New Experiment Allows Rats with Spinal Cord Injuries to Walk and Climb
The recent article published in Science entitled "Restoring voluntary control of locomotion after paralyzing spinal cord injury" by van den Brand et al.1 is a great basic scientific demonstration of the degree of plasticity and endogenous re-organization both above and below the injury level associated with recovery. The article implies three principles that may be beneficial to recovery from spinal cord injury: (1) Neural stimulation is required both above and below the injury-locomotor training, epidural stimulation, cognitive engagement, (2) chemical stimulation (i.e., serotonin system stimulation), and (3) task-specific training in which the individual is cognitively engaged. But, as I stated to the Associated Press, with regards to van Brand et al's research, "It's a natural extension of exciting work that's been done by many groups2."
Clinically, at ICSCI, we have been utilizing the principles suggested in this article in humans since coining the term Activity Based Restorative Therapy or ABRT in 20023,4. A key concept of ABRT is not only optimizing neural activation both above and below the injury level, utilizing task-specific, engaged training in rehabilitation, and the use of FES to increase the gain on the central pattern generator (CPG)5, but also to enhance physical integrity and offset predictable medical complications6. Use of selective serotonin reuptake inhibitors (SSRIs) or serotonin agonists is useful but far from sufficient in the real clinical setting because most individuals are taking maximally tolerable levels of oral Baclofen, which inhibits the nervous system and this is a much bigger issue7,8. At ICSCI, we can successfully wean most individuals off baclofen once ABRT is begun.
Our work over the past five years on direct central nervous system (CNS) tract stimulation above the level of the injury9 (i.e., pyramidal tract stimulation and direct cortical stimulation) complements our work studying stimulation below the injury level10. Our studies show that electrical activation of specific tracts can produce profound regeneration specific to the simulated tract.
The key focus of ICSCI's basic and clinical research groups is now understanding the mechanisms underlying ABRT11,12 and developing markers to track response to treatment. To this end we have been directing major efforts towards non-invasive functional imaging (fMRI and RSfMRI imaging) and advanced structural imaging (DTI/MT imaging)13,14 strategies and the relationship between epigenetics to the variability in response to injury and recovery observed in our clinical patients. These scientific approaches complement our other areas of focus which include stem cell15,16 and biomaterials17 research.
Clinically, at ICSCI we have been using the principles of ABRT (some of which were used in the Science experiment) for a decade18, not just for recovery of gait, but for all areas of sensory-motor and day-to-day function19 (i.e., hand function).
The real take-home message is a message of hope: the approach to paralysis treatment studied in the recent Science article can be translated to the clinic now rather than in decades, unlike pharmacologic approaches or cell implants which both require lengthy approvals and complicated, expensive trials to prove their effectiveness. The approaches discussed in this statement can be translated today and are being done here at ICSCI. Furthermore, we are actively translating what we have learned in recovery from spinal cord injury to related CNS injuries20.
These are exciting times for advancing knowledge toward a pragmatic cure for paralysis.
John W. McDonald, MD, PhD
Director –International Center for Spinal Cord Injury
Kennedy Krieger Institute
- VAN DEN BRAND R, HEUTSCHI J, BARRAUD Q, DIGIOVANNA J, BARTHOLDI K, HUERLIMANN M, FRIEDLI L, VOLLENWEIDER I, MARTIN MORAUD E, DUIS S, DOMINIC N, MICERA S, MUSIENKO P, COURTINE G. Restoring Voluntary Control of Locomotion after Paralyzing Spinal Cord Injury. Science. 2012 June; 336(6085):1182-1185
- RITTER M. Experiment lets spine-injured rats walk, climb. Associated Press. 2012 May 31.
- MCDONALD JW, GRILL WM, PECKHAM PH, HEETDERKS W, KOCSIS J, and WEINRICH M. At the interface: Convergence of neural regeneration and neural prostheses for restoration of function. J. Rehabil. Res. Dev. 2001 Nov-Dec; 38: 633-39. PMID: 11767971
- MCDONALD JW, BECKER D, SADOWSKY CL, JANE SR. JA, CONTURO TE and SCHULTZ LM. Late Recovery following Spinal Cord Injury. Case Report and Review of the Literature. J. Neurosurg. 2002 Sep; 97(2 Suppl):252-65. Erratum in: J. Neurosurg. 2002 Oct; 97(3 Suppl): 405-406. PMID: 12296690
- SADOWSKY CL and MCDONALD JW. Activity-based restorative therapies: Concepts and applications in spinal cord injury-related neurorehabilitation. Dev. Disabilities Res. Rev. 2009; 15(2): 112-16.
