Search

Background. Preformed donor-specific HLA antibodies (DSA) are a well-known risk factor in kidney transplantation. There is still considerable debate, however, about the optimal risk stratification among patients with preformed DSA. Additionally, data on the prognostic value of different crossmatch assays in DSA-positive patients are scarce. Methods. DSA-positive living kidney transplant recipients were selected from a multicenter study examining 4233 consecutive renal transplants. An additional 7 patients from 2 further centers were included. Flow cytometric crossmatches (FXM), Luminex-based crossmatches, and virtual crossmatches based on C1q- and C3d-binding antibodies (C1qXM and C3dXM) were performed retrospectively using pretransplant sera and lymphocytes isolated from fresh samples. These samples were obtained from 44 donor and recipient pairs from 12 centers. Clinical outcome data and the control group without DSA were compiled from the previous study and were supplemented by data on 10-y death-censored graft survival (10yGS). Results. Between 19% (C3dXM) and 46% (FXM) of crossmatches were positive. Crossmatch-positive patients showed high incidences of antibody-mediated rejection (AMR) within 6 mo (up to 60% in B-cell FXM+ patients). The incidence of AMR in crossmatch-negative patients ranged between 5% (FXM−) and 13% (C1qXM−). 10yGS was significantly impaired in patients with positive T-cell FXM and total FXM compared with both patients without DSA and those with DSA with negative FXM. Conclusions. Especially FXM are useful for risk stratification, as the outcome of DSA-positive, FXM-negative patients is similar to that of DSA-negative patients, whereas FXM-positive patients have both more AMR and decreased 10yGS. Because of their lower sensitivity, the significance of Luminex-based crossmatches, C1qXM, and C3dXM would have to be examined in patients with stronger DSA.

Background: Aortic valve calcification correlates with the severity of aortic valve stenosis and a high calcium score is associated with conduction disturbances and paravalvular leakage after transcatheter aortic valve replacement. The 3mensio Structural Heart is a semiautomated software package to facilitate aortic root analysis by multislice computed tomography.The aim of the contemporary study is to validate a semiautomated calcium quantification scoring tool with a conventional manual calcium quantification tool. Methods: Fifty randomly selected patients who underwent multislice computed tomography for preprocedural planning were retrospectively selected to compare the semiautomated aortic valve Agatston calcium score by 3mensio with the manually obtained score using IntelliSpace Portal as standard reference. Results: Patients had a mean age of 76.7 ± 7.4 years and 60% were male. The median Agatston score was 3390 [interquartile range 1877-4509] with 3mensio and 3434 [interquartile range 1839-4620] with IntelliSpace.The mean difference was -0.18 [95% confidence interval (CI) −53.8 to 53.4]. The intraclass correlation coefficient between the Agatston scores using IntelliSpace and 3mensio showed an excellent correlation of 0.995 [95% CI 0.992-0.997], p ≤ 0.001. The interobserver and intraobserver variability was 0.993 ([95% CI 0.961-0.998], p ≤ 0.001) and 0.995([95%CI 0.981-0.999], p =

Background. Cardiovascular disease is a major cause of morbidity and mortality in kidney transplant recipients. Trial evidence to improve cardiovascular outcomes is limited by inconsistent reporting of outcomes, which may also lack patient-relevance. This study aimed to assess the range and consistency of cardiovascular outcomes reported by contemporary trials in kidney transplant recipients. Methods. A systematic review of all randomized controlled trials involving adult kidney transplant recipients that reported at least 1 cardiovascular outcome from January 2012 to December 2019 was performed, including Embase, MEDLINE, Cochrane, and ClinicalTrials.gov electronic databases. Trial characteristics were extracted and all levels of specification of the cardiovascular outcome measures reported were analyzed (the measure definition, metric‚ and method of aggregation). Measures assessing a similar aspect of cardiovascular disease were categorized into outcomes. Results. From 93 eligible trials involving 27 609 participants, 490 outcome measures were identified. The outcome measures were grouped into 38 outcomes. A cardiovascular composite was the most common outcome reported (40 trials, 43%) followed by cardiovascular mortality (42%) and acute coronary syndrome (31%). Cardiovascular composite was also the most heterogeneous outcome with 77 measures reported followed by cardiovascular mortality (n = 58) and inflammatory biomarkers (n = 51). The most common cardiovascular composite outcome components reported were major cardiovascular events (18 trials), stroke unspecified (11 trials), and myocardial infarction unspecified (10 trials). Conclusions. There is substantial heterogeneity in cardiovascular outcome reporting in kidney transplant trials.

Background. Targeting interleukin-6 (IL-6) was shown to counteract donor-specific antibody production and antibody-mediated rejection (AMR) activity. It is not known whether, or to what extent, IL-6 antagonism modulates biomarkers indicative of tissue damage (donor-derived cell-free DNA [dd-cfDNA]) and parenchymal inflammation (C-X-C motif chemokine ligand [CXCL] 10). Methods. We report a secondary endpoint analysis of a phase 2 trial of anti-IL-6 antibody clazakizumab in late AMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to treatment with clazakizumab or placebo over 12 wk (part A), followed by an extension in which all recipients received clazakizumab through week 52 (part B). Biomarkers were evaluated at day 0 and after 12 and 52 wk, respectively. Results. Fractional dd-cfDNA (dd-cfDNA[%]) did not significantly change under clazakizumab, with no differences between study arms (clazakizumab versus placebo) at week 12 (1.65% [median; interquartile range: 0.91%–2.78%] versus 0.97% [0.56%–2.30%]; P = 0.25) and no significant decrease from weeks 12 to 52 (1.15% [0.70%–2.38%] versus 1.0% [0.61%–1.70%]; P = 0.25). Similarly, urine CXCL10 was not different between groups at week 12 (55.7 [41.0–91.4] versus 60.2 [48.8–208.7.0] pg/mg creatinine; P = 0.44) and did not change over part B (CXCL10 [pg/mg creatinine]: from 58 [46.3–93.1] to 67.4 [41.5–132.0] pg/mL creatinine; P = 0.95). Similar results were obtained for serum CXCL10. There was no association between biomarker levels and resolution of molecular and morphologic AMR activity. Conclusions. Our results suggest that IL-6 blockade does not significantly affect levels of dd-cfDNA[%] and CXCL10. Subtle responses to this therapeutic principle may be overlooked by early biomarker surveillance.

Background. Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell–mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study. Methods. Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity. Results. Eighty-two patients (13%) had acute TCMR grade I–III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I–III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center’s diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69). Conclusions. This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.

Background. Donor-derived cell-free DNA (dd-cfDNA) is increasingly recognized as a valuable biomarker for acute transplant injury, with possible indications in the detection of cellular or humoral rejection and the guidance of immunosuppressive therapy. There is an ongoing debate on whether relative or absolute quantification of dd-cfDNA is more reliable for the detection of acute transplant injury. Methods. We retrospectively reviewed all 22 kidney transplant recipients who underwent dd-cfDNA measurements (percentage and absolute) between April 2020 and April 2021 at our institution. Of these, 9 (41%) showed discrepancies between absolute (cutoff: 50 copies/mL) and relative (cutoff: 0.5%) quantification in at least 1 dd-cfDNA measurement. Results. We report on 9 of 22 cases with discrepancies in relative and absolute quantification of dd-cfDNA, which were predominantly late posttransplant patients. We found bacterial and viral infections, as well as low leukocyte count from chronic myeloid leukaemia treatment, to be reasons for variability in total cell-free DNA (cfDNA), leading to inter- and intraindividual variability in relative dd-cfDNA quantification. When correlating dd-cfDNA quantification and biopsy results, as well as clinical course, our data indicate that relying solely on relative dd-cfDNA can lead to false-negative and false-positive results. Conclusions. In summary, these cases argue that absolute quantification of dd-cfDNA is better suited in patients with underlying conditions affecting total cfDNA levels and suggest using both absolute and relative dd-cfDNA together for higher reliability and interindividual comparability in the clinical setting. Especially for patients with chronic active antibody–mediated rejection, further studies on the use of dd-cfDNA are desirable.

