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Spinal Cord Injury:


This research has focused on the development of novel treatments for spinal cord injury (SCI). We have worked to find methods to promote functional recovery as well as to alleviate neuropathic pain (NP). We have studied the role of cyclooxygenase 2 (COX2) inhibitors on functional recovery following acute SCI, the effect of stem cell and olfactory nerve ensheathing cell transplantation on recovery of function following SCI, and the influence of folic acid metabolism on functional recovery following SCI. Our studies have included genetic analysis of both the acute and chronically injured spinal cord using Genechip as well as RTPCR technologies. We have reported genetic changes observed in the dorsal column of the spinal cord of rats subjected to a loose ligation of the sciatic nerve, and found interesting alterations in the expression of several genes known to play a role in nociception. These alterations resolved as the behavioral evidence of allodynia resolved. We have established an rat model for the assessment of “thermal hyperalgesia” a behavior following spinal cord injury and intend to use this model to perform an in depth analysis of the factors responsible for the development of neuropathic pain following spinal cord injury.


Several research papers on various aspects of SCI mechanisms and therapeutic applications have been published. Some of these publications evaluated WNK1, cation-dependent chloride transporters activation (NKCC1) and inhibition by bumetanide, cannabinoid receptors specially CB2 (anti-hyperalgesic effect of WIN 55,212-2), anti-hyperalgesic effects of bradykinin (B1) and vanilloid-1 (TRPV1) receptor antagonists, rolipram (specific PDE4 inhibitor) effect on thermal hyperalgesia, cyclooxygenase-2 (Cox2) inhibitor (meloxicam) and PPAR-gamma induction and ghrelin for control of SCI-induced neuropathic pain. I also presented the research findings at six national and three international meetings. I regularly supervise the undergraduate and med students working in the SCI lab. My research expertise encompasses all aspects of the present proposal including induction of SCI, monitoring functional recovery, measurements of neuropathic pain and evaluating the molecular mechanisms. In this project, I will co-supervise the experiments conducted by other scientists, students and research specialists, write the manuscripts and plan the day to day research work of the lab.  Recently submitted research papers including "Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury

 

Recently in a rat model of contusion SCI (cSCI) we have reported expression and activity of matrix metalloproteinases (MMPs; MMP9 and MMP2) in spinal cord injured rats.  As an upstream modulator of inflammatory cytokine production, MMPs cleave the pro-form of cytokines into the active form and play a significant role in regulating the components of the extra-cellular matrix surrounding the cell via tissue remodeling, signaling, and inflammation within the nervous system.  We have characterized the expression and activity levels of MMP9 in the acute phase and MMP2 in the late phase, respectively. SCI-induced NP and its association with the cellular and molecular changes in the interactions between extracellular signaling kinase, β-catenin, and MMP2. Wnt/ β-catenin signaling controls the development of the blood-brain barrier, which suggests its use as a therapeutic agent in limiting damage to the blood spinal cord barrier. Our preliminary data suggests that the initial down-regulation of phosphorylated extracellular signaling kinase may lead to the up-regulation of both β-catenin and MMP2 in SCI and neuropathic pain.  These findings support the idea that MMP9 and MMP2 be used as a potential therapeutic target for SCI treatment.

We also have ongoing collaborative projects underway with members of the University of Wisconsin. This research team includes researchers from the department of neurological surgery as well as Anesthesiology department of medical school. These experiments are designed to assess the novel mechanisms of cell-based and gene-based therapy of SCI/NP. In this study we hypothesize that early inhibition of MMP9 and/or delayed enhancement of MMP2 activity in the spinal cord will improve functional recovery after injury. The study will be aimed at: testing whether the early inhibition of MMP9 will alleviate the infiltration of inflammatory cells, diminish the disruption of the blood spinal cord barrier (BSCB), and improve functional recovery using TIMP1-lacZ-neutrophil therapy. Other projects are designed to determine whether MMP-9 produced by macrophages induce myelinated axon damage using TIMP1-lacZ-macrophage therapy.  Finally, we are determining whether the late increase in MMP2 enhances functional recovery following SCI using MMP2-lacZ-macrophage therapy.



Clinical Research Interests:

Evidence Based Guidelines:

Dr. Resnick has published numerous clinical practice guidelines and remains involved in the development and review of such documents through his role as a member of the Congress Of Neurological Surgeon’s Guidelines Committee, Director of the North American Spine Society Research Council, and a member of the AANS/CNS Joint Guidelines Committee.  The practice and teaching of evidence based neurosurgery and spinal surgery are a major part of his academic mission.

