit organization and functional properties. These observations suggest that excessive neural activity, as occurs during seizures, might influence developing neural circuitry with long-term outcomes that depend on age at the time of seizures. We systematically examined long-term structural and functional consequences of seizures induced in rats by kainic acid, pentylenetetrazol, and hyperthermia across postnatal ages from birth through postnatal day 90 in adulthood (P90). Magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and electrophysiological methods at ⩾P95 following seizures induced from P1 to P90 demonstrated consistent patterns of gross atrophy, microstructural abnormalities in the corpus callosum (CC) and hippocampus, and functional alterations in hippocampal circuitry at ⩾P95 that were independent of the method of seizure induction and varied systematically as a function of age at the time of seizures. Three distinct epochs were observed in which seizures resulted in distinct long-term structural and functional outcomes at ⩾P95. Seizures prior to P20 resulted in DTI abnormalities in CC and hippocampus in the absence of gross cerebral atrophy, and increased paired-pulse inhibition (PPI) in the dentate gyrus (DG) at ⩾P95. Seizures after P30 induced a different pattern of DTI abnormalities in the fimbria and hippocampus accompanied by gross cerebral atrophy with increases in lateral ventricular volume, as well as increased PPI in the DG at ⩾P95. In contrast, seizures between P20 and P30 did not result in cerebral atrophy or significant imaging abnormalities in the hippocampus or white matter, but irreversibly decreased PPI in the DG compared to normal adult controls. These age-specific long-term structural and functional outcomes identify P20-30 as a potential critical period in hippocampal development defined by distinctive long-term structural and functional properties in adult hippocampal circuitry, including loss of capacity for seizure-induced plasticity in adulthood that could influence epileptogenesis and other hippocampal-dependent behaviors and functional properties.
• Bai, R., Koay, C. G., Basser, P. J., & Hutchinson, E. B. (2014). A framework for accurate determination of the T₂ distribution from multiple echo magnitude MRI images.. Journal of magnetic resonance (San Diego, Calif. : 1997), 244, 53-63. doi:10.1016/j.jmr.2014.04.016
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  Measurement of the T2 distribution in tissues provides biologically relevant information about normal and abnormal microstructure and organization. Typically, the T2 distribution is obtained by fitting the magnitude MR images acquired by a multi-echo MRI pulse sequence using an inverse Laplace transform (ILT) algorithm. It is well known that the ideal magnitude MR signal follows a Rician distribution. Unfortunately, studies attempting to establish the validity and efficacy of the ILT algorithm assume that these input signals are Gaussian distributed. Violation of the normality (or Gaussian) assumption introduces unexpected artifacts, including spurious cerebrospinal fluid (CSF)-like long T2 components; bias of the true geometric mean T2 values and in the relative fractions of various components; and blurring of nearby T2 peaks in the T2 distribution. Here we apply and extend our previously proposed magnitude signal transformation framework to map noisy Rician-distributed magnitude multi-echo MRI signals into Gaussian-distributed signals with high accuracy and precision. We then perform an ILT on the transformed data to obtain an accurate T2 distribution. Additionally, we demonstrate, by simulations and experiments, that this approach corrects the aforementioned artifacts in magnitude multi-echo MR images over a large range of signal-to-noise ratios.
• Hutchinson, E. B., Sobakin, A. S., Meyerand, M. E., Eldridge, M., & Ferrazzano, P. (2013). Diffusion tensor MRI of spinal decompression sickness. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc, 40(1), 23-31.
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  In order to develop more sensitive imaging tools for clinical use and basic research of spinal decompression sickness (DCS), we used diffusion tensor MRI (DTI) validated by histology to assess DCS-related tissue injury in sheep spinal cords. DTI is based on the measurement of water diffusion indices, including fractional anisotropy (FA) and mean diffusion (MD) to detect tissue microstructural abnormalities. In this study, we measured FA and MD in white and gray matter spinal cord regions in samples taken from sheep following hyperbaric exposure to 60-132 fsw and 0-180 minutes of oxygen pre-breathing treatment before rapid decompression. The main finding of the study was that decompression from >60 fsw resulted in reduced FA that was associated with cell death and disrupted tissue microstructure in spinal cord white matter tracts. Additionally, animals exposed to prolonged oxygen pre-breathing prior to decompression demonstrated reduced MD in spinal cord gray matter regions regardless of dive depth. To our knowledge, this is the first study to demonstrate the utility of DTI for the investigation of DCS-related injury and to define DTI biomarkers of spinal DCS.