Background. Tofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant. Methods. Patients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results. Results. Tofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%). Conclusions. Long-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages that facilitate high spatial resolution and high SNR images, cutting-edge diffusion contrasts, and direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work concludes a three-part series of recommendations and considerations for preclinical dMRI. Herein, we describe best practices for dMRI of ex vivo tissue, with a focus on image pre-processing, data processing, and comparisons with microscopy. In each section, we attempt to provide guidelines and recommendations but also highlight areas for which no guidelines exist (and why), and where future work should lie. We end by providing guidelines on code sharing and data sharing and point toward open-source software and databases specific to small animal and ex vivo imaging., (© 2025 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Small-animal diffusion MRI (dMRI) has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the resultant data. This work aims to present selected considerations and recommendations from the diffusion community on best practices for preclinical dMRI of in vivo animals. We describe the general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss why some may be more or less appropriate for different studies. We, then, give recommendations for in vivo acquisition protocols, including decisions on hardware, animal preparation, and imaging sequences, followed by advice for data processing including preprocessing, model-fitting, and tractography. Finally, we provide an online resource that lists publicly available preclinical dMRI datasets and software packages to promote responsible and reproducible research. In each section, we attempt to provide guides and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should focus. Although we mainly cover the central nervous system (on which most preclinical dMRI studies are focused), we also provide, where possible and applicable, recommendations for other organs of interest. An overarching goal is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge., (© 2025 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: To investigate microstructural alterations induced by perfusion fixation in brain tissues using advanced diffusion MRI techniques and estimate their potential impact on the application of ex vivo models to in vivo microstructure., Methods: We used oscillating gradient spin echo (OGSE) and b-tensor encoding diffusion MRI to examine in vivo and ex vivo microstructural differences in the marmoset brain. OGSE was used to shorten effective diffusion times, whereas b-tensor encoding allowed for the differentiation of isotropic and anisotropic kurtosis. Additionally, we performed Monte Carlo simulations to estimate the potential microstructural changes in the tissues., Results: We report large changes (˜50%-60%) in kurtosis frequency dispersion (OGSE) and in both anisotropic and isotropic kurtosis (b-tensor encoding) after perfusion fixation. Structural MRI showed an average volume reduction of about 10%. Monte Carlo simulations indicated that these alterations could likely be attributed to extracellular fluid loss possibly combined with axon beading and increased dot compartment signal fraction. Little evidence was observed for reductions in axonal caliber., Conclusion: Our findings shed light on advanced MRI parameter changes that are induced by perfusion fixation and potential microstructural sources for these changes. This work also suggests that caution should be exercised when applying ex vivo models to infer in vivo tissue microstructure, as significant differences may arise., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: After mild traumatic brain injury (mTBI), the brain is labile for weeks and months and vulnerable to repeated concussions. During this time, patients are exposed to everyday circumstances that, in themselves, affect brain metabolism and blood flow and neural processing. How commonplace activities interact with the injured brain is unknown. The present study in an animal model investigated the extent to which three commonly experienced exposures-daily caffeine usage, chronic sleep loss, and chronic sleep aid medication-affect the injured brain in the chronic phase., Methods: Subclinical trauma by repeated mTBIs was produced by our head rotational acceleration injury model, which causes brain injury consistent with the mechanism of concussion in humans. Forty-eight hours after a third mTBI, chronic administrations of caffeine, sleep restriction, or zolpidem (sedative hypnotic) began and were continued for 70 days. On Days 30 and 60 post injury, resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed., Results: Chronic caffeine, sleep restriction, and zolpidem each changed the subclinical brain characteristics of mTBI at both 30 and 60 days post injury, detected by different MRI modalities. Each treatment caused microstructural alterations in DTI metrics in the insular cortex and retrosplenial cortex compared with mTBI, but also uniquely affected other gray and white matter regions. Zolpidem administration affected the largest number of individual structures in mTBI at both 30 and 60 days, and not necessarily toward normalization (sham treatment). Chronic sleep restriction changed local functional connectivity at 30 days in diametrical opposition to chronic caffeine ingestion, and both treatment outcomes were different from sham, mTBI-only and zolpidem comparisons. The results indicate that commonly encountered exposures modify subclinical brain activity and structure long after healing is expected to be complete., Conclusions: Changes in activity and structure detected by fMRI are widely understood to reflect changes in the functions of the affected region which conceivably underlie mTBI neuropathology and symptomatology in the chronic phase after injury., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a promising technique for assessing spinal cord injury (SCI) that has historically been challenged by the presence of metallic stabilization hardware. This study leverages recent advances in metal-artifact resistant multi-spectral DW-MRI to enable diffusion quantification throughout the spinal cord even after fusion stabilization. Twelve participants with cervical spinal cord injuries treated with fusion stabilization and 49 asymptomatic able-bodied control participants underwent multi-spectral DW-MRI evaluation. Apparent diffusion coefficient (ADC) values were calculated in axial cord sections. Statistical modeling assessed ADC differences across cohorts and within distinct cord regions of the SCI participants (at, above, or below injured level). Computed models accounted for subject demographics and injury characteristics. ADC was found to be elevated at injured levels compared with non-injured levels (z = 3.2, p  = 0.001), with ADC at injured levels decreasing over time since injury (z = -9.2, p < 0.001). Below the injury level, ADC was reduced relative to controls (z = -4.4, p < 0.001), with greater reductions after more severe injuries that correlated with lower extremity motor scores (z = 2.56, p  = 0.012). No statistically significant differences in ADC above the level of injury were identified. By enabling diffusion analysis near fusion hardware, the multi-spectral DW-MRI technique allowed intuitive quantification of cord diffusion changes after SCI both at and away from injured levels. This demonstrates the approach's potential for assessing post-surgical spinal cord integrity throughout stabilized regions.

Arterial spin labeling (ASL) has been widely used to evaluate arterial blood and perfusion dynamics, particularly in the brain, but its application to the spinal cord has been limited. The purpose of this study was to optimize vessel-selective pseudocontinuous arterial spin labeling (pCASL) for angiographic and perfusion imaging of the rat cervical spinal cord. A pCASL preparation module was combined with a train of gradient echoes for dynamic angiography. The effects of the echo train flip angle, label duration, and a Cartesian or radial readout were compared to examine their effects on visualizing the segmental arteries and anterior spinal artery (ASA) that supply the spinal cord. Lastly, vessel-selective encoding with either vessel-encoded pCASL (VE-pCASL) or super-selective pCASL (SS-pCASL) were compared. Vascular territory maps were obtained with VE-pCASL perfusion imaging of the spinal cord, and the interanimal variability was evaluated. The results demonstrated that longer label durations (200 ms) resulted in greater signal-to-noise ratio in the vertebral arteries, improved the conspicuity of the ASA, and produced better quality maps of blood arrival times. Cartesian and radial readouts demonstrated similar image quality. Both VE-pCASL and SS-pCASL adequately labeled the right or left vertebral arteries, which revealed the interanimal variability in the segmental artery with variations in their location, number, and laterality. VE-pCASL also demonstrated unique interanimal variations in spinal cord perfusion with a right-sided dominance across the six animals. Vessel-selective pCASL successfully achieved visualization of the arterial inflow dynamics and corresponding perfusion territories of the spinal cord. These methodological developments provide unique insights into the interanimal variations in the arterial anatomy and dynamics of spinal cord perfusion., (© 2024 John Wiley & Sons Ltd.)