 

Comparative Effectiveness Research:

A pioneer in the utilization of registry based data collection to provide important clinical information to clinicians, Dr. Resnick has been instrumental in the design and development of the Neuropoint SD project (through NPA), as well as the N2QOD database, the WISPOS project, and the NASS Registry.  Currently, grant supported clinical outcomes research is investigating the efficacy of surgical versus non-surgical management of common lumbar spine disorders.

 

Personnel

 

Spinal Cord Injury Laboratory:
 •  Daniel K. Resnick, MD MS
 •  Gurwattan Miranpuri, PhD

 

Funding

 

University of Wisconsin Department of Neurosurgery

AANS/CNS Joint Section on Disorders of the Spine

Congress of Neurological Surgeons

Wallace Foundation

Agency for Healthcare Research and Quality

 

Recent Publications (2009-June 2012)

 
  1. Watters WC 3rd, Baisden J, Bono CM, Heggeness MH, Resnick DK, Shaffer WO, Toton JF. Antibiotic prophylaxis in spine surgery: an evidence-based clinical guideline for the use of prophylactic antibiotics in spine surgery. The Spine Journal 9: 142-146, 2009 (Epub ahead of print July 9, 2008)
  2. Watters, WC, Bono CM, , Gilbert T, Kreiner DS, Mazanec D, Shaffer WO, Baisden J, Easa J, Fernand R, Ghiselli G, Heggeness MH, Mendel R, O’Neill C, Reitman C, Resnick DK, Summers J,, Timmons R, Toton JF: An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Degenerative Lumbar Spondylolisthesis.  The Spine Journal 9(7): 609-614, 2009.
  3. Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the surgical management of cervical degenerative disease: Introduction and methodology. Journal of Neurosurgery: Spine 11(2): 101-103. 2009
  4. Holly L, Choudhri T, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Mummaneni P, Ryken T, Vresilovik E, Resnick DK: Guidelines for the management of cervical degenerative disease. Clinical prognostic indicators of surgical outcome in cervical spondylotic myelopathy. Journal of Neurosurgery: Spine 11(2): 112-118, 2009
  5. Holly L, Choudhri T, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Mummaneni P, Ryken T, Vresilovik E, Resnick DK:Guidelines for the management of cervical degenerative disease: Functional outcomes assessment. Journal of Neurosurgery: Spine 11(2): 238-244, 2009
  6. Mummaneni P, Kaiser MG, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovic E, Resnick DK: Guidelines for the management of cervical degenerative disease: Cervical surgical techniques for the treatment of cervical degenerative myelopathy. Journal of Neurosurgery: Spine 11(2): 130-141, 2009
  7. Mummaneni P, Matz PG, Kaiser MG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovic E, Resnick DK: Guidelines for the surgical management of cervical degenerative disease: Anterior cervical surgery for the treatment of cervical degenerative myelopathy. Journal of Neurosurgery: Spine 11(2): 170-173, 2009
  8. Kaiser MG, Mummaneni P, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovic E, Resnick DK: Guidelines for the management of cervical degenerative disease: Management of anterior cervical pseudoarthrosis. Journal of Neurosurgery: Spine 11(2): 228-237, 2009
  9. Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the management of cervical degenerative disease: Cervical laminoplasty for the treatment of cervical degenerative myelopathy. Journal of Neurosurgery: Spine 11(2): 157-169, 2009
  10. Kaiser MG, Mummaneni P, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovic E, Resnick DK: Guidelines for the management of cervical degenerative disease: Radiographic assessment of subaxial fusion. Journal of Neurosurgery: Spine 11(2): 221-227, 2009
  11. Resnick DK, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Matz PG: Guidelines for the management of cervical degenerative disease: Electrophysiological monitoring during surgery for cervical degenerative myelopathy and radiculopathy. Journal of Neurosurgery: Spine 11(2): 245-252, 2009
  12. Anderson PA, Matz PG,  Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the management of cervical degenerative disease: Laminectomy and fusion for the treatment of cervical degenerative myelopathy. Journal of Neurosurgery: Spine 11(2): 150-156, 2009
