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  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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