Design of the COMEBACK and BACKHOME Studies, Longitudinal Cohorts for Comprehensive Deep Phenotyping of Adults with Chronic Low-Back Pain (cLBP): a part of the BACPAC Research Program.

Objective: The University of California, San Francisco (UCSF) Core Center for Patient-centric, Mechanistic Phenotyping in Chronic Low Back Pain (REACH) is one of the three NIH Back Pain Consortium (BACPAC) Research Programs Mechanistic Research Centers (MRCs). The goal of UCSF REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. The primary objective of this research project is to address the critical need for new diagnostic and prognostic markers, and associated patient classification protocols for chronic low back pain (cLBP) treatment. Design: To meet this objective, REACH is conducting two large investigator-initiated translational research cohort studies called: The Longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain (cLBP) Adults Study (comeBACK) and the Chronic Low-Back Pain (cLBP) in Adults Study (BACKHOME). Setting: comeBACK is a longitudinal multicenter in-person observational study of 450 adults with chronic low back pain designed to perform comprehensive deep phenotyping. While, the BACKHOME study is a site-less longitudinal observational e-cohort of approximately 3000 U.S. adults with cLBP. To our knowledge, BACKHOME is the largest prospective remote registry of nationwide adults with cLBP. Methods: Both the comeBACK and BACKHOME studies are collecting a robust and comprehensive set of risk factors, outcomes, and covariates in order to perform deep phenotyping of cLBP patients based on combined biopsychosocial variables to: define cLBP subtypes, establish phenotyping tools for routine clinical evaluation, and lead to improved cLBP outcomes in the future. The data from both studies will be used to establish techniques to develop a patient-centric definition of treatment success and to analyze cLBP patient traits to define clinically useful cLBP phenotypes, using a combination of traditional data analyses and deep learning methods. Conclusions: These 2 pivotal studies, in conjunction with the ancillary studies being performed in both comeBACK and BACKHOME, and the other BACPAC-consortium research projects, we will be able to address a number of diagnostic and therapeutic issues in this complex and diverse patient population with cLBP. These studies will help clarify biopsychosocial mechanisms of cLBP with the aim to provide a foundation to improve the evaluation of treatment effectiveness and to spur new avenues of therapeutic research, including personalized outcome measures that constitute a clinically meaningful treatment effect for individual cLBP patients.

Establishing a Gold Standard for Noninvasive Identification of Painful Lumbar Discs: Prospective Comparison of Magnetic Resonance Spectroscopy vs Low-Pressure Provocation Discography.

PURPOSE: Verifying lumbar disc pain can present a clinical challenge. Low-pressure provocative discography (PD) has served as the gold standard, although it is invasive and often a challenge to interpret. We reported that magnetic resonance spectroscopy (MRS) biomarkers accurately predict PD results in lumbar discs and improved outcomes for patients with surgery at positive MRS levels versus nonsurgery. To further substantiate MRS for diagnosing painful discs, we report a prospective comparison of 2 MRS-derived measures: NOCISCORE (pain) and SI-SCORE (degeneration severity). METHODS: Lumbar MRS and software-based postprocessing (NOCISCAN-LS, Aclarion Inc.) was performed in 44 discs in 14 patients (prospective cohort [PC]). PC data were compared to prior data used to establish the NOCISCORE (training cohort [TC]). The NOCISCORE was converted to an ordinal value (high/intermediate/low; NOCI+/mild/-) and compared against painful (P) versus nonpainful (NP) control diagnosis (PD) for 19 discs where PD was performed in the PC (12 NP; 7 P). Sensitivity, specificity, and positive and negative predictive values were calculated. The SI-SCORE was compared against MRI Pfirrmann Grades for 465 discs in 126 patients (PC plus TC). RESULTS: For the PC, MRS (NOCI+/-) compared to PD (P/NP) with an accuracy of 87% and sensitivity and specificity of 100%. The positive and negative predictive values of MRS were 100%. NOCISCOREs were significantly higher for PD+ versus PD- discs for PC and TC (P < 0.05), and the NOCISCORE distributions for PD+/- group were not statistically different between the PC and TC (P > 0.05). SI-SCORES differed between Pfirrmann Grades 1 and 2 (less degenerated) versus Grades 3 and 4 (more degenerated; P < 0.05), with a progressively decreasing trend with Pfirrmann Grades 1-5. CONCLUSION: These current data provide prospective confirmation of the predictive value of disc MRS for distinguishing painful discs and for assessing the disc structural integrity. CLINICAL RELEVANCE: NOCISCAN is an adoptable, noninvasive, and objectively quantitative test to improve management of low back pain patients.

