Research Grant Reports
The research summaries below represent work supported through NASS grant funding and conducted by recipients during their award periods. Each report provides an overview of the study’s background, objectives, methods, and key findings, offering insight into how funded research is contributing to improved understanding, diagnosis, and treatment of spine-related conditions.
Localization of Low Back Pain Source by S1R PET/MRI
Ethan Schonfeld, MS1; Ghani Haider, MD2; James Poe, BS1; Neelan Mariayanagam, MD, PhD1; Kelly Yoo, MD, PhD1; Gordon Li, MD1; Sandip Biswal, MD3; Anand Veeravagu, MD1,2,4
1Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 2Neurosurgery Artificial Intelligence Lab, Stanford University School of Medicine, Stanford, California 3Department of Radiology, Stanford University School of Medicine, Stanford, California 4Principal Investigator & Recipient of 2021 NASS Translational Research Grant
Background Context
Surgical intervention for low back pain (LBP) results in Failed Back Surgery Syndrome (FBSS) in an estimated 40% of cases. 80-90% of standard diagnostic exams fail to identify the nociceptive source of LBP, leading to non-specific therapy, FBSS, and long-term opioid prescription. Standard imaging often finds false positives or no findings at all. Sigma–1 Receptors (S1R) have been strongly implicated in nociception, offering the opportunity to localize LBP using a novel S1R radioligand. However, it is unknown whether S1R is expressed in human LBP pain generator tissue.
Purpose
The novel Sigma-1 Receptor (S1R) PET/MRI can localize low back pain generators and reduce FBSS from improved patient and target selection.
Methods of Research
Patients presenting with LBP to a single fellowship-trained complex spine neurosurgeon at a large academic center were treated according to standard of care. All patients (N=11) underwent a staged Anterior Lumbar Interbody Fusion (ALIF) and posterior fusion. Excised intervertebral disc samples, resected according to standard of care, were immunostained for S1R and evaluated by a board-certified pathologist. Pain relief was clinically assessed after at least two months and a year post-operatively. 6 LBP patients pre-operatively received the S1R PET/MRI. 8 healthy controls received the S1R PET/MRI.
Results
20 intervertebral disc tissue samples were collected from 11 patients. S1R staining was positive in 10 of 11 patients, in cartilaginous disc (9/11), and in collagenous disc material (9/11). All patients reported a significant improvement or resolution of their back pain at the 3-month post-operative time interval. S1R staining was noted for patients with or without pre-operative lumbar radiculopathy. Patients with S1R staining in both cartilaginous and collagenous tissue at all surgical levels were correlated with worsened pre-operative pain profiles and improved post-operative pain outcomes. S1R PET/MRI signal was abnormally elevated in a variety of tissues (e.g., spinal nerve, facet joints, spinal canal, paraspinal muscles) and strongly correlated with MRI and pain profile. Healthy control patients had closely clustered SUV max<2.5 across multiple spine anatomical tissue types (facet joint, neural foramen, lateral recess, intervertebral disc, spinal canal and ligamentum flavum).
Conclusion
The current study provides in vivo evidence that S1R is expressed in local pain generators in human LBP. Degree of staining, disc tissue type stained, and levels positively stained may be established in future work as markers of pathology severity and pain resolution prediction. We offer preliminary in vivo evidence that S1R PET/MRI identifies nociceptive LBP generators. Furthermore, we characterize the distribution of the S1R PET/MRI in healthy control patients, demonstrating the low uptake in the non-LBP state.