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subject's sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1±6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44≤r≤0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21≥r≥-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20≥r≥-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39≤r≤0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22≥r≥-0.25). Linear mixture of sex and age explained 26±10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33±11% when body height was added into the mixture model. Age itself explained only 2±2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure., Competing Interests: Declaration of interests Since June 2022, Dr. A.K. Smith has been employed by GE HealthCare. This article was co-authored by Dr. Smith in his personal capacity. The opinions expressed in the article are his in and do not necessarily reflect the views of GE HealthCare. Since August 2022, Dr. M. M. Laganà has been employed by Canon Medical Systems srl, Rome, Italy. This article was co-authored by Dr. M. M. Laganà in her personal capacity. The opinions expressed in the article are her own and do not necessarily reflect the views of Canon Medical Systems. Since September 2023, Dr. Papp has been an employee of Siemens Healthcare AB, Sweden. This article was co-authored by Dr. Papp in his personal capacity. The views and opinions expressed in this article are his own and do not necessarily reflect the views of Siemens Healthcare AB, or Siemens Healthineers AG. Since January 2024, Dr. Barry has been employed by the National Institute of Biomedical Imaging and Bioengineering at the NIH. This article was co-authored by Robert Barry in his personal capacity. The opinions expressed in the article are his own and do not necessarily reflect the views of the NIH, the Department of Health and Human Services, or the United States government. Guillaume Gilbert is an employee of Philips Healthcare. S Llufriu received compensation for consulting services and speaker honoraria from Biogen Idec, Novartis, Bristol Myer Squibb Genzyme, Sanofi Jansen and Merck. The Max Planck Institute for Human Cognitive and Brain Sciences and Wellcome Centre for Human Neuroimaging have institutional research agreements with Siemens Healthcare. NW holds a patent on acquisition of MRI data during spoiler gradients (US 10,401,453 B2). NW was a speaker at an event organized by Siemens Healthcare and was reimbursed for the travel expenses. The other authors declare no competing interests.

Little evidence exists about how mild traumatic brain injury (mTBI) is affected by commonly encountered exposures of sleep loss, sleep aids, and caffeine that might be potential therapeutic opportunities. In addition, while propofol sedation is administered in severe TBI, its potential utility in mild TBI is unclear. Each of these exposures is known to have pronounced effects on cerebral metabolism and blood flow and neurochemistry. We hypothesized that they each interact with cerebral metabolic dynamics post-injury and change the subclinical characteristics of mTBI. MTBI in rats was produced by head rotational acceleration injury that mimics the biomechanics of human mTBI. Three mTBIs spaced 48 h apart were used to increase the likelihood that vulnerabilities induced by repeated mTBI would be manifested without clinically relevant structural damage. After the third mTBI, rats were immediately sleep deprived or administered caffeine or suvorexant (an orexin antagonist and sleep aid) for the next 24 h or administered propofol for 5 h. Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were performed 24 h after the third mTBI and again after 30 days to determine changes to the brain mTBI phenotype. Multi-modal analyses on brain regions of interest included measures of functional connectivity and regional homogeneity from rs-fMRI, and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Each intervention changed the mTBI profile of subclinical effects that presumably underlie healing, compensation, damage, and plasticity. Sleep loss during the acute post-injury period resulted in dramatic changes to functional connectivity. Caffeine, propofol sedation and suvorexant were especially noteworthy for differential effects on microstructure in gray and white matter regions after mTBI. The present results indicate that commonplace exposures and short-term sedation alter the subclinical manifestations of repeated mTBI and therefore likely play roles in symptomatology and vulnerability to damage by repeated mTBI., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

Degenerative cervical myelopathy (DCM) is the commonest cause of spinal cord dysfunction in older adults and is characterized by chronic cervical spinal cord compression. Spinal cord stress and strain during neck motion are also known contributors to the pathophysiology of DCM, yet these factors are not routinely assessed for surgical planning. The aim of this study was to measure spinal cord stress/strain in DCM using patient-specific 3D finite element models (FEMs) and determine whether spinal cord compression is the primary determinant of spinal cord stress/strain. Three-dimensional patient-specific FEMs were created for six DCM patients (mild [n = 2], moderate [n = 2] and severe [n = 2]). Flexion and extension of the cervical spine were simulated with a pure moment load of 2 Nm. Segmental spinal cord von Mises stress and maximum principal strain were measured. Measures of spinal cord compression and segmental range of motion (ROM) were included in a regression analysis to determine associations with spinal cord stress and strain. Segmental ROM in flexion-extension and axial rotation was independently associated with spinal cord stress (p < 0.001) and strain (p < 0.001), respectively. This relationship was not seen for lateral bending. Segmental ROM had a stronger association with spinal stress and strain as compared to spinal cord compression. Compared to the severity of spinal cord compression, segmental ROM is a stronger determinant spinal cord stress and strain. Surgical procedures that address segmental ROM in addition to cord compression may best optimize spinal cord biomechanics in DCM., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: To explore filtered diffusion-weighted imaging (fDWI), in comparison with conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), as a predictor for long-term locomotor and urodynamic (UD) outcomes in Yucatan minipig model of spinal cord injury (SCI). Additionally, electrical conductivity of neural tissue using D-waves above and below the injury was measured to assess correlations between fDWI and D-waves data., Methods: Eleven minipigs with contusion SCI at T8-T10 level underwent MRI at 3T 4 h. post-SCI. Parameters extracted from region of interest analysis included D axial from fDWI at injury site, fractional anisotropy and radial diffusivity from DTI above the injury site along with measures of edema length and cord width at injury site from T 2 -weighted images. Locomotor recovery was assessed pre- and weekly post-SCI through porcine thoracic injury behavior scale (PTIBS) and UD were performed pre- and at 12 weeks of SCI. D-waves latency and amplitude differences were recorded before and immediately after SCI., Results: Two groups of pigs were found based on the PTIBS at week 12 (p < 0.0001) post-SCI and were labeled "poor" and "good" recovery. D-waves amplitude decreased below injury and increased above injury. UD outcomes pre/post SCI changed significantly. Conventional MRI metrics from T 2 -weighted images were significantly correlated with diffusion MRI metrics. D axial at injury epicenter was diminished by over 50% shortly after SCI, and it differentiated between good and poor locomotor recovery and UD outcomes., Interpretation: Similar to small animal studies, fDWI from acute imaging after SCI is a promising predictor for functional outcomes in large animals., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background Context: Finite element modeling (FEM) is an established tool to analyze the biomechanics of complex systems. Advances in computational techniques have led to the increasing use of spinal cord FEMs to study cervical spinal cord pathology. There is considerable variability in the creation of cervical spinal cord FEMs and to date there has been no systematic review of the technique. The aim of this study was to review the uses, techniques, limitations, and applications of FEMs of the human cervical spinal cord., Methods: A literature search was performed through PubMed and Scopus using the words finite element analysis, spinal cord, and biomechanics. Studies were selected based on the following inclusion criteria: (1) use of human spinal cord modeling at the cervical level; (2) model the cervical spinal cord with or without the osteoligamentous spine; and (3) the study should describe an application of the spinal cord FEM., Results: Our search resulted in 369 total publications, 49 underwent reviews of the abstract and full text, and 23 were included in the study. Spinal cord FEMs are used to study spinal cord injury and trauma, pathologic processes, and spine surgery. Considerable variation exists in the derivation of spinal cord geometries, mathematical models, and material properties. Less than 50% of the FEMs incorporate the dura mater, cerebrospinal fluid, nerve roots, and denticulate ligaments. Von Mises stress, and strain of the spinal cord are the most common outputs studied. FEM offers the opportunity for dynamic simulation, but this has been used in only four studies., Conclusions: Spinal cord FEM provides unique insight into the stress and strain of the cervical spinal cord in various pathological conditions and allows for the simulation of surgical procedures. Standardization of modeling parameters, anatomical structures and inclusion of patient-specific data are necessary to improve the clinical translation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

Purpose: To evaluate pseudo-continuous arterial spin labeling (pCASL) and velocity-selective arterial spin labeling (VSASL) for quantification of spinal cord blood flow (SCBF) in the rat thoracolumbar spinal cord., Methods: Labeling efficiency (LE) was compared between pCASL and three VSASL variants in simulations and both phantom and in vivo experiments at 9.4 T. For pCASL, the effects of label plane position and shimming were systematically evaluated. For VSASL, the effects of composite pulses and phase cycling were evaluated to reduce artifacts. Additionally, vessel suppression, respiratory, and cardiac gating were evaluated to reduce motion artifacts. pCASL and VSASL maps of spinal cord blood flow were acquired with the optimized protocols., Results: LE of the descending aorta was larger in pCASL compared to VSASL variants. In pCASL, LE off-isocenter was improved by local shimming positioned at the label plane and the anatomical level of labeling for the thoracic cord was only viable at the level of the T10 vertebra. Cardiac gating was essential to reduce motion artifacts. Both pCASL and VSASL successfully demonstrated comparable SCBF values in the thoracolumbar cord., Conclusion: pCASL demonstrated high and consistent LE in the thoracic aorta, and VSASL was also feasible, but with reduced efficiency. A combination of cardiac gating and recording of actual post-label delays was important for accurate SCBF quantification. These results highlight the challenges and solutions to achieve sufficient ASL labeling and contrast at high field in organs prone to motion., (© 2023 International Society for Magnetic Resonance in Medicine.)

