Dr. Michael Zeineh received a B.S. in Biology at Caltech in 1995 and obtained his M.D.-Ph.D. from UCLA in 2003. After internship also at UCLA, he went on to radiology residency and neuroradiology fellowship both at Stanford. He has been faculty in Stanford Neuroradiology since 2010. He spearheads many initiatives in advanced clinical imaging at Stanford, including clinical fMRI and DTI. Simultaneously, he runs a lab with the goal of discovering new imaging abnormalities in neurodegenerative disorders, with a focus on detailed microcircuitry in regions such as the hippocampal formation using advanced, multi-modal in vivo and ex vivo methods, with applications to neurodegenerative disorders such as Alzheimer’s disease and mild traumatic brain injury.

Clinical Focus

  • Clinical Functional MRI
  • Clinical Diffusion Tensor Imaging
  • Diagnostic Neuroimaging

Academic Appointments

Honors & Awards

  • Clinical Scientist Development Award, Doris Duke Charitable Foundation (7/1/15-6/30/18)
  • Research Scholar Award, RSNA (7/1/13-6/30/16)
  • ISMRM Clinical Stipend, International Society for Magnetic Resonance in Medicine (2013)
  • ISMRM Clinical Stipend, International Society for Magnetic Resonance in Medicine (2012)
  • ISMRM Clinical Stipend, International Society for Magnetic Resonance in Medicine (2011)
  • ISMRM Travel Award, International Society for Magnetic Resonance in Medicine (2010)
  • Emil Bogen Research Prize, UCLA (2003)
  • Western Student Medical Research Forum, Bertakis Speaker Award (2002)
  • Burroughs Wellcome Travel Award for Research in England, Burroughs Wellcome Fund (2001)
  • Human Brain Mapping Travel Award, Organization for Human Brain Mapping (2001)
  • Kavan Prize for Neuroscience, UCLA (2001)
  • Hortense Fischbaugh Pollack Scholarship, UCLA (2000)
  • NIMH NRSA MH12167 (Bookheimer PI) Project: Unfolding the Human Hippocampus with Functional MRI, National Institutes of Health (NIH) (1998-2000)
  • Merit Award/Scholarship, Caltech (1994-1995)
  • Summer Undergraduate Research Fellowship, Caltech (1994)
  • Merit Award/Scholarship, Caltech (1993-1994)
  • Barry M. Goldwater Scholarship, Servite High School (1993)
  • Tau Beta Pi, Caltech (1993)

Professional Education

  • Internship: UCLA GME Office (2004) CA
  • Medical Education: UCLA GME Office (2003) CA
  • Board Certification: American Board of Radiology, Neuroradiology (2011)
  • Fellowship: Stanford University - Fellowship (2009) CA
  • Board Certification: American Board of Radiology, Diagnostic Radiology (2008)
  • Residency: Stanford University - Fellowship (2008) CA

2023-24 Courses

Stanford Advisees

All Publications

  • Microstructural Alterations in Tract Development in College Football and Volleyball Players: A Longitudinal Diffusion MRI Study. Neurology Goubran, M., Mills, B. D., Georgiadis, M., Karimpoor, M., Mouchawar, N., Sami, S., Dennis, E. L., Akers, C., Mitchell, L., Boldt, B., Douglas, D., DiGiacomo, P. S., Rosenberg, J., Grant, G., Wintermark, M., Camarillo, D. B., Zeineh, M. 2023


    BACKGROUND AND OBJECTIVES: Repeated impacts in high-contact sports like American football can affect the brain's microstructure, which can be studied using diffusion MRI. Most imaging studies are cross-sectional, do not include low-contact players as controls, or lack advanced tract-specific microstructural metrics. We aimed to investigate longitudinal changes in high-contact collegiate athletes compared to low-contact controls using advanced diffusion MRI and automated fiber quantification.METHODS: We examined brain microstructure in high-contact (football) and low-contact (volleyball) collegiate athletes with up to 4 years of follow-up. Inclusion criteria included university and team enrollment. Exclusion criteria included history of neurosurgery, severe brain injury, major neurologic or substance abuse disorder. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of sub-concussive and concussive impacts, and associations between diffusion changes with clinical, behavioral, and sports-related measures.RESULTS: Forty-nine football and twenty-four volleyball players (271 total scans) were included. Football players had significantly divergent trajectories in multiple microstructural metrics and tracts. Longitudinal increases in fractional anisotropy and axonal water fraction, and decreases in radial/mean diffusivity and orientation dispersion index, were present in volleyball but absent in football players (all findings |T-statistic|> 3.5, p-value < .0001). This pattern was present in the callosum forceps minor, superior longitudinal fasciculus, thalamic radiation, and cingulum hippocampus. Longitudinal differences were more prominent and observed in more tracts in concussed football players (n=24, |T|> 3.6, p < .0001). An analysis of immediate-post concussion scans (n=12) demonstrated a transient localized increase in axial diffusivity, mean/radial kurtosis in the uncinate and cingulum hippocampus (|T| > 3.7, p < .0001). Finally, within football players, those with high position-based impact risk demonstrated increased intra-cellular volume fraction longitudinally (T = 3.6, p < .0001).DISCUSSION: The observed longitudinal changes seen in football, and especially concussed athletes, could reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, non-decreasing axonal dispersion. This prospective longitudinal study demonstrates divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and repeated sub-concussive impact-related alteration of white matter development in football athletes.

    View details for DOI 10.1212/WNL.0000000000207543

    View details for PubMedID 37479529

  • Longitudinal alterations of cerebral blood flow in high-contact sports. Annals of neurology Karimpoor, M., Georgiadis, M., Zhao, M. Y., Goubran, M., Moein Taghavi, H., Mills, B. D., Tran, D., Mouchawar, N., Sami, S., Wintermark, M., Grant, G., Camarillo, D. B., Moseley, M. E., Zaharchuk, G., Zeineh, M. M. 2023


    Repetitive head trauma is common in high-contact sports. Cerebral blood flow (CBF) can measure changes in brain perfusion that could indicate injury. Longitudinal studies with a control group are necessary to account for interindividual and developmental effects. We investigated whether exposure to head impacts causes longitudinal CBF changes.We prospectively studied 63 American football (high-contact cohort) and 34 volleyball (low-contact controls) male collegiate athletes, tracking CBF using 3D-pseudo-continuous arterial-spin-labeling (ASL) MRI for up to four years. Regional relative CBF (rCBF, normalized to cerebellar CBF) was computed after co-registering to T1-weighted images. A linear-mixed-effects model assessed the relationship of rCBF to sport, time, and their interaction. Within football players, we modeled rCBF against position-based head impact risk and baseline SCAT (Standardized Concussion Assessment Tool) score. Additionally, we evaluated early (1-5 days) and delayed (3-6 months) post-concussion rCBF changes (in-study concussion).Supratentorial gray matter rCBF declined in football compared to volleyball (sport-time interaction p=0.012), with a strong effect in the parietal lobe (p=0.002). Football players with higher position-based impact-risk had lower occipital rCBF over time (interaction p=0.005), while players with lower baseline SCAT score (worse performance) had relatively decreased rCBF in the cingulate-insula over time (interaction effect: p=0.007). Both cohorts showed a left-right rCBF asymmetry that decreased over time. Football players with an in-study concussion exhibited an early increase in occipital lobe rCBF (p=0.0166).These results suggest head impacts may result in an early increase in rCBF, but cumulatively a long-term decrease in rCBF. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ana.26718

    View details for PubMedID 37306544

  • Using light and X-ray scattering to untangle complex neuronal orientations and validate diffusion MRI. eLife Menzel, M., GraSSel, D., Rajkovic, I., Zeineh, M. M., Georgiadis, M. 2023; 12


    Disentangling human brain connectivity requires an accurate description of nerve fiber trajectories, unveiled via detailed mapping of axonal orientations. However, this is challenging because axons can cross one another on a micrometer scale. Diffusion magnetic resonance imaging (dMRI) can be used to infer axonal connectivity because it is sensitive to axonal alignment, but it has limited spatial resolution and specificity. Scattered light imaging (SLI) and small-angle X-ray scattering (SAXS) reveal axonal orientations with microscopic resolution and high specificity, respectively. Here, we apply both scattering techniques on the same samples and cross-validate them, laying the groundwork for ground-truth axonal orientation imaging and validating dMRI. We evaluate brain regions that include unidirectional and crossing fibers in human and vervet monkey brain sections. SLI and SAXS quantitatively agree regarding in-plane fiber orientations including crossings, while dMRI agrees in the majority of voxels with small discrepancies. We further use SAXS and dMRI to confirm theoretical predictions regarding SLI determination of through-plane fiber orientations. Scattered light and X-ray imaging can provide quantitative micrometer 3D fiber orientations with high resolution and specificity, facilitating detailed investigations of complex fiber architecture in the animal and human brain.

    View details for DOI 10.7554/eLife.84024

    View details for PubMedID 37166005

  • Imaging crossing fibers in mouse, pig, monkey, and human brain using small-angle X-ray scattering. Acta biomaterialia Georgiadis, M., Menzel, M., Reuter, J. A., Born, D., Kovacevich, S., Alvarez, D., Taghavi, H. M., Schroeter, A., Rudin, M., Gao, Z., Guizar-Sicairos, M., Weiss, T. M., Axer, M., Rajkovic, I., Zeineh, M. M. 2023


    Myelinated axons (nerve fibers) efficiently transmit signals throughout the brain via action potentials. Multiple methods that are sensitive to axon orientations, from microscopy to magnetic resonance imaging, aim to reconstruct the brain's structural connectome. As billions of nerve fibers traverse the brain with various possible geometries at each point, resolving fiber crossings is necessary to generate accurate structural connectivity maps. However, doing so with specificity is a challenging task because signals originating from oriented fibers can be influenced by brain (micro)structures unrelated to myelinated axons. X-ray scattering can specifically probe myelinated axons due to the periodicity of the myelin sheath, which yields distinct peaks in the scattering pattern. Here, we show that small-angle X-ray scattering (SAXS) can be used to detect myelinated, axon-specific fiber crossings. We first demonstrate the capability using strips of human corpus callosum to create artificial double- and triple-crossing fiber geometries, and we then apply the method in mouse, pig, vervet monkey, and human brains. We compare results to polarized light imaging (3D-PLI), tracer experiments, and to outputs from diffusion MRI that sometimes fails to detect crossings. Given its specificity, capability of 3-dimensional sampling and high resolution, SAXS could serve as a ground truth for validating fiber orientations derived using diffusion MRI as well as microscopy-based methods. STATEMENT OF SIGNIFICANCE: : To study how the nerve fibers in our brain are interconnected, scientists need to visualize their trajectories, which often cross one another. Here, we show the unique capacity of small-angle X-ray scattering (SAXS) to study these fiber crossings without use of labelling, taking advantage of SAXS's specificity to myelin - the insulating sheath that is wrapped around nerve fibers. We use SAXS to detect double and triple crossing fibers and unveil intricate crossings in mouse, pig, vervet monkey, and human brains. This non-destructive method can uncover complex fiber trajectories and validate other less specific imaging methods (e.g., MRI or microscopy), towards accurate mapping of neuronal connectivity in the animal and human brain.

    View details for DOI 10.1016/j.actbio.2023.04.029

    View details for PubMedID 37098400

  • Medial Temporal Lobe Anatomy. Neuroimaging clinics of North America van Staalduinen, E. K., Zeineh, M. M. 2022; 32 (3): 475-489


    The medial temporal lobe (MTL) is a complex anatomic region encompassing the hippocampal formation, parahippocampal region, and amygdaloid complex. To enable the reader to understand the well-studied regional anatomic relationships and cytoarchitecture that form the basis of functional connectivity, the authors have created a detailed yet approachable anatomic reference for clinicians and scientists, with special attention to MR imaging. They have focused primarily on the hippocampal formation, discussing its gross structural features, anatomic relationships, and subfield anatomy and further discuss hippocampal terminology and development, hippocampal connectivity, normal anatomic variants, clinically relevant disease processes, and automated hippocampal segmentation software.

    View details for DOI 10.1016/j.nic.2022.04.012

    View details for PubMedID 35843657

  • Iron and Alzheimer's Disease: From Pathology to Imaging. Frontiers in human neuroscience Tran, D., DiGiacomo, P., Born, D. E., Georgiadis, M., Zeineh, M. 2022; 16: 838692


    Alzheimer's disease (AD) is a debilitating brain disorder that afflicts millions worldwide with no effective treatment. Currently, AD progression has primarily been characterized by abnormal accumulations of beta-amyloid within plaques and phosphorylated tau within neurofibrillary tangles, giving rise to neurodegeneration due to synaptic and neuronal loss. While beta-amyloid and tau deposition are required for clinical diagnosis of AD, presence of such abnormalities does not tell the complete story, and the actual mechanisms behind neurodegeneration in AD progression are still not well understood. Support for abnormal iron accumulation playing a role in AD pathogenesis includes its presence in the early stages of the disease, its interactions with beta-amyloid and tau, and the important role it plays in AD related inflammation. In this review, we present the existing evidence of pathological iron accumulation in the human AD brain, as well as discuss the imaging tools and peripheral measures available to characterize iron accumulation and dysregulation in AD, which may help in developing iron-based biomarkers or therapeutic targets for the disease.

    View details for DOI 10.3389/fnhum.2022.838692

    View details for PubMedID 35911597

  • The Presence of the Temporal Horn Exacerbates the Vulnerability of Hippocampus During Head Impacts. Frontiers in bioengineering and biotechnology Zhou, Z., Li, X., Domel, A. G., Dennis, E. L., Georgiadis, M., Liu, Y., Raymond, S. J., Grant, G., Kleiven, S., Camarillo, D., Zeineh, M. 2022; 10: 754344


    Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.

    View details for DOI 10.3389/fbioe.2022.754344

    View details for PubMedID 35392406

  • Neuroradiologic Evaluation of MRI in High-Contact Sports. Frontiers in neurology McAllister, D., Akers, C., Boldt, B., Mitchell, L. A., Tranvinh, E., Douglas, D., Goubran, M., Rosenberg, J., Georgiadis, M., Karimpoor, M., DiGiacomo, P., Mouchawar, N., Grant, G., Camarillo, D., Wintermark, M., Zeineh, M. M. 2021; 12: 701948


    Background and Purpose: Athletes participating in high-contact sports experience repeated head trauma. Anatomical findings, such as a cavum septum pellucidum, prominent CSF spaces, and hippocampal volume reductions, have been observed in cases of mild traumatic brain injury. The extent to which these neuroanatomical findings are associated with high-contact sports is unknown. The purpose of this study was to determine whether there are subtle neuroanatomic differences between athletes participating in high-contact sports compared to low-contact athletic controls. Materials and Methods: We performed longitudinal structural brain MRI scans in 63 football (high-contact) and 34 volleyball (low-contact control) male collegiate athletes with up to 4 years of follow-up, evaluating a total of 315 MRI scans. Board-certified neuroradiologists performed semi-quantitative visual analysis of neuroanatomic findings, including: cavum septum pellucidum type and size, extent of perivascular spaces, prominence of CSF spaces, white matter hyperintensities, arterial spin labeling perfusion asymmetries, fractional anisotropy holes, and hippocampal size. Results: At baseline, cavum septum pellucidum length was greater in football compared to volleyball controls (p = 0.02). All other comparisons were statistically equivalent after multiple comparison correction. Within football at baseline, the following trends that did not survive multiple comparison correction were observed: more years of prior football exposure exhibited a trend toward more perivascular spaces (p = 0.03 uncorrected), and lower baseline Standardized Concussion Assessment Tool scores toward more perivascular spaces (p = 0.02 uncorrected) and a smaller right hippocampal size (p = 0.02 uncorrected). Conclusion: Head impacts in high-contact sport (football) athletes may be associated with increased cavum septum pellucidum length compared to low-contact sport (volleyball) athletic controls. Other investigated neuroradiology metrics were generally equivalent between sports.

    View details for DOI 10.3389/fneur.2021.701948

    View details for PubMedID 34456852

    View details for PubMedCentralID PMC8385770

  • Neuroradiologic Evaluation of MRI in High-Contact Sports FRONTIERS IN NEUROLOGY McAllister, D., Akers, C., Boldt, B., Mitchell, L. A., Tranvinh, E., Douglas, D., Goubran, M., Rosenberg, J., Georgiadis, M., Karimpoor, M., DiGiacomo, P., Mouchawar, N., Grant, G., Camarillo, D., Wintermark, M., Zeineh, M. M. 2021; 12
  • Nusinersen Treatment in Adults With Spinal Muscular Atrophy. Neurology. Clinical practice Duong, T., Wolford, C., McDermott, M. P., Macpherson, C. E., Pasternak, A., Glanzman, A. M., Martens, W. B., Kichula, E., Darras, B. T., De Vivo, D. C., Zolkipli-Cunningham, Z., Finkel, R. S., Zeineh, M., Wintermark, M., Sampson, J., Hagerman, K. A., Young, S. D., Day, J. W. 2021; 11 (3): e317-e327


    Objective: To determine changes in motor and respiratory function after treatment with nusinersen in adults with spinal muscular atrophy (SMA) during the first two years of commercial availability in the USA.Methods: Data were collected prospectively on adult (age >17 years at treatment initiation) SMA participants in the Pediatric Neuromuscular Clinical Research (PNCR) Network. Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation. Patient-reported experiences, safety laboratory tests and adverse events were monitored. The mean annual rate of change over time was determined for outcome measures using linear mixed effects models.Results: Forty-two adult SMA participants (mean age: 34 years, range 17-66) receiving nusinersen for a mean of 12.5 months (range 3-24 months) were assessed. Several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. Participants also reported qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes. All participants tolerated nusinersen with normal surveillance labs and no significant adverse events.Conclusions: Trends of improvement emerged in functional motor, patient-reported, and respiratory measures, suggesting nusinersen may be efficacious in adults with SMA. Larger well-controlled studies and additional outcome measures are needed to firmly establish the efficacy of nusinersen in adults with SMA.Classification of Evidence: This study provides Class IV evidence regarding nusinersen tolerability and efficacy based on reported side effects and pulmonary and physical therapy assessments in an adult SMA cohort.