Type 2 diabetes impairs annulus fibrosus fiber deformation and rotation under disc compression in the University of California Davis type 2 diabetes mellitus (UCD-T2DM) rat model.

Understanding the biomechanical behavior of the intervertebral disc is crucial for studying disease mechanisms and developing tissue engineering strategies for managing disc degeneration. We used synchrotron small-angle X-ray scattering to investigate how changes to collagen behavior contribute to alterations in the disc's ability to resist compression. Coccygeal motion segments from 6-month-old lean Sprague-Dawley rats ( n=7) and diabetic obese University of California Davis type 2 diabetes mellitus (UCD-T2DM) rats ( n=6, diabetic for 68±7 days) were compressed during simultaneous synchrotron scanning to measure collagen strain at the nanoscale (beamline 7.3.3 of the Advanced Light Source). After compression, the annulus fibrosus was assayed for nonenzymatic cross-links. In discs from lean rats, resistance to compression involved two main energy-dissipation mechanisms at the nanoscale: (1) rotation of the two groups of collagen fibrils forming the annulus fibrosus and (2) straightening (uncrimping) and stretching of the collagen fibrils. In discs from diabetic rats, both mechanisms were significantly impaired. Specifically, diabetes reduced fibril rotation by 31% and reduced collagen fibril strain by 30% (compared to lean discs). The stiffening of collagen fibrils in the discs from diabetic rats was consistent with a 31% higher concentration of nonenzymatic cross-links and with evidence of earlier onset plastic deformations such as fibril sliding and fibril-matrix delamination. These findings suggest that fibril reorientation, stretching, and straightening are key deformation mechanisms that facilitate whole-disc compression, and that type 2 diabetes impairs these efficient and low-energy elastic deformation mechanisms, thereby altering whole-disc behavior and inducing the earlier onset of plastic deformation.

An exploration of knowledge-organizing technologies to advance transdisciplinary back pain research.

Chronic low back pain (LBP) is influenced by a broad spectrum of patient-specific factors as codified in domains of the biopsychosocial model (BSM). Operationalizing the BSM into research and clinical care is challenging because most investigators work in silos that concentrate on only one or two BSM domains. Furthermore, the expanding, multidisciplinary nature of BSM research creates practical limitations as to how individual investigators integrate current data into their processes of generating impactful hypotheses. The rapidly advancing field of artificial intelligence (AI) is providing new tools for organizing knowledge, but the practical aspects for how AI may advance LBP research and clinical are beginning to be explored. The goals of the work presented here are to: (1) explore the current capabilities of knowledge integration technologies (large language models (LLM), similarity graphs (SGs), and knowledge graphs (KGs)) to synthesize biomedical literature and depict multimodal relationships reflected in the BSM, and; (2) highlight limitations, implementation details, and future areas of research to improve performance. We demonstrate preliminary evidence that LLMs, like GPT-3, may be useful in helping scientists analyze and distinguish cLBP publications across multiple BSM domains and determine the degree to which the literature supports or contradicts emergent hypotheses. We show that SG representations and KGs enable exploring LBP's literature in novel ways, possibly providing, trans-disciplinary perspectives or insights that are currently difficult, if not infeasible to achieve. The SG approach is automated, simple, and inexpensive to execute, and thereby may be useful for early-phase literature and narrative explorations beyond one's areas of expertise. Likewise, we show that KGs can be constructed using automated pipelines, queried to provide semantic information, and analyzed to explore trans-domain linkages. The examples presented support the feasibility for LBP-tailored AI protocols to organize knowledge and support developing and refining trans-domain hypotheses.

Magnetic resonance spectroscopy (MRS) identification of chemically painful lumbar discs leads to improved 6-, 12-, and 24-month outcomes for discogenic low back pain surgeries.