Mutations in ASAH1 have been linked to two allegedly distinct disorders: Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). We have previously reported FD-like phenotypes in mice harboring a single amino acid substitution in acid ceramidase (ACDase), P361R, known to be pathogenic in humans (P361R-Farber). Here we describe a mouse model with an SMA-PME-like phenotype (P361R-SMA). P361R-SMA mice live 2-3-times longer than P361R-Farber mice and have different phenotypes including progressive ataxia and bladder dysfunction, which suggests neurological dysfunction. We found profound demyelination, loss of axons, and altered sphingolipid levels in P361R-SMA spinal cords; severe pathology was restricted to the white matter. Our model can serve as a tool to study the pathological effects of ACDase deficiency on the central nervous system and to evaluate potential therapies for SMA-PME., (© 2023. The Author(s).)

Traumatic spinal cord injury causes rapid neuronal and vascular injury, and predictive biomarkers are needed to facilitate acute patient management. This study examined the progression of magnetic resonance imaging (MRI) biomarkers after spinal cord injury and their ability to predict long-term neurological outcomes in a rodent model, with an emphasis on diffusion-weighted imaging (DWI) markers of axonal injury and perfusion-weighted imaging of spinal cord blood flow (SCBF). Adult Sprague-Dawley rats received a cervical contusion injury of varying severity (injured = 30, sham = 9). MRI at 4 h, 48-h, and 12-weeks post-injury included T 1 , T 2 , perfusion, and DWI. Locomotor outcome was assessed up to 12 weeks post-injury. At 4 h, the deficit in SCBF was larger than the DWI lesion, and although SCBF partially recovered by 48 h, the DWI lesion expanded. At 4 h, the volume of the SCBF deficit ( R 2  = 0.56, p adj < 0.01) was significantly correlated with 12-week locomotor outcome, whereas DWI ( R 2  = 0.30, p adj < 0.01) was less predictive of outcome. At 48 h, SCBF ( R 2  = 0.41, p adj < 0.01) became less associated with outcome, and DWI ( R 2  = 0.38, p adj < 0.01) lesion volume became more closely related to outcome. Spinal cord perfusion has unique spatiotemporal dynamics compared with diffusion measures of axonal damage and highlights the importance of acute perfusion abnormalities. Perfusion and diffusion offer complementary and clinically relevant insight into physiological and structural abnormalities following spinal cord injury beyond those afforded by T 1 or T 2 contrasts.

Degenerative cervical myelopathy (DCM) is the commonest cause of cervical spinal cord dysfunction in older adults and is characterized by spinal cord compression and stress during neck motion. Although surgical decompression eliminates static spinal cord compression, cord stress resulting from flexion-extension motion of the spinal column has not been determined for single and multi-level surgical interventions. The effect of surgery on spinal cord stress is expected to change with the number of surgical levels as well as patient-specific anatomy. Using a MRI-derived patient-specific finite element model, we simulated 1-, 2- and 3-level anterior cervical diskectomy and fusion (ACDF) surgery for DCM. A substantial decrease in spinal cord stress at the level of spinal cord decompression was noted in all simulations. This was associated with a considerable increase in spinal cord stress rostral to the surgical level, and the magnitude of stress was higher in multi-level surgery. Increased spinal cord stress at the rostral adjacent segment correlated with increased segmental range of motion (r = 0.69, p = 0.002) and disk pressure (r = 0.57, p = 0.05). Together, these results indicate that ACDF for DCM is associated with adverse spinal cord stress patterns adjacent to the fusion construct, and further research is needed to determine if the altered stress is associated with clinical outcomes after surgery for DCM., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Spinal cord stress/strain during neck motion contributes to spinal cord dysfunction in degenerative cervical myelopathy (DCM), yet the effect of surgery on spinal cord biomechanics is unknown. It is expected that motion-preserving and fusion surgeries for DCM will have distinct effects on spinal cord biomechanics. The aim of this study was to compare changes in spinal cord biomechanics after laminectomy with fusion, laminectomy, and laminoplasty using a patient-specific finite element model (FEM) for DCM., Methods: A patient-specific FEM of the cervical spine and spinal cord was created using MRI from a subject with mild DCM. Multilevel laminectomy with fusion, laminectomy, and laminoplasty were simulated for DCM using the patient-specific FEM. Spinal cord von Mises stress and maximum principal strain during neck flexion-extension, lateral bending, and axial rotation were recorded. Segmental range of motion, intradiscal pressure, and capsular ligament strain were also measured. FEM outputs were calculated as a change with respect to the preoperative values and compared between the three models., Results: Across the surgical levels, spinal cord stress increased after laminectomy for neck flexion (+50%), neck extension (+37.8%), and axial rotation (+23%). Similarly, spinal cord strain increased in neck extension (+118.4%) and axial rotation (+75.1%) after laminectomy. Laminoplasty was associated with greater spinal cord stress in neck flexion (+57.4%) and increased strain in lateral bending (+56.7%) and axial rotation (+20.9%). Compared with laminectomy and laminoplasty, spinal cord biomechanics for laminectomy with fusion revealed significantly reduced median extension stress (13.7 kPa vs 9.7 kPa, p = 0.03), lateral bending strain (0.01 vs 0.007, p = 0.007), axial rotation stress (3.7 kPa vs 2.1 kPa, p = 0.04), and axial rotation strain (0.017 vs 0.009, p = 0.04)., Conclusions: Spinal cord strain decreased in neck flexion in all three models, yet spinal cord stress increased with neck flexion for laminectomy and laminoplasty. Changes in spinal cord biomechanics for laminoplasty parallel those for laminectomy with fusion except during neck flexion, lateral bending, and axial rotation. Compared with motion-preserving approaches such as laminectomy and laminoplasty, laminectomy with fusion was associated with the lowest spinal cord stress and strain in flexion-extension, lateral bending, and axial rotation of the neck.

Multimodal microstructural MRI has shown increased sensitivity and specificity to changes in various brain disease and injury models in the preclinical setting. Here, we present an in vivo longitudinal dataset, including a subset of ex vivo data, acquired as control data and to investigate microstructural changes in the healthy mouse brain. The dataset consists of structural T2-weighted imaging, magnetization transfer ratio and saturation imaging, and advanced quantitative diffusion MRI (dMRI) methods. The dMRI methods include oscillating gradient spin echo (OGSE) dMRI and microscopic anisotropy (μA) dMRI, which provide additional insight by increasing sensitivity to smaller spatial scales and disentangling fiber orientation dispersion from true microstructural changes, respectively. The technical skills required to analyze microstructural MRI data are complex and include MRI sequence development, acquisition, and computational neuroimaging expertise. Here, we share unprocessed and preprocessed data, and scalar maps of quantitative MRI metrics. We envision utility of this dataset in the microstructural MRI field to develop and test biophysical models, methods that model temporal brain dynamics, and registration and preprocessing pipelines., (© 2023. The Author(s).)