    View details for DOI 10.1212/CPJ.0000000000001033

    View details for PubMedID 34476123

  • Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue. Nature communications Georgiadis, M., Schroeter, A., Gao, Z., Guizar-Sicairos, M., Liebi, M., Leuze, C., McNab, J. A., Balolia, A., Veraart, J., Ades-Aron, B., Kim, S., Shepherd, T., Lee, C. H., Walczak, P., Chodankar, S., DiGiacomo, P., David, G., Augath, M., Zerbi, V., Sommer, S., Rajkovic, I., Weiss, T., Bunk, O., Yang, L., Zhang, J., Novikov, D. S., Zeineh, M., Fieremans, E., Rudin, M. 2021; 12 (1): 2941


    Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.

    View details for DOI 10.1038/s41467-021-22719-7

    View details for PubMedID 34011929

  • Exploring valence states of abnormal mineral deposits in biological tissues using correlative microscopy and spectroscopy techniques: A case study on ferritin and iron deposits from Alzheimer's disease patients. Ultramicroscopy Zeng, Y., DiGiacomo, P. S., Madsen, S. J., Zeineh, M. M., Sinclair, R. 2021: 113254


    Abnormal accumulation of inorganic trace elements in a human brain, such as iron, zinc and aluminum, oftentimes manifested as deposits and accompanied by a chemical valence change, is pathologically relevant to various neurodegenerative diseases. In particular, Fe2+ has been hypothesized to produce free radicals that induce oxidative damage and eventually cause Alzheimer's disease (AD). However, traditional biomedical techniques, e.g. histology staining, are limited in studying the chemical composition and valence states of these inorganic deposits. We apply commonly used physical (phys-) science methods such as X-ray energy dispersive spectroscopy (EDS), focused-ion beam (FIB) and electron energy loss spectroscopy (EELS) in transmission electron microscopy in conjunction with magnetic resonance imaging (MRI), histology and optical microscopy (OM) to study the valence states of iron deposits in AD patients. Ferrous ions are found in all deposits in brain tissues from three AD patients, constituting 0.22-0.50 of the whole iron content in each specimen. Such phys-techniques are rarely used in medical science and have great potential to provide unique insight into biomedical problems.

    View details for DOI 10.1016/j.ultramic.2021.113254

    View details for PubMedID 33781589

  • Hippocampal subfield imaging and fractional anisotropy show parallel changes in Alzheimer's disease tau progression using simultaneous tau-PET/MRI at 3T. Alzheimer's & dementia (Amsterdam, Netherlands) Carlson, M. L., Toueg, T. N., Khalighi, M. M., Castillo, J., Shen, B., Azevedo, E. C., DiGiacomo, P., Mouchawar, N., Chau, G., Zaharchuk, G., James, M. L., Mormino, E. C., Zeineh, M. M. 2021; 13 (1): e12218


    Introduction: Alzheimer's disease (AD) is the most common form of dementia, characterized primarily by abnormal aggregation of two proteins, tau and amyloid beta. We assessed tau pathology and white matter connectivity changes in subfields of the hippocampus simultaneously in vivo in AD.Methods: Twenty-four subjects were scanned using simultaneous time-of-flight 18F-PI-2620 tau positron emission tomography/3-Tesla magnetic resonance imaging and automated segmentation.Results: We observed extensive tau elevation in the entorhinal/perirhinal regions, intermediate tau elevation in cornu ammonis 1/subiculum, and an absence of tau elevation in the dentate gyrus, relative to controls. Diffusion tensor imaging showed parahippocampal gyral fractional anisotropy was lower in AD and mild cognitive impairment compared to controls and strongly correlated with early tau accumulation in the entorhinal and perirhinal cortices.Discussion: This study demonstrates the potential for quantifiable patterns of 18F-PI2620 binding in hippocampus subfields, accompanied by diffusion and volume metrics, to be valuable markers of AD.

    View details for DOI 10.1002/dad2.12218

    View details for PubMedID 34337132

  • Comparison of diffusion MRI and CLARITY fiber orientation estimates in both gray and white matter regions of human and primate brain. NeuroImage Leuze, C., Goubran, M., Barakovic, M., Aswendt, M., Tian, Q., Hsueh, B., Crow, A., Weber, E. M., Steinberg, G. K., Zeineh, M., Plowey, E. D., Daducci, A., Innocenti, G., Thiran, J., Deisseroth, K., McNab, J. A. 2020; 228: 117692


    Diffusion MRI (dMRI) represents one of the few methods for mapping brain fiber orientations non-invasively. Unfortunately, dMRI fiber mapping is an indirect method that relies on inference from measured diffusion patterns. Comparing dMRI results with other modalities is a way to improve the interpretation of dMRI data and help advance dMRI technologies. Here, we present methods for comparing dMRI fiber orientation estimates with optical imaging of fluorescently labeled neurofilaments and vasculature in 3D human and primate brain tissue cuboids cleared using CLARITY. The recent advancements in tissue clearing provide a new opportunity to histologically map fibers projecting in 3D, which represents a captivating complement to dMRI measurements. In this work, we demonstrate the capability to directly compare dMRI and CLARITY in the same human brain tissue and assess multiple approaches for extracting fiber orientation estimates from CLARITY data. We estimate the three-dimensional neuronal fiber and vasculature orientations from neurofilament and vasculature stained CLARITY images by calculating the tertiary eigenvector of structure tensors. We then extend CLARITY orientation estimates to an orientation distribution function (ODF) formalism by summing multiple sub-voxel structure tensor orientation estimates. In a sample containing part of the human thalamus, there is a mean angular difference of 19o±15o between the primary eigenvectors of the dMRI tensors and the tertiary eigenvectors from the CLARITY neurofilament stain. We also demonstrate evidence that vascular compartments do not affect the dMRI orientation estimates by showing an apparent lack of correspondence (mean angular difference=49o±23o) between the orientation of the dMRI tensors and the structure tensors in the vasculature stained CLARITY images. In a macaque brain dataset, we examine how the CLARITY feature extraction depends on the chosen feature extraction parameters. By varying the volume of tissue over which the structure tensor estimates are derived, we show that orientation estimates are noisier with more spurious ODF peaks for sub-voxels below 30m3 and that, for our data, the optimal gray matter sub-voxel size is between 62.5m3 and 125m3. The example experiments presented here represent an important advancement towards robust multi-modal MRI-CLARITY comparisons.

    View details for DOI 10.1016/j.neuroimage.2020.117692

    View details for PubMedID 33385546

  • Correlative Microscopy to Localize and Characterize Iron Deposition in Alzheimer's Disease. Journal of Alzheimer's disease reports Madsen, S. J., DiGiacomo, P. S., Zeng, Y., Goubran, M., Chen, Y., Rutt, B. K., Born, D., Vogel, H., Sinclair, R., Zeineh, M. M. 2020; 4 (1): 525–36


    Background: Recent evidence suggests that the accumulation of iron, specifically ferrous Fe2+, may play a role in the development and progression of neurodegeneration in Alzheimer's disease (AD) through the production of oxidative stress.Objective: To localize and characterize iron deposition and oxidation state in AD, we analyzed human hippocampal autopsy samples from four subjects with advanced AD that have been previously characterized with correlative MRI-histology.Methods: We perform scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and electron energy loss spectroscopy (EELS) in the higher resolution transmission electron microscope on the surface and cross-sections of specific iron-rich regions of interest.Results: Specific previously analyzed regions were visualized using SEM and confirmed to be iron-rich deposits using EDS. Subsequent analysis using focused ion beam cross-sectioning and SEM characterized the iron deposition throughout the 3-D volumes, confirming the presence of iron throughout the deposits, and in two out of four specimens demonstrating colocalization with zinc. Analysis of traditional histology slides showed the analyzed deposits overlapped both with amyloid and tau deposition. Following higher resolution analysis of a single iron deposit using scanning transmission electron microscope (STEM), we demonstrated the potential of monochromated STEM-EELS to discern the relative oxidation state of iron within a deposit.Conclusion: These findings suggest that iron is present in the AD hippocampus and can be visualized and characterized using combined MRI and EM techniques. An altered relative oxidation state may suggest a direct link between iron and oxidative stress in AD. These methods thus could potentially measure an altered relative oxidation state that could suggest a direct link between iron and oxidative stress in AD. Furthermore, we have demonstrated the ability to analyze metal deposition alongside commonly used histological markers of AD pathology, paving the way for future insights into the molecular interactions between Abeta, tau, iron, and other putative metals, such as zinc.

    View details for DOI 10.3233/ADR-200234

    View details for PubMedID 33532700

  • COVID-19-induced anosmia associated with olfactory bulb atrophy. Neuroradiology Chiu, A., Fischbein, N., Wintermark, M., Zaharchuk, G., Yun, P. T., Zeineh, M. 2020


    As the global COVID-19 pandemic evolves, our knowledge of the respiratory and non-respiratory symptoms continues to grow. One such symptom, anosmia, may be a neurologic marker of coronavirus infection and the initial presentation of infected patients. Because this symptom is not routinely investigated by imaging, there is conflicting literature on neuroimaging abnormalities related to COVID-19-related anosmia. We present a novel case of COVID-19 anosmia with definitive olfactory bulb atrophy compared with pre-COVID imaging. The patient had prior MR imaging related to a history of prolactinoma that provided baseline volumes of her olfactory bulbs. After a positive diagnosis of COVID-19 and approximately 2 months duration of anosmia, an MRI was performed that showed clear interval olfactory bulb atrophy. This diagnostic finding is of prognostic importance and indicates that the olfactory entry point to the brain should be further investigated to improve our understanding of COVID infectious pathophysiology.

    View details for DOI 10.1007/s00234-020-02554-1

    View details for PubMedID 32930820

  • Simultaneous FDG-PET/MRI detects hippocampal subfield metabolic differences in AD/MCI. Scientific reports Carlson, M. L., DiGiacomo, P. S., Fan, A. P., Goubran, M., Khalighi, M. M., Chao, S. Z., Vasanawala, M., Wintermark, M., Mormino, E., Zaharchuk, G., James, M. L., Zeineh, M. M. 2020; 10 (1): 12064


    The medial temporal lobe is one of the most well-studied brain regions affected by Alzheimer's disease (AD). Although the spread of neurofibrillary pathology in the hippocampus throughout the progression of AD has been thoroughly characterized and staged using histology and other imaging techniques, it has not been precisely quantified in vivo at the subfield level using simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI). Here, we investigate alterations in metabolism and volume using [18F]fluoro-deoxyglucose (FDG) and simultaneous time-of-flight (TOF) PET/MRI with hippocampal subfield analysis of AD, mild cognitive impairment (MCI), and healthy subjects. We found significant structural and metabolic changes within the hippocampus that can be sensitively assessed at the subfield level in a small cohort. While no significant differences were found between groups for whole hippocampal SUVr values (p=0.166), we found a clear delineation in SUVr between groups in the dentate gyrus (p=0.009). Subfield analysis may be more sensitive for detecting pathological changes using PET-MRI in AD compared to global hippocampal assessment.

    View details for DOI 10.1038/s41598-020-69065-0

    View details for PubMedID 32694602

  • Deep Flow-Net for EPI Distortion Estimation. NeuroImage Zahneisen, B., Baeumler, K., Zaharchuk, G., Fleischmann, D., Zeineh, M. 2020: 116886


    INTRODUCTION: Geometric distortions along the phase encoding direction caused by off-resonant spins are a major issue in EPI based functional and diffusion imaging. The widely used blip up/down approach estimates the underlying distortion field from a pair of images with inverted phase encoding direction. Typically, iterative methods are used to find a solution to the ill-posed problem of finding the displacement field that maps up/down acquisitions onto each other. Here, we explore the use of a deep convolutional network to estimate the displacement map from a pair of input images.METHODS: We trained a deep convolutional U-net architecture that was previously used to estimate optic flow between moving images to learn to predict the distortion map from an input pair of distorted EPI acquisitions. During the training step, the network minimizes a loss function (similarity metric) that is calculated from corrected input image pairs. This approach does not require the explicit knowledge of the ground truth distortion map, which is difficult to get for real life data.RESULTS: We used data from a total of Ntrain=22 healthy subjects to train our network. A separate dataset of Ntest=12 patients including some with abnormal findings and unseen acquisition modes, e.g. LR-encoding, coronal orientation) was reserved for testing and evaluation purposes. We compared our results to FSL's topup function with default parameters that served as the gold standard. We found that our approach results in a correction accuracy that is virtually identical to the optimum found by an iterative search, but with reduced computational time.CONCLUSION: By using a deep convolutional network, we can reduce the processing time to a few seconds per volume, which is significantly faster than iterative approaches like FSL's topup which takes around 10min on the same machine (but using only 1 CPU). This facilitates the use of a blip up/down scheme for all diffusion-weighted acquisitions and potential real-time EPI distortion correction without sacrificing accuracy.

    View details for DOI 10.1016/j.neuroimage.2020.116886

    View details for PubMedID 32389728

  • Longitudinal alteration of cortical thickness and volume in high-impact sports. NeuroImage Mills, B. D., Goubran, M. n., Parivash, S. N., Dennis, E. L., Rezaii, P. n., Akers, C. n., Bian, W. n., Mitchell, L. A., Boldt, B. n., Douglas, D. n., Sami, S. n., Mouchawar, N. n., Wilson, E. W., DiGiacomo, P. n., Parekh, M. n., Do, H. n., Lopez, J. n., Rosenberg, J. n., Camarillo, D. n., Grant, G. n., Wintermark, M. n., Zeineh, M. n. 2020: 116864


    Collegiate football athletes are subject to repeated head impacts. The purpose of this study was to determine whether this exposure can lead to changes in brain structure. This prospective cohort study was conducted with up to 4 years of follow-up on 63 football (high-impact) and 34 volleyball (control) male collegiate athletes with a total of 315 MRI scans (after exclusions: football n=50, volleyball n= 24, total scans=273) using high-resolution structural imaging. Volumetric and cortical thickness estimates were derived using FreeSurfer 5.3's longitudinal pipeline. A linear mixed-effects model assessed the effect of group (football vs. volleyball), time from baseline MRI, and the interaction between group and time. We confirmed an expected developmental decrement in cortical thickness and volume in our cohort (p<0.001). Superimposed on this, total cortical gray matter volume (p = .03) and cortical thickness within the left hemisphere (p=.04) showed a group by time interaction, indicating less age-related volume reduction and thinning in football compared to volleyball athletes. At the regional level, sport by time interactions on thickness and volume were identified in the left orbitofrontal (p=.001), superior temporal (p=.001), and postcentral regions (p< .001). Additional cortical thickness interactions were found in the left temporal pole (p=.003) and cuneus (p=.005). At the regional level, we also found main effects of sport in football athletes characterized by reduced volume in the right hippocampus (p=.003), right superior parietal cortical gray (p<.001) and white matter (p<.001), and increased volume of the left pallidum (p=.002). Within football, cortical thickness was higher with greater years of prior play (left hemisphere p=.013, right hemisphere p=.005), and any history of concussion was associated with less cortical thinning (left hemisphere p=.010, right hemisphere p=.011). Additionally, both position-associated concussion risk (p=.002) and SCAT scores (p=.023) were associated with less of the expected volume decrement of deep gray structures. This prospective longitudinal study comparing football and volleyball athletes shows divergent age-related trajectories of cortical thinning, possibly reflecting an impact-related alteration of normal cortical development. This warrants future research into the underlying mechanisms of impacts to the head on cortical maturation.

    View details for DOI 10.1016/j.neuroimage.2020.116864

    View details for PubMedID 32360690

  • Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases. European journal of nuclear medicine and molecular imaging Mormino, E. C., Toueg, T. N., Azevedo, C. n., Castillo, J. B., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hall, J. N., Fan, A. n., Trelle, A. N., Harrison, M. B., Hunt, M. P., Sha, S. J., Deutsch, G. n., James, M. n., Fredericks, C. A., Koran, M. E., Zeineh, M. n., Poston, K. n., Greicius, M. D., Khalighi, M. n., Davidzon, G. A., Shen, B. n., Zaharchuk, G. n., Wagner, A. D., Chin, F. T. 2020


    In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD).Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient.Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

    View details for DOI 10.1007/s00259-020-04923-7

    View details for PubMedID 32572562

  • A within-coil optical prospective motion-correction system for brain imaging at 7T. Magnetic resonance in medicine DiGiacomo, P. n., Maclaren, J. n., Aksoy, M. n., Tong, E. n., Carlson, M. n., Lanzman, B. n., Hashmi, S. n., Watkins, R. n., Rosenberg, J. n., Burns, B. n., Skloss, T. W., Rettmann, D. n., Rutt, B. n., Bammer, R. n., Zeineh, M. n. 2020


    Motion artifact limits the clinical translation of high-field MR. We present an optical prospective motion correction system for 7 Tesla MRI using a custom-built, within-coil camera to track an optical marker mounted on a subject.The camera was constructed to fit between the transmit-receive coils with direct line of sight to a forehead-mounted marker, improving upon prior mouthpiece work at 7 Tesla MRI. We validated the system by acquiring a 3D-IR-FSPGR on a phantom with deliberate motion applied. The same 3D-IR-FSPGR and a 2D gradient echo were then acquired on 7 volunteers, with/without deliberate motion and with/without motion correction. Three neuroradiologists blindly assessed image quality. In 1 subject, an ultrahigh-resolution 2D gradient echo with 4 averages was acquired with motion correction. Four single-average acquisitions were then acquired serially, with the subject allowed to move between acquisitions. A fifth single-average 2D gradient echo was acquired following subject removal and reentry.In both the phantom and human subjects, deliberate and involuntary motion were well corrected. Despite marked levels of motion, high-quality images were produced without spurious artifacts. The quantitative ratings confirmed significant improvements in image quality in the absence and presence of deliberate motion across both acquisitions (P < .001). The system enabled ultrahigh-resolution visualization of the hippocampus during a long scan and robust alignment of serially acquired scans with interspersed movement.We demonstrate the use of a within-coil camera to perform optical prospective motion correction and ultrahigh-resolution imaging at 7 Tesla MRI. The setup does not require a mouthpiece, which could improve accessibility of motion correction during 7 Tesla MRI exams.