• Hutchinson, E. B., Rutecki, P. A., Alexander, A. L., & Sutula, T. P. (2012). Fisher statistics for analysis of diffusion tensor directional information. Journal of neuroscience methods, 206(1), 40-5.
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  A statistical approach is presented for the quantitative analysis of diffusion tensor imaging (DTI) directional information using Fisher statistics, which were originally developed for the analysis of vectors in the field of paleomagnetism. In this framework, descriptive and inferential statistics have been formulated based on the Fisher probability density function, a spherical analogue of the normal distribution. The Fisher approach was evaluated for investigation of rat brain DTI maps to characterize tissue orientation in the corpus callosum, fornix, and hilus of the dorsal hippocampal dentate gyrus, and to compare directional properties in these regions following status epilepticus (SE) or traumatic brain injury (TBI) with values in healthy brains. Direction vectors were determined for each region of interest (ROI) for each brain sample and Fisher statistics were applied to calculate the mean direction vector and variance parameters in the corpus callosum, fornix, and dentate gyrus of normal rats and rats that experienced TBI or SE. Hypothesis testing was performed by calculation of Watson's F-statistic and associated p-value giving the likelihood that grouped observations were from the same directional distribution. In the fornix and midline corpus callosum, no directional differences were detected between groups, however in the hilus, significant (p
• Hutchinson, E. B., Sutula, T. P., Alexander, A. L., & Rutecki, P. (2012). Fisher statistics for analysis of diffusion tensor directional information. Journal of Neuroscience Methods. doi:10.1016/j.jneumeth.2012.02.004
• Cengiz, P., Uluc, K., Kendigelen, P., Akture, E., Song, C., Zhang, L., Lee, J., Budoff, G. E., Meyerand, E., Sun, D., Ferrazzano, P., & Hutchinson, E. B. (2011). Chronic neurological deficits in mice after perinatal hypoxia and ischemia correlate with hemispheric tissue loss and white matter injury detected by MRI.. Developmental neuroscience, 33(3-4), 270-9. doi:10.1159/000328430
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  We investigated the effects of perinatal hypoxia-ischemia (HI) on brain injury and neurological functional outcome at postnatal day (P)30 through P90. HI was induced by exposing P9 mice to 8% O(2) for 55 min using the Vannucci HI model. Following HI, mice were treated with either vehicle control or Na(+)/H(+) exchanger isoform 1 (NHE1) inhibitor HOE 642. The animals were examined by the accelerating rotarod test at P30 and the Morris water maze (MWM) test at P60. T(2)-weighted MRI was conducted at P90. Diffusion tensor imaging (DTI) was subsequently performed in ex vivo brains, followed by immunohistochemical staining for changes in myelin basic protein (MBP) and neurofilament protein expression in the corpus callosum (CC). Animals at P30 after HI showed deficits in motor and spatial learning. T(2) MRI detected a wide spectrum of brain injury in these animals. A positive linear correlation was observed between learning deficits and the degree of tissue loss in the ipsilateral hemisphere and hippocampus. Additionally, CC DTI fractional anisotropy (FA) values correlated with MBP expression. Both FA and MBP values correlated with performance on the MWM test. HOE 642-treated mice exhibited improved spatial learning and memory, and less white matter injury in the CC. These findings suggest that HI-induced cerebral atrophy and CC injury contribute to the development of deficits in learning and memory, and that inhibition of NHE1 is neuroprotective in part by reducing white matter injury. T(2)-weighted MRI and DTI are useful indicators of functional outcome after perinatal HI.
• Hutchinson, E., Pulsipher, D., Dabbs, K., Myers y Gutierrez, A., Sheth, R., Jones, J., Seidenberg, M., Meyerand, E., & Hermann, B. (2010). Children with new-onset epilepsy exhibit diffusion abnormalities in cerebral white matter in the absence of volumetric differences. Epilepsy research, 88(2-3), 208-14.
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  The purpose of this investigation was to examine the diffusion properties of cerebral white matter in children with recent onset epilepsy (n=19) compared to healthy controls (n=11). Subjects underwent DTI with quantification of mean diffusion (MD), fractional anisotropy (FA), axial diffusivity (D(ax)) and radial diffusivity (D(rad)) for regions of interest including anterior and posterior corpus callosum, fornix, cingulum, and internal and external capsules. Quantitative volumetrics were also performed for the corpus callosum and its subregions (anterior, midbody and posterior) and total lobar white and gray matter for the frontal, parietal, temporal and occipital lobes. The results demonstrated no group differences in total lobar gray or white matter volumes or volume of the corpus callosum and its subregions, but did show reduced FA and increased D(rad) in the posterior corpus callosum and cingulum. These results provide the earliest indication of microstructural abnormality in cerebral white matter among children with idiopathic epilepsies. This abnormality occurs in the context of normal volumetrics and suggests disruption in myelination processes.