Numerous epidemiological studies have found co-morbidity between non-severe traumatic brain injury (TBI) and substance misuse in both civilian and military populations. Preclinical studies have also identified this relationship for some misused substances. We have previously demonstrated that repeated blast traumatic brain injury (rbTBI) increased oxycodone seeking without increasing oxycodone self-administration, suggesting that the neurological sequelae of traumatic brain injury can elevate opioid misuse liability. Here, we determined the chronicity of this effect by testing different durations of time between injury and oxycodone self-administration and durations of abstinence. We found that the subchronic (four weeks), but not the acute (three days) or chronic (four months) duration between injury and oxycodone self-administration was associated with increased drug seeking and re-acquisition of self-administration following a 10-day abstinence. Examination of other abstinence durations (two days, four weeks, or four months) revealed no effect of rbTBI on drug seeking at any of the abstinence durations tested. Together, these data indicate that there is a window of vulnerability after TBI when oxycodone self-administration is associated with elevated drug seeking and relapse-related behaviors., Competing Interests: Conflict of interest The authors declare no competing financial interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Predicting functional outcomes from spinal cord injury (SCI) at the acute setting is important for patient management. This work investigated the relationship of early magnetic resonance imaging (MRI) biomarkers in a rat model of cervical contusion SCI with long-term functional outcome and tissue sparing. Forty rats with contusion injury at C5 at either the spinal cord midline (bilateral) or over the lateral cord (unilateral) were examined using in vivo multi-modal quantitative MRI at 1 day post-injury. The extent of T 2 -weighted hyperintensity reflecting edema was greater in the bilateral model compared with the unilateral injury. Diffusion tensor imaging (DTI) exhibited microscopic damage in similar regions of the cord as reductions in fractional anisotropy (FA) and mean diffusivity (MD), but DTI parameter maps were also confounded by the presence of vasogenic edema that locally increased FA and MD. In comparison, filtered diffusion-weighted imaging (fDWI) more clearly delineated the location of acute axonal damage without effects of vasogenic edema. Pairwise correlation analysis revealed that 28-day motor functional outcomes were most strongly associated with the extent of edema (R = -0.69). Principal component analysis identified close associations of motor functional score with tissue sparing, the extent of edema, lesion area, and injury type (unilateral or bilateral). Among the diffusion MRI parameters, lesion areas measured with fDWI had the strongest association with functional outcome (R = -0.41). Voxelwise correlation analysis identified a locus of white matter damage associated with function in the dorsal white matter, although this was likely driven by variance across the two injury patterns (unilateral and bilateral injury). Nonetheless, correlation with motor function within the damaged region found in the voxelwise analysis outperformed morphological lesion area measurement as a predictor of chronic function. Collectively, this study characterized anatomical and diffusion MRI signatures of acute SCI at cervical spine and their association with chronic functional outcomes and histological results.

Secondary damage obstructs functional recovery for individuals who have sustained a spinal cord injury (SCI). Two processes significantly contributing to tissue damage after trauma are spinal cord hemorrhage and inflammation: more specifically, the recruitment and activation of immune cells, frequently driven by pro-inflammatory factors. Cytokines are inflammatory mediators capable of modulating the immune response. While cytokines are necessary to elicit inflammation for proper healing, excessive inflammation can result in destructive processes. The pro-inflammatory cytokines IL-12 and IL-23 are pathogenic in multiple autoimmune diseases. The cytokine subunit IL-12p40 is necessary to form bioactive IL-12 and IL-23. In this study, we examined the relationship between spinal cord hemorrhage and IL-12-related factors, as well as the impact of IL-12p40 (IL-12/IL-23) on secondary damage and functional recovery after SCI. Using in vivo magnetic resonance imaging and protein tissue analyses, we demonstrated a positive correlation between IL-12 and tissue hemorrhage. Receptor and ligand subunits of IL-12 were significantly upregulated after injury and colocalized with astrocytes, demonstrating a myriad of opportunities for IL-12 to induce an inflammatory response. IL-12p40 -/- mice demonstrated significantly improved functional recovery and reduced lesion sizes compared to wild-type mice. Targeted gene array analysis in wild-type and IL-12p40 -/- female mice after SCI revealed an upregulation of genes associated with worsened recovery after SCI. Taken together, our data reveal a pathogenic role of IL-12p40 in the secondary damage after SCI, hindering functional recovery. IL-12p40 (IL-12/IL-23) is thus an enticing neuroinflammatory target for further study as a potential therapeutic target to benefit recovery in acute SCI., (© 2022 Wiley Periodicals LLC.)

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human., Competing Interests: KW was employed by the Gryphon Bio, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Stemper, Shah, Chiariello, McCarthy, Jessen, Sarka, Seifert, Budde, Wang, Olsen and McCrea.)

Traumatic brain injury (TBI) and drug addiction are common comorbidities, but it is unknown if the neurological sequelae of TBI contribute to this relationship. We have previously reported elevated oxycodone seeking after drug self-administration in rats that received repeated blast TBI (rbTBI). TBI and exposure to drugs of abuse can each change structural and functional neuroimaging outcomes, but it is unknown if there are interactive effects of injury and drug exposure. To determine the effects of TBI and oxycodone exposure, we subjected rats to rbTBI and oxycodone self-administration and measured drug seeking and several neuroimaging measures. We found interactive effects of rbTBI and oxycodone on fractional anisotropy (FA) in the nucleus accumbens (NAc) and that FA in the medial prefrontal cortex (mPFC) was correlated with drug seeking. We also found an interactive effect of injury and drug on widespread functional connectivity and regional homogeneity of the blood oxygen level dependent (BOLD) response, and that intra-hemispheric functional connectivity in the infralimbic medial prefrontal cortex positively correlated with drug seeking. In conclusion, rbTBI and oxycodone self-administration had interactive effects on structural and functional magnetic resonance imaging (MRI) measures, and correlational effects were found between some of these measures and drug seeking. These data support the hypothesis that TBI and opioid exposure produce neuroadaptations that contribute to addiction liability., (© 2022 Society for the Study of Addiction.)

Background and Purpose: Microstructure imaging with advanced diffusion MRI (dMRI) techniques have shown increased sensitivity and specificity to microstructural changes in various disease and injury models. Oscillating gradient spin echo (OGSE) dMRI, implemented by varying the oscillating gradient frequency, and microscopic anisotropy (μA) dMRI, implemented via tensor valued diffusion encoding, may provide additional insight by increasing sensitivity to smaller spatial scales and disentangling fiber orientation dispersion from true microstructural changes, respectively. The aims of this study were to characterize the test-retest reproducibility of in vivo OGSE and μA dMRI metrics in the mouse brain at 9.4 Tesla and provide estimates of required sample sizes for future investigations., Methods: Twelve adult C57Bl/6 mice were scanned twice (5 days apart). Each imaging session consisted of multifrequency OGSE and μA dMRI protocols. Metrics investigated included μA, linear diffusion kurtosis, isotropic diffusion kurtosis, and the diffusion dispersion rate (Λ), which explores the power-law frequency dependence of mean diffusivity. The dMRI metric maps were analyzed with mean region-of-interest (ROI) and whole brain voxel-wise analysis. Bland-Altman plots and coefficients of variation (CV) were used to assess the reproducibility of OGSE and μA metrics. Furthermore, we estimated sample sizes required to detect a variety of effect sizes., Results: Bland-Altman plots showed negligible biases between test and retest sessions. ROI-based CVs revealed high reproducibility for most metrics (CVs < 15%). Voxel-wise CV maps revealed high reproducibility for μA (CVs ~ 10%), but low reproducibility for OGSE metrics (CVs ~ 50%)., Conclusion: Most of the μA dMRI metrics are reproducible in both ROI-based and voxel-wise analysis, while the OGSE dMRI metrics are only reproducible in ROI-based analysis. Given feasible sample sizes (10-15), μA metrics and OGSE metrics may provide sensitivity to subtle microstructural changes (4-8%) and moderate changes (> 6%), respectively., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: In traumatic spinal cord injury, DTI is sensitive to injury but is unable to differentiate multiple pathologies. Axonal damage is a central feature of the underlying cord injury, but prominent edema confounds its detection. The purpose of this study was to examine a filtered DWI technique in patients with acute spinal cord injury., Materials and Methods: The MR imaging protocol was first evaluated in a cohort of healthy subjects at 3T ( n  = 3). Subsequently, patients with acute cervical spinal cord injury ( n  = 8) underwent filtered DWI concurrent with their acute clinical MR imaging examination <24 hours postinjury at 1.5T. DTI was obtained with 25 directions at a b-value of 800 s/mm 2 . Filtered DWI used spinal cord-optimized diffusion-weighting along 26 directions with a "filter" b-value of 2000 s/mm 2 and a "probe" maximum b-value of 1000 s/mm 2 . Parallel diffusivity metrics obtained from DTI and filtered DWI were compared., Results: The high-strength diffusion-weighting perpendicular to the cord suppressed signals from tissues outside of the spinal cord, including muscle and CSF. The parallel ADC acquired from filtered DWI at the level of injury relative to the most cranial region showed a greater decrease (38.71%) compared with the decrease in axial diffusivity acquired by DTI (17.68%)., Conclusions: The results demonstrated that filtered DWI is feasible in the acute setting of spinal cord injury and reveals spinal cord diffusion characteristics not evident with conventional DTI., (© 2021 by American Journal of Neuroradiology.)