    View details for DOI 10.1002/mrm.28211

    View details for PubMedID 32077521

  • Lateral impacts correlate with falx cerebri displacement and corpus callosum trauma in sports-related concussions. Biomechanics and modeling in mechanobiology Hernandez, F., Giordano, C., Goubran, M., Parivash, S., Grant, G., Zeineh, M., Camarillo, D. 2019


    Corpus callosum trauma has long been implicated in mild traumatic brain injury (mTBI), yet the mechanism by which forces penetrate this structure is unknown. We investigated the hypothesis that coronal and horizontal rotations produce motion of the falx cerebri that damages the corpus callosum. We analyzed previously published head kinematics of 115 sports impacts (2 diagnosed mTBI) measured with instrumented mouthguards and used finite element (FE) simulations to correlate falx displacement with corpus callosum deformation. Peak coronal accelerations were larger in impacts with mTBI (8592rad/s2avg.) than those without (1412rad/s2avg.). From FE simulations, coronal acceleration was strongly correlated with deep lateral motion of the falx center (r=0.85), while horizontal acceleration was correlated with deep lateral motion of the falx periphery (r>0.78). Larger lateral displacement at the falx center and periphery was correlated with higher tract-oriented strains in the corpus callosum body (r=0.91) and genu/splenium (r>0.72), respectively. The relationship between the corpus callosum and falx was unique: removing the falx from the FE model halved peak strains in the corpus callosum from 35% to 17%. Consistent with model results, we found indications of corpus callosum trauma in diffusion tensor imaging of the mTBI athletes. For a measured alteration of consciousness, depressed fractional anisotropy and increased mean diffusivity indicated possible damage to the mid-posterior corpus callosum. Our results suggest that the corpus callosum may be sensitive to coronal and horizontal rotations because they drive lateral motion of a relatively stiff membrane, the falx, in the direction of commissural fibers below.

    View details for PubMedID 30859404

  • Multimodal image registration and connectivity analysis for integration of connectomic data from microscopy to MRI. Nature communications Goubran, M. n., Leuze, C. n., Hsueh, B. n., Aswendt, M. n., Ye, L. n., Tian, Q. n., Cheng, M. Y., Crow, A. n., Steinberg, G. K., McNab, J. A., Deisseroth, K. n., Zeineh, M. n. 2019; 10 (1): 5504


    3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders.

    View details for DOI 10.1038/s41467-019-13374-0

    View details for PubMedID 31796741

  • Longitudinal changes in hippocampal subfield volume associated with collegiate football. Journal of neurotrauma Parivash, S. N., Goubran, M. n., Mills, B. D., Rezaii, P. n., Thaler, C. n., Wolman, D. n., Bian, W. n., Mitchell, L. A., Boldt, B. n., Douglas, D. n., Wilson, E. n., Choi, J. n., Xie, L. n., Yushkevich, P. n., Digiacomo, P. n., Wongsripuemtet, J. n., Parekh, M. n., Fiehler, J. n., Do, H. n., Lopez, J. n., Rosenerg, J. n., Camarillo, D. B., Grant, G. n., Wintermark, M. n., Zeineh, M. n. 2019


    Collegiate football athletes are subject to repeated head impacts that may cause brain injury. The hippocampus is composed of several distinct subfields with possible differential susceptibility to injury. The purpose of this study is to determine whether there are longitudinal changes in hippocampal subfield volume in collegiate football. A prospective cohort study was conducted over a 5-year period tracking 63 football and 34 volleyball male collegiate athletes. Athletes underwent high-resolution structural magnetic resonance imaging, and automated segmentation provided hippocampal subfield volumes. At baseline, football athletes demonstrated a smaller subiculum volume than volleyball athletes (-67.77 mm3, P=.012). A regression analysis performed within football athletes similarly demonstrated a smaller subiculum volume among those at increased concussion risk based on athlete position (P=.001). For the longitudinal analysis, a linear mixed-effects model assessed the interaction between sport and time, revealing a significant decrease in CA1 volume in football athletes without an in-study concussion compared to volleyball athletes (volume difference per year=-35.22 mm3, P=.005). This decrease in CA1 volume over time was significant when football athletes were examined in isolation from volleyball athletes (P=.011). Thus, this prospective longitudinal study showed a decrease in CA1 volume over time in football athletes, in addition to baseline differences that were identified in the downstream subiculum. Hippocampal changes may have important implications for high-contact sports.

    View details for PubMedID 31044639

  • MR susceptibility contrast imaging using a 2D simultaneous multi-slice gradient-echo sequence at 7T. PloS one Bian, W., Kerr, A. B., Tranvinh, E., Parivash, S., Zahneisen, B., Han, M. H., Lock, C. B., Goubran, M., Zhu, K., Rutt, B. K., Zeineh, M. M. 2019; 14 (7): e0219705


    PURPOSE: To develop a 7T simultaneous multi-slice (SMS) 2D gradient-echo sequence for susceptibility contrast imaging, and to compare its quality to 3D imaging.METHODS: A frequency modulated and phase cycled RF pulse was designed to simultaneously excite multiple slices in multi-echo 2D gradient-echo imaging. The imaging parameters were chosen to generate images with susceptibility contrast, including T2*-weighted magnitude/phase images, susceptibility-weighted images and quantitative susceptibility/R2* maps. To compare their image quality with 3D gradient-echo imaging, both 2D and 3D imaging were performed on 11 healthy volunteers and 4 patients with multiple sclerosis (MS). The signal to noise ratio (SNR) in gray and white matter and their contrast to noise ratio (CNR) was simulated for the 2D and 3D magnitude images using parameters from the imaging. The experimental SNRs and CNRs were measured in gray/white matter and deep gray matter structures on magnitude, phase, R2* and QSM images from volunteers and the visibility of MS lesions on these images from patients was visually rated. All SNRs and CNRs were compared between the 2D and 3D imaging using a paired t-test.RESULTS: Although the 3D magnitude images still had significantly higher SNRs (by 13.0~17.6%), the 2D magnitude and QSM images generated significantly higher gray/white matter or globus pallidus/putamen contrast (by 13.3~87.5%) and significantly higher MS lesion contrast (by 5.9~17.3%).CONCLUSION: 2D SMS gradient-echo imaging can serve as an alternative to often used 3D imaging to obtain susceptibility-contrast-weighted images, with an advantage of providing better image contrast and MS lesion sensitivity.

    View details for DOI 10.1371/journal.pone.0219705

    View details for PubMedID 31314813

  • Neuroimaging Radiological Interpretation System for Acute Traumatic Brain Injury JOURNAL OF NEUROTRAUMA Wintermark, M., Li, Y., Ding, V. Y., Xu, Y., Jiang, B., Ball, R. L., Zeineh, M., Gean, A., Sanelli, P. 2018; 35 (22): 2665–72
  • Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor NEUROIMAGE-CLINICAL Tian, Q., Wintermark, M., Elias, W., Ghanouni, P., Halpern, C. H., Henderson, J. M., Huss, D. S., Goubran, M., Thaler, C., Airan, R., Zeineh, M., Pauly, K., McNab, J. A. 2018; 19: 572–80
  • Direct Visualization and Mapping of the Spatial Course of Fiber Tracts at Microscopic Resolution in the Human Hippocampus CEREBRAL CORTEX Zeineh, M. M., Palomero-Gallagher, N., Axer, M., Graessel, D., Goubran, M., Wree, A., Woods, R., Amunts, K., Zilles, K. 2017; 27 (3): 1779-1794


    While hippocampal connectivity is essential to normal memory function, our knowledge of human hippocampal circuitry is largely inferred from animal studies. Using polarized light microscopy at 1.3 µm resolution, we have directly visualized the 3D course of key medial temporal pathways in 3 ex vivo human hemispheres and 2 ex vivo vervet monkey hemispheres. The multiple components of the perforant path system were clearly identified: Superficial sheets of fibers emanating from the entorhinal cortex project to the presubiculum and parasubiculum, intermixed transverse and longitudinal angular bundle fibers perforate the subiculum and then project to the cornu ammonis (CA) fields and dentate molecular layer, and a significant alvear component runs from the angular bundle to the CA fields. From the hilus, mossy fibers localize to regions of high kainate receptor density, and the endfolial pathway, mostly investigated in humans, merges with the Schaffer collaterals. This work defines human hippocampal pathways underlying mnemonic function at an unprecedented resolution.

    View details for DOI 10.1093/cercor/bhw010

    View details for Web of Science ID 000397636600007

  • The "White Gray Sign" Identifies the Central Sulcus on 3T High-Resolution T1-Weighted Images AMERICAN JOURNAL OF NEURORADIOLOGY Kaneko, O. F., Fischbein, N. J., Rosenberg, J., Wintermark, M., Zeineh, M. M. 2017; 38 (2): 276-280


    The central sulcus is an important anatomic landmark, but most methods of identifying it rely on variable gyral and sulcal patterns. We describe and assess the accuracy of reduced gray-white contrast along the central sulcus, an observation we term the "white gray sign."We conducted a retrospective review of 51 fMRIs with a T1-weighted 3D inversion recovery fast-spoiled gradient-echo and concomitant hand-motor fMRI, which served as confirmation for the location of the central sulcus. To measure gray-white contrast across the central and adjacent sulci, we performed a quantitative analysis of 25 normal hemispheres along the anterior and posterior cortices and intervening white matter of the pre- and postcentral gyri. 3D inversion recovery fast-spoiled gradient-echo axial images from 51 fMRIs were then evaluated by 2 raters for the presence of the white gray sign as well as additional established signs of the central sulcus: the bracket, cortical thickness, omega, and T signs.The mean gray-white contrast along the central sulcus was 0.218 anteriorly and 0.237 posteriorly, compared with 0.320 and 0.295 along the posterior precentral and anterior postcentral sulci, respectively (P < .001). Both raters correctly identified the central sulcus in all 35 normal and 16 abnormal hemispheres. The white gray sign had the highest agreement of all signs between raters and was rated as present the most often among all the signs.Reduced gray-white contrast around the central sulcus is a reliable sign for identification of the central sulcus on 3D inversion recovery fast-spoiled gradient-echo images.

    View details for DOI 10.3174/ajnr.A5014

    View details for Web of Science ID 000393170100016

    View details for PubMedID 27932507

  • In Vivo 7T MR Quantitative Susceptibility Mapping Reveals Opposite Susceptibility Contrast between Cortical and White Matter Lesions in Multiple Sclerosis AMERICAN JOURNAL OF NEURORADIOLOGY Bian, W., Tranvinh, E., Tourdias, T., Han, M., Liu, T., Wang, Y., Rutt, B., Zeineh, M. M. 2016; 37 (10): 1808-1815


    Magnetic susceptibility measured with quantitative susceptibility mapping has been proposed as a biomarker for demyelination and inflammation in patients with MS, but investigations have mostly been on white matter lesions. A detailed characterization of cortical lesions has not been performed. The purpose of this study was to evaluate magnetic susceptibility in both cortical and WM lesions in MS by using quantitative susceptibility mapping.Fourteen patients with MS were scanned on a 7T MR imaging scanner with T1-, T2-, and T2*-weighted sequences. The T2*-weighted sequence was used to perform quantitative susceptibility mapping and generate tissue susceptibility maps. The susceptibility contrast of a lesion was quantified as the relative susceptibility between the lesion and its adjacent normal-appearing parenchyma. The susceptibility difference between cortical and WM lesions was assessed by using a t test.The mean relative susceptibility was significantly negative for cortical lesions (P < 10(-7)) but positive for WM lesions (P < 10(-22)). A similar pattern was also observed in the cortical (P = .054) and WM portions (P = .043) of mixed lesions.The negative susceptibility in cortical lesions suggests that iron loss dominates the susceptibility contrast in cortical lesions. The opposite susceptibility contrast between cortical and WM lesions may reflect both their structural (degree of myelination) and pathologic (degree of inflammation) differences, in which the latter may lead to a faster release of iron in cortical lesions.

    View details for DOI 10.3174/ajnr.A4830

    View details for Web of Science ID 000383984600014

    View details for PubMedID 27282860

  • Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease NEUROSURGICAL FOCUS Ali, R., Goubran, M., Choudhri, O., Zeineh, M. M. 2015; 39 (5)


    The goal of this paper was to review the effectiveness of using 7-T MRI to study neuroimaging biomarkers for Alzheimer's disease (AD). The authors reviewed the literature for articles published to date on the use of 7-T MRI to study AD. Thus far, there are 3 neuroimaging biomarkers for AD that have been studied using 7-T MRI in AD tissue: 1) neuroanatomical atrophy; 2) molecular characterization of hypointensities; and 3) microinfarcts. Seven-Tesla MRI has had mixed results when used to study the 3 aforementioned neuroimaging biomarkers for AD. First, in the detection of neuroanatomical atrophy, 7-T MRI has exciting potential. Historically, noninvasive imaging of neuroanatomical atrophy during AD has been limited by suboptimal resolution. However, now there is compelling evidence that the high resolution of 7-T MRI may help overcome this hurdle. Second, in detecting the characterization of hypointensities, 7-T MRI has had varied success. PET scans will most likely continue to lead in the noninvasive imaging of amyloid plaques; however, there is emerging evidence that 7-T MRI can accurately detect iron deposits within activated microglia, which may help shed light on the role of the immune system in AD pathogenesis. Finally, in the detection of microinfarcts, 7-T MRI may also play a promising role, which may help further elucidate the relationship between cerebrovascular health and AD progression.

    View details for DOI 10.3171/2015.9.FOCUS15326

    View details for Web of Science ID 000364508000004

  • Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiology of aging Zeineh, M. M., Chen, Y., Kitzler, H. H., Hammond, R., Vogel, H., Rutt, B. K. 2015; 36 (9): 2483-2500


    Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

    View details for DOI 10.1016/j.neurobiolaging.2015.05.022

    View details for PubMedID 26190634

  • Ultra-high resolution in-vivo 7.0 T structural imaging of the human hippocampus reveals the endfolial pathway NEUROIMAGE Parekh, M. B., Rutt, B. K., Purcell, R., Chen, Y., Zeineh, M. M. 2015; 112: 1-6


    The hippocampus is a very important structure in memory formation and retrieval, as well as in various neurological disorders such as Alzheimer's disease, epilepsy and depression. It is composed of many intricate subregions making it difficult to study the anatomical changes that take place during disease. The hippocampal hilus may have a unique neuroanatomy in humans compared to that in monkeys and rodents, with field CA3h greatly enlarged in humans compared to that in rodents, and a white-matter pathway, called the endfolial pathway, possibly only present in humans. In this study we have used newly developed 7.0T whole brain imaging sequence, balanced steady-state free precession (bSSFP) that can achieve 0.4mm isotropic images to study, in vivo, the anatomy of the hippocampal hilus. A detailed hippocampal subregional segmentation was performed according to anatomic atlases segmenting the following regions: CA4, CA3, CA2, CA1, SRLM (stratum radiatum lacunosum moleculare), alveus, fornix, and subiculum along with its molecular layer. We also segmented a hypointense structure centrally within the hilus that resembled the endfolial pathway. To validate that this hypointense signal represented the endfolial pathway, we acquired 0.1mm isotropic 8-phase cycle bSSFP on an excised specimen, and then sectioned and stained the specimen for myelin using an anti-myelin basic protein antibody (SMI 94). A structure tensor analysis was calculated on the myelin-stained section to show directionality of the underlying fibers. The endfolial pathway was consistently visualized within the hippocampal body in vivo in all subjects. It is a central pathway in the hippocampus, with unknown relevance in neurodegenerative disorders, but now that it can be visualized noninvasively, we can study its function and alterations in neurodegeneration.