  13. Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the management of cervical degenerative disease: The natural history of cervical spondylotic myelopathy. Journal of Neurosurgery: Spine 11(2): 104-111, 2009
  14. Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the surgical management of cervical degenerative disease: Anterior cervical decompression for radiculopathy. Journal of Neurosurgery: Spine 11(2): 174-182, 2009
  15.  Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovik E, Resnick DK: Guidelines for the surgical management of cervical degenerative disease: Techniques for anterior cervical decompression for radiculopathy. Journal of Neurosurgery: Spine 11(2): 183-197, 2009
  16. Mummaneni P, Kaiser MG, Matz PG, Anderson PA, Choudhri T, Groff M, Heary R, Holly L, Ryken T, Vresilovic E, Resnick DK: Guidelines for the management of cervical degenerative disease: Preoperative patient selection by MRI, CT, EMG: Does the test predict surgical outcomes in patients undergoing cervical surgery. Journal of Neurosurgery: Spine 11(2): 119-129, 2009
  17. Ryken T, Heary R, Matz PG, Anderson PA, Choudhri T, Groff M, Holly L, Mummaneni P, Vresilovik E, Resnick DK:Guidelines for the management of cervical degenerative disease: Cervical laminectomy for the treatment of cervical degenerative myelopathy. Journal of Neurosurgery: Spine 11(2): 142-149, 2009
  18. Heary R, Ryken T, Matz PG, Anderson PA, Choudhri T, Groff M, Holly L, Mummaneni P, Vresilovik E, Resnick DK:Guidelines for the management of cervical degenerative disease: Cervical lamino-foraminotomy for the treatment of cervical degenerative radiculopathy. Journal of Neurosurgery: Spine 11(2): 198-202, 2009
  19. Ryken T, Heary R, Matz PG, Anderson PA, Choudhri T, Groff M, Holly L, Mummaneni P, Vresilovik E, Resnick DK Guidelines for the surgical management of cervical degenerative disease: Techniques for cervical interbody grafting. Journal of Neurosurgery: Spine 11(2): 203-220, 2009
  20. Chou R, Baisden J, Carragee EJ, Resnick DK, Shaffer WO, Loeser JD et al: Surgery for Low Back Pain: An Evidence-based Clinical Practice Guideline from the American Pain Society.   Spine 34(10): 1094-1109, 2009
  21. Chou R, Loeser JD, Owens DK, Rosenquist RW, Atlas SJ, Baisden J, Carragee EJ, Grabois SP, Murphy DR, Resnick DK, Stanos SP, Shaffer WO, Wall EM: Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain.  Spine 34(10): 1066-1077, 2009
  22. Bono CM, Watters WC III, Heggeness MH, Resnick DK, Shaffer WO, Baisden J, Ben Galim P, Easa JE, Fernand R, Lamer T, Matz PG, Mendel RC, Patel RK, Reitman CA, Toton JF: Antithrombotic Therapies in Spinal Surgery.  The Spine Journal 12: 1046-1051, 2009.
  23. Resnick DK, Rajpal S, Steinmetz MP: Perils and pitfalls in the interpretation of medical evidence.  The Spine Journal 9(11): 905-909, 2009
  24. Rajpal S, Gordon DB, Pellino TA, Strayer AL, Trost GR, Zdeblick TA, Resnick DK: Forget IV PCA: Oral multimodal analgesia for spine surgery.  Journal of Spinal Disorders and Techniques 23: 139-145, 2010.
  25. Anderson PA, Tontz WL, Resnick DK: Clearance of the asymptomatic cervical spine: a metanalysis.  The Journal of Orthopedic Trauma 24 (2): 100-106, 2010.
  26. Sun D, Hasbargen T, Miranpuri G, Lin L, Resnick DK: Role of NKCC1 and KCC2 in the development of neuropathic pain following spinal cord injury.  Annals of the New York Academy of Sciences 1198: 168-172, 2010.
  27. Patel N, Resnick DK: Complications of occipitocervical fixation.  Neurosurgery 67(5): 1396-1402, 2010
  28. Clark ZJ, Miranpuri GS, Resnick DK: In vivo applications of siRNA to study pain.  Annals of Neurosciences 17(3): 142-145, 2010
  29. Bono CM, Ghiselli G, Gilbert, Thomas J, Kreiner D.S., Reitman C, Summers J.T., Baisden J., Easa J, Fernand R, Lamer T., Matz P., Mazanec D., Resnick DK, Shaffer W.O., Sharma A, Timmons R.,  Toton J: An Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Cervical Radiculopathy from Degenerative Disorders. The Spine Journal 11(1): 64-72, 2011