Despite the potential to guide clinical management of spinal cord injury and disease, noninvasive methods of monitoring perfusion status of the spinal cord clinically remain an unmet need. In this study, we optimized pseudo-continuous arterial spin labeling (pCASL) for the rodent cervical spinal cord and demonstrate its utility in identifying perfusion deficits in an acute contusion injury model. High-resolution perfusion sagittal images with reduced imaging artifacts were obtained with optimized background suppression and imaging readout. Following moderate contusion injury, perfusion was clearly and reliably decreased at the site of injury. Implementation of time-encoded pCASL confirmed injury site perfusion deficits with blood flow measurements corrected for variability in arterial transit times. The noninvasive protocol of pCASL in the spinal cord can be utilized in future applications to examine perfusion changes after therapeutic interventions in the rat and translation to patients may offer critical implications for patient management.

Purpose: Diffusion MRI provides unique contrast important for the detection and examination of pathophysiology after acute neurologic insults, including spinal cord injury. Diffusion weighted imaging of the rodent spinal cord has typically been evaluated with axial EPI readout. However, Diffusion weighted imaging is prone to motion artifacts, whereas EPI is prone to susceptibility artifacts. In the context of acute spinal cord injury, diffusion filtering has previously been shown to improve detection of injury by minimizing the confounding effects of edema. We propose a diffusion-preparation module combined with a rapid acquisition with relaxation enhancement readout to minimize artifacts for sagittal imaging., Methods: Sprague-Dawley rats with cervical contusion spinal cord injury were scanned at 9.4 Tesla. The sequence optimization included the evaluation of motion-compensated encoding diffusion gradients, gating strategy, and different spinal cord-specific diffusion-weighting schemes., Results: A diffusion-prepared rapid acquisition with relaxation enhancement achieved high-quality images free from susceptibility artifacts with both second-order motion-compensated encoding and gating necessary for reduction of motion artifacts. Axial diffusivity obtained from the filtered diffusion-encoding scheme had greater lesion-to-healthy tissue contrast (52%) compared to the similar metric from DTI (25%)., Conclusion: This work demonstrated the feasibility of high-quality diffusion sagittal imaging in the rodent cervical cord with diffusion-prepared relaxation enhancement. The sequence and results are expected to improve injury detection and evaluation in acute spinal cord injury., (© 2021 International Society for Magnetic Resonance in Medicine.)

In the evaluation of spinal trauma, diagnostic imaging is of paramount importance. Computed tomography (CT), flexion/extension radiographs, and MRI are complementary modalities. CT is typically obtained in the initial setting of spinal trauma and provides detailed information about osseous structures. MRI provides detailed information about structural injury to the spinal cord. Diffusion tensor imaging provides microstructural information about the integrity of the axons and myelin sheaths, but its clinical use is limited. Novel imaging techniques may be better suited for the acute clinical setting and are under development for potential future clinical use., Competing Interests: Disclosure The authors and Mayank Kaushal have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the traumatically injured spinal cord, decreased perfusion is believed to contribute to secondary tissue damage beyond the primary mechanical impact, and restoration of perfusion is believed to be a promising therapeutic target. However, methods to monitor spinal cord perfusion non-invasively are limited. Perfusion magnetic resonance imaging (MRI) techniques established for the brain have not been routinely adopted to the spinal cord. The purpose of this study was to examine the relationship between spinal cord blood flow (SCBF) and injury severity in a rat thoracic spinal cord contusion injury (SCI) model using flow-sensitive alternating inversion recovery (FAIR) with two variants of the label position. SCBF as a marker of severity was compared to T 1 mapping and to spinal cord-optimized diffusion weighted imaging (DWI) with filtered parallel apparent diffusion coefficient. Thirty-eight rats underwent a T10 contusion injury with varying severities (8 sham; 10 mild; 10 moderate; 10 severe) with MRI performed at 1 day post injury at the lesion site and follow-up neurological assessments using the Basso, Beattie, Bresnahan (BBB) locomotor scoring up to 28 days post injury. Using whole-cord regions of interest at the lesion epicenter, SCBF was decreased with injury severity and had a significant correlation with BBB scores at 28 days post injury. Importantly, estimates of arterial transit times (ATT) in the injured spinal cord were not altered after injury, which suggests that FAIR protocols optimized to measure SCBF provide more value in the context of acute traumatic injury to the cord. T 1 -relaxation time constants were strongly related to injury severity and had a larger extent of changes than either SCBF or DWI measures. These findings suggest that perfusion decreases in the spinal cord can be monitored non-invasively after injury, and multi-parametric MRI assessments of perfusion, diffusion, and relaxation capture unique features of the pathophysiology of preclinical injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diffusion tensor distribution (DTD) imaging builds on principles from diffusion, solid-state and low-field NMR spectroscopies, to quantify the contents of heterogeneous voxels as nonparametric distributions, with tensor "size", "shape" and orientation having direct relations to corresponding microstructural properties of biological tissues. The approach requires the acquisition of multiple images as a function of the magnitude, shape and direction of the diffusion-encoding gradients, leading to long acquisition times unless fast image read-out techniques like EPI are employed. While in previous in vivo human brain studies performed at 3 T this proved a viable option, porting these measurements to very high magnetic fields and/or to heterogeneous organs induces B 0 - and B 1 -inhomogeneity artifacts that challenge the limits of EPI. To overcome such challenges, we demonstrate here that high spatial resolution DTD of mouse brain can be carried out at 15.2 T with a surface-cryoprobe, by relying on SPatiotemporal ENcoding (SPEN) imaging sequences. These new acquisition and data-processing protocols are demonstrated with measurements on in vivo mouse brain, and validated with synthetic phantoms designed to mimic the diffusion properties of white matter, gray matter and cerebrospinal fluid. While still in need of full extensions to 3D mappings and of scanning additional animals to extract more general physiological conclusions, this work represents another step towards the model-free, noninvasive in vivo characterization of tissue microstructure and heterogeneity in animal models, at ≈0.1 mm resolutions., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Sport-related concussion (SRC) is common in contact sports, but there remains a lack of reliable, unbiased biomarkers of brain injury and recovery. Although the symptoms of SRC generally resolve over a period of days to weeks, the lack of a biomarker impairs detection and return-to-play decisions. To this date, the pathophysiological recovery profile and relationships between brain changes and symptoms remained unclear. In the current study, diffusion kurtosis imaging (DKI) was used to monitor the effects of SRC on the brain and the trajectory of recovery in concussed American football players ( n  = 96) at <48 h, and 8, 15, and 45 days post-injury, who were compared with a matched group of uninjured players ( n  = 82). The concussed group reported significantly higher symptoms within 48 h after injury than controls, which resolved by the 8-day follow-up. The concussed group also demonstrated poorer performance on balance testing at <48 h and 8 days than controls. There were no significant differences between the groups in the Standardized Assessment of Concussion (SAC), a cognitive screening measure. DKI data were acquired with 3 mm isotropic resolution, and analyzed using tract-based spatial statistics (TBSS). Additionally, voxel- and region of interest-based analyses were also conducted. At <48 h, the concussed group showed significantly higher axial kurtosis than the control group. These differences increased in extent and magnitude at 8 days, then receded at 15 days, and returned to the normal levels by 45 days. Kurtosis fractional anisotropy (FA) exhibited a delayed response, with a consistent increase by days 15 and 45. The results indicate that changes detected in the acute period appear to be prolonged compared with clinical recovery, but additional brain changes not observable acutely appear to progress. Although further studies are needed to understand the pathological features of DKI changes after SRC, these findings highlight a potential disparity between clinical symptoms and pathophysiological recovery after SRC.