    View details for DOI 10.1016/j.neuroimage.2015.02.029

    View details for Web of Science ID 000353203400001

    View details for PubMedID 25701699

  • Right arcuate fasciculus abnormality in chronic fatigue syndrome. Radiology Zeineh, M. M., Kang, J., Atlas, S. W., Raman, M. M., Reiss, A. L., Norris, J. L., Valencia, I., Montoya, J. G. 2015; 274 (2): 517-526


    Purpose To identify whether patients with chronic fatigue syndrome ( CFS chronic fatigue syndrome ) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms. Materials and Methods Fifteen patients with CFS chronic fatigue syndrome were identified by means of retrospective review with an institutional review board-approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging ( DTI diffusion-tensor imaging ) acquisitions and arterial spin labeling ( ASL arterial spin labeling ). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI diffusion-tensor imaging data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy ( FA fractional anisotropy ) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI diffusion-tensor imaging , FA fractional anisotropy was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL arterial spin labeling . Results In the CFS chronic fatigue syndrome population, FA fractional anisotropy was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA fractional anisotropy was also increased in the right inferior longitudinal fasciculus ( ILF inferior longitudinal fasciculus ) (P = .0008). In patients with CFS chronic fatigue syndrome , right anterior arcuate FA fractional anisotropy increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS chronic fatigue syndrome (mean ± standard deviation, 467 581 mm(3) ± 47 610 for patients vs 504 864 mm(3) ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF inferior longitudinal fasciculus end point, the occipital lobe (T = 5.36). ASL arterial spin labeling showed no significant differences. Conclusion Bilateral white matter atrophy is present in CFS chronic fatigue syndrome . No differences in perfusion were noted. Right hemispheric increased FA fractional anisotropy may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA fractional anisotropy may serve as a biomarker for CFS chronic fatigue syndrome . © RSNA, 2014 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.14141079

    View details for PubMedID 25353054

  • Ultrahigh-resolution imaging of the human brain with phase-cycled balanced steady-state free precession at 7 T. Investigative radiology Zeineh, M. M., Parekh, M. B., Zaharchuk, G., Su, J. H., Rosenberg, J., Fischbein, N. J., Rutt, B. K. 2014; 49 (5): 278-289


    The objectives of this study were to acquire ultra-high resolution images of the brain using balanced steady-state free precession (bSSFP) at 7.0 T and to identify the potential utility of this sequence.Eight volunteers participated in this study after providing informed consent. Each volunteer was scanned with 8 phase cycles of bSSFP at 0.4-mm isotropic resolution using 0.5 number of excitations and 2-dimensional parallel acceleration of 1.75 × 1.75. Each phase cycle required 5 minutes of scanning, with pauses between the phase cycles allowing short periods of rest. The individual phase cycles were aligned and then averaged. The same volunteers underwent scanning using 3-dimensional (3D) multiecho gradient recalled echo at 0.8-mm isotropic resolution, 3D Cube T2 at 0.7-mm isotropic resolution, and thin-section coronal oblique T2-weighted fast spin echo at 0.22 × 0.22 × 2.0-mm resolution for comparison. Two neuroradiologists assessed image quality and potential research and clinical utility.The volunteers generally tolerated the scan sessions well, and composite high-resolution bSSFP images were produced for each volunteer. Rater analysis demonstrated that bSSFP had a superior 3D visualization of the microarchitecture of the hippocampus, very good contrast to delineate the borders of the subthalamic nucleus, and relatively good B1 homogeneity throughout. In addition to an excellent visualization of the cerebellum, subtle details of the brain and skull base anatomy were also easier to identify on the bSSFP images, including the line of Gennari, membrane of Liliequist, and cranial nerves. Balanced steady-state free precession had a strong iron contrast similar to or better than the comparison sequences. However, cortical gray-white contrast was significantly better with Cube T2 and T2-weighted fast spin echo.Balanced steady-state free precession can facilitate ultrahigh-resolution imaging of the brain. Although total imaging times are long, the individually short phase cycles can be acquired separately, improving examination tolerability. These images may be beneficial for studies of the hippocampus, iron-containing structures such as the subthalamic nucleus and line of Gennari, and the basal cisterns and their contents.

    View details for DOI 10.1097/RLI.0000000000000015

    View details for PubMedID 24473366

  • Ultra-high resolution diffusion tensor imaging of the microscopic pathways of the medial temporal lobe NEUROIMAGE Zeineh, M. M., Holdsworth, S., Skare, S., Atlas, S. W., Bammer, R. 2012; 62 (3): 2065-2082


    Diseases involving the medial temporal lobes (MTL) such as Alzheimer's disease and mesial temporal sclerosis pose an ongoing diagnostic challenge because of the difficulty in identifying conclusive imaging features, particularly in pre-clinical states. Abnormal neuronal connectivity may be present in the circuitry of the MTL, but current techniques cannot reliably detect those abnormalities. Diffusion tensor imaging (DTI) has shown promise in defining putative abnormalities in connectivity, but DTI studies of the MTL performed to date have shown neither dramatic nor consistent differences across patient populations. Conventional DTI methodology provides an inadequate depiction of the complex microanatomy present in the medial temporal lobe because of a typically employed low isotropic resolution of 2.0-2.5 mm, a low signal-to-noise ratio (SNR), and echo-planar imaging (EPI) geometric distortions that are exacerbated by the inhomogeneous magnetic environment at the skull base. In this study, we pushed the resolving power of DTI to near-mm isotropic voxel size to achieve a detailed depiction of mesial temporal microstructure at 3 T. High image fidelity and SNR at this resolution are achieved through several mechanisms: (1) acquiring multiple repetitions of the minimum field of view required for hippocampal coverage to boost SNR; (2) utilizing a single-refocused diffusion preparation to enhance SNR further; (3) performing a phase correction to reduce Rician noise; (4) minimizing distortion and maintaining left-right distortion symmetry with axial-plane parallel imaging; and (5) retaining anatomical and quantitative accuracy through the use of motion correction coupled with a higher-order eddy-current correction scheme. We combined this high-resolution methodology with a detailed segmentation of the MTL to identify tracks in all subjects that may represent the major pathways of the MTL, including the perforant pathway. Tractography performed on a subset of the data identified similar tracks, although they were lesser in number. This detailed analysis of MTL substructure may have applications to clinical populations.

    View details for DOI 10.1016/j.neuroimage.2012.05.065

    View details for Web of Science ID 000307369000073

    View details for PubMedID 22677150

  • Advances in high-resolution imaging and computational unfolding of the human hippocampus NEUROIMAGE Ekstrom, A. D., Bazih, A. J., Suthana, N. A., Al-Hakim, R., Ogura, K., Zeineh, M., Burggren, A. C., Bookheimer, S. Y. 2009; 47 (1): 42-49


    The hippocampus is often a difficult structure to visualize with magnetic resonance imaging (MRI) and functional MRI (fMRI) due to its convoluted nature and susceptibility to signal dropout. Improving our ability to pinpoint changes in neural activity using fMRI in this structure remains an important challenge. Current fMRI/MRI methods typically do not permit visualization of the hippocampus and surrounding cortex at a resolution less than 1 mm. We present here improvements to our previous methods for obtaining structural MR images of the hippocampus, which provided an in-plane resolution of 0.4 mm(2) mm and two-dimensional "flat" maps of the hippocampus with an interpolated isotropic resolution of 0.4 mm(3) (Engel, S.A., Glover, G.H., and Wandell, B.A., (1997). Retinotopic organization in human visual cortex and the spatial precision of functional MRI. Cereb. Cortex 7, 181-192.; Zeineh, M.M., Engel, S.A., and Bookheimer, S.Y., (2000). Application of cortical unfolding techniques to functional MRI of the human hippocampal region. NeuroImage 11, 668-683.). We present changes to existing structural imaging sequences that now augment the resolution of previous scans, permitting visualization of the anterior portion of CA1, parts of the dentate gyrus, and CA23. These imaging improvements are of relevance generally to the field of imaging because they permit higher overall resolution imaging of the hippocampus than previously possible (at 3 T). We also introduce a novel application of a computational interpolation method that improves our ability to capture the convoluted three-dimensional shape of the hippocampus. Furthermore, we have developed a quantitative method for obtaining group activation patterns based on producing averaged flat maps using vector field warping techniques, allowing localization of activations to specific hippocampal subregions across groups of subjects. Together, these methods provide a means to improve imaging of neural activity in the human hippocampus and surrounding cortex during cognitive tasks.

    View details for DOI 10.1016/j.neuroimage.2009.03.017

    View details for Web of Science ID 000266975300007

    View details for PubMedID 19303448

    View details for PubMedCentralID PMC2689320

  • Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers NEUROIMAGE Burggren, A. C., Zeineh, M. M., Ekstrom, A. D., Braskie, M. N., Thompson, P. M., Small, G. W., Bookheimer, S. Y. 2008; 41 (4): 1177-1183


    Our objective was to investigate whether asymptomatic carriers of apolipoprotein E epsilon4 [APOE-4] demonstrate pathological differences and atrophy in medial temporal lobe (MTL) subregions. We measured cortical thickness and volume in MTL subregions (hippocampal CA fields 1, 2 and 3; dentate gyrus; entorhinal cortex; subiculum; perirhinal cortex; parahippocampal cortex; and fusiform gyrus) using a high-resolution in-plane (0.4x0.4 mm) MRI sequence in 30 cognitively normal volunteers (14 APOE-4 carriers, 16 non-carriers, mean age 57 years). A cortical unfolding procedure maximized the visibility of this convoluted cortex, providing cortical ribbon thickness measures throughout individual subregions of the hippocampus and surrounding cortex. APOE-4 carriers had reduced cortical thickness compared with non-carriers in entorhinal cortex (ERC) and the subiculum (Sub), but not in the main hippocampal body or perirhinal cortex. Average cortical thickness was 14.8% lower (p=1.0e(- 6)) for ERC and 12.6% lower (p=6.8e(- 5)) for Sub in APOE-4 carriers. Standard volumetric measures of the same regions showed similar, but non-significant trends. Cognitively intact carriers of APOE-4 show regionally specific thinning of the cortical ribbon compared to APOE-3 carriers; cortical thickness may be a more sensitive measure of pathological differences in genetic risk subjects than standard volumetry.

    View details for DOI 10.1016/j.neuroimage.2008.03.039

    View details for Web of Science ID 000256620400001

    View details for PubMedID 18486492

    View details for PubMedCentralID PMC2601686

  • A dissociation of encoding and retrieval processes in the human hippocampus JOURNAL OF NEUROSCIENCE Eldridge, L. L., Engel, S. A., Zeineh, M. M., Bookheimer, S. Y., Knowlton, B. J. 2005; 25 (13): 3280-3286


    The hippocampal formation performs two related but distinct memory functions: encoding of novel information and retrieval of episodes. Little evidence, however, resolves how these two processes are implemented within the same anatomical structure. Here we use high-resolution functional magnetic resonance imaging to show that distinct subregions of the hippocampus are differentially involved in encoding and retrieval. We found that regions early in the hippocampal circuit (dentate gyrus and CA fields 2 and 3) were selectively active during episodic memory formation, whereas a region later in the circuit (the subiculum) was active during the recollection of the learning episode. Different components of the hippocampal circuit likely contribute to different degrees to the two basic memory functions.

    View details for Web of Science ID 000228038200004

    View details for PubMedID 15800182

  • Dynamics of the hippocampus during encoding and retrieval of face-name pairs SCIENCE Zeineh, M. M., Engel, S. A., Thompson, P. M., Bookheimer, S. Y. 2003; 299 (5606): 577-580


    The medial temporal lobe (MTL) is critical in forming new memories, but how subregions within the MTL carry out encoding and retrieval processes in humans is unknown. Using new high-resolution functional magnetic resonance imaging (fMRI) acquisition and analysis methods, we identified mnemonic properties of different subregions within the hippocampal circuitry as human subjects learned to associate names with faces. The cornu ammonis (CA) fields 2 and 3 and the dentate gyrus were active relative to baseline only during encoding, and this activity decreased as associations were learned. Activity in the subiculum showed the same temporal decline, but primarily during retrieval. Our results demonstrate that subdivisions within the hippocampus make distinct contributions to new memory formation.

    View details for Web of Science ID 000180559800054

    View details for PubMedID 12543980

  • Application of cortical unfolding techniques to functional MRI of the human hippocampal region NEUROIMAGE Zeineh, M. M., Engel, S. A., Bookheimer, S. Y. 2000; 11 (6): 668-683


    We describe a new application of cortical unfolding to high-resolution functional magnetic resonance imaging (fMRI) of the human hippocampal region. This procedure includes techniques to segment and unfold the hippocampus, allowing the fusiform, parahippocampal, perirhinal, entorhinal, subicular, and CA fields to be viewed and compared across subjects. Transformation parameters derived from unfolding high-resolution structural images are applied to coplanar, functional images, yielding two-dimensional "unfolded" activation maps of hippocampi. The application of these unfolding techniques greatly enhances the ability of fMRI to localize and characterize signal changes within the medial temporal lobe. Use of this method on a novelty-encoding paradigm reveals a temporal dissociation between activation along the collateral sulcus and activation in the hippocampus proper.

    View details for Web of Science ID 000087963600009

    View details for PubMedID 10860795

  • Padded Helmet Shell Covers in American Football: A Comprehensive Laboratory Evaluation with Preliminary On-Field Findings. Annals of biomedical engineering Cecchi, N. J., Callan, A. A., Watson, L. P., Liu, Y., Zhan, X., Vegesna, R. V., Pang, C., Le Flao, E., Grant, G. A., Zeineh, M. M., Camarillo, D. B. 2023


    Protective headgear effects measured in the laboratory may not always translate to the field. In this study, we evaluated the impact attenuation capabilities of a commercially available padded helmet shell cover in the laboratory andon the field. In the laboratory, we evaluated the padded helmet shell cover's efficacy in attenuating impact magnitude across six impact locations and three impact velocities when equipped to three different helmet models. In a preliminary on-field investigation, we used instrumented mouthguards to monitor head impact magnitude in collegiate linebackers during practice sessions while not wearing the padded helmet shell covers (i.e., bare helmets) for one season and whilst wearing the padded helmet shell covers for another season. The addition of the padded helmet shell cover was effective in attenuating the magnitude of angular head accelerations and two brain injury risk metrics (DAMAGE, HARM) across most laboratory impact conditions, but did not significantly attenuate linear head accelerations for all helmets. Overall, HARM values were reduced in laboratory impact tests by an average of 25% at 3.5m/s (range: 9.7 to 39.6%), 18% at 5.5m/s (range: -5.5 to 40.5%), and 10% at 7.4m/s (range: -6.0 to 31.0%). However, on the field, no significant differences in any measure of head impact magnitude were observed between the bare helmet impacts and padded helmet impacts. Further laboratory tests were conducted to evaluate the ability of the padded helmet shell cover to maintain its performance after exposure to repeated, successive impacts and across a range of temperatures. This research provides a detailed assessment of padded helmet shell covers and supports the continuation of in vivo helmet research to validate laboratory testing results.

    View details for DOI 10.1007/s10439-023-03169-2

    View details for PubMedID 36917295

  • Machine-learning-based head impact subtyping based on the spectral densities of the measurable head kinematics. Journal of sport and health science Zhan, X., Li, Y., Liu, Y., Cecchi, N. J., Raymond, S. J., Zhou, Z., Alizadeh, H. V., Ruan, J., Barbat, S., Tiernan, S., Gevaert, O., Zeineh, M. M., Grant, G. A., Camarillo, D. B. 2023


    Traumatic brain injury can be caused by head impacts, but many brain injury risk estimation models are not equally accurate across the variety of impacts that patients may undergo, and the characteristics of different types of impacts are not well studied. We investigated the spectral characteristics of different head impact types with kinematics classification.Data was analyzed from 3262 head impacts from lab reconstruction, American football, mixed martial arts, and publicly available car crash data. A random forest classifier with spectral densities of linear acceleration and angular velocity was built to classify head impact types (e.g., football, car crash, mixed martial arts). To test the classifier robustness, another 271 lab-reconstructed impacts were obtained from 5 other instrumented mouthguards. Finally, with the classifier, type-specific, nearest-neighbor regression models were built for brain strain.The classifier reached a median accuracy of 96% over 1000 random partitions of training and test sets. The most important features in the classification included both low-frequency and high-frequency features, both linear acceleration features and angular velocity features. Different head impact types had different distributions of spectral densities in low- and high-frequency ranges (e.g., the spectral densities of MMA impacts were higher in the high-frequency range than in the low-frequency range). The type-specific regression showed a generally higher R2-value than baseline models without classification.The machine-learning-based classifier enables a better understanding of the impact kinematics spectral density in different sports, and it can be applied to evaluate the quality of impact-simulation systems and on-field data augmentation.

    View details for DOI 10.1016/j.jshs.2023.03.003

    View details for PubMedID 36921692

  • Cardiogenic control of affective behavioural state. Nature Hsueh, B., Chen, R., Jo, Y., Tang, D., Raffiee, M., Kim, Y. S., Inoue, M., Randles, S., Ramakrishnan, C., Patel, S., Kim, D. K., Liu, T. X., Kim, S. H., Tan, L., Mortazavi, L., Cordero, A., Shi, J., Zhao, M., Ho, T. T., Crow, A., Yoo, A. W., Raja, C., Evans, K., Bernstein, D., Zeineh, M., Goubran, M., Deisseroth, K. 2023


    Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that wereactivated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.

    View details for DOI 10.1038/s41586-023-05748-8

    View details for PubMedID 36859543

  • Laboratory And On-field Testing Of A Commercially Available Padded Helmet Cover Cecchi, N. J., Callan, A. A., Watson, L. P., Liu, Y., Zhan, X., Zeineh, M. M., Grant, G. A., Camarillo, D. B. LIPPINCOTT WILLIAMS & WILKINS. 2022: 45
  • Piecewise Multivariate Linearity Between Kinematic Features and Cumulative Strain Damage Measure (CSDM) Across Different Types of Head Impacts. Annals of biomedical engineering Zhan, X., Li, Y., Liu, Y., Cecchi, N. J., Gevaert, O., Zeineh, M. M., Grant, G. A., Camarillo, D. B. 2022


    In a previous study, we found that the relationship between brain strain and kinematic features cannot be described by a generalized linear model across different types of head impacts. In this study, we investigate if such a linear relationship exists when partitioning head impacts using a data-driven approach. We applied the K-means clustering method to partition 3161 impacts from various sources including simulation, college football, mixed martial arts, and car crashes. We found piecewise multivariate linearity between the cumulative strain damage (CSDM; assessed at the threshold of 0.15) and head kinematic features. Compared with the linear regression models without partition and the partition according to the types of head impacts, K-means-based data-driven partition showed significantly higher CSDM regression accuracy, which suggested the presence of piecewise multivariate linearity across types of head impacts. Additionally, we compared the piecewise linearity with the partitions based on individual features used in clustering. We found that the partition with maximum angular acceleration magnitude at 4706 rad/s2 led to the highest piecewise linearity. This study may contribute to an improved method for the rapid prediction of CSDM in the future.