  30. Krueger EM, Miranpuri GS, Resnick DK: Emerging role of WNK-1 in pathological central nervous system signaling.  Annals of Neurosciences 18(2): 70-75, 2011
  31. Golder FJ, Fuller DD, Barr MRL, Resnick DK, Mitchell, GS:  Breathing patterns after mid-cervical spinal contusion in rats.  Experimental Neurology 231(1): 97-103, 2011.
  32. Ahmed MM,  King KC, Miranpuri GS, Resnick DK: New therapeutic targets for spinal cord injury-induced neuropathic pain. Annals of Neurosciences 18(4): 162-167, 2011
  33. Glassman SJ, Carreon L, Anderson PL, Resnick DK: A Diagnostic Classification for Lumbar Spine Registry Development.  The Spine Journal 11: 1108-1116, 2011
  34. Agrawal B, Brooks N, Resnick DK: Development of a population based registry for spinal disorders- WISPOS.  Journal of Neurosurgery: Focus (33): E15, 2012
  35. Ahmed M, Rajpal S, Sweeney C, Gerovac TA, Allcock B, McChesney S, Patel A, Tilghman J, Miranpuri GS, Resnick DK: Cannabanoid subtype 2 receptors modulate the antihyperalgesic effect of WIN 55,212-12 in rats with neuropathic SCI pain. In press, The Spine Journal, 2012
  36. Hartjen C, Resnick DK, Hse J, Zucherman J, Hsu E, Skidmore G: Two-Year Evaluation of the X-STOP Interspinous Process Decompression System in Different Primary Patient Populations with Neurogenic Intermittent Claudication due to Lumbar Spinal Stenosis.  In press, The Spine Journal, 2012
  37. Figueiredo N, Figueiredo IE, Resnick DK: Tetraplegia or paraplegia with brachial diparesis? What is the most appropriate designation for the motor deficit in patients with lower cervical spinal cord injury? Neurological Sciences, DO1 10.1007/s10072-012-1160-4, 2012
  38. Figueiredo N, Brooks N, Resnick DK: Evidence-based review and guidelines for the management of myxopapillary and intramedullary ependymoma.  In press, Journal Neurosurgical Sciences, 2012
  39. Macias MY, Miranpuri GW, Resnick DK, Kurpad SN: Post SCI Hyperalgesic Peak Expression of Vanilloid-1, Bradykinin-1 and -2 Receptor mRNA Following C17.2 NSC Transplantation.  Submitted to Experimental Neurochemistry, 2012
  40. Riew KD, Kuklo TR, Resnick DK, Anderson PA: Does Neck Pain Associated with Radiculopathy or Myelopathy Improve with Surgery?    Manuscript submitted to Journal of Bone and Joint Surgery, 2012
  41. Lake W, Ahmed MM, Resnick DK: Progressive kyphosis following multilevel facet rhizotomy.  In press, The Spine Journal, 2012
  42. King KC, Ugalde J, Lehman E, Raab L, Kim T, Wesley VJ, Khan N, Schomberg D, Miranpuri GS,   Resnick DK: Activation of Matrix Mettaloproteinase-2 following spinal cord injury induced thermal hyperalgesia.  Submitted to Molecular Pain, 2012
  43. Lake WS, Brooks N, Agrawal B, Resnick DK: Registry design for Comparative Effectiveness Research in Spinal Disorders. Submitted to Journal of Comparative Effectiveness, 2012
  44. King KC, Ugalde J, Lehman E, Raab L, Kim TH, Wesley VJ, Khan N, Gill N, Miranpuri GS, Resnick DK: Activation of Matrix Metalloproteinase-2 following spinal cord injury induced neuropathic pain.  Submitted to Molecular Pain, 2012
  45. Walters BC, Hadley MN, Ghogawala Z, Resnick DK, Waters WC, Mummaneni P, Eck J, Sharan A, Groff MW, Dailey AT, Choudhri TF, Wang J, Kaiser MG: Chapter 1: Introduction and methodology. Submitted to J. Neurosurgery Spine, 2012
  46. Ghogawala Z, Resnick DK, Eck J, Waters WC, Mummaneni P, Sharan A, Groff MW, Dailey AT, Choudhri TF, Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 2:  Assessment of functional outcome following lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  47. Ghogawala Z, Waters WC, Sharan A, Mummaneni P, Groff MW, Dailey AT, Choudhri TF, Eck J, Wang J, Resnick DK, Walters BC, Hadley MN, Kaiser MG: Chapter 3: Assessment of economic outcome of lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  48. Choudhri TF, Mummaneni P, Dailey AT, Ghogawala Z, Resnick DK, Waters WC, Eck J, Sharan A, Groff MW, Wang J, Walters BC, Hadley MN, Kaiser MG; Chapter 4: Radiographic assessment of lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  49. Choudhri TF, Dailey AT, Waters WC, Mummaneni P, Eck J, Sharan