PURPOSE: MRS was shown to reliably quantify relative levels of degenerative pain biomarkers, differentiating painful versus non-painful discs in patients with chronic discogenic low back pain (DLBP), and this correlates with surgical success rates. We now report results based on more patients and longer follow-up. METHODS: Disc MRS was performed in DLBP patients who subsequently received lumbar surgery. Custom post-processing (NOCISCAN-LS®; Aclarion Inc.) calculated disc-specific NOCISCORES® that reflect relative differences in degenerative pain biomarkers for diagnosing chemically painful discs. Outcomes in 78 patients were evaluated using Oswestry Disability Index (ODI) scores. Surgical success (≥ 15-point ODI improvement) was compared between surgeries that were "Concordant" (Group C) versus "Discordant" (Group D) with NOCISCORE-based diagnosis for painful discs. RESULTS: Success rates were higher for Group C versus Group D: 6 months (88% vs. 62%; p = 0.01), 12 months (91% vs. 56%; p < 0.001), and 24 months (85% vs. 63%; p = 0.07). Success rates for Group C surgeries were also higher than Group D surgeries in a variety of sub-group comparisons. Group C had a greater reduction in ODI from pre-operative to follow-up than Group D [absolute change (% change), (p)]: 6 months: - 35 (- 61%) versus - 23 (- 39%), (p < 0.05); 12 months: - 39 (- 69%) versus - 22 (- 39%), (p < 0.01); and 24 months: - 38 (- 66%) versus - 26 (- 48%), (p < 0.05). CONCLUSION: More successful, sustained outcomes were obtained when surgically treating chemically painful discs identified by NOCISCAN-LS post-processed disc MRS exams. Results suggest that NOCISCAN-LS provides a valuable new diagnostic tool to help clinicians better select treatment levels.

Multi-domain biopsychosocial postoperative recovery trajectories associate with patient outcomes following lumbar fusion.

PURPOSE: The purpose of this study is to describe and assess the impact of multi-domain biopsychosocial (BPS) recovery on outcomes following lumbar spine fusion. We hypothesized that discrete patterns of BPS recovery (e.g., clusters) would be identified, and then associated with postoperative outcomes and preoperative patient data. METHODS: Patient-reported outcomes for pain, disability, depression, anxiety, fatigue, and social roles were collected at multiple timepoints for patients undergoing lumbar fusion between baseline and one year. Multivariable latent class mixed models assessed composite recovery as a function of (1) pain, (2) pain and disability, and (3) pain, disability, and additional BPS factors. Patients were assigned to clusters based on their composite recovery trajectories over time. RESULTS: Using all BPS outcomes from 510 patients undergoing lumbar fusion, three multi-domain postoperative recovery clusters were identified: Gradual BPS Responders (11%), Rapid BPS Responders (36%), and Rebound Responders (53%). Modeling recovery from pain alone or pain and disability alone failed to generate meaningful or distinct recovery clusters. BPS recovery clusters were associated with number of levels fused and preoperative opioid use. Postoperative opioid use (p < 0.01) and hospital length of stay (p < 0.01) were associated with BPS recovery clusters even after adjusting for confounding factors. CONCLUSION: This study describes distinct clusters of recovery following lumbar spine fusion derived from multiple BPS factors, which are related to patient-specific preoperative factors and postoperative outcomes. Understanding postoperative recovery trajectories across multiple health domains will advance our understanding of how BPS factors interact with surgical outcomes and could inform personalized care plans.

Intradiscal treatment of the cartilage endplate for improving solute transport and disc nutrition.

Poor nutrient transport through the cartilage endplate (CEP) is a key factor in the etiology of intervertebral disc degeneration and may hinder the efficacy of biologic strategies for disc regeneration. Yet, there are currently no treatments for improving nutrient transport through the CEP. In this study we tested whether intradiscal delivery of a matrix-modifying enzyme to the CEP improves solute transport into whole human and bovine discs. Ten human lumbar motion segments harvested from five fresh cadaveric spines (38-66 years old) and nine bovine coccygeal motion segments harvested from three adult steers were treated intradiscally either with collagenase enzyme or control buffer that was loaded in alginate carrier. Motion segments were then incubated for 18 h at 37 °C, the bony endplates removed, and the isolated discs were compressed under static (0.2 MPa) and cyclic (0.4-0.8 MPa, 0.2 Hz) loads while submerged in fluorescein tracer solution (376 Da; 0.1 mg/ml). Fluorescein concentrations from site-matched nucleus pulposus (NP) samples were compared between discs. CEP samples from each disc were digested and assayed for sulfated glycosaminoglycan (sGAG) and collagen contents. Results showed that enzymatic treatment of the CEP dramatically enhanced small solute transport into the disc. Discs with enzyme-treated CEPs had up to 10.8-fold (human) and 14.0-fold (bovine) higher fluorescein concentration in the NP compared to site-matched locations in discs with buffer-treated CEPs (p < 0.0001). Increases in solute transport were consistent with the effects of enzymatic treatment on CEP composition, which included reductions in sGAG content of 33.5% (human) and 40% (bovine). Whole disc biomechanical behavior-namely, creep strain and disc modulus-was similar between discs with enzyme- and buffer-treated CEPs. Taken together, these findings demonstrate the potential for matrix modification of the CEP to improve the transport of small solutes into whole intact discs.