    View details for DOI 10.1007/s10439-022-03020-0

    View details for PubMedID 35922726

  • High-resolution hippocampal diffusion tensor imaging of mesial temporal sclerosis in refractory epilepsy. Epilepsia Chau Loo Kung, G., Chiu, A., Davey, Z., Mouchawar, N., Carlson, M., Moein Taghavi, H., Martin, D., Graber, K., Razavi, B., McNab, J., Zeineh, M. 2022


    OBJECTIVE: We explore the possibility of using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to discern microstructural abnormalities in the hippocampus indicative of mesial temporal sclerosis (MTS) at the subfield level.METHODS: We analyzed data from 57 patients with refractory epilepsy who previously underwent 3.0-T magnetic resonance imaging (MRI) including DTI as a standard part of presurgical workup. We collected information about each subject's seizure semiology, conventional electroencephalography (EEG), high-density EEG, positron emission tomography reports, surgical outcome, and available histopathological findings to assign a final diagnostic category. We also reviewed the radiology MRI report to determine the radiographic category. DTI- and NODDI-based metrics were obtained in the hippocampal subfields.RESULTS: By examining diffusion characteristics among subfields in the final diagnostic categories, we found lower orientation dispersion indices and elevated axial diffusivity in the dentate gyrus in MTS compared to no MTS. By similarly examining among subfields in the different radiographic categories, we found all diffusion metrics were abnormal in the dentate gyrus and CA1. We finally examined whether diffusion imaging would better inform a radiographic diagnosis with respect to the final diagnosis, and found that dentate diffusivity suggested subtle changes that may help confirm a positive radiologic diagnosis.SIGNIFICANCE: The results suggest that diffusion metric analysis at the subfield level, especially in dentate gyrus and CA1, maybe useful for clinical confirmation of MTS.

    View details for DOI 10.1111/epi.17330

    View details for PubMedID 35751514

  • Changes In The Cerebello-thalamo-cortical Network After MR-guided Focused Ultrasound Thalamotomy. Brain connectivity Thaler, C., Tian, Q., WIntermark, M., Ghanouni, P., Halpern, C., Henderson, J., Airan, R., Zeineh, M., Goubran, M., Leuze, C., Fiehler, J., Butts Pauly, K., McNab, J. A. 2022


    Object In recent years, transcranial MR-guided focused ultrasound (tcMRgFUS) has been established as a potential treatment option for movement disorders, including essential tremor. So far, however, little is known about the impact of tcMRgFUS on structural connectivity. The objective of this study was to detect microstructural changes in tremor- and motor-related white matter tracts in essential tremor patients treated with tcMRgFUS thalamotomy. Methods Eleven patients diagnosed with essential tremor were enrolled in this tcMRgFUS thalamotomy study. For each patient, 3T MRI including structural and diffusion MRI were acquired and the Clinical Rating Scale for Tremor was assessed prior to the procedure as well as one year after the treatment. Diffusion MRI tractography was performed to identify the cerebello-thalamo-cortical tract (CTCT), the medial lemniscus (ML) and the corticospinal tract (CST) in both hemispheres on pre-treatment data. Pre-treatment tractography results were co-registered to post-treatment diffusion data. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD), were averaged across the tracts in the pre- and post-treatment data. Results The mean value of tract-specific DTI metrics changed significantly within the thalamic lesion and in the CTCT on the treated side (p<0.05). Changes of DTI-derived indices within the CTCT correlated well with lesion overlap (FA: r=-0.54, p=0.04; MD: r=0.57, p=0.04); RD: r=0.67, p=0.036). Furthermore, a trend was seen for the correlation between changes of DTI-derived indices within the CTCT and clinical improvement (FA: r=0.58; p=0.062; MD: r=-0.52, p=0.64; RD: r=-0.61 p=0.090). Conclusions Microstructural changes were detected within the CTCT after tcMRgFUS and these changes correlated well with lesion-tract overlap. Our results show that diffusion MRI is able to detect the microstructural effects of tcMRgFUS, thereby further elucidating the treatment mechanism and ultimately to improve targeting prospectively.

    View details for DOI 10.1089/brain.2021.0157

    View details for PubMedID 35678063

  • Magnetic resonance imaging-guided laser interstitial thermal therapy for refractory focal epilepsy in a patient with a fully implanted RNS system: illustrative case. Journal of neurosurgery. Case lessons Buch, V. P., Mirro, E. A., Purger, D. A., Zeineh, M., Wilmer-Fierro, K., Razavi, B., Halpern, C. H. 2022; 3 (21): CASE22117


    BACKGROUND: The resective surgery plus responsive neurostimulation (RNS) system is an effective treatment for patients with refractory focal epilepsy. Furthermore, the long-term intracranial electroencephalography data provided by the system can inform a future resection or ablation procedure. RNS patients may undergo 1.5-T magnetic resonance imaging (MRI) under the conditions specified in the RNS system MRI guidelines; however, it was unknown if the MRI artifact would limit intraoperative laser interstitial thermal therapy (LITT) in a patient with a fully implanted RNS system.OBSERVATIONS: The authors were able to complete a successful awake LITT of epileptogenic tissue in a 1.5-T MRI scanner on the ipsilateral side to an implanted RNS system.LESSONS: If a future LITT procedure is probable, the neurostimulator should be placed contralateral to the side of the potential ablation. Using twist drill holes versus burr holes for depth lead placement may assist in future laser bone anchor seating. Before a LITT procedure in a patient with the neurostimulator ipsilateral to the ablation, 1.5-T MRI thermography scanning should be scheduled preoperatively to assess artifact in the proposed ablation zone. Per the RNS system MRI guidelines, the patient must be positioned supine and awake, with no more than 30 minutes of active scan time before a 30-minute pause.

    View details for DOI 10.3171/CASE22117

    View details for PubMedID 35734233

  • Find the spatial co-variation of brain deformation with principal component analysis. IEEE transactions on bio-medical engineering Zhan, X., Liu, Y., Cecchi, N. J., Gevaert, O., Zeineh, M., Grant, G., Camarillo, D. B. 2022; PP


    Strain and strain rate are effective traumatic brain injury metrics. In finite element (FE) head model, thousands of elements were used to represent the spatial distribution of these metrics. Owing that these metrics are resulted from brain inertia, their spatial distribution can be represented in more concise pattern. Since head kinematic features and brain deformation vary largely across head impact types, we apply principal component analysis (PCA) to find the spatial co-variation of injury metrics (maximum principal strain (MPS), MPS rate (MPSR) and MPS ×MPSR) in four impact types: simulation, football, mixed martial arts and car crashes, and use the PCA to find patterns in these metrics and improve the machine learning head model (MLHM).We applied PCA to decompose the injury metrics for all impacts in each impact type, and investigate the spatial co-variation using the first principal component (PC1). Furthermore, we developed a MLHM to predict PC1 and then inverse-transform to predict for all brain elements. The accuracy, the model complexity and the size of training dataset of PCA-MLHM are compared with previous MLHM.PC1 explained >80% variance on the datasets. Based on PC1 coefficients, the corpus callosum and midbrain exhibit high variance on all datasets. Finally, the PCA-MLHM reduced model parameters by 74% with a similar MPS estimation accuracy.The brain injury metric in a dataset can be decomposed into mean components and PC1 with high explained variance.The spatial co-variation analysis enables better interpretation of the patterns in brain injury metrics. It also improves the efficiency of MLHM.

    View details for DOI 10.1109/TBME.2022.3163230

    View details for PubMedID 35349430

  • Physics-Informed Machine Learning Improves Detection of Head Impacts. Annals of biomedical engineering Raymond, S. J., Cecchi, N. J., Alizadeh, H. V., Callan, A. A., Rice, E., Liu, Y., Zhou, Z., Zeineh, M., Camarillo, D. B. 2022


    In this work we present a new physics-informed machine learning model that can be used to analyze kinematic data from an instrumented mouthguard and detect impacts to the head. Monitoring player impacts is vitally important to understanding and protecting from injuries like concussion. Typically, to analyze this data, a combination of video analysis and sensor data is used to ascertain the recorded events are true impacts and not false positives. In fact, due to the nature of using wearable devices in sports, false positives vastly outnumber the true positives. Yet, manual video analysis is time-consuming. This imbalance leads traditional machine learning approaches to exhibit poor performance in both detecting true positives and preventing false negatives. Here, we show that by simulating head impacts numerically using a standard Finite Element head-neck model, a large dataset of synthetic impacts can be created to augment the gathered, verified, impact data from mouthguards. This combined physics-informed machine learning impact detector reported improved performance on test datasets compared to traditional impact detectors with negative predictive value and positive predictive values of 88 and 87% respectively. Consequently, this model reported the best results to date for an impact detection algorithm for American football, achieving an F1 score of 0.95. In addition, this physics-informed machine learning impact detector was able to accurately detect true and false impacts from a test dataset at a rate of 90% and 100% relative to a purely manual video analysis workflow. Saving over 12 h of manual video analysis for a modest dataset, at an overall accuracy of 92%, these results indicate that this model could be used in place of, or alongside, traditional video analysis to allow for larger scale and more efficient impact detection in sports such as American Football.

    View details for DOI 10.1007/s10439-022-02911-6

    View details for PubMedID 35303171

  • Investigating Simultaneity for Deep Learning-Enhanced Actual Ultra-Low-Dose Amyloid PET/MR Imaging. AJNR. American journal of neuroradiology Chen, K. T., Adeyeri, O., Toueg, T. N., Zeineh, M., Mormino, E., Khalighi, M., Zaharchuk, G. 1800


    BACKGROUND AND PURPOSE: Diagnostic-quality amyloid PET images can be created with deep learning using actual ultra-low-dose PET images and simultaneous structural MR imaging. Here, we investigated whether simultaneity is required; if not, MR imaging-assisted ultra-low-dose PET imaging could be performed with separate PET/CT and MR imaging acquisitions.MATERIALS AND METHODS: We recruited 48 participants: Thirty-two (20 women; mean, 67.7 [SD, 7.9] years) were used for pretraining; 328 (SD, 32) MBq of [18F] florbetaben was injected. Sixteen participants (6 women; mean, 71.4 [SD. 8.7] years of age) were scanned in 2 sessions, with 6.5 (SD, 3.8) and 300 (SD, 14) MBq of [18F] florbetaben injected, respectively. Structural MR imaging was acquired simultaneously with PET (90-110minutes postinjection) on integrated PET/MR imaging in 2 sessions. Multiple U-Net-based deep networks were trained to create diagnostic PET images. For each method, training was done with the ultra-low-dose PET as input combined with MR imaging from either the ultra-low-dose session (simultaneous) or from the standard-dose PET session (nonsimultaneous). Image quality of the enhanced and ultra-low-dose PET images was evaluated using quantitative signal-processing methods, standardized uptake value ratio correlation, and clinical reads.RESULTS: Qualitatively, the enhanced images resembled the standard-dose image for both simultaneous and nonsimultaneous conditions. Three quantitative metrics showed significant improvement for all networks and no differences due to simultaneity. Standardized uptake value ratio correlation was high across different image types and network training methods, and 31/32 enhanced image pairs were read similarly.CONCLUSIONS: This work suggests that accurate amyloid PET images can be generated using enhanced ultra-low-dose PET and either nonsimultaneous or simultaneous MR imaging, broadening the utility of ultra-low-dose amyloid PET imaging.

    View details for DOI 10.3174/ajnr.A7410

    View details for PubMedID 35086799

  • Translational models of mild traumatic brain injury tissue biomechanics Current Opinion in Biomedical Engineering Zhan, X., Oeur, A., Liu, Y., Zeineh, M. M., Grant, G. A., Margulies, S. S., Camarillo, D. B. 2022; 24
  • Towards a comprehensive delineation of white matter tract-related deformation. Journal of neurotrauma Zhou, Z., Li, X., Liu, Y., Fahlstedt, M., Georgiadis, M., Zhan, X., Raymond, S. J., Grant, G., Kleiven, S., Camarillo, D. B., Zeineh, M. 2021


    Finite element (FE) models of the human head are valuable instruments to explore the mechanobiological pathway from external loading, localized brain response, and resultant injury risks. The injury predictability of these models depends on the use of effective criteria as injury predictors. The FE-derived normal deformation along white matter (WM) fiber tracts (i.e., tract-oriented strain) has recently been suggested as an appropriate predictor for axonal injury. However, the tract-oriented strain only represents a partial depiction of the WM fiber tract deformation. A comprehensive delineation of tract-related deformation may improve the injury predictability of the FE head model by delivering new tract-related criteria as injury predictors. Thus, the present study performed a theoretical strain analysis to comprehensively characterize the WM fiber tract deformation by relating the strain tensor of the WM element to its embedded fiber tract. Three new tract-related strains with exact analytical solutions were proposed, measuring the normal deformation perpendicular to the fiber tracts (i.e., tract-perpendicular strain), and shear deformation along and perpendicular to the fiber tracts (i.e., axial-shear strain and lateral-shear strain, respectively). The injury predictability of these three newly-proposed strain peaks along with the previously-used tract-oriented strain peak and maximum principal strain (MPS) were evaluated by simulating 151 impacts with known outcome (concussion or non-concussion). The results preliminarily showed that four tract-related strain peaks exhibited superior performance than MPS in discriminating concussion and non-concussion cases. This study presents a comprehensive quantification of WM tract-related deformation and advocates the use of orientation-dependent strains as criteria for injury prediction, which may ultimately contribute to an advanced mechanobiological understanding and enhanced computational predictability of brain injury.

    View details for DOI 10.1089/neu.2021.0195

    View details for PubMedID 34617451

  • Identifying Factors Associated with Head Impact Kinematics and Brain Strain in High School American Football via Instrumented Mouthguards. Annals of biomedical engineering Cecchi, N. J., Domel, A. G., Liu, Y., Rice, E., Lu, R., Zhan, X., Zhou, Z., Raymond, S. J., Sami, S., Singh, H., Rangel, I., Watson, L. P., Kleiven, S., Zeineh, M., Camarillo, D. B., Grant, G. 2021


    Repeated head impact exposure and concussions are common in American football. Identifying the factors associated with high magnitude impacts aids in informing sport policy changes, improvements to protective equipment, and better understanding of the brain's response to mechanical loading. Recently, the Stanford Instrumented Mouthguard (MiG2.0) has seen several improvements in its accuracy in measuring head kinematics and its ability to correctly differentiate between true head impact events and false positives. Using this device, the present study sought to identify factors (e.g., player position, helmet model, direction of head acceleration, etc.) that are associated with head impact kinematics and brain strain in high school American football athletes. 116 athletes were monitored over a total of 888 athlete exposures. 602 total impacts were captured and verified by the MiG2.0's validated impact detection algorithm. Peak values of linear acceleration, angular velocity, and angular acceleration were obtained from the mouthguard kinematics. The kinematics were also entered into a previously developed finite element model of the human brain to compute the 95th percentile maximum principal strain. Overall, impacts were (mean ± SD) 34.0 ± 24.3 g for peak linear acceleration, 22.2 ± 15.4 rad/s for peak angular velocity, 2979.4 ± 3030.4 rad/s2 for peak angular acceleration, and 0.262 ± 0.241 for 95th percentile maximum principal strain. Statistical analyses revealed that impacts resulting in Forward head accelerations had higher magnitudes of peak kinematics and brain strain than Lateral or Rearward impacts and that athletes in skill positions sustained impacts of greater magnitude than athletes in line positions. 95th percentile maximum principal strain was significantly lower in the observed cohort of high school football athletes than previous reports of collegiate football athletes. No differences in impact magnitude were observed in athletes with or without previous concussion history, in athletes wearing different helmet models, or in junior varsity or varsity athletes. This study presents novel information on head acceleration events and their resulting brain strain in high school American football from our advanced, validated method of measuring head kinematics via instrumented mouthguard technology.

    View details for DOI 10.1007/s10439-021-02853-5

    View details for PubMedID 34549342

  • Identifying Risk Factors For Head Impact Exposure In High School Football Using A Validated Instrumented Mouthguard Cecchi, N. J., Domel, A. G., Liu, Y., Raymond, S. J., Zeineh, M., Camarillo, D., Grant, G. LIPPINCOTT WILLIAMS & WILKINS. 2021: 148
  • Altered sense of self during seizures in the posteromedial cortex. Proceedings of the National Academy of Sciences of the United States of America Parvizi, J., Braga, R. M., Kucyi, A., Veit, M. J., Pinheiro-Chagas, P., Perry, C., Sava-Segal, C., Zeineh, M., van Staalduinen, E. K., Henderson, J. M., Markert, M. 2021; 118 (29)


    The posteromedial cortex (PMC) is known to be a core node of the default mode network. Given its anatomical location and blood supply pattern, the effects of targeted disruption of this part of the brain are largely unknown. Here, we report a rare case of a patient (S19_137) with confirmed seizures originating within the PMC. Intracranial recordings confirmed the onset of seizures in the right dorsal posterior cingulate cortex, adjacent to the marginal sulcus, likely corresponding to Brodmann area 31. Upon the onset of seizures, the patient reported a reproducible sense of self-dissociation-a condition he described as a distorted awareness of the position of his body in space and feeling as if he had temporarily become an outside observer to his own thoughts, his "me" having become a separate entity that was listening to different parts of his brain speak to each other. Importantly, 50-Hz electrical stimulation of the seizure zone and a homotopical region within the contralateral PMC induced a subjectively similar state, reproducibly. We supplement our clinical findings with the definition of the patient's network anatomy at sites of interest using cortico-cortical-evoked potentials, experimental and resting-state electrophysiological connectivity, and individual-level functional imaging. This rare case of patient S19_137 highlights the potential causal importance of the PMC for integrating self-referential information and provides clues for future mechanistic studies of self-dissociation in neuropsychiatric populations.

