Alan C. Seifert

Background: Modic changes (MC) are painful vertebral bone marrow lesions. Three interconvertible types represent different pathology stages with MC1 being the most painful, MC2 less painful, and MC3 asymptomatic. Bacterial ( Cutibacterium acnes ( C. acnes )–mediated) and non‐bacterial etiologies are both suggested to induce MC1, but it remains unclear whether MC conversion is etiology‐specific. This has important implications for patient management and the development of MC therapies. Aims: To assess MC‐subtype lesion prevalence and pain‐like behavior over time in an etiology‐specific MC rat model. Methods: Four‐to‐five‐month‐old Sprague–Dawley rats underwent sham ( n = 12) surgery or endplate injury followed by an intradiscal injection of 2.5 μL of either TNF‐α (1000 ng/mL PBS) ( n = 19) or C. acnes (3.2 × 10 ⁸ CFU/mL in PBS) ( n = 18) to mimic aspects of bacterial versus non‐bacterial MC etiologies. MC‐subtype prevalence was evaluated by magnetic resonance imaging at 1, 8, and 14 weeks post‐injury. Disc degeneration, bone marrow lesion neutrophil elastase and CD19 immunoreactivity, spinal cord sensitization, and pain‐like behavior (von Frey) were assessed, and contributors to pain‐like behavior were identified (random forest). Results: C. acnes injection caused higher MC1‐like lesion prevalence than TNF‐α and Sham at all‐time points and higher spinal cord substance P expression at 14 weeks post‐injury. MC2‐like lesions increased over time in TNF‐α‐injected discs and were more prevalent at 14 weeks post‐injury than C. acnes . C. acnes injection resulted in bone marrow lesions with higher neutrophil elastase‐ and CD19 immunoreactivity. MC1‐like lesions contributed strongest to pain‐like behavior, although von Frey did not differ between groups. Conclusion: Intradiscal C. acnes injection sustained MC1‐like lesions in an etiology‐specific lumbar MC rat model, suggesting that patients with bacterial MC etiology may be more likely to persist in painful MC1.

Purpose: The depth within the body, small diameter, long length, and varying tissue surrounding the spinal cord impose specific considerations when designing RF coils. The optimal coil configuration for 7 T cervical spinal cord MRI is unknown and currently there are very few coil options. The purpose of this work was (1) to establish a quality control protocol for evaluating 7 T cervical spinal cord coils, and (2) to use that protocol to evaluate the performance of four different coil designs.Methods: Three healthy volunteers and a custom anthropomorphic phantom (the traveling spines cohort) were scanned at seven 7 T imaging centers using a common protocol and each center's specific cervical spinal cord coil. Four different coil designs were tested (two in‐house, one Rapid Biomedical, and one MRI.TOOLS design).Results: The Rapid Biomedical coil was found to have the highest efficiency, whereas one of the in‐house designs (NeuroPoly Lab) had the highest SNR and the largest spinal cord coverage. The MRI.TOOLS coil had the most uniform profile along the cervical spinal cord; however, it was limited in its ability to provide the requested flip angles (especially for larger individuals). The latter was also the case for the second in‐house coil (MSSM).Conclusion: The results of this study serve as a guide for the spinal cord MRI community in selecting the most suitable coil based on specific requirements and offer a standardized protocol for assessing future coils.

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 correlates 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). Intracranial volume (ICV) correlates with body height (r = 0.46) and the brain volumes and CSA-WM (0.37 ≤ r ≤ 0.77). In comparison, age correlates with cortical GM volume, precentral GM volume, and cortical thickness (-0.21 ≥ r ≥ -0.27). Body weight correlates with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20 ≥ r ≥ -0.23). Body weight further correlates 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 correlates with brain volumes (0.39 ≤ r ≤ 0.64), and 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 age, sex, or sex and age, explained 2 ± 2%, 24 ± 10%, or 26 ± 10%, of data variance in brain volumetry and SC CSA. The amount of explained variance increased to 33 ± 11%, 41 ± 17%, or 46 ± 17%, when body height, ICV, or body height and ICV were added into the mixture model. In females, the explained variances halved suggesting another unidentified biological factor(s) determining females’ central nervous system (CNS) morphology. In conclusion, body size and ICV are significant biological variables. 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; and body size and ICV should be considered as covariates in statistical analyses. Normalization of different brain regions with ICV diminishes their correlations with body size, but simultaneously amplifies ICV-related variance (r = 0.72 ± 0.07) and suppresses volume variance of the different brain regions (r = 0.12 ± 0.19) in the normalized measurements.