ISSLS Prize in Bioengineering Science 2023: Age- and sex-related differences in lumbar intervertebral disc degeneration between patients with chronic low back pain and asymptomatic controls.

PURPOSE: Clinical management of disc degeneration in patients with chronic low back pain (cLBP) is hampered by the challenge of distinguishing pathologic changes relating to pain from physiologic changes related to aging. The goal of this study was to use imaging biomarkers of disc biochemical composition to distinguish degenerative changes associated with cLBP from normal aging. METHODS: T1ρ MRI data were acquired from 133 prospectively enrolled subjects for this observational study (80 cLBP, 53 controls; mean ± SD age = 43.9 ± 13.4 years; 61 females, 72 males). The mean T1ρ relaxation time in the nucleus pulposus (NP-T1ρ; n = 650 discs) was used as a quantitative biomarker of disc biochemical composition. Linear regression was used to assess associations between NP-T1ρ and age, sex, spinal level, and study group, and their interactions. RESULTS: NP-T1ρ values were lower in cLBP patients than controls (70.8 ± 22.8 vs. 76.4 ± 22.2 ms, p = 0.009). Group differences were largest at L5-S1 (ΔT1ρcLBP-control = -11.3 ms, p < 0.0001), representing biochemical deterioration typically observed over a 9-12 year period (NP-T1ρ declined by 0.8-1.1 ms per year [95% CI]). Group differences were large in younger patients and diminished with age. Finally, the age-dependence of disc degeneration was stronger in controls than cLBP patients. CONCLUSION: Aging effects on the biochemical composition of the L5-S1 disc may involve a relatively uniform set of factors from which many cLBP patients deviate. NP-T1ρ values at L5-S1 may be highly relevant to clinical phenotyping, particularly in younger individuals.

The relative influence of model parameters on finite element analysis simulations of intervertebral body fusion device static compression performance.

Non-clinical mechanical performance testing is a critical aspect of intervertebral body fusion device (IBFD) development and regulatory evaluation. Recently, stakeholders have begun leveraging computational modeling and simulations such as finite element analysis (FEA) in addition to traditional bench testing. FEA offers advantages such as reduced experiment time, lower costs associated with elimination of bench testing (e.g. specimen manufacture and test execution), and elucidating quantities of interest that traditional testing cannot provide (e.g. stress and strain distributions). However, best practices for FEA of IBFDs are not well defined, and modeler decision making can significantly influence simulation setup and results. Therefore, the goal of this study was to determine the relative influence of modeling parameters when using FEA to assess non-clinical mechanical performance of IBFDs. FEA was used to conduct a series of IBFD static uniaxial compression simulations. Several parameters relating to implant geometry, loading/boundary conditions, and material properties were carefully controlled to assess their relative influence on two output variables (IBFD stiffness and yield load). Results were most influenced by device geometry, while the effects of boundary conditions and material properties were more significant within IBFDs of identical or similar geometries. These results will aid stakeholders in the development of standardized best practices for using FEA to assess non-clinical mechanical performance of IBFDs.

Magnetic Resonance Imaging of the Lumbar Spine: Recommendations for Acquisition and Image Evaluation from the BACPAC Spine Imaging Working Group.