    View details for DOI 10.1073/pnas.2100522118

    View details for PubMedID 34272280

  • Predictive Factors of Kinematics in Traumatic Brain Injury from Head Impacts Based on Statistical Interpretation. Annals of biomedical engineering Zhan, X., Li, Y., Liu, Y., Domel, A. G., Alizadeh, H. V., Zhou, Z., Cecchi, N. J., Raymond, S. J., Tiernan, S., Ruan, J., Barbat, S., Gevaert, O., Zeineh, M. M., Grant, G. A., Camarillo, D. B. 2021


    Brain tissue deformation resulting from head impacts is primarily caused by rotation and can lead to traumatic brain injury. To quantify brain injury risk based on measurements of kinematics on the head, finite element (FE) models and various brain injury criteria based on different factors of these kinematics have been developed, but the contribution of different kinematic factors has not been comprehensively analyzed across different types of head impacts in a data-driven manner. To better design brain injury criteria, the predictive power of rotational kinematics factors, which are different in (1) the derivative order (angular velocity, angular acceleration, angular jerk), (2) the direction and (3) the power (e.g., square-rooted, squared, cubic) of the angular velocity, were analyzed based on different datasets including laboratory impacts, American football, mixed martial arts (MMA), NHTSA automobile crashworthiness tests and NASCAR crash events. Ordinary least squares regressions were built from kinematics factors to the 95% maximum principal strain (MPS95), and we compared zero-order correlation coefficients, structure coefficients, commonality analysis, and dominance analysis. The angular acceleration, the magnitude and the first power factors showed the highest predictive power for the majority of impacts including laboratory impacts, American football impacts, with few exceptions (angular velocity for MMA and NASCAR impacts). The predictive power of rotational kinematics about three directions (x: posterior-to-anterior, y: left-to-right, z: superior-to-inferior) of kinematics varied with different sports and types of head impacts.

    View details for DOI 10.1007/s10439-021-02813-z

    View details for PubMedID 34244908

  • Time Window of Head Impact Kinematics Measurement for Calculation of Brain Strain and Strain Rate in American Football. Annals of biomedical engineering Liu, Y., Domel, A. G., Cecchi, N. J., Rice, E., Callan, A. A., Raymond, S. J., Zhou, Z., Zhan, X., Li, Y., Zeineh, M. M., Grant, G. A., Camarillo, D. B. 2021


    Wearable devices have been shown to effectively measure the head's movement during impacts in sports like American football. When a head impact occurs, the device is triggered to collect and save the kinematic measurements during a predefined time window. Then, based on the collected kinematics, finite element (FE) head models can calculate brain strain and strain rate, which are used to evaluate the risk of mild traumatic brain injury. To find a time window that can provide a sufficient duration of kinematics for FE analysis, we investigated 118 on-field video-confirmed football head impacts collected by the Stanford Instrumented Mouthguard. The simulation results based on the kinematics truncated to a shorter time window were compared with the original to determine the minimum time window needed for football. Because the individual differences in brain geometry influence these calculations, we included six representative brain geometries and found that larger brains need a longer time window of kinematics for accurate calculation. Among the different sizes of brains, a pre-trigger time of 40ms and a post-trigger time of 70ms were found to yield calculations of brain strain and strain rate that were not significantly different from calculations using the original 200ms time window recorded by the mouthguard. Therefore, approximately 110ms is recommended for complete modeling of impacts for football.

    View details for DOI 10.1007/s10439-021-02821-z

    View details for PubMedID 34231091

  • Mammary Lobular Carcinoma-Like Salivary Gland Carcinoma: Report of a Rare Case. Head and neck pathology Lei, L., Van Staalduinen, E., Troxell, M., Ozawa, M. G., Zeineh, M., Berry, G. 2021


    Salivary and mammary glands are both exocrine organs sharing multiple tumorigenic processes. To the best of our knowledge, salivary gland tumors mimicking invasive lobular carcinoma of the breast have not yet been described. Herein, we report a case of a 62-year-old male who presented with progressive facial paralysis. Pathologic examination revealed an ill-defined epithelial neoplasm exhibiting discohesive growth set within an extensively fibrotic stroma. Both perineural and intraneural invasion were present. E-cadherin and p120 immunostaining showed aberrant cytoplasmic expression. Targeted next-generation sequencing detected a frameshift mutation of the CTNNA1 gene as the only known pathogenic variant. The patient was treated with surgical resection, immunotherapy, and chemotherapy. Currently, he is alive with disease twenty months after disease onset.

    View details for DOI 10.1007/s12105-021-01344-2

    View details for PubMedID 34115320

  • A new open-access platform for measuring and sharing mTBI data. Scientific reports Domel, A. G., Raymond, S. J., Giordano, C., Liu, Y., Yousefsani, S. A., Fanton, M., Cecchi, N. J., Vovk, O., Pirozzi, I., Kight, A., Avery, B., Boumis, A., Fetters, T., Jandu, S., Mehring, W. M., Monga, S., Mouchawar, N., Rangel, I., Rice, E., Roy, P., Sami, S., Singh, H., Wu, L., Kuo, C., Zeineh, M., Grant, G., Camarillo, D. B. 2021; 11 (1): 7501


    Despite numerous research efforts, the precise mechanisms of concussion have yet to be fully uncovered. Clinical studies on high-risk populations, such as contact sports athletes, have become more common and give insight on the link between impact severity and brain injury risk through the use of wearable sensors and neurological testing. However, as the number of institutions operating these studies grows, there is a growing need for a platform to share these data to facilitate our understanding of concussion mechanisms and aid in the development of suitable diagnostic tools. To that end, this paper puts forth two contributions: (1) a centralized, open-access platform for storing and sharing head impact data, in collaboration with the Federal Interagency Traumatic Brain Injury Research informatics system (FITBIR), and (2) a deep learning impact detection algorithm (MiGNet) to differentiate between true head impacts and false positives for the previously biomechanically validated instrumented mouthguard sensor (MiG2.0), all of which easily interfaces with FITBIR. We report 96% accuracy using MiGNet, based on a neural network model, improving on previous work based on Support Vector Machines achieving 91% accuracy, on an out of sample dataset of high school and collegiate football head impacts. The integrated MiG2.0 and FITBIR system serve as a collaborative research tool to be disseminated across multiple institutions towards creating a standardized dataset for furthering the knowledge of concussion biomechanics.

    View details for DOI 10.1038/s41598-021-87085-2

    View details for PubMedID 33820939

  • Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics Simmons, D. A., Mills, B. D., Butler Iii, R. R., Kuan, J., McHugh, T. L., Akers, C., Zhou, J., Syriani, W., Grouban, M., Zeineh, M., Longo, F. M. 2021


    Huntington's disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

    View details for DOI 10.1007/s13311-021-01023-8

    View details for PubMedID 33786806

  • Correction to: Validation and Comparison of Instrumented Mouthguards for Measuring Head Kinematics and Assessing Brain Deformation in Football Impacts. Annals of biomedical engineering Liu, Y., Domel, A. G., Yousefsani, S. A., Kondic, J., Grant, G., Zeineh, M., Camarillo, D. B. 2021; 49 (3): 1119-1120

    View details for DOI 10.1007/s10439-020-02701-y

    View details for PubMedID 33725223

  • Validation and Comparison of Instrumented Mouthguards for Measuring Head Kinematics and Assessing Brain Deformation in Football Impacts (vol 48, pg 2580, 2020) ANNALS OF BIOMEDICAL ENGINEERING Liu, Y., Domel, A. G., Yousefsani, S., Kondic, J., Grant, G., Zeineh, M., Camarillo, D. B. 2021
  • High-resolution Structural Magnetic Resonance Imaging and Quantitative Susceptibility Mapping. Magnetic resonance imaging clinics of North America Yedavalli, V., DiGiacomo, P., Tong, E., Zeineh, M. 2021; 29 (1): 13–39


    High-resolution 7-T imaging and quantitative susceptibility mapping produce greater anatomic detail compared with conventional strengths because of improvements in signal/noise ratio and contrast. The exquisite anatomic details of deep structures, including delineation of microscopic architecture using advanced techniques such as quantitative susceptibility mapping, allows improved detection of abnormal findings thought to be imperceptible on clinical strengths. This article reviews caveats and techniques for translating sequences commonly used on 1.5 or 3 T to high-resolution 7-T imaging. It discusses for several broad disease categories how high-resolution 7-T imaging can advance the understanding of various diseases, improve diagnosis, and guide management.

    View details for DOI 10.1016/j.mric.2020.09.002

    View details for PubMedID 33237013

  • White matter tract-oriented deformation is dependent on real-time axonal fiber orientation. Journal of neurotrauma Zhou, Z. n., Domel, A. G., Li, X. n., Grant, G. n., Kleiven, S. n., Camarillo, D. B., Zeineh, M. n. 2021


    Traumatic axonal injury (TAI) is a critical public health issue with its pathogenesis remaining largely elusive. Finite element (FE) head models are promising tools to bridge the gap between mechanical insult, localized brain response, and resultant injury. In particular, the FE-derived deformation along the direction of white matter (WM) tracts (i.e., tract-oriented strain) has been shown to be an appropriate predictor for TAI. However, the evolution of fiber orientation in time during the impact and its potential influence on the tract-oriented strain remains unknown. To address this question, the present study leveraged an embedded element approach to track real-time fiber orientation during impacts. A new scheme to calculate the tract-oriented strain was proposed by projecting the strain tensors from pre-computed simulations along the temporal fiber direction instead of its static counterpart directly obtained from diffuse tensor imaging. The results revealed that incorporating the real-time fiber orientation not only altered the direction but also amplified the magnitude of the tract-oriented strain, resulting in a generally more extended distribution and a larger volume ratio of WM exposed to high deformation along fiber tracts. These effects were exacerbated with the impact severities characterized by the acceleration magnitudes. Results of this study provide insights into how best to incorporate fiber orientation in head injury models and derive the WM tract-oriented deformation from computational simulations, which is important for furthering our understanding of the underlying mechanisms of TAI.

    View details for DOI 10.1089/neu.2020.7412

    View details for PubMedID 33446060

  • The relationship between brain injury criteria and brain strain across different types of head impacts can be different Journal of Royal Society Interface Zhan, X., Li, Y., Liu, Y., Domel, A. G., Vahid Alidazeh, H., Raymond, S. J., Ruan, J., Barbat, S., Tienan, S., Gevaert, O., Zeineh, M., Grant, G., Camarillo, D. 2021; 18 (20210260)

    View details for DOI 10.1098/rsif.2021.0260

  • Rapid Estimation of Entire Brain Strain Using Deep Learning Models IEEE Transactions on Biomedical Engineering Zhan, X., Liu, Y., Raymond, S. J., Vahid Alizadeh, H., Domel, A. G., Gevaert, O., Zeineh, M. M., Grant, G. A., Camarillo, D. 2021: 11


    Many recent studies suggest that brain deformation resulting from head impacts are linked to the corresponding clinical outcome, such as mild traumatic brain injury (mTBI). Even if several finite element (FE) head models have been developed and validated to calculate brain deformation based on impact kinematics, the clinical application of these FE head models is limited due to the time-consuming nature of FE simulations. This work aims to accelerate the brain deformation calculation and thus improve the potential for clinical applications.We propose a deep learning head model with a five-layer deep neural network and feature engineering, and trained and tested the model on 2511 head impacts from a combination of head model simulations and on-field college football and mixed martial arts impacts.The proposed deep learning head model can calculate the maximum principal strain (Green Lagrange) for every element in the entire brain in less than 0.001 s with an average root mean squared error of 0.022 and a standard deviation of 0.001 over twenty repeats with random data partition and model initialization.Trained and tested using the dataset of 2511 head impacts, this model can be applied to various sports in the calculation of brain strain with accuracy, and its applicability can even further be extended by incorporating data from other types of head impacts.In addition to the potential clinical application in real-time brain deformation monitoring, this model will help researchers estimate the brain strain from a large number of head impacts more efficiently than using FE models.

    View details for DOI 10.1109/TBME.2021.3073380

  • Optimizing the Frame Duration for Data-Driven Rigid Motion Estimation in Brain PET Imaging. Medical physics Spangler-Bickell, M. G., Hurley, S. A., Deller, T. W., Jansen, F. n., Bettinardi, V. n., Carlson, M. n., Zeineh, M. n., Zaharchuk, G. n., McMillan, A. B. 2021


    Data-driven rigid motion estimation for PET brain imaging is usually performed using data frames sampled at low temporal resolution to reduce the overall computation time and to provide adequate signal-to-noise ratio in the frames. In recent work it has been demonstrated that list-mode reconstructions of ultra-short frames are sufficient for motion estimation and can be performed very quickly. In this work we take the approach of using image-based registration of reconstructions of very short frames for data-driven motion estimation, and optimize a number of reconstruction and registration parameters (frame duration, MLEM iterations, image pixel size, post-smoothing filter, reference image creation, and registration metric) to ensure accurate registrations while maximizing temporal resolution and minimizing total computation time.Data from 18 F-uorodeoxyglucose (FDG) and 18 F-orbetaben (FBB) tracer studies with varying count rates are analysed, for PET/MR and PET/CT scanners. For framed reconstructions using various parameter combinations inter-frame motion is simulated and image-based registrations are performed to estimate that motion.For FDG and FBB tracers using 4 × 105 true and scattered coincidence events per frame ensures that 95% of the registrations will be accurate to within 1 mm of the ground truth. This corresponds to a frame duration of 0:5 - 1 sec for typical clinical PET activity levels. Using 4 MLEM iterations with no subsets, a transaxial pixel size of 4 mm, a post-smoothing filter with 4-6 mm full-width at half-maximum, and averaging two or more frames to create the reference image provides an optimal set of parameters to produce accurate registrations while keeping the reconstruction and processing time low.It is shown that very short frames (≤ 1 sec) can be used to provide accurate and quick data-driven rigid motion estimates for use in an event-by-event motion corrected reconstruction.

    View details for DOI 10.1002/mp.14889

    View details for PubMedID 33880778

  • True ultra-low-dose amyloid PET/MRI enhanced with deep learning for clinical interpretation. European journal of nuclear medicine and molecular imaging Chen, K. T., Toueg, T. N., Koran, M. E., Davidzon, G. n., Zeineh, M. n., Holley, D. n., Gandhi, H. n., Halbert, K. n., Boumis, A. n., Kennedy, G. n., Mormino, E. n., Khalighi, M. n., Zaharchuk, G. n. 2021


    While sampled or short-frame realizations have shown the potential power of deep learning to reduce radiation dose for PET images, evidence in true injected ultra-low-dose cases is lacking. Therefore, we evaluated deep learning enhancement using a significantly reduced injected radiotracer protocol for amyloid PET/MRI.Eighteen participants underwent two separate 18F-florbetaben PET/MRI studies in which an ultra-low-dose (6.64 ± 3.57 MBq, 2.2 ± 1.3% of standard) or a standard-dose (300 ± 14 MBq) was injected. The PET counts from the standard-dose list-mode data were also undersampled to approximate an ultra-low-dose session. A pre-trained convolutional neural network was fine-tuned using MR images and either the injected or sampled ultra-low-dose PET as inputs. Image quality of the enhanced images was evaluated using three metrics (peak signal-to-noise ratio, structural similarity, and root mean square error), as well as the coefficient of variation (CV) for regional standard uptake value ratios (SUVRs). Mean cerebral uptake was correlated across image types to assess the validity of the sampled realizations. To judge clinical performance, four trained readers scored image quality on a five-point scale (using 15% non-inferiority limits for proportion of studies rated 3 or better) and classified cases into amyloid-positive and negative studies.The deep learning-enhanced PET images showed marked improvement on all quality metrics compared with the low-dose images as well as having generally similar regional CVs as the standard-dose. All enhanced images were non-inferior to their standard-dose counterparts. Accuracy for amyloid status was high (97.2% and 91.7% for images enhanced from injected and sampled ultra-low-dose data, respectively) which was similar to intra-reader reproducibility of standard-dose images (98.6%).Deep learning methods can synthesize diagnostic-quality PET images from ultra-low injected dose simultaneous PET/MRI data, demonstrating the general validity of sampled realizations and the potential to reduce dose significantly for amyloid imaging.