• Hutchinson, E. B., & Kelley, D. J. (2008). Diffusion tensor imaging of cortical surface development. The Journal of neuroscience : the official journal of the Society for Neuroscience, 28(19), 4846-7.
• Stefanovic, B., Hutchinson, E., Yakovleva, V., Schram, V., Russell, J. T., Belluscio, L., Koretsky, A. P., & Silva, A. C. (2008). Functional reactivity of cerebral capillaries. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 28(5), 961-72.
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  The spatiotemporal evolution of cerebral microcirculatory adjustments to functional brain stimulation is the fundamental determinant of the functional specificity of hemodynamically weighted neuroimaging signals. Very little data, however, exist on the functional reactivity of capillaries, the vessels most proximal to the activated neuronal population. Here, we used two-photon laser scanning microscopy, in combination with intracranial electrophysiology and intravital video microscopy, to explore the changes in cortical hemodynamics, at the level of individual capillaries, in response to steady-state forepaw stimulation in an anesthetized rodent model. Overall, the microcirculatory response to functional stimulation was characterized by a pronounced decrease in vascular transit times (20%+/-8%), a dilatation of the capillary bed (10.9%+/-1.2%), and significant increases in red blood cell speed (33.0%+/-7.7%) and flux (19.5%+/-6.2%). Capillaries dilated more than the medium-caliber vessels, indicating a decreased heterogeneity in vessel volumes and increased blood flow-carrying capacity during neuronal activation relative to baseline. Capillary dilatation accounted for an estimated approximately 18% of the total change in the focal cerebral blood volume. In support of a capacity for focal redistribution of microvascular flow and volume, significant, though less frequent, local stimulation-induced decreases in capillary volume and erythrocyte speed and flux also occurred. The present findings provide further evidence of a strong functional reactivity of cerebral capillaries and underscore the importance of changes in the capillary geometry in the hemodynamic response to neuronal activation.
• Hutchinson, E. B., Pan, X., Zurbuchen, M. A., Liu, Y. W., Schiffer, P., Rosario, M. M., Sheu, B. L., Schlom, D. G., Haeni, J. H., & Tian, W. (2007). Epitaxial growth and magnetic properties of the first five members of the layered Srn+1RunO3n+1 oxide series. Applied Physics Letters. doi:10.1063/1.2430941
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  Epitaxial thin films of the n=1–5 members of the layered Srn+1RunO3n+1 oxide series were produced by reactive molecular-beam epitaxy. X-ray diffraction and high-resolution transmission electron microscopy confirm that these films are epitaxially oriented and nearly phase pure (>98%). The Sr2RuO4 (n=1) and Sr3Ru2O7 (n=2) samples show no ferromagnetic transition in the range from 5to300K, while the Sr4Ru3O10 (n=3), Sr5Ru4O13 (n=4), and Sr6Ru5O16 (n=5) samples show ferromagnetic transitions at 85, 95, and 130K, respectively.
• Hutchinson, E. B., Stefanovic, B., Koretsky, A. P., & Silva, A. C. (2006). Spatial flow-volume dissociation of the cerebral microcirculatory response to mild hypercapnia. NeuroImage, 32(2), 520-30.