Purpose: Diffusion-weighted imaging has undergone substantial investigation as a potential tool for advanced assessment of spinal cord health. Unfortunately, commonly encountered surgically implanted spinal hardware has historically disrupted these studies. This preliminary investigation applies the recently developed multispectral diffusion-weighted PROPELLER technique to quantitative assessment of the spinal cord immediately adjacent to metallic spinal fusion instrumentation., Methods: Morphological and diffusion-weighted MRI of the spinal cord was collected from 5 subjects with implanted cervical spinal fusion hardware. Conventional and multispectral diffusion-weighted images were also collected on a normative non-instrumented control cohort and utilized for methodological stability analysis. Variance of the ADC values derived from the normative control group was then analyzed on a subject-by-subject basis and qualitatively correlated with clinical morphological interpretations., Results: Normative control ADC values within the spinal cord were stable across DWI methods for a b value of 600 s/mm 2 , though this stability degraded at lower b value levels. Susceptibility artifacts precluded conventional DWI analysis of the cord in subjects with spinal fusion hardware in 4 of the 5 test cases. On the contrary, multispectral PROPELLER DWI produced viable ADC measurements within the cord of all 5 instrumented subjects. Instrumented cord regions without obvious pathology (N = 4) showed ADC values that were lower than expected, whereas one subject with diagnosed myelomalacia showed abnormally elevated ADC., Conclusions: In the absence of instrumentation, multispectral DWI provides quantitative capabilities that match with those of conventional DWI approaches. In a preliminary instrumented subject analysis, cord ADC values showed both expected and unexpected variations from the normative cohort. These slides can be retrieved under Electronic Supplementary Material.

Clinical methods for determining the severity of traumatic spinal cord injury (SCI) and long-term functional outcome in the acute setting are limited in their prognostic accuracy because of the heterogeneity of injury and dynamic injury progression. The aim of this study was to evaluate the time course and sensitivity of advanced magnetic resonance imaging (MRI) methods to neurological function after SCI in a rat contusion model. Rats received a graded contusion injury at T10 using a weight-drop apparatus. MRI consisted of morphological measures from T 2 -weighted imaging, quantitative T 2 imaging, and diffusion-weighted imaging (DWI) at 1, 30, and 90 days post-injury (dpi). The derived metrics were compared with neurological function assessed using weekly Basso, Beattie, and Bresnahan (BBB) locomotor scoring and return of reflexive micturition function. At the acute time point (1 dpi), diffusion metrics sensitive to axonal injury at the injury epicenter had the strongest correlation with time-matched BBB scores and best predicted 90-dpi BBB scores. At 30 dpi, axonal water fraction derived from DWI and T 2 values were both correlated with time-matched locomotor scores. At the chronic time point (90 dpi), cross-sectional area was most closely correlated to BBB. Overall, the results demonstrate differential sensitivity of MRI metrics at different time points after injury, but the metrics follow the expected pathology of acute axonal injury followed by continued degeneration and finally a terminal level of atrophy. Specificity of DWI in the acute setting may make it impactful as a prognostic tool while T 2 imaging provided the most information about injury severity in chronic injury.

Degenerative spondylotic myelopathy is the most common cause of spinal dysfunction, as well as nontraumatic spastic paraparesis and quadriparesis. Although conventional MRI is the gold standard for radiographic evaluation of the spinal cord, it has limited application for determining prognosis and recovery. In the last decade, diffusion tensor imaging (DTI), which is based on the property of preferential diffusion of water molecules, has gained popularity in evaluating patients with cervical spondylotic myelopathy (CSM). The use of DTI allows for evaluation of microstructural changes in the spinal cord not otherwise detected on routine conventional MRI. In this review, the authors describe the application of DTI in CSM evaluation and its role as an imaging biomarker to predict disease severity and prognosis.

Each year, traumatic brain injuries (TBI) affect millions worldwide. Mild TBIs (mTBI) are the most prevalent and can lead to a range of neurobehavioral problems, including substance abuse. A single blast exposure, inducing mTBI alters the medial prefrontal cortex, an area implicated in addiction, for at least 30 days post injury in rats. Repeated blast exposures result in greater physiological and behavioral dysfunction than single exposure; however, the impact of repeated mTBI on addiction is unknown. In this study, the effect of mTBI on various stages of oxycodone use was examined. Male Sprague Dawley rats were exposed to a blast model of mTBI once per day for 3 days. Rats were trained to self-administer oxycodone during short (2 h) and long (6 h) access sessions. Following abstinence, rats underwent extinction and two cued reinstatement sessions. Sham and rbTBI rats had similar oxycodone intake, extinction responding and cued reinstatement of drug seeking. A second group of rats were trained to self-administer oxycodone with varying reinforcement schedules (fixed ratio (FR)-2 and FR-4). Under an FR-2 schedule, rbTBI-exposed rats earned fewer reinforcers than sham-exposed rats. During 10 extinction sessions, the rbTBI-exposed rats exhibited significantly more seeking for oxycodone than the sham-injured rats. There was a positive correlation between total oxycodone intake and day 1 extinction drug seeking in sham, but not in rbTBI-exposed rats. Together, this suggests that rbTBI-exposed rats are more sensitive to oxycodone-associated cues during reinstatement than sham-exposed rats and that rbTBI may disrupt the relationship between oxycodone intake and seeking., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Diffusion tensor imaging (DTI) is increasingly utilized as a sensitive tool for studying brain maturation and injuries during the neonatal period. In this study, we acquired high resolution in vivo DTI data from neonatal rat brains from postnatal day 2 (P2) to P10 and correlated temporal changes in DTI derived markers with microstructural organization of glia, axons, and dendrites during this critical period of brain development. Group average images showed dramatic temporal changes in brain morphology, fractional anisotropy (FA) and mean diffusivity (MD). Most cortical regions showed a monotonous decline in FA and an initial increase in MD from P2 to P8 that declined slightly by P10. Qualitative histology revealed rapid maturation of the glial and dendritic networks in the developing cortex. In the cingulate and motor cortex, the decreases in FA over time significantly correlated with structural anisotropy values computed from histological sections stained with glial and dendritic markers. However, in the sensory and visual cortex, other factors probably contributed to the observed decreases in FA. We did not observe any significant correlations between FA and structural anisotropy computed from the axonal histological marker.

Diffusion tensor imaging (DTI) has demonstrated success as a biomarker of spinal cord injury (SCI) severity as shown from numerous pre-clinical studies. However, artifacts from stabilization hardware at the lesion have precluded its use for longitudinal assessments. Previous research has documented ex vivo diffusion changes in the spinal cord both caudal and cranial to the injury epicenter. The aim of this study was to use a rat contusion model of SCI to evaluate the utility of in vivo cervical DTI after a thoracic injury. Forty Sprague-Dawley rats underwent a thoracic contusion (T8) of mild, moderate, severe, or sham severity. Magnetic resonance imaging (MRI) of the cervical cord was performed at 2, 30, and 90 days post-injury, and locomotor performance was assessed weekly using the Basso, Bresnahan, and Beattie (BBB) scoring scale. The relationships between BBB scores and MRI were assessed using region of interest analysis and voxel-wise linear regression of DTI, and free water elimination (FWE) modeling to reduce partial volume effects. At 90 days, axial diffusivity (AD FWE ), mean diffusivity (MD FWE ), and free water fraction (FWF FWE ) using the FWE model were found to be significantly correlated with BBB score. FWE was found to be more predictive of injury severity than conventional DTI, specifically at later time-points. This study validated the use of FWE technique in spinal cord and demonstrated its sensitivity to injury remotely.

Background: Fractional anisotropy (FA) of the high cervical cord correlates with upper limb function in acute cervical cord injury. We investigated the correlation between preoperative FA at the level of maximal compression and functional recovery in a group of patients after decompressive surgery for cervical spondylotic myelopathy (CSM)., Objective: To determine the usefulness of FA as a biomarker for severity of CSM and as a prognostic biomarker for improvement after surgery., Methods: Patients received diffusion tensor imaging (DTI) scans preoperatively. FA values of the whole cord cross-section at the level of maximal compression and upper cervical cord (C1-2) were calculated. Functional status was measured using the modified Japanese Orthopedic Association (mJOA) scale preoperatively and at follow-up up to 2 yr. Regression analysis between FA and mJOA was performed. DTI at C4-7 was obtained in controls., Results: Forty-four CSM patients enrolled prior to decompression were compared with 24 controls. FA at the level of maximal compression correlated positively with preoperative mJOA score. Preoperative FA correlated inversely with recovery throughout the postoperative period. This was statistically significant at 12 mo postoperation and nearly so at 6 and 24 mo. Patients with preoperative FA <0.55 had a statistically significant difference in outcome compared to FA >0.55., Conclusion: In the largest longitudinal study of this kind, FA promises a valid biomarker for severity of CSM and postoperative improvement. FA is an objective measure of function and could provide a basis for prognosis. FA is particularly useful if preoperative values are less than 0.55.

