SCIENCE TIMES
9. Greenberg DS, Soreq H. MicroRNA therapeutics in neurological disease [published online ahead of print March 14, 2014]. Curr Pharm Des.
Complete Spinal Cord Injury: An Indication for Spinal Cord Stimulation?
T
Figure. Proposed models for extracellular vesicle transfer of RNA from immune cells to the brain. Possible modes of RNA transfer from blood to brain: A, exosomes (EVs) are released from blood cells into the bloodstream, where they can cross the blood-brain barrier and fuse with neurons. B, alternatively, leukocytes may enter the brain, and only exosomes released within a short distance to the target cell are able to bind and release their content. EV, extracellular vesicles. Modified from Ridder et al.6
authors showed that reprogrammed Purkinje neurons displayed a dramatically different microRNA profile compared with their nonreprogrammed neighbors. Further histological analysis revealed that in addition to Purkinje cells, genetic recombination and reporter gene expression occurred in a broad variety of neuronal populations, including dopaminergic neurons in the substantia nigra, cortical neurons, and granular cell neurons in hippocampal areas CA1 and CA3. In this study, Ridder et al reveal a basic biological pathway that has broad implications for future investigations. There is great potential for the use of exosomes as delivery vectors for therapeutic cargo to the central nervous system, but further research clearly is necessary to determine how they are packaged, how they cross the blood-brain barrier, and how they target different cell types.7 Although the development of RNA-based therapeutics for neurological disease is a promising opportunity, the role of the mRNA and microRNA cargo transferred by exosomes, which has been called exosomal shuttle RNA by 1 group,8 is extremely challenging to understand because RNAs may regulate numerous targets within their destination cell.9 The authors should be congratulated for their elegant and thorough work, which sheds light on a previously unrecognized mechanism of intercellular communication to the central nervous system that may have potential therapeutic implications for multiple neurological diseases.
NEUROSURGERY
Benjamin M. Zussman, MD Christopher P. Deibert, MD Johnathan A. Engh, MD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
REFERENCES 1. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-934. 2. Vezzani A, Rüegg S. The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction. Epilepsia. 2011;52(suppl 3): 1-4. 3. Könnecke H, Bechmann I. The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas. Clin Dev Immunol. 2013; 2013:914104. 4. Prins RM, Liau LM. Immunology and immunotherapy in neurosurgical disease. Neurosurgery. 2003;53 (1):144-152. 5. Johansson CB, Youssef S, Koleckar K, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol. 2008;10(5):575-583. 6. Ridder K, Keller S, Dams M, et al. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol. 2014;12(6): e1001874. 7. Wood MJ, O’loughlin AJ, Samira L. Exosomes and the blood-brain barrier: implications for neurological diseases. Ther Deliv. 2011;2(9):1095-1099. 8. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6): 654-659.
he long-term prognosis after complete spinal cord injury remains very limited. Despite maximal supportive care and intensive therapy, function below the level of injury rarely makes detectable improvement. A primary strategy investigators have used to treat spinal cord injury is to promote regeneration of the spinal cord by encouraging axonal regrowth across the damaged segment. However, achieving this has proven to be easier said than done. Angeli et al1 have taken a different strategy to promote functional recovery in these individuals: epidural spinal cord stimulation distal to the level of injury combined with intensive stepand-stand training. By modulating the activity of the lumbosacral spinal network with spinal cord stimulation, these investigators showed for the first time that patients with complete spinal cord injuries can regain voluntary movement. Previously, this group revolutionized the field by reporting the first-ever use of spinal cord stimulation to successfully improve motor function in a patient with an incomplete injury.2 This first patient had preserved dorsal column function, and it was hypothesized that this function was fundamental to the recovery that was seen. In the present study, Angeli et al sought to evaluate whether patients with complete injuries could still demonstrate recovery in the absence of sensory function. Sixteen contact paddle-style spinal cord stimulator electrodes were implanted in 2 patients with complete injuries at the level of the T1112 vertebrae over the L1-S1 spinal cord segments. Interestingly, these implants were performed at least 2 years after injury. Patients then underwent a lengthy stand-and-step training program in the presence of epidural stimulation (Figure). While undergoing stimulation, the 2 patients with complete spinal cord injuries demonstrated the ability to perform movements of their lower extremities to verbal command. When stimulation was off, no voluntary movement could be detected. Appropriate functioning of ankle and toe muscles was achieved during dorsiflexion testing with epidural stimulation. Moreover, reciprocal inhibition of antagonist muscles was also detected. In the
VOLUME 75 | NUMBER 4 | OCTOBER 2014 | N23
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Figure. Timeline of implantation and experimental sessions for all participants. Blue arrows show time points when clinical evaluations took place. ES, epidural stimulation. Reprinted from Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans; Brain; 2014, volume 137 (Pt 5); 1394-1409, by permission of Oxford University Press.