Management of patients suffering from low back pain (LBP) is challenging and requires development of diagnostic techniques to identify specific patient subgroups and phenotypes in order to customize treatment and predict clinical outcome. The Back Pain Consortium (BACPAC) Research Program Spine Imaging Working Group has developed standard operating procedures (SOPs) for spinal imaging protocols to be used in all BACPAC studies. These SOPs include procedures to conduct spinal imaging assessments with guidelines for standardizing the collection, reading/grading (using structured reporting with semi-quantitative evaluation using ordinal rating scales), and storage of images. This article presents the approach to image acquisition and evaluation recommended by the BACPAC Spine Imaging Working Group. While the approach is specific to BACPAC studies, it is general enough to be applied at other centers performing magnetic resonance imaging (MRI) acquisitions in patients with LBP. The herein presented SOPs are meant to improve understanding of pain mechanisms and facilitate patient phenotyping by codifying MRI-based methods that provide standardized, non-invasive assessments of spinal pathologies. Finally, these recommended procedures may facilitate the integration of better harmonized MRI data of the lumbar spine across studies and sites within and outside of BACPAC studies.

Spatial distribution of fat infiltration within the paraspinal muscles: implications for chronic low back pain.

PURPOSE: Fat infiltration (FI) of the paraspinal muscles (PSMs) measured using MRI is an aspect of muscle quality and is considered to be worse in chronic low back pain (cLBP) patients. However, there is not a clear association between paraspinal muscle FI and cLBP, leaving the clinical importance of paraspinal muscle composition unestablished. The spatial distribution of FI in the PSMs may inform mechanistic understanding of non-specific cLBP as it relates to degenerative intervertebral disc (IVD) pathology. We hypothesized that paraspinal muscle fat-mapping would reveal distinct FI distribution patterns in relation to cLBP symptoms and proximity to symptomatic IVD degeneration. METHODS: From advanced-sequence water-fat MRI of 40 axial cLBP patients and 21 controls, we examined the spatial distribution of paraspinal muscle FI in relation to the center of rotation at the L4L5 disc. Using statistical parametric mapping, we compared FI patterns for multifidus (MF), erector spinae (ES), and psoas between patients and controls, and to the presence and severity of adjacent degenerative IVD pathology. RESULTS: The spatial distribution of PSMs FI differs between PSMs and according to symptoms and the adjacent degenerative IVD pathology. Furthermore, the region of MF closest to the disc center of rotation appears most susceptible to FI in the presence of symptomatic IVD degeneration. CONCLUSION: Our study identified spatial distribution patterns of FI in the PSMs as a potential diagnostic biomarker that may also provide granular mechanistic insights into spine biomechanics related to cLBP, as well as advancing the use of prior summary measures limited to overall muscle FI.

Magnetic Resonance Imaging Characteristics Associated with Treatment Success from Basivertebral Nerve Ablation: An Aggregated Cohort Study of Multicenter Prospective Clinical Trials Data.

OBJECTIVE: Investigate associations between endplate and motion segment magnetic resonance imaging (MRI) characteristics and treatment outcomes following basivertebral nerve radiofrequency ablation (BVN RFA) in patients with clinically suspected vertebral endplate pain (VEP). DESIGN: Aggregated cohort study of 296 participants treated with BVN RFA from three prospective clinical trials. METHODS: Baseline MRI characteristics were analyzed using stepwise logistic regression to identify factors associated with treatment success. Predictive models used three definitions of treatment success: (1) ≥50% low back pain (LBP) visual analog scale (VAS), (2) ≥15-point Oswestry Disability Index (ODI), and (3) ≥50% VAS or ≥15-point ODI improvements at 3-months post-BVN RFA. RESULTS: The presence of lumbar facet joint fluid (odds ratio [OR] 0.586) reduced the odds of BVN RFA treatment success in individuals with clinically suspected VEP. In patients with a less advanced degenerative disc disease (DDD) profile, a > 50% area of the endplate with bone marrow intensity changes (BMIC) was predictive of treatment success (OR 4.689). Both regressions areas under the curve (AUCs) were under 70%, indicating low predictive value. All other vertebral endplate, intervertebral disc, nerve roots facet joint, spinal segmental alignment, neuroforamina, lateral recesses, and central canal MRI characteristics were not associated with BVN RFA success. CONCLUSIONS: In patients with vertebrogenic low back pain with Modic changes, the presence of degenerative findings of the anterior and posterior column was not associated with a clinically important impact on BVN RFA treatment success. None of the models demonstrated strong predictive value, indicating that the use of objective imaging biomarkers (Type 1 and/or 2 Modic changes) and a correlating presentation of pain remain the most useful patient selection factors for BVN RFA.