A, Groff MW, Wang J, Resnick DK, Ghogawala Z, Walters BC, Hadley MN, Kaiser MG; Chapter 5: Correlation between radiographic and functional outcome of lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  50. Eck J, Sharan A, Resnick DK, Waters WC, Ghogawala Z, Dailey AT, Mummaneni P, Groff, MW, Choudhri TF, Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 6: Magnetic resonance imaging and discography for patient selection for lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  51. Eck J, Sharan A, Ghogawala Z, Resnick DK, Waters WC, Mummaneni P, Groff, MW, Dailey AT, Choudhri TF, Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 7: Lumbar fusion for intractable low-back pain without stenosis or spondylolisthesis. Submitted to J. Neurosurgery Spine, 2012
  52. Wang J, Groff MW,  Mummaneni P, Ghogawala Z, Resnick DK, Waters WC, Dailey AT, Choudhri TF, Eck J , Sharan A, Walters BC, Hadley MN, Kaiser MG: Chapter 8: Lumbar fusion for disc herniation and radiculopathy. Submitted to J. Neurosurgery Spine, 2012
  53. Resnick DK, Ghogawala Z, Waters WC, Mummaneni P, Dailey AT, Choudhri TF, Eck J, Sharan A, Groff, MW,  Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 9: Lumbar fusion in patients with stenosis and spondylolisthesis. Submitted to J. Neurosurgery Spine, 2012
  54. Resnick DK, Waters WC, Mummaneni P, Ghogawala Z, Dailey AT, Choudhri TF, Eck J, Sharan A, Groff, MW,  Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 10: Lumbar fusion following decompression with stenosis without spondylolisthesis. Submitted to J. Neurosurgery Spine, 2012
  55. Mummaneni P, Sharan A, Groff MW, Ghogawala Z, Resnick DK, Waters WC, Dailey AT, Choudhri TF, Eck J , Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 11: Interbody techniques for lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  56. Groff MW, Dailey AT, Ghogawala Z, Resnick DK, Waters WC, Mummaneni P, Choudhri TF, Eck J , Sharan A, Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 12: Pedicle screw fixation as an adjunct to posterolateral lumbar fusion for low-back pain. Submitted to J. Neurosurgery Spine, 2012
  57. Waters WC, Resnick DK, Eck J, Ghogawala Z, Mummaneni P, Dailey AT, Choudhri TF, Sharan A, Groff MW, Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 13: Injection therapies, low-back pain, and lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  58. Dailey AT, Ghogawala Z, Resnick DK, Waters WC, Mummaneni P, Choudhri TF, Eck J, Sharan A, Groff MW, Wang J, Walters BC, Hadley MN, Kaiser MG; Chapter 14: Brace therapy as an adjunct to or substitute for lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  59. Sharan A, Groff MW, Dailey AT, Ghogawala Z, Resnick DK, Waters WC, Mummaneni P, Choudhri TF, Eck J , Wang J, Walters BC, Hadley MN, Kaiser MG: Chapter 15: Electrophysiological monitoring and lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  60. Kaiser MG, Resnick DK, Waters WC , Ghogawala Z,  Eck J , Groff, MW, Mummaneni P, Dailey AT, Choudhri TF, Sharan, A, Wang J, Walters BC, Hadley MN; Chapter 16: Bone graft extenders and substitutes as an adjunct for lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  61. Kaiser MG, Eck J , Groff MW, Ghogawala Z, Waters WC, Mummaneni P, Dailey AT, Choudhri TF, Sharan, A, Wang J, Walters BC, Hadley MN, Resnick DK; Chapter 17: Bone growth stimulators as an adjunct for lumbar fusion. Submitted to J. Neurosurgery Spine, 2012
  62. Schomberg D, Ahmed MM, Miranpuri G, Olsen J, Resnick DK:  Neuropathic Pain: Role of Inflammation, Immune Response, and Ion Channel Activity in Central Mechanisms following Spinal Cord Injury, Submitted to Pain Research and Treatment, 2012
  63. Lee HK, Ahmed M, King K, Miranpuri G, Kahle KT, Resnick DK, Sun D: Persistent phosphorylation of NKCC1 and WNK1 in the epicenter of the spinal cord following contusion injury.  Submitted to  Spine, 2012
  64. Figueredo N, Brooks N, Trost G, Baskaya M, Resnick DK: Intraspinal ependymomas- case series and review of the literature. Submitted to British Journal of Neurosurgery, 2012

 

 

 

 



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