presence of stimulation, patients could execute graded responses that matched the amount of efforts asked of them. To determine the level of control the individuals possessed, they were asked to alternate the movements as rapidly as possible. One of the 2 patients was able to oscillate flexor and extensor function with stimulation. The patients were also tested regarding whether visual or auditory stimuli could be processed and serve as cues for movement. Indeed, movement could be executed and modulated in response to these cues. Finally, the investigators evaluated whether an intensive training program improved patient functioning. With this training, patients were able to initiate movements of greater force at lower stimulation thresholds. This treatment paradigm of using submotor threshold stimulation to generate motor
N24 | VOLUME 75 | NUMBER 4 | OCTOBER 2014
recovery in chronically paralyzed individuals is a novel therapeutic strategy. The combination of epidural stimulation with intensive training demonstrated that in the setting of increased spinal cord excitability, spinal networks could actively learn and improve their ability to recruit motor pools. A few theories may explain how epidural stimulation works. One possibility is that existing clinically silent descending fibers are present that become more excitable and able to recruit motor pools only after epidural stimulation. Another is that reticulospinal pathways possess connections with distal corticospinal tracts via commissural interneurons. Thus, increasing the excitability of these pathways allows the recruitment of motor pools. Details of the mechanism await full elucidation. Although this new approach is in its infancy, it provides neurosurgeons one of the first-ever
clinical tools with potential to improve recovery for patients with severe spinal cord injuries. Its success could be even more dramatic in patients with less severe injuries. Stephen Johnson, MD Robert M. Friedlander, MD Edward A. Monaco III, MD, PhD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
REFERENCES 1. Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014;137(pt 5):1394-1409. 2. Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011;377(9781):1938-1947.
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
9. Greenberg DS, Soreq H. MicroRNA therapeutics in neurological disease [published online ahead of print March 14, 2014]. Curr Pharm Des.
Complete Spinal Cord Injury: An Indication for Spinal Cord Stimulation?
T
Figure. Proposed models for extracellular vesicle transfer of RNA from immune cells to the brain. Possible modes of RNA transfer from blood to brain: A, exosomes (EVs) are released from blood cells into the bloodstream, where they can cross the blood-brain barrier and fuse with neurons. B, alternatively, leukocytes may enter the brain, and only exosomes released within a short distance to the target cell are able to bind and release their content. EV, extracellular vesicles. Modified from Ridder et al.6
authors showed that reprogrammed Purkinje neurons displayed a dramatically different microRNA profile compared with their nonreprogrammed neighbors. Further histological analysis revealed that in addition to Purkinje cells, genetic recombination and reporter gene expression occurred in a broad variety of neuronal populations, including dopaminergic neurons in the substantia nigra, cortical neurons, and granular cell neurons in hippocampal areas CA1 and CA3. In this study, Ridder et al reveal a basic biological pathway that has broad implications for future investigations. There is great potential for the use of exosomes as delivery vectors for therapeutic cargo to the central nervous system, but further research clearly is necessary to determine how they are packaged, how they cross the blood-brain barrier, and how they target different cell types.7 Although the development of RNA-based therapeutics for neurological disease is a promising opportunity, the role of the mRNA and microRNA cargo transferred by exosomes, which has been called exosomal shuttle RNA by 1 group,8 is extremely challenging to understand because RNAs may regulate numerous targets within their destination cell.9 The authors should be congratulated for their elegant and thorough work, which sheds light on a previously unrecognized mechanism of intercellular communication to the central nervous system that may have potential therapeutic implications for multiple neurological diseases.