Investigating Intrinsic Spinal Cord Stress in Degenerative Cervical Myelopathy Using Patient-Specific 3D Modeling
Aditya Vedantam, MD1,2; Narayan Yoganandan, PhD1; Matthew Budde PhD1
1The Medical College of Wisconsin, Milwaukee, WI 2Principal Investigator & Recipient of 2022 NASS Young Investigator Clinical Research Grant
Background Context
Degenerative cervical myelopathy (DCM) is the commonest cause of spinal cord dysfunction in older adults and an important cause of disability and impaired quality of life. Diagnosis, surgical planning and prognostication in DCM are complicated by a dissociation of the clinical phenotype and radiologic assessment of the spinal cord. Intrinsic biomechanical forces in the cervical spinal cord during neck motion are known contributors to axonal and myelin injury in DCM. Direct measurement of intrinsic spinal cord forces is not feasible in humans, and therefore it is not known how these forces relate to neurological injury and function in DCM. Biophysical modeling of the spinal cord can quantify intrinsic spinal cord forces specific to an individual subject’s spinal geometry. This technique is expected to improve the evaluation of ongoing spinal cord damage, thereby boosting the accuracy of diagnosis and prognosis in DCM.
Purpose
To determine how intrinsic spinal cord forces relate to spinal cord damage and neurological dysfunction in DCM.
Methods of Research
DCM patients scheduled for elective cervical spine surgery were recruited from a single academic medical center. All patients underwent pre-surgical cervical spinal cord filtered diffusion weighted imaging (fDWI) and magnetization transfer imaging (MT) to quantify axonal injury and demyelination respectively. Patient-specific finite element models were generated from anatomical MRIs. Magnitude and spatial distribution of spinal cord stress/strain was measured for each individual patient during simulated neck flexion and extension. Spinal cord stress/strain were related to neck range of motion and sagittal alignment as well as fDWI and MT metrics. Patients also underwent pre-surgical and early post-surgical testing of upper limb function (grip strength with hand dynamometer, GRASSP-M and QuickDASH), balance function (Berg Balance Scale) and gait (30m walk test). Standard symptom scales were recorded using the modified Japanese Orthopedic Association (mJOA), Neck Disability Index (NDI), Myelopathy Disability Index.
Results
Using patient-specific FEMs, we found that increased segmental range of motion as well as kyphosis were associated with elevated spinal cord stress and strain. Although, spinal cord compression contributed to spinal cord stress and strain, range of motion and sagittal alignment were important contributors to adverse spinal cord tension in DCM.
Increased maximum spinal cord strain during neck extension was significantly associated with greater white matter (B= -0.2, p=0.004) damage as measured by the whole cord average FA. Increased maximum spinal cord strain was also associated with increased MD (B= 0.04, p=0.04) and RD (B= 0.06, p=0.01) of the white matter tracts indicating greater white matter edema and demyelination respectively. At the level of maximum spinal cord compression, greater axonal injury (FA) in the ventral funiculi was associated with increased spinal cord stress (B=18.9,p=0.04) and strain (B= -0.12, p=0.02). Similarly, greater demyelination (RD) in the ventral funiculi was associated with increased spinal cord stress (B= 7.3, p=0.04) and strain (B= 0.04, p=0.04).
Our analysis of 20 DCM patients showed that increased spinal cord strain in flexion was significantly correlated with decreased hand sensation (right: r= -0.52, p=0.028; left: r= -0.5, p=0.03). Increased spinal cord stress (r= -0.61, p=0.02) and strain (r= -0.69, p=0.006) during neck flexion was correlated with smaller improvement in balance function (measured using Berg Balance Scale) at 3 months after surgery. Increased spinal cord strain during flexion was also linked to smaller improvement in pinch strength (r= -0.6, p=0.039) after surgery.
Conclusion
Spinal cord stress and strain is elevated in DCM during neck motion. Neck range of motion and kyphosis contribute to increased spinal cord stress and strain. Greater spinal cord stress and strain during neck movement was associated with greater axonal injury, demyelination and white matter edema in DCM. For the first time, we show in vivo evidence of increased spinal cord damage with adverse spinal cord tension in DCM.
Higher dynamic spinal cord stress and strain during neck flexion was correlated with baseline hand dysfunction and predicted poorer recovery of hand and balance function at 3 months after surgery. The results highlight the contribution of neck movement, particularly neck flexion, to spinal cord dysfunction and recovery in DCM.