We aim to assess a straightforward technique to enhance spectral quality in the brain, particularly in the cerebellum, during 7 T MRI scans. This is achieved through a wireless RF array insert designed to mitigate signal dropouts caused by the limited transmit field efficiency in the inferior part of the brain. We recently developed a wireless RF array to improve MRI and ¹H‐MRS at 7 T by augmenting signal via inductive coupling between the wireless RF array and the MRI coil. In vivo experiments on a Siemens 7 T whole‐body human scanner with a Nova 1Tx/32Rx head coil quantified the impact of the dorsal cervical array in improving signal in the posterior fossa, including the cerebellum, where the transmit efficiency of the coil is inherently low. The ¹H‐MRS experimental protocol consisted of paired acquisition of data sets, both with and without the RF array, using the semi‐LASER and SASSI sequences. The overall results indicate that the localized ¹H‐MRS is improved significantly in the presence of the array. Comparison of in vivo ¹H‐MRS plots in the presence versus absence of the array demonstrated an average SNR enhancement of a factor of 2.2. LCModel analysis reported reduced Cramér–Rao lower bounds, indicating more confident fits. This wireless RF array can significantly increase detection sensitivity. It may reduce the RF transmission power and data acquisition time for ¹H‐MRS and MRI applications, specifically at 7 T, where ¹H‐MRS requires a high‐power RF pulse. The array could provide a cost‐effective and efficient solution to improve detection sensitivity for human ¹H‐MRS and MRI in the regions with lower transmit efficiency.

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.

Although functional magnetic resonance imaging (fMRI) is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B₀. Increasing field strength enables higher spatial resolution and improved sensitivity to blood oxygenation level‐dependent (BOLD) signal, but amplifies the effects of B₀ inhomogeneity. In this work, we present the first task fMRI in the spinal cord at 7 T. Further, we compare the performance of single‐shot and multi‐shot 2D echo‐planar imaging (EPI) protocols, which differ in sensitivity to spatial and temporal B₀ inhomogeneity. The cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single‐shot 2D EPI at 0.75 mm in‐plane resolution and multi‐shot 2D EPI at 0.75 and 0.6 mm in‐plane resolutions. All protocols used 3 mm slice thickness. For each protocol, the BOLD response to 13 10‐s noxious thermal stimuli applied to the right thumb was acquired in a 10‐min fMRI run. Image quality, temporal signal to noise ratio (SNR), and BOLD activation (percent signal change and z‐stat) at both individual‐ and group‐level were evaluated between the protocols. Temporal SNR was highest in single‐shot and multi‐shot 0.75 mm protocols. In group‐level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual‐level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single‐shot 0.75 mm generally produced the highest mean z‐statistic, while multi‐shot 0.60 mm produced the best‐localized activation clusters and the least geometric distortion. Larger than expected within‐subject segmental variation of BOLD activation along the cord was observed. Group‐level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single‐shot or multi‐shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment.Practitioner Points: First stimulus task fMRI results in the spinal cord at 7 T. Single‐shot 0.75 mm 2D EPI produced the highest mean z‐statistic. Multi‐shot 0.60 mm 2D EPI provided the best‐localized activation and least distortion.

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. Methods: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. Discussion: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

Background: Intervertebral disc (IVD) disorders (e.g., herniation) directly contribute to back pain, which is a leading cause of global disability. Next‐generation treatments for IVD herniation need advanced preclinical testing to evaluate their ability to repair large defects, prevent reherniation, and limit progressive degeneration. This study tested whether experimental, injectable, and nonbioactive biomaterials could slow IVD degeneration in an ovine discectomy model.Methods: Ten skeletally mature sheep (4–5.5 years) experienced partial discectomy injury with cruciate‐style annulus fibrosus (AF) defects and 0.1 g nucleus pulposus (NP) removal in the L1–L2, L2–L3, and L3–L4 lumbar IVDs. L4–L5 IVDs were Intact controls. IVD injury levels received: (1) no treatment (Injury), (2) poly (ethylene glycol) diacrylate (PEGDA), (3) genipin‐crosslinked fibrin (FibGen), (4) carboxymethylcellulose–methylcellulose (C‐MC), or (5) C‐MC and FibGen (FibGen + C‐MC). Animals healed for 12 weeks, then IVDs were assessed using computed tomography (CT), magnetic resonance (MR) imaging, and histopathology.Results: All repaired IVDs retained ~90% of their preoperative disc height and showed minor degenerative changes by Pfirrmann grading. All repairs had similar disc height loss and Pfirrmann grade as Injury IVDs. Adhesive AF sealants (i.e., PEGDA and FibGen) did not herniate, although repair caused local endplate (EP) changes and inflammation. NP repair biomaterials (i.e., C‐MC) and combination repair (i.e., FibGen + C‐MC) exhibited lower levels of degeneration, less EP damage, and less severe inflammation; however, C‐MC showed signs of herniation via biomaterial expulsion.Conclusions: All repair IVDs were noninferior to Injury IVDs by IVD height loss and Pfirrmann grade. C‐MC and FibGen + C‐MC IVDs had the best outcomes, and may be appropriate for enhancement with bioactive factors (e.g., cells, growth factors, and miRNAs). Such bioactive factors appear to be necessary to prevent injury‐induced IVD degeneration. Application of AF sealants alone (i.e., PEGDA and FibGen) resulted in EP damage and inflammation, particularly for PEGDA IVDs, suggesting further material refinements are needed.

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Tissue Pathology Study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. Methods: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Casual inference methods will be employed to investigate associations between risk factors and pathologic outcomes. Discussion: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC. Clinicaltrials.gov number: NCT05292274