    View details for DOI 10.1007/s00259-020-05151-9

    View details for PubMedID 33416955

  • High Quality Isotropic Whole-body PET Imaging Using MR Priors Khalighi, M., Deller, T., Spangler-Bickell, M., Wangerin, K., Holley, D., Halbert, K., Zeineh, M., Zaharchuk, G., Mormino, E., Iagaru, A., Moseley, M. SOC NUCLEAR MEDICINE INC. 2020
  • 3D Printed Models of Brain and Intracranial Electrodes for Epilepsy Education and Surgical Planning Ardestani, P., Gifford, K., Bogart, K., Walters, S., Zeineh, M., Fleischmann, D., Razavi, B. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Electrophysiological dynamics of antagonistic brain networks reflect attentional fluctuations. Nature communications Kucyi, A., Daitch, A., Raccah, O., Zhao, B., Zhang, C., Esterman, M., Zeineh, M., Halpern, C. H., Zhang, K., Zhang, J., Parvizi, J. 2020; 11 (1): 325


    Neuroimaging evidence suggests that the default mode network (DMN) exhibits antagonistic activity with dorsal attention (DAN) and salience (SN) networks. Here we use human intracranial electroencephalography to investigate the behavioral relevance of fine-grained dynamics within and between these networks. The three networks show dissociable profiles of task-evoked electrophysiological activity, best captured in the high-frequency broadband (HFB; 70-170Hz) range. On the order of hundreds of milliseconds, HFB responses peak fastest in the DAN, at intermediate speed in the SN, and slowest in the DMN. Lapses of attention (behavioral errors) are marked by distinguishable patterns of both pre- and post-stimulus HFB activity within each network. Moreover, the magnitude of temporally lagged, negative HFB coupling between the DAN and DMN (but not SN and DMN) is associated with greater sustained attention performance and is reduced during wakeful rest. These findings underscore the behavioral relevance of temporally delayed coordination between antagonistic brain networks.

    View details for DOI 10.1038/s41467-019-14166-2

    View details for PubMedID 31949140

  • Validation and Comparison of Instrumented Mouthguards for Measuring Head Kinematics and Assessing Brain Deformation in Football Impacts. Annals of biomedical engineering Liu, Y. n., Domel, A. G., Yousefsani, S. A., Kondic, J. n., Grant, G. n., Zeineh, M. n., Camarillo, D. B. 2020


    Because of the rigid coupling between the upper dentition and the skull, instrumented mouthguards have been shown to be a viable way of measuring head impact kinematics for assisting in understanding the underlying biomechanics of concussions. This has led various companies and institutions to further develop instrumented mouthguards. However, their use as a research tool for understanding concussive impacts makes quantification of their accuracy critical, especially given the conflicting results from various recent studies. Here we present a study that uses a pneumatic impactor to deliver impacts characteristic to football to a Hybrid III headform, in order to validate and compare five of the most commonly used instrumented mouthguards. We found that all tested mouthguards gave accurate measurements for the peak angular acceleration, the peak angular velocity, brain injury criteria values (mean average errors < 13, 8, 13%, respectively), and the mouthguards with long enough sampling time windows are suitable for a convolutional neural network-based brain model to calculate the brain strain (mean average errors < 9%). Finally, we found that the accuracy of the measurement varies with the impact locations yet is not sensitive to the impact velocity for the most part.

    View details for DOI 10.1007/s10439-020-02629-3

    View details for PubMedID 32989591

  • Substantia Nigra Volume Dissociates Bradykinesia and Rigidity from Tremor in Parkinson's Disease: A 7 Tesla Imaging Study. Journal of Parkinson's disease Poston, K. L., Ua Cruadhlaoich, M. A., Santoso, L. F., Bernstein, J. D., Liu, T., Wang, Y., Rutt, B., Kerchner, G. A., Zeineh, M. M. 2020; 10 (2): 591–604


    BACKGROUND: In postmortem analysis of late stage Parkinson's disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor.OBJECTIVE: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI.METHODS: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty).RESULTS: We found that smaller SN correlated with longer disease duration (r = -0.49, p = 0.004), more severe MDS-UPDRS motor score (r = -0.42, p = 0.016), and more severe bradykinesia-rigidity subscore (r = -0.47, p = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume.CONCLUSIONS: In mild-to-moderate PD, SN volume relates to motor manifestations in a motor domain-specific and laterality-dependent manner. Non-invasive in vivo 7.0 Tesla QSM may serve as a biomarker in longitudinal studies of SN atrophy and in studies of people at risk for developing PD.

    View details for DOI 10.3233/JPD-191890

    View details for PubMedID 32250317

  • The ENIGMA sports injury working group:- an international collaboration to further our understanding of sport-related brain injury. Brain imaging and behavior Koerte, I. K., Esopenko, C. n., Hinds, S. R., Shenton, M. E., Bonke, E. M., Bazarian, J. J., Bickart, K. C., Bigler, E. D., Bouix, S. n., Buckley, T. A., Choe, M. C., Echlin, P. S., Gill, J. n., Giza, C. C., Hayes, J. n., Hodges, C. B., Irimia, A. n., Johnson, P. K., Kenney, K. n., Levin, H. S., Lin, A. P., Lindsey, H. M., Lipton, M. L., Max, J. E., Mayer, A. R., Meier, T. B., Merchant-Borna, K. n., Merkley, T. L., Mills, B. D., Newsome, M. R., Porfido, T. n., Stephens, J. A., Tartaglia, M. C., Ware, A. L., Zafonte, R. D., Zeineh, M. M., Thompson, P. M., Tate, D. F., Dennis, E. L., Wilde, E. A., Baron, D. n. 2020


    Sport-related brain injury is very common, and the potential long-term effects include a wide range of neurological and psychiatric symptoms, and potentially neurodegeneration. Around the globe, researchers are conducting neuroimaging studies on primarily homogenous samples of athletes. However, neuroimaging studies are expensive and time consuming, and thus current findings from studies of sport-related brain injury are often limited by small sample sizes. Further, current studies apply a variety of neuroimaging techniques and analysis tools which limit comparability among studies. The ENIGMA Sports Injury working group aims to provide a platform for data sharing and collaborative data analysis thereby leveraging existing data and expertise. By harmonizing data from a large number of studies from around the globe, we will work towards reproducibility of previously published findings and towards addressing important research questions with regard to diagnosis, prognosis, and efficacy of treatment for sport-related brain injury. Moreover, the ENIGMA Sports Injury working group is committed to providing recommendations for future prospective data acquisition to enhance data quality and scientific rigor.

    View details for DOI 10.1007/s11682-020-00370-y

    View details for PubMedID 32720179

  • Rigid Motion Correction for Brain PET/MR Imaging using Optical Tracking. IEEE transactions on radiation and plasma medical sciences Spangler-Bickell, M. G., Khalighi, M. M., Hoo, C., DiGiacomo, P. S., Maclaren, J., Aksoy, M., Rettmann, D., Bammer, R., Zaharchuk, G., Zeineh, M., Jansen, F. 2019; 3 (4): 498-503


    A significant challenge during high-resolution PET brain imaging on PET/MR scanners is patient head motion. This challenge is particularly significant for clinical patient populations who struggle to remain motionless in the scanner for long periods of time. Head motion also affects the MR scan data. An optical motion tracking technique, which has already been demonstrated to perform MR motion correction during acquisition, is used with a list-mode PET reconstruction algorithm to correct the motion for each recorded event and produce a corrected reconstruction. The technique is demonstrated on real Alzheimer's disease patient data for the GE SIGNA PET/MR scanner.

    View details for DOI 10.1109/TRPMS.2018.2878978

    View details for PubMedID 31396580

    View details for PubMedCentralID PMC6686883

  • Stability of Blood Biomarkers of Traumatic Brain Injury. Journal of neurotrauma Rezaii, P., Grant, G., Zeineh, M., Richardson, K. J., Coburn, M. L., Bet, A. M., Weber, A., Jiang, B., Li, Y., Ubungen, K., Routh, G., Wheatcroft, A. M., Paulino, A., Hayes, R. L., Steinberg, G. K., Wintermark, M. 2019


    Blood biomarker tests were recently approved for clinical diagnosis of traumatic brain injury (TBI), yet there are still fundamental questions which need attention. One such question is the stability of putative biomarkers in blood over the course of several days after injury if the sample is unable to be processed into serum or plasma and stored at low temperatures. Blood may not be able to be stored at ultra-low temperatures in austere combat or sports environments. In this prospective study of 20 adult patients with positive head computed tomography imaging findings, the stability of three biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], and S100B) in whole blood and in serum stored at 4-5°C was evaluated over the course of 72 hours after blood collection. The amount of time whole blood and serum were refrigerated had no significant effect on GFAP concentration in plasma obtained from whole blood and in serum (p=0.6256 and p=0.3687, respectively), UCH-L1 concentration in plasma obtained from whole blood and in serum (p=0.0611 and p=0.5189, respectively), and S100B concentration in serum (p=0.4663). Concentration levels of GFAP, UCH-L1, and S100B in blood collected from patients with TBI were found to be stable at 4-5°C for at least 3 days after blood draw. This study suggests that the levels of the three diagnostic markers above are still valid for diagnostic TBI tests if the sample is stored in 4-5°C refrigerated conditions.

    View details for PubMedID 30968744

  • Nusinersen Efficacy in Adults with Spinal Muscular Atrophy Day, J., Wolford, C., MacPherson, C., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Zeineh, M., Sampson, J., Hagerman, K., Duong, T. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Validation of the NeuroImaging Radiological Interpretation System for Acute Traumatic Brain Injury. Journal of computer assisted tomography Zhou, B. n., Ding, V. Y., Li, Y. n., Ball, R. L., Jiang, B. n., Zhu, G. n., Boothroyd, D. n., Zeineh, M. n., Gean, A. n., Wintermark, M. n. 2019


    The aim of the study was to refine and validate the NeuroImaging Radiological Interpretation System (NIRIS), which was developed to predict management and clinical outcome based on noncontrast head computerized tomography findings in patients suspected of acute traumatic brain injury (TBI).We assessed the performance of the NIRIS score in a prospective, single-center cohort of patients suspected of TBI (n = 648) and compared the performance of NIRIS with that of the Marshall and Rotterdam scoring systems. We also revised components of the NIRIS scoring system using decision tree methodologies implemented on pooled data from the retrospective and prospective studies (N = 1190).The NIRIS performed similarly to the Marshall and Rotterdam scoring systems in predicting mortality and markedly better in terms of predicting more granular elements of disposition and management of TBI patients, such as admission, follow-up imaging, intensive care unit stay, and neurosurgical procedures. The revised NIRIS classification correctly predicted disposition and outcome in 91.2% (331/363) after excluding patients with other major extracranial traumatic injuries or intracranial nontraumatic injuries.The present study further demonstrates the predictive value of NIRIS in guiding standardized clinical management and decision-making regarding treatment options for TBI patients.

    View details for DOI 10.1097/RCT.0000000000000913

    View details for PubMedID 31490891

  • Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease. NeuroImage. Clinical La, C. n., Linortner, P. n., Bernstein, J. D., Ua Cruadhlaoich, M. A., Fenesy, M. n., Deutsch, G. K., Rutt, B. K., Tian, L. n., Wagner, A. D., Zeineh, M. n., Kerchner, G. A., Poston, K. L. 2019; 23: 101824


    Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life.We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD.In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05).In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

    View details for PubMedID 31054380

  • Experience using Spinraza to treat adults with spinal muscular atrophy Day, J., Wolford, C., Macpherson, C., Hagerman, K., Paulose, S., Zeineh, M., Martens, W., McDermott, M., Darras, B., De Vivo, D., Cunningham, Z., Finkel, R., Sampson, J., Duong, T. PERGAMON-ELSEVIER SCIENCE LTD. 2018: S81
  • RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke. Stroke Ito, M., Aswendt, M., Lee, A. G., Ishizaka, S., Cao, Z., Wang, E. H., Levy, S. L., Smerin, D. L., McNab, J. A., Zeineh, M., Leuze, C., Goubran, M., Cheng, M. Y., Steinberg, G. K. 2018; 49 (9): 2191-2199


    Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.

    View details for DOI 10.1161/STROKEAHA.118.021508

    View details for PubMedID 30354987

    View details for PubMedCentralID PMC6205731

  • Resting-State Functional MRI: Everything That Nonexperts Have Always Wanted to Know. AJNR. American journal of neuroradiology Lv, H., Wang, Z., Tong, E., Williams, L. M., Zaharchuk, G., Zeineh, M., Goldstein-Piekarski, A. N., Ball, T. M., Liao, C., Wintermark, M. 2018; 39 (8): 1390–99


    Resting-state fMRI was first described by Biswal et al in 1995 and has since then been widely used in both healthy subjects and patients with various neurologic, neurosurgical, and psychiatric disorders. As opposed to paradigm- or task-based functional MR imaging, resting-state fMRI does not require subjects to perform any specific task. The low-frequency oscillations of the resting-state fMRI signal have been shown to relate to the spontaneous neural activity. There are many ways to analyze resting-state fMRI data. In this review article, we will briefly describe a few of these and highlight the advantages and limitations of each. This description is to facilitate the adoption and use of resting-state fMRI in the clinical setting, helping neuroradiologists become familiar with these techniques and applying them for the care of patients with neurologic and psychiatric diseases.

    View details for PubMedID 29348136

  • Resting-State Functional MRI: Everything That Nonexperts Have Always Wanted to Know AMERICAN JOURNAL OF NEURORADIOLOGY Lv, H., Wang, Z., Tong, E., Williams, L. M., Zaharchuk, G., Zeineh, M., Goldstein-Piekarski, A. N., Ball, T. M., Liao, C., Wintermark, M. 2018; 39 (8): 1390–99

    View details for DOI 10.3174/ajnr.A5527

    View details for Web of Science ID 000441271400010

  • NeuroImaging Radiological Interpretation System (NIRIS) for Acute Traumatic Brain Injury (TBI). Journal of neurotrauma Wintermark, M., Li, Y., Ding, V. Y., Xu, Y., Jiang, B., Ball, R. L., Zeineh, M., Gean, A., Sanelli, P. 2018


    To develop an outcome-based NeuroImaging Radiological Interpretation System (NIRIS) for acute traumatic brain injury (TBI) patients that would standardize the interpretation of non-contrast head CTs and consolidate imaging findings into ordinal severity categories that would inform specific patient management actions and that could be used as a clinical decision support tool. We retrospectively identified all patients transported to our emergency department by ambulance or helicopter, for whom a trauma alert was triggered per established criteria and who underwent a non-contrast head CT due to suspicion of TBI, between November 2015 and April 2016. Two neuroradiologists reviewed the non-contrast head CTs and assessed the TBI imaging common data elements (CDEs), as defined by the National Institutes of Health (NIH). Using descriptive statistics and receiver operating characteristic curve analyses to identify imaging characteristics and associated thresholds that best distinguished among outcomes, we classified patients into five mutually exclusive categories: 0-discharge from the emergency department; 1-follow-up brain imaging and/or admission; 2-admission to an advanced care unit; 3-neurosurgical procedure; 4-death up to 6 months after TBI. Sensitivity of NIRIS with respect to each patient's true outcome was then evaluated and compared to that of the Marshall and Rotterdam scoring systems for TBI. In our cohort of 542 TBI patients, NIRIS was developed to predict discharge (182 patients), follow-up brain imaging/admission (187 patients), need for advanced care unit (151 patients). neurosurgical procedures (10 patients) and death (12 patients). NIRIS performed similarly to the Marshall and Rotterdam scoring systems in terms of predicting mortality. We developed an interpretation system for neuroimaging using the CDEs that informs specific patient management actions and could be used as a clinical decision support tool for patients with TBI. Our NIRIS classification, with evidence-based grouping of the CDEs into actionable categories, will need to be validated in different TBI populations.

    View details for PubMedID 29665763

  • Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor. NeuroImage. Clinical Tian, Q., Wintermark, M., Jeffrey Elias, W., Ghanouni, P., Halpern, C. H., Henderson, J. M., Huss, D. S., Goubran, M., Thaler, C., Airan, R., Zeineh, M., Pauly, K. B., McNab, J. A. 2018; 19: 572–80


    Purpose: To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET).Materials and methods: Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment.Results: The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = -0.929, -0.75, -0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post-treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = -0.719, -0.976, -0.707, -0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively).Conclusion: Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy.

    View details for PubMedID 29984165

  • The separate effects of lipids and proteins on brain MRI contrast revealed through tissue clearing. NeuroImage Leuze, C., Aswendt, M., Ferenczi, E., Liu, C. W., Hsueh, B., Goubran, M., Tian, Q., Steinberg, G., Zeineh, M. M., Deisseroth, K., McNab, J. A. 2017


    Despite the widespread use of magnetic resonance imaging (MRI) of the brain, the relative contribution of different biological components (e.g. lipids and proteins) to structural MRI contrasts (e.g., T1, T2, T2*, proton density, diffusion) remains incompletely understood. This limitation can undermine the interpretation of clinical MRI and hinder the development of new contrast mechanisms. Here, we determine the respective contribution of lipids and proteins to MRI contrast by removing lipids and preserving proteins in mouse brains using CLARITY. We monitor the temporal dynamics of tissue clearance via NMR spectroscopy, protein assays and optical emission spectroscopy. MRI of cleared brain tissue showed: 1) minimal contrast on standard MRI sequences; 2) increased relaxation times; and 3) diffusion rates close to free water. We conclude that lipids, present in myelin and membranes, are a dominant source of MRI contrast in brain tissue.