Traumatic brain injury (TBI) commonly results in cognitive and psychiatric problems. Cognitive impairments occur in approximately 30% of patients suffering from mild TBI (mTBI), and correlational evidence from clinical studies indicates that substance abuse may be increased following mTBI. However, understanding the lasting cognitive and psychiatric problems stemming from mTBI is difficult in clinical settings where pre-injury assessment may not be possible or accurate. Therefore, we used a previously characterized blast model of mTBI (bTBI) to examine cognitive- and addiction-related outcomes. We previously demonstrated that this model leads to bilateral damage of the medial prefrontal cortex (mPFC), a region critical for cognitive function and addiction. Rats were exposed to bTBI and tested in operant learning tasks several weeks after injury. bTBI rats made more errors during acquisition of a cue discrimination task compared to sham treated rats. Surprisingly, we observed no differences between groups in set shifting and delayed matching to sample, tasks known to require the mPFC. Separate rats performed cocaine self-administration. No group differences were found in intake or extinction, and only subtle differences were observed in drug-primed reinstatement 3-4 months after injury. These findings indicate that bTBI impairs acquisition of a visual discrimination task and that bTBI does not significantly increase the ability of cocaine exposure to trigger drug seeking.

Diffusion weighted magnetic resonance imaging (DWI) and related techniques such as diffusion tensor imaging (DTI) are uniquely sensitive to the microstructure of the brain and spinal cord. In the acute aftermath of nervous system injury, for example, DWI reveals changes caused by injury that remains invisible on other MRI contrasts such as T 2 -weighted imaging. This ability has led to a demonstrated clinical utility in cerebral ischemia. However, despite strong promise in preclinical models and research settings, DWI has not been as readily adopted for other acute injuries such as traumatic spinal cord, brain, or peripheral nerve injury. Furthermore, the precise biophysical mechanisms that underlie DWI and DTI changes are not fully understood. In this report, we review the DWI and DTI changes that occur in acute neurological injury of cerebral ischemia, spinal cord injury, traumatic brain injury, and peripheral nerve injury. Their associations with the underlying biology are examined with an emphasis on the role of acute axon and dendrite beading. Lastly, emerging DWI techniques to overcome the limitations of DTI are discussed as these may offer the needed improvements to translate to clinical settings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Diffusion-weighted imaging (DWI) is a powerful tool for investigating spinal cord injury (SCI), but has limited specificity for axonal damage, which is the most predictive feature of long-term functional outcome. In this study, a technique designed to detect acute axonal injury, filter-probe double diffusion encoding (FP-DDE), is compared with standard DWI for predicting long-term functional and cellular outcomes., Methods: This study extends FP-DDE to predict long-term functional and histological outcomes in a rat SCI model of varying severities (n = 58). Using a 9.4T magnetic resonance imaging (MRI) system, a whole-cord FP-DDE spectroscopic voxel was acquired in 3 minutes at the lesion site and compared to DWI at 48 hours postinjury. Relationships with chronic (30-day) locomotor and histological outcomes were evaluated with linear regression., Results: The FP-DDE measure of parallel diffusivity (ADC || ) was significantly related to chronic hind limb locomotor functional outcome (R 2  = 0.63, p < 0.0001), and combining this measurement with acute functional scores demonstrated prognostic benefit versus functional testing alone (p = 0.0007). Acute ADC || measurements were also more closely related to the number of injured axons measured 30 days after the injury than standard DWI. Furthermore, acute FP-DDE images showed a clear and easily interpretable pattern of injury that closely corresponded with chronic MRI and histology observations., Interpretation: Collectively, these results demonstrate FP-DDE benefits from greater specificity for acute axonal damage in predicting functional and histological outcomes with rapid acquisition and fully automated analysis, improving over standard DWI. FP-DDE is a promising technique compatible with clinical settings, with potential research and clinical applications for evaluation of spinal cord pathology. Ann Neurol 2018;83:37-50., (© 2018 American Neurological Association.)

Degenerative cervical myelopathy (DCM) is a common neurologic condition that is often treated with surgery. Imaging plays a central role in the management of DCM, including diagnosis, preoperative planning, postoperative assessment, and prognostication. Radiographs, CT, and MRI offer unique and complementary assessments, and all have important uses in current clinical practice. Emerging microstructural and functional MRI techniques have the potential to have a major impact, potentially transforming practice by offering earlier and more accurate diagnosis, monitoring for deterioration, and prediction of outcomes. In the future, it can be expected that imaging will play an even greater role in DCM management., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diffusion tensor imaging (DTI) is a promising biomarker of spinal cord injury (SCI). In the acute aftermath, DTI in SCI animal models consistently demonstrates high sensitivity and prognostic performance, yet translation of DTI to acute human SCI has been limited. In addition to technical challenges, interpretation of the resulting metrics is ambiguous, with contributions in the acute setting from both axonal injury and edema. Novel diffusion MRI acquisition strategies such as double diffusion encoding (DDE) have recently enabled detection of features not available with DTI or similar methods. In this work, we perform a systematic optimization of DDE using simulations and an in vivo rat model of SCI and subsequently implement the protocol to the healthy human spinal cord. First, two complementary DDE approaches were evaluated using an orientationally invariant or a filter-probe diffusion encoding approach. While the two methods were similar in their ability to detect acute SCI, the filter-probe DDE approach had greater predictive power for functional outcomes. Next, the filter-probe DDE was compared to an analogous single diffusion encoding (SDE) approach, with the results indicating that in the spinal cord, SDE provides similar contrast with improved signal to noise. In the SCI rat model, the filter-probe SDE scheme was coupled with a reduced field of view (rFOV) excitation, and the results demonstrate high quality maps of the spinal cord without contamination from edema and cerebrospinal fluid, thereby providing high sensitivity to injury severity. The optimized protocol was demonstrated in the healthy human spinal cord using the commercially-available diffusion MRI sequence with modifications only to the diffusion encoding directions. Maps of axial diffusivity devoid of CSF partial volume effects were obtained in a clinically feasible imaging time with a straightforward analysis and variability comparable to axial diffusivity derived from DTI. Overall, the results and optimizations describe a protocol that mitigates several difficulties with DTI of the spinal cord. Detection of acute axonal damage in the injured or diseased spinal cord will benefit the optimized filter-probe diffusion MRI protocol outlined here.

Diffusion MRI is arguably the method of choice for characterizing white matter microstructure in vivo. Over the typical duration of diffusion encoding, the displacement of water molecules is conveniently on a length scale similar to that of the underlying cellular structures. Moreover, water molecules in white matter are largely compartmentalized which enables biologically-inspired compartmental diffusion models to characterize and quantify the true biological microstructure. A plethora of white matter models have been proposed. However, overparameterization and mathematical fitting complications encourage the introduction of simplifying assumptions that vary between different approaches. These choices impact the quantitative estimation of model parameters with potential detriments to their biological accuracy and promised specificity. First, we review biophysical white matter models in use and recapitulate their underlying assumptions and realms of applicability. Second, we present up-to-date efforts to validate parameters estimated from biophysical models. Simulations and dedicated phantoms are useful in assessing the performance of models when the ground truth is known. However, the biggest challenge remains the validation of the "biological accuracy" of estimated parameters. Complementary techniques such as microscopy of fixed tissue specimens have facilitated direct comparisons of estimates of white matter fiber orientation and densities. However, validation of compartmental diffusivities remains challenging, and complementary MRI-based techniques such as alternative diffusion encodings, compartment-specific contrast agents and metabolites have been used to validate diffusion models. Finally, white matter injury and disease pose additional challenges to modeling, which are also discussed. This review aims to provide an overview of the current state of models and their validation and to stimulate further research in the field to solve the remaining open questions and converge towards consensus.