Pain Location and Exacerbating Activities Associated with Treatment Success Following Basivertebral Nerve Ablation: An Aggregated Cohort Study of Multicenter Prospective Clinical Trial Data.

OBJECTIVE: Develop pain location "maps" and investigate the relationship between low back pain (LBP)-exacerbating activities and treatment response to basivertebral nerve radiofrequency ablation (BVN RFA) in patients with clinically suspected vertebral endplate pain (VEP). DESIGN: Aggregated cohort study of 296 patients treated with BVN RFA at 33 centers in three prospective trials. METHODS: Participant demographics, pain diagrams, and LBP-exacerbating activities were analyzed for predictors using stepwise logistic regression. Treatment success definitions were: (1) ≥50% LBP visual analog scale (VAS), (2) ≥15-point Oswestry Disability Index (ODI), and (3) ≥50% VAS or ≥15-point ODI improvements at 3 months post-BVN RFA. RESULTS: Midline LBP correlated with BVN RFA treatment success in individuals with clinically-suspected VEP. Duration of pain ≥5 years (OR 2.366), lack of epidural steroid injection within 6 months before BVN RFA (OR 1.800), lack of baseline opioid use (OR 1.965), LBP exacerbation with activity (OR 2.099), and a lack of LBP with spinal extension (OR 1.845) were factors associated with increased odds of treatment success. Regressions areas under the curve (AUCs) were under 70%, indicative of low predictive value. CONCLUSIONS: This study demonstrates that midline LBP correlates with BVN RFA treatment success in individuals with VEP. While none of the regression models demonstrated strong predictive value, the pain location and exacerbating factors identified in this analysis may aid clinicians in identifying patients where VEP should be more strongly suspected. The use of objective imaging biomarkers (Type 1 and/or 2 Modic changes) and a correlating presentation of anterior spinal element pain remain the most useful patient selection factors for BVN RFA.

Unsupervised Machine Learning on Motion Capture Data Uncovers Movement Strategies in Low Back Pain.

Chronic low back pain (LBP) is a leading cause of disability and opioid prescriptions worldwide, representing a significant medical and socioeconomic problem. Clinical heterogeneity of LBP limits accurate diagnosis and precise treatment planning, culminating in poor patient outcomes. A current priority of LBP research is the development of objective, multidimensional assessment tools that subgroup LBP patients based on neurobiological pain mechanisms, to facilitate matching patients with the optimal therapies. Using unsupervised machine learning on full body biomechanics, including kinematics, dynamics, and muscle forces, captured with a marker-less depth camera, this study identified a forward-leaning sit-to-stand strategy (STS) as a discriminating movement biomarker for LBP subjects. A forward-leaning STS strategy, as opposed to a vertical rise strategy seen in the control participants, is less efficient and results in increased spinal loads. Inefficient STS with the subsequent higher spinal loading may be a biomarker of poor motor control in LBP patients as well as a potential source of the ongoing symptomology.

Compensatory biomechanics and spinal loading during dynamic maneuvers in patients with chronic low back pain.

PURPOSE: This study explores the biomechanics underlying the sit-to-stand (STS) functional maneuver in chronic LBP patients to understand how different spinal disorders and levels of pain severity relate to unique compensatory biomechanical behaviors. This work stands to further our understanding of the relationship between spinal loading and symptoms in LBP patients. METHODS: We collected in-clinic motion data from 44 non-specific LBP (NS-LBP) and 42 spinal deformity LBP (SD-LBP) patients during routine clinical visits. An RGB-depth camera tracked 3D joint positions from the frontal view during unassisted, repeated STS maneuvers. Patient-reported outcomes (PROs) for back pain (VAS) and low back disability (ODI) were collected during the same clinical visit. RESULTS: Between patient groups, SD-LBP patients had 14.3% greater dynamic sagittal vertical alignment (dSVA) and 10.1% greater peak spine torque compared to NS-LBP patients (p < 0.001). SD-LBP patients also had 11.8% greater hip torque (p < 0.001) and 86.7% greater knee torque (p = 0.04) compared to NS-LBP patients. There were no significant differences between patient groups in regard to anterior or vertical torso velocities, but anterior and vertical torso velocities correlated with both VAS (r = - 0.38, p < 0.001) and ODI (r = - 0.29, p = 0.01). PROs did not correlate with other variables. CONCLUSION: Patients with LBP differ in movement biomechanics during an STS transfer as severity of symptoms may relate to different compensatory strategies that affect spinal loading. Further research aims to establish relationships between movement and PROs and to inform targeted rehabilitation approaches.