    View details for DOI 10.1016/j.neuroimage.2017.04.021

    View details for PubMedID 28411157

  • Early uptake Amyloid PET imaging correlates strongly with cerebral blood flow based on arterial spin labeling MRI: a simultaneous PET/MRI study Zaharchuk, G., Fan, A., Gulaka, P., Guo, J., Poston, K., Greicius, M., Sha, S., Vasanawala, M., Zeineh, M. SAGE PUBLICATIONS INC. 2017: 224–25
  • Reducing Functional MR Imaging Acquisition Times by Optimizing Workflow. Radiographics Chwang, W. B., Iv, M., Smith, J., Kalnins, A., Mickelsen, J., Bammer, R., Fleischmann, D., Larson, D. B., Wintermark, M., Zeineh, M. 2017; 37 (1): 316-322


    Functional magnetic resonance (MR) imaging is a complex, specialized examination that is able to noninvasively measure information critical to patient care such as hemispheric language lateralization ( 1 ). Diagnostic functional MR imaging requires extensive patient interaction as well as the coordinated efforts of the entire health care team. We observed in our practice at an academic center that the times to perform functional MR imaging examinations were excessively lengthy, making scheduling of the examination difficult. The purpose of our project was to reduce functional MR imaging acquisition times by increasing the efficiency of our workflow, using specific quality tools to drive improvement of functional MR imaging. We assembled a multidisciplinary team and retrospectively reviewed all functional MR imaging examinations performed at our institution from January 2013 to August 2015. We identified five key drivers: (a) streamlined protocols, (b) consistent patient monitoring, (c) clear visual slides and audio, (d) improved patient understanding, and (e) minimized patient motion. We then implemented four specific interventions over a period of 10 months: (a) eliminating intravenous contrast medium, (b) reducing repeated language paradigms, (c) updating technologist and physician checklists, and (d) updating visual slides and audio. Our mean functional MR imaging acquisition time was reduced from 76.3 to 53.2 minutes, while our functional MR imaging examinations remained of diagnostic quality. As a result, we reduced our routine scheduling time for functional MR imaging from 2 hours to 1 hour, improving patient comfort and satisfaction as well as saving time for additional potential MR imaging acquisitions. Our efforts to optimize functional MR imaging workflow constitute a practice quality improvement project that is beneficial for patient care and can be applied broadly to other functional MR imaging practices. (©)RSNA, 2017.

    View details for DOI 10.1148/rg.2017160035

    View details for PubMedID 28076003

  • MRI and histopathologic study of a novel cholesterol-fed rabbit model of xanthogranuloma. Journal of magnetic resonance imaging Chen, Y., Hamilton, A. M., Parkins, K. M., Wang, J., Rogers, K. A., Zeineh, M. M., Rutt, B. K., Ronald, J. A. 2016; 44 (3): 673-682


    To develop a rabbit model of xanthogranuloma based on supplementation of dietary cholesterol. The aim of this study was to analyze the xanthogranulomatous lesions using magnetic resonance imaging (MRI) and histological examination.Rabbits were fed a low-level cholesterol (CH) diet (n = 10) or normal chow (n = 5) for 24 months. In vivo brain imaging was performed on a 3T MR system using fast imaging employing steady state acquisition, susceptibility-weighted imaging, spoiled gradient recalled, T1 -weighted inversion recovery imaging and T1 relaxometry, PD-weighted and T2 -weighted spin-echo imaging and T2 relaxometry, iterative decomposition of water and fat with echo asymmetry and least-squares estimation, ultrashort TE MRI (UTE-MRI), and T2* relaxometry. MR images were evaluated using a Likert scale for lesion presence and quantitative analysis of lesion size, ventricular volume, and T1 , T2 , and T2* values of lesions was performed. After imaging, brain specimens were examined using histological methods.In vivo MRI revealed that 6 of 10 CH-fed rabbits developed lesions in the choroid plexus. Region-of-interest analysis showed that for CH-fed rabbits the mean lesion volume was 8.5 ± 2.6 mm(3) and the volume of the lateral ventricle was significantly increased compared to controls (P < 0.01). The lesions showed significantly shorter mean T2 values (35 ± 12 msec, P < 0.001), longer mean T1 values (1581 ± 146 msec, P < 0.05), and shorter T2* values (22 ± 13 msec, P < 0.001) compared to adjacent brain structures. The ultrashort T2* components were visible using UTE-MRI. Histopathologic evaluation of lesions demonstrated features of human xanthogranuloma.Rabbits fed a low-level CH diet develop sizable intraventricular masses that have similar histopathological features as human xanthogranuloma. Multiparametric MRI techniques were able to provide information about the complex composition of these lesions. J. Magn. Reson. Imaging 2016;44:673-682.

    View details for DOI 10.1002/jmri.25213

    View details for PubMedID 26921220

    View details for PubMedCentralID PMC4983483

  • Non-Relative Value Unit-Generating Activities Represent One-Fifth of Academic Neuroradiologist Productivity. AJNR. American journal of neuroradiology Wintermark, M., Zeineh, M., Zaharchuk, G., Srivastava, A., Fischbein, N. 2016; 37 (7): 1206-1208


    A neuroradiologist's activity includes many tasks beyond interpreting relative value unit-generating imaging studies. Our aim was to test a simple method to record and quantify the non-relative value unit-generating clinical activity represented by consults and clinical conferences, including tumor boards.Four full-time neuroradiologists, working an average of 50% clinical and 50% academic activity, systematically recorded all the non-relative value unit-generating consults and conferences in which they were involved during 3 months by using a simple, Web-based, computer-based application accessible from smartphones, tablets, or computers. The number and type of imaging studies they interpreted during the same period and the associated relative value units were extracted from our billing system.During 3 months, the 4 neuroradiologists working an average of 50% clinical activity interpreted 4241 relative value unit-generating imaging studies, representing 8152 work relative value units. During the same period, they recorded 792 non-relative value unit-generating study reviews as part of consults and conferences (not including reading room consults), representing 19% of the interpreted relative value unit-generating imaging studies.We propose a simple Web-based smartphone app to record and quantify non-relative value unit-generating activities including consults, clinical conferences, and tumor boards. The quantification of non-relative value unit-generating activities is paramount in this time of a paradigm shift from volume to value. It also represents an important tool for determining staffing levels, which cannot be performed on the basis of relative value unit only, considering the importance of time spent by radiologists on non-relative value unit-generating activities. It may also influence payment models from medical centers to radiology departments or practices.

    View details for DOI 10.3174/ajnr.A4701

    View details for PubMedID 26939630

  • Diffusion Tensor Imaging of TBI: Potentials and Challenges. Topics in magnetic resonance imaging Douglas, D. B., Iv, M., Douglas, P. K., Anderson, A., Vos, S. B., Bammer, R., Zeineh, M., Wintermark, M. 2015; 24 (5): 241-251


    Neuroimaging plays a critical role in the setting in traumatic brain injury (TBI). Diffusion tensor imaging (DTI) is an advanced magnetic resonance imaging technique that is capable of providing rich information on the brain's neuroanatomic connectome. The purpose of this article is to systematically review the role of DTI and advanced diffusion techniques in the setting of TBI, including diffusion kurtosis imaging (DKI), neurite orientation dispersion and density imaging, diffusion spectrum imaging, and q-ball imaging. We discuss clinical applications of DTI and review the DTI literature as it pertains to TBI. Despite the continued advancements in DTI and related diffusion techniques over the past 20 years, DTI techniques are sensitive for TBI at the group level only and there is insufficient evidence that DTI plays a role at the individual level. We conclude by discussing future directions in DTI research in TBI including the role of machine learning in the pattern classification of TBI.

    View details for DOI 10.1097/RMR.0000000000000062

    View details for PubMedID 26502306

  • Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol NEUROIMAGE Yushkevich, P. A., Amaral, R. S., Augustinack, J. C., Bender, A. R., Bernstein, J. D., Boccardi, M., Bocchetta, M., Burggren, A. C., Carr, V. A., Chakravarty, M. M., Chetelat, G., Daugherty, A. M., Davachi, L., Ding, S., Ekstrom, A., Geerlings, M. I., Hassan, A., Huang, Y., Iglesias, J. E., La Joie, R., Kerchner, G. A., LaRocque, K. F., Libby, L. A., Malykhin, N., Mueller, S. G., Olsen, R. K., Palombo, D. J., Parekh, M. B., Pluta, J. B., Preston, A. R., Pruessner, J. C., Ranganath, C., Raz, N., Schlichting, M. L., Schoemaker, D., Singh, S., Stark, C. E., Suthana, N., Tompary, A., Turowski, M. M., Van Leemput, K., Wagner, A. D., Wang, L., Winterburn, J. L., Wisse, L. E., Yassa, M. A., Zeineh, M. M. 2015; 111: 526-541


    An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

    View details for DOI 10.1016/j.neuroimage.2015.01.004

    View details for PubMedID 25596463

  • Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clinical lung cancer Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2014; 15 (3): 202-206


    Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.

    View details for DOI 10.1016/j.cllc.2013.12.009

    View details for PubMedID 24524822

  • Shared vulnerability of two synaptically-connected medial temporal lobe areas to age and cognitive decline: a seven tesla magnetic resonance imaging study. journal of neuroscience Kerchner, G. A., Bernstein, J. D., Fenesy, M. C., Deutsch, G. K., Saranathan, M., Zeineh, M. M., Rutt, B. K. 2013; 33 (42): 16666-16672


    The medial temporal lobe (MTL) is the first brain area to succumb to neurofibrillary tau pathology in Alzheimer's disease (AD). Postmortem human tissue evaluation suggests that this pathology propagates in an ordered manner, with the entorhinal cortex (ERC) and then CA1 stratum radiatum and stratum lacunosum-moleculare (CA1-SRLM)-two monosynaptically connected structures-exhibiting selective damage. Here, we hypothesized that, if ERC and CA1-SRLM share an early vulnerability to AD pathology, then atrophy should occur in a proportional manner between the two structures. We tested this hypothesis in living humans, using ultra-high field 7.0 T MRI to make fine measurements of MTL microstructure. Among a pool of age-matched healthy controls and patients with amnestic mild cognitive impairment and mild AD, we found a significant correlation between ERC and CA1-SRLM size that could not be explained by global atrophy affecting the MTL. Of the various structures that contribute axons or dendrites into the CA1-SRLM neuropil, only ERC emerged as a significant predictor of CA1-SRLM size in a linear regression analysis. In contrast, other synaptically connected elements of the MTL did not exhibit size correlations. CA1-SRLM and ERC structural covariance was significant for older controls and not patients, whereas the opposite pattern emerged for a correlation between CA1-SRLM and episodic memory performance. Interestingly, CA1-SRLM and ERC were the only MTL structures to atrophy in older controls relative to a younger comparison group. Together, these findings suggest that ERC and CA1-SRLM share vulnerability to both age and AD-associated atrophy.

    View details for DOI 10.1523/JNEUROSCI.1915-13.2013

    View details for PubMedID 24133269

    View details for PubMedCentralID PMC3797378

  • Hippocampal CA1 apical neuropil atrophy and memory performance in Alzheimer's disease NEUROIMAGE Kerchner, G. A., Deutsch, G. K., Zeineh, M., Dougherty, R. F., Saranathan, M., Rutt, B. K. 2012; 63 (1): 194-202


    Memory loss is often the first and most prominent symptom of Alzheimer's disease (AD), coinciding with the spread of neurofibrillary pathology from the entorhinal cortex (ERC) to the hippocampus. The apical dendrites of hippocampal CA1 pyramidal neurons, in the stratum radiatum/stratum lacunosum-moleculare (SRLM), are among the earliest targets of this pathology, and atrophy of the CA1-SRLM is apparent in postmortem tissue from patients with mild AD. We previously demonstrated that CA1-SRLM thinning is also apparent in vivo, using ultra-high field 7-Tesla (7T) MRI to obtain high-resolution hippocampal microstructural imaging. Here, we hypothesized that CA1-SRLM thickness would correlate with episodic memory performance among patients with mild AD. We scanned nine patients, using an oblique coronal T2-weighted sequence through the hippocampal body with an in-plane resolution of 220 μm, allowing direct visual identification of subfields - dentate gyrus (DG)/CA3, CA2, CA1, and ERC - and hippocampal strata - SRLM and stratum pyramidale (SP). We present a novel semi-automated method of measuring stratal width that correlated well with manual measurements. We performed multi-domain neuropsychological evaluations that included three tests of episodic memory, yielding composite scores for immediate recall, delayed recall, and delayed recognition memory. Strong correlations occurred between delayed recall performance and the widths of CA1-SRLM (r(2)=0.69; p=0.005), CA1-SP (r(2)=0.5; p=0.034), and ERC (r(2)=0.62; p=0.012). The correlation between CA1-SRLM width and delayed recall lateralized to the left hemisphere. DG/CA3 size did not correlate significantly with any aspect of memory performance. These findings highlight a role for 7T hippocampal microstructural imaging in revealing focal structural pathology that correlates with the central cognitive feature of AD.

    View details for DOI 10.1016/j.neuroimage.2012.06.048

    View details for Web of Science ID 000308770300020

    View details for PubMedID 22766164

    View details for PubMedCentralID PMC3677969

  • Prolonged Survival in Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Metastases (LM) in the Modern Treatment Era Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S243–S243
  • Hippocampal CA1 Apical Neuropil Atrophy and Memory Performance in Alzheimer Disease Kerchner, G., Deutsch, G., Zeineh, M., Dougherty, R., Rutt, B. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI NEUROIMAGE Kitzler, H. H., Su, J., Zeineh, M., Harper-Little, C., Leung, A., Krernenchutzky, M., Deoni, S. C., Rutt, B. K. 2012; 59 (3): 2670-2677


    Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2=0.37; p<0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p<0.001) and discriminated relapsing-remitting from secondary-progressive patients (p<0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.

    View details for DOI 10.1016/j.neuroimage.2011.08.052

    View details for Web of Science ID 000299494000066

    View details for PubMedID 21920444

    View details for PubMedCentralID PMC3673309

  • Hippocampal CA1 Apical Neuropil Atrophy and Memory Performance in Alzheimer Disease Kerchner, G. A., Deutsch, G. K., Zeineh, M., Dougherty, R. F., Rutt, B. K. WILEY-BLACKWELL. 2012: S45
  • Challenges of High-resolution Diffusion Imaging of the Human Medial Temporal Lobe in Alzheimer Disease. Topics in magnetic resonance imaging Zeineh, M. M., Holdsworth, S., Skare, S., Atlas, S. W., Bammer, R. 2010; 21 (6): 355-365


    The human medial temporal lobe performs an essential role in memory formation and retrieval. Diseases involving the hippocampus such as Alzheimer disease present a unique opportunity for advanced imaging techniques to detect abnormalities at an early stage. In particular, it is possible that diffusion imaging will measure abnormal microarchitecture beyond the realm of macroscopic imaging. However, this task is formidable because of the detailed anatomy of the medial temporal lobe, the difficulties in obtaining high-quality diffusion images of adequate resolution, and the challenges in diffusion data processing. Moreover, it is unclear if any differences will be significant for an individual patient or simply groups of patients. Successful endeavors will need to address each of these challenges in an integrated fashion. The rewards of such analysis may be detection of microscopic disease in vivo, which could represent a landmark accomplishment for the field of neuroradiology.

    View details for DOI 10.1097/RMR.0b013e31823f6413

    View details for PubMedID 22158129

    View details for PubMedCentralID PMC3238799

  • Double reverse intestinal malrotation: a novel rotational anomaly and its surgical correction JOURNAL OF PEDIATRIC SURGERY Nehra, D., Zeineh, M., Rodriguez, F., Dutta, S. 2007; 42 (3): 578-581


    Reverse intestinal rotation is the rarest developmental anomaly of intestinal rotation and fixation. We present a case of an adolescent girl with chronic intermittent abdominal pain who was found to have a novel rotational abnormality that we have termed "double reverse intestinal malrotation." The imaging studies, operative findings, and the surgical correction are presented.

    View details for DOI 10.1016/j.jpedsurg.2006.10.061

    View details for Web of Science ID 000245002900028

    View details for PubMedID 17336206

  • Unfolding the human hippocampus with high resolution structural and functional MRI ANATOMICAL RECORD Zeineh, M. M., Engel, S. A., Thompson, P. M., Bookheimer, S. Y. 2001; 265 (2): 111-120


    The hippocampus is a region of the brain that is crucial to memory function. Functional neuroimaging allows for the noninvasive investigation of the neurophysiology of human memory by observing changes in blood flow in the brain. We have developed a technique that employs high-resolution functional magnetic resonance imaging (fMRI) in combination with cortical unfolding to provide activation maps of the hippocampal region that surpass in anatomic and functional detail other methods of in vivo human brain mapping of the medial temporal lobe. We explain the principles behind this method and illustrate its application to a novelty-encoding paradigm.

    View details for Web of Science ID 000167843100006

    View details for PubMedID 11323773

  • Rapid and effective correction of RF inhomogeneity for high field magnetic resonance imaging HUMAN BRAIN MAPPING Cohen, M. S., DuBois, R. M., Zeineh, M. M. 2000; 10 (4): 204-211


    The well-known variability in the distribution of high frequency electromagnetic fields in the human body causes problems in the analysis of structural information in high field magnetic resonance images. We describe a method of compensating for the purely intensity-based effects. In our simple and rapid correction algorithm, we first use statistical means to determine the background image noise level and the edges of the image features. We next populate all "noise" pixels with the mean signal intensity of the image features. These data are then smoothed by convolution with a gaussian filter using Fourier methods. Finally, the original data that are above the noise level are normalized to the smoothed images, thereby eliminating the lowest spatial frequencies in the final, corrected data. Processing of a 124 slice, 256 x 256 volume dataset requires under 70 sec on a laptop personal computer. Overall, the method is less prone to artifacts from edges or from sensitivity to absolute head position than are other correction techniques. Following intensity correction, the images demonstrated obvious qualitative improvement and, when subjected to automated segmentation tools, the accuracy of segmentation improved, in one example, from 35.3% to 84.7% correct, as compared to a manually-constructed gold standard.

    View details for Web of Science ID 000088595200006

    View details for PubMedID 10949058