NEUROSURGERY
Benjamin M. Zussman, MD Christopher P. Deibert, MD Johnathan A. Engh, MD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
REFERENCES 1. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918-934. 2. Vezzani A, Rüegg S. The pivotal role of immunity and inflammatory processes in epilepsy is increasingly recognized: introduction. Epilepsia. 2011;52(suppl 3): 1-4. 3. Könnecke H, Bechmann I. The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas. Clin Dev Immunol. 2013; 2013:914104. 4. Prins RM, Liau LM. Immunology and immunotherapy in neurosurgical disease. Neurosurgery. 2003;53 (1):144-152. 5. Johansson CB, Youssef S, Koleckar K, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nat Cell Biol. 2008;10(5):575-583. 6. Ridder K, Keller S, Dams M, et al. Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation. PLoS Biol. 2014;12(6): e1001874. 7. Wood MJ, O’loughlin AJ, Samira L. Exosomes and the blood-brain barrier: implications for neurological diseases. Ther Deliv. 2011;2(9):1095-1099. 8. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6): 654-659.
he long-term prognosis after complete spinal cord injury remains very limited. Despite maximal supportive care and intensive therapy, function below the level of injury rarely makes detectable improvement. A primary strategy investigators have used to treat spinal cord injury is to promote regeneration of the spinal cord by encouraging axonal regrowth across the damaged segment. However, achieving this has proven to be easier said than done. Angeli et al1 have taken a different strategy to promote functional recovery in these individuals: epidural spinal cord stimulation distal to the level of injury combined with intensive stepand-stand training. By modulating the activity of the lumbosacral spinal network with spinal cord stimulation, these investigators showed for the first time that patients with complete spinal cord injuries can regain voluntary movement. Previously, this group revolutionized the field by reporting the first-ever use of spinal cord stimulation to successfully improve motor function in a patient with an incomplete injury.2 This first patient had preserved dorsal column function, and it was hypothesized that this function was fundamental to the recovery that was seen. In the present study, Angeli et al sought to evaluate whether patients with complete injuries could still demonstrate recovery in the absence of sensory function. Sixteen contact paddle-style spinal cord stimulator electrodes were implanted in 2 patients with complete injuries at the level of the T1112 vertebrae over the L1-S1 spinal cord segments. Interestingly, these implants were performed at least 2 years after injury. Patients then underwent a lengthy stand-and-step training program in the presence of epidural stimulation (Figure). While undergoing stimulation, the 2 patients with complete spinal cord injuries demonstrated the ability to perform movements of their lower extremities to verbal command. When stimulation was off, no voluntary movement could be detected. Appropriate functioning of ankle and toe muscles was achieved during dorsiflexion testing with epidural stimulation. Moreover, reciprocal inhibition of antagonist muscles was also detected. In the
VOLUME 75 | NUMBER 4 | OCTOBER 2014 | N23
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
Figure. Timeline of implantation and experimental sessions for all participants. Blue arrows show time points when clinical evaluations took place. ES, epidural stimulation. Reprinted from Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans; Brain; 2014, volume 137 (Pt 5); 1394-1409, by permission of Oxford University Press.
presence of stimulation, patients could execute graded responses that matched the amount of efforts asked of them. To determine the level of control the individuals possessed, they were asked to alternate the movements as rapidly as possible. One of the 2 patients was able to oscillate flexor and extensor function with stimulation. The patients were also tested regarding whether visual or auditory stimuli could be processed and serve as cues for movement. Indeed, movement could be executed and modulated in response to these cues. Finally, the investigators evaluated whether an intensive training program improved patient functioning. With this training, patients were able to initiate movements of greater force at lower stimulation thresholds. This treatment paradigm of using submotor threshold stimulation to generate motor
N24 | VOLUME 75 | NUMBER 4 | OCTOBER 2014
recovery in chronically paralyzed individuals is a novel therapeutic strategy. The combination of epidural stimulation with intensive training demonstrated that in the setting of increased spinal cord excitability, spinal networks could actively learn and improve their ability to recruit motor pools. A few theories may explain how epidural stimulation works. One possibility is that existing clinically silent descending fibers are present that become more excitable and able to recruit motor pools only after epidural stimulation. Another is that reticulospinal pathways possess connections with distal corticospinal tracts via commissural interneurons. Thus, increasing the excitability of these pathways allows the recruitment of motor pools. Details of the mechanism await full elucidation. Although this new approach is in its infancy, it provides neurosurgeons one of the first-ever
clinical tools with potential to improve recovery for patients with severe spinal cord injuries. Its success could be even more dramatic in patients with less severe injuries. Stephen Johnson, MD Robert M. Friedlander, MD Edward A. Monaco III, MD, PhD University of Pittsburgh Medical Center Pittsburgh, Pennsylvania
REFERENCES 1. Angeli CA, Edgerton VR, Gerasimenko YP, Harkema SJ. Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans. Brain. 2014;137(pt 5):1394-1409. 2. Harkema S, Gerasimenko Y, Hodes J, et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. 2011;377(9781):1938-1947.
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