The contributions of cartilage endplate composition and vertebral bone marrow fat to intervertebral disc degeneration in patients with chronic low back pain.

PURPOSE: The composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration. METHODS: MRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19-65 [mean ± SD, min-max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables. RESULTS: CEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43). CONCLUSION: Poor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.

Using hierarchical unsupervised learning to integrate and reduce multi-level and multi-paraspinal muscle MRI data in relation to low back pain.

PURPOSE: The paraspinal muscles (PSM) are a key feature potentially related to low back pain (LBP), and their structure and composition can be quantified using MRI. Most commonly, quantifying PSM measures across individual muscles and individual spinal levels renders numerous separate metrics that are analyzed in isolation. However, comprehensive multivariate approaches would be more appropriate for analyzing the PSM within an individual. To establish and test these methods, we hypothesized that multivariate summaries of PSM MRI measures would associate with the presence of LBP symptoms (i.e., pain intensity). METHODS: We applied hierarchical multiple factor analysis (hMFA), an unsupervised integrative method, to clinical PSM MRI data from unique cohort datasets including a longitudinal cohort of astronauts with pre- and post-spaceflight data and a cohort of chronic LBP subjects and asymptomatic controls. Three specific use cases were investigated: (1) predicting longitudinal changes in pain using combinations of baseline PSM measures; (2) integrating baseline and post-spaceflight MRI to assess longitudinal change in PSM and how it relates to pain; and (3) integrating PSM quality and adjacent spinal pathology between LBP patients and controls. RESULTS: Overall, we found distinct complex relationships with pain intensity between particular muscles and spinal levels. Subjects with high asymmetry between left and right lean muscle composition and differences between spinal segments PSM quality and structure are more likely to increase in pain reported outcome after prolonged time in microgravity. Moreover, changes in PSM quality and structure between pre and post-spaceflight relate to increase in pain after prolonged microgravity. Finally, we show how unsupervised hMFA recapitulates previous research on the association of CEP damage and LBP diagnostic. CONCLUSION: Our analysis considers the spine as a multi-segmental unit as opposed to a series of discrete and isolated spine segments. Integrative and multivariate approaches can be used to distill large and complex imaging datasets thereby improving the clinical utility of MRI-based biomarkers, and providing metrics for further analytical goals, including phenotyping.

Influence of patient-specific factors when comparing multifidus fat infiltration between chronic low back pain patients and asymptomatic controls.

Introduction: Many studies have attempted to link multifidus (MF) fat infiltration with muscle quality and chronic low back pain (cLBP), but there is no consensus on these relationships. Methods: In this cross-sectional cohort study, 39 cLBP patients and 18 asymptomatic controls were included. The MF muscle was manually segmented at each lumbar disc level and fat fraction (FF) measurements were taken from the corresponding advanced imaging water-fat images. We assessed the distribution patterns of MF fat from L1L2 to L5S1 and compared these patterns between groups. The sample was stratified by age, sex, body mass index (BMI), subject-reported pain intensity (VAS), and subject-reported low back pain disability (oswestry disability index, ODI). Results: Older patients had significantly different MF FF distribution patterns compared to older controls (p < 0.0001). Male patients had 34.8% higher mean lumbar spine MF FF compared to male controls (p = 0.0006), significantly different MF FF distribution patterns (p = 0.028), 53.7% higher mean MF FF measurements at L2L3 (p = 0.037), and 50.6% higher mean MF FF measurements at L3L4 (p = 0.041). Low BMI patients had 29.7% higher mean lumbar spine MF FF compared to low BMI controls (p = 0.0077). High BMI patients only had 4% higher mean lumbar spine MF FF compared to high BMI controls (p = 0.7933). However, high BMI patients had significantly different MF FF distribution patterns compared to high BMI controls (p = 0.0324). Low VAS patients did not significantly differ from the control cohort for any of our outcomes of interest; however, high VAS patients had 24.3% higher mean lumbar spine MF FF values (p = 0.0011), significantly different MF FF distribution patterns (p < 0.0001), 34.7% higher mean MF FF at L2L3 (p = 0.040), and 34.6% higher mean MF FF at L3L4 (p = 0.040) compared to the control cohort. Similar trends were observed for ODI. Conclusions: This study suggests that when the presence of paraspinal muscle fat infiltration is not characteristic of an individual's age, sex, and BMI, it may be associated with lower back pain.