- RECIO AC, FELTER CE, SCHNEIDER AC, MCDONALD JW (2012) High-voltage electrical stimulation for the management of Stage III and IV pressure ulcers among adults with spinal cord injury: Demonstration of its utility for recalcitrant wounds below the level of injury. J Spinal Cord Med, 2012; 35(1):58-63.
- BELEGU V, OUDEGA M, GARY DS and MCDONALD JW. Restoring function after spinal cord injury: promoting spontaneous regeneration with stem cells and activity-based therapies. Neurosurg. Clin. N. Am. 2007 Jan; 18(1):143-68. PMID: 17244561
- Li et al., submitted.
- LI Q, BRUS-RAMER M, MARTIN JH, MCDONALD JW. Electrical stimulation of the medullary pyramid promotes proliferation and differentiation of oligodendrocyte progenitor cells in the corticospinal tract of the adult rat. Neurosci. Letts. 2010 July 26; 479(2): 128-33. PMID: 20493923
- BECKER D, GARY DS, ROSENZWEIG ES, GRILL WM, and MCDONALD JW. Functional electrical stimulation helps replenish progenitor cells in the injured spinal cord of adult rats. Exp. Neurol. 2010 April; 222(2): 211-218. PMID: 20059998
- GARY DS, MALONE M, CAPESTANY P, HOUDAYER T, MCDONALD JW. Electrical field stimulation promotes the survival of MBP+ Oligodendrocytes in mixed cortical cultures. J Neurosci Res, 2012 January; 90(1):72-83. PMID: 21932370
- YANG, GARY, MALONE, DRIA, MCDONALD, THAKOR. Axon myelination and electrical stimulation in microfluidic, compartmentalized cell culture platform. Neuromol Med. Accepted. In press.
- CORBETTA M, BURTON H, SINCLAIR RJ, CONTURO TE, AKBUDAK E, and MCDONALD JW. Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery. Proc. Natl. Acad. Sci. 2002 Dec 24; 99(26): 17066-71. Epub 2002 Dec 11. PMID: 12477938
- SMITH SA, JONES CK, GIFFORD A, BELEGU V, CHODKOWSKI, BA FARRELL JAD, LANDMAN BA, REICH DS, CALABRESI PA, MCDONALD JW and VAN ZIJL PCM. Reproducibility of tract-specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 Tesla. NMR Biomed. 2010 February; 23(2): 207-17. PMID: 19924726
- MCDONALD JW, LIU X-Z, QU Y, LIU S, TURETSKY D, MICKEY SK, GOTTLIEB DI and CHOI DW. Transplanted embryonic stem cells survive, differentiate, and promote recovery in injured rat spinal cord. Nature Med. 1999 Dec; 5:1410-12. PMID: 10581084
- LIU S, QU Y, STEWART T, HOWARD M, CHAKRABORTTY S, HOLEKAMP T and MCDONALD JW. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proc. Natl. Acad. Sci. 2000 May 23; 97: 6126-31. PMID: 10823956
- HURTADO A, CREGG JM, WANG HB, WENDELL DF, OUDEGA M, GILBERT JR, MCDONALD JW. Robust CNS regeneration after complete spinal cord transaction using aligned poly-l-lactic acid microfibers. Biomaterials, 2011 May; 32(26):6068-79. PMID: 21636129
- MARTIN R, SADOWSKY C, OBST K, MEYER B, MCDONALD J. Functional electrical stimulation in SCI: From theory to practice. Topics in Spinal Cord Injury Rehabilitation. 2012; 18(1): 28-33.
- Martin et al., in press.
- SADOWSKY CL, BECKER D, BOSQUES G, DEAN JM, MCDONALD JW, FROHMAN EM. Rehabilitation in Transvere Myelitis. American Academy of Neurology -- Continuum. 2011; 17(14): 816-830.
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