Bio

Bio


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 an assistant professor of radiology since 2010. Combining clinical acumen in neuroradiology with advanced MRI acquisition and image processing as well as histologic validation, Dr. Zeineh hopes to advance the care of patients with neurodegenerative disorders. In particular, he is interested in Alzheimer's disease, sports-related mild traumatic brain injury, and chronic fatigue syndrome. Additionally, he is specifically interested and has over 20 years of experience studying hippocampal anatomy and pathology.

Clinical Focus


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

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: Neuroradiology, American Board of Radiology (2011)
  • Fellowship:Stanford University - Fellowship (2009) CA
  • Board Certification: Diagnostic Radiology, American Board of Radiology (2008)
  • Residency:Stanford University - Fellowship (2008) CA

Teaching

2019-20 Courses


Stanford Advisees


Publications

All Publications


  • 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

    Abstract

    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

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

    Abstract

    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

  • 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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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): 2191–99
  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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): 2191–99

    Abstract

    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 PubMedID 30354987

  • 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

    Abstract

    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

    Abstract

    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

  • 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
  • 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

    Abstract

    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

  • 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): 315-321

    Abstract

    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 Web of Science ID 000397205200021

  • 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

    Abstract

    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

  • 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

    Abstract

    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 PubMedID 28411157

  • 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

    Abstract

    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

  • 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

    Abstract

    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

    Abstract

    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

  • 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., Gräßel, D., Goubran, M., Wree, A., Woods, R., Amunts, K., Zilles, K. 2016

    Abstract

    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 PubMedID 26874183

  • Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR. EJNMMI physics Goubran, M., Douglas, D., Chao, S., Quon, A., Tripathi, P., Holley, D., Vasanawala, M., Zaharchuk, G., Zeineh, M. 2015; 2: A73-?

    View details for DOI 10.1186/2197-7364-2-S1-A73

    View details for PubMedID 26956334

  • Correlation between arterial spin labeling MRI and dynamic FDG on PET-MR in Alzheimer's disease and non-Alzhiemer's disease patients. EJNMMI physics Douglas, D., Goubran, M., Wilson, E., Xu, G., Tripathi, P., Holley, D., Chao, S., Wintermark, M., Quon, A., Zeineh, M., Vasanawala, M., Zaharchuk, G. 2015; 2: A83-?

    View details for DOI 10.1186/2197-7364-2-S1-A83

    View details for PubMedID 26956345

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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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 Web of Science ID 000358803400005

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease. Neurosurgical focus Ali, R., Goubran, M., Choudhri, O., Zeineh, M. M. 2015; 39 (5): E4

    Abstract

    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 PubMedID 26646928

  • 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

    Abstract

    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

    Abstract

    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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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

  • 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

    Abstract

    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