Biomechanical changes in the lumbar spine following spaceflight and factors associated with postspaceflight disc herniation.

BACKGROUND CONTEXT: For chronic low back pain, the causal mechanisms between pathological features from imaging and patient symptoms are unclear. For instance, disc herniations can often be present without symptoms. There remains a need for improved knowledge of the pathophysiological mechanisms that explore spinal tissue damage and clinical manifestations of pain and disability. Spaceflight and astronaut health provides a rare opportunity to study potential low back pain mechanisms longitudinally. Spaceflight disrupts diurnal loading on the spine and several lines of evidence indicate that astronauts are at a heightened risk for low back pain and disc herniation following spaceflight. PURPOSE: To examine the relationship between prolonged exposure to microgravity and the elevated incidence of postflight disc herniation, we conducted a longitudinal study to track the spinal health of twelve NASA astronauts before and after approximately 6 months in space. We hypothesize that the incidence of postflight disc herniation and low back complaints associates with spaceflight-included muscle atrophy and pre-existing spinal pathology. STUDY DESIGN: This is a prospective longitudinal study. PATIENT SAMPLE: Our sample included a cohort of twelve astronaut crewmembers. OUTCOME MEASURES: From 3T MRI, we quantified disc water content (ms), disc degeneration (Pfirrmann grade), vertebral endplate irregularities, facet arthropathy and/ fluid, high intensity zones, disc herniation, multifidus total cross-sectional area (cm2), multifidus lean muscle cross-sectional area (cm2), and muscle quality/composition (%). From quantitative fluoroscopy we quantified, maximum flexion-extension ROM (°), maximum lateral bending ROM (°), and maximum translation (%). Lastly, patient outcomes and clinical notes were used for identifying postflight symptoms associated with disc herniations from 3T MRI. METHODS: Advanced imaging data from 3T MRI were collected at three separate time points in relation to spending six months in space: (1) within a year before launch ("pre-flight"), (2) within a week after return to Earth ("post-flight"), and (3) between 1 and 2 months after return to Earth ("recovery"). Fluoroscopy of segmental kinematics was collected at preflight and postflight timepoints. We assessed the effect of spaceflight and postflight recovery on longitudinal changes in spinal structure and function, as well as differences between crew members who did and did not present a symptomatic disc herniation following spaceflight. RESULTS: Half of our astronauts (n=6) experienced new symptoms associated with a new or previously asymptomatic lumbar disc protrusion or extrusion following spaceflight. We observed decreased multifidus muscle quality following spaceflight in the lower lumbar spine, with a reduced percentage of lean muscle at L4L5 (-6.2%, p=.009) and L5S1 (-7.0%, p=.006) associated with the incidence of new disc herniation. Additionally, we observed reduced lumbar segment flexion-extension ROM for L2L3 (-17.2%, p=.006) and L3L4 (-20.5%, p=.02) following spaceflight, and furthermore that reduced ROM among the upper three lumbar segments (-24.1%, p=.01) associated with the incidence of disc herniation. Existing endplate pathology was most prevalent in the upper lumbar spine and associated with reduced segmental ROM (-20.5%, p=.02). CONCLUSIONS: In conclusion from a 10-year study investigating the effects of spaceflight on the lumbar spine and risk for disc herniation, we found the incidence of lumbar disc herniation following spaceflight associates with compromised multifidus muscle quality and spinal segment kinematics, as well as pre-existing spinal endplate irregularities. These findings suggest differential effects of spinal stiffness and muscle loss in the upper versus lower lumbar spine regions that may specifically provoke risk for symptomatic disc herniation in the lower lumbar spine following spaceflight. Results from this study provide a unique longitudinal assessment of mechanisms and possible risk factors for developing disc herniations and related low back pain. Furthermore, these findings will help inform physiologic countermeasures to maintain spinal health in astronauts during long-duration missions in space.