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  The spatial and temporal response of the cerebral microcirculation to mild hypercapnia was investigated via two-photon laser-scanning microscopy. Cortical vessels, traversing the top 200 microm of somatosensory cortex, were visualized in alpha-chloralose-anesthetized Sprague-Dawley rats equipped with a cranial window. Intraluminal vessel diameters, transit times of fluorescent dextrans and red blood cells (RBC) velocities in individual capillaries were measured under normocapnic (PaCO2= 32.6 +/- 2.6 mm Hg) and slightly hypercapnic (PaCO2= 45 +/- 7 mm Hg) conditions. This gentle increase in PaCO2 was sufficient to produce robust and significant increases in both arterial and venous vessel diameters, concomitant to decreases in transit times of a bolus of dye from artery to venule (14%, P < 0.05) and from artery to vein (27%, P < 0.05). On the whole, capillaries exhibited a significant increase in diameter (16 +/- 33%, P < 0.001, n = 393) and a substantial increase in RBC velocities (75 +/- 114%, P < 0.001, n = 46) with hypercapnia. However, the response of the cerebral microvasculature to modest increases in PaCO2 was spatially heterogeneous. The maximal relative dilatation (range: 5-77%; mean +/- SD: 25 +/- 34%, P < 0.001, n = 271) occurred in the smallest capillaries (1.6 microm-4.0 microm resting diameter), while medium and larger capillaries (4.4 microm-6.8 microm resting diameter) showed no significant changes in diameter (P > 0.08, n = 122). In contrast, on average, RBC velocities increased less in the smaller capillaries (39 +/- 5%, P < 0.002, n = 22) than in the medium and larger capillaries (107 +/- 142%, P < 0.003, n = 24). Thus, the changes in capillary RBC velocities were spatially distinct from the observed volumetric changes and occurred to homogenize cerebral blood flow along capillaries of all diameters.
• Hutchinson, E. B., Mallouk, T. E., Amma, A., Liu, Y. W., Rosario, M. M., Bell, L., Tian, M., Wang, J., & Wang, H. (2004). Metallic contacts with individual Ru nanowires prepared by electrochemical deposition and the suppression of superconductivity in ultrasmall Ru grains. Applied Physics Letters. doi:10.1063/1.1763982

Proceedings Publications

• Dieckhaus, L. A., Comrie, C. J., McDermott, K. E., Gray, D. T., Barnes, C. A., & Hutchinson, E. B. (2022, May). Beyond Fractional Anisotropy: A Comparative Study of Myelin Water Fraction and Propagator Anisotropy in the Bonnet Macaque Brain. In International Society for Magnetic Resonance in Medicine.
• Bilgin, A., Do, L., Martin, P. A., Lockhart, E., Bernstein, A. S., Ugonna, C., Dieckhaus, L., Comrie, C., Hutchinson, E. B., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2021). Accelerating Diffusion Tensor Imaging of the Rat Brain using Deep Learning. In Annual Meeting of the International Society for Magnetic Resonance in Medicine.
• Dieckhaus, L. A., McDermott, K. E., Gray, D. T., Hutchinson, E. B., & Barnes, C. A. (2021, Fall). MRI micro- and macrostructural biomarkers linked to nonpathological brain aging in macaques. In Society for Neuroscience.
• Galons, J., Harkins, K., Does, M., Trouard, T. P., & Hutchinson, E. B. (2020, April). Quantitative myelin imaging in the ferret brain for traumatic brain injury research. In International Society for Magnetic Resonance in Medicine.
• Hutchinson, E. B., Gangoli, M., McKee, A., Kim, J., Pajevic, S., & Basser, P. J. (2020, April). Correspondence of diffusion tensor and propagator metrics with quantitative histologic outcomes in chronic traumatic encephalopathy. In International Society for Magnetic Resonance in Medicine.
• Kamali, A., Dieckhaus, L. A., Peters, E., Hutchinson, E. B., Laksari, K., & Pires, P. (2021, Oct.). The Golden Hour: Early outcomes of traumatic brain injury and stroke. In Biomedical Engineering Society.
• Jenkins, J., Chang, L., Irfanoglu, M. O., Pierpaoli, C., & Hutchinson, E. B. (2016). Harmonization of methods to facilitate reproducibility in medical data processing: Applications to diffusion tensor magnetic resonance imaging. In 2016 IEEE International Conference on Big Data (Big Data), 3992-3994.
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  Data and methodology sharing is essential for progression of scientific research. Several research groups have built tools for medical big data (MBD) processing applicable to Diffusion Tensor MRI (DTI) processing pipelines. In this paper, we propose a framework enabling methodology sharing (i.e. harmonization) to facilitate the reproducibility in DTI processing.

Presentations

• Hutchinson, E. B. (2021, Fall). Microstructural MRI validation and translational studies to improve detection of neuropathology following brain injury. BrainMap SeminarMartinos Center, MGH.
• Hutchinson, E. B., Pires, P., & Witte, R. S. (2021, Feb.). Mouse Brain Photoacoustic Imaging to Detect Hyper-Acute Pathophysiology Following Traumatic Brain Injury, Ischemia and Hemorrhage.. VisualSonics Live Imaging Workshop: “From Brain to Belly”VisualSonics.