REVIEW REVIEW
Role of Central Plasticity in the Outcome of Peripheral Nerve Regeneration Chandan B. Mohanty, MCh Dhananjaya Bhat, MCh Bhagavatula Indira Devi, MCh Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India Correspondence: Bhagavatula Indira Devi, MCh, Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, India, 560029. E-mail: [email protected], [email protected] Received, July 16, 2014. Accepted, April 22, 2015. Published Online, June 18, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.
The optimal refinement in nerve repair techniques has reached a plateau, making it imperative to continually explore newer avenues for improving the clinical outcome of peripheral nerve regeneration. The aim of this short review is to discuss the role and mechanism of brain plasticity in nerve regeneration, as well as to explore the possible application of this knowledge for improving the clinical outcome following nerve repair. KEY WORDS: Central reorganization, Nerve injury, Nerve transfer, Plasticity, Regeneration Neurosurgery 77:418–423, 2015
DOI: 10.1227/NEU.0000000000000851
T
he role of central nervous system plasticity in peripheral nerve regeneration is seldom covered in textbooks that are exclusively devoted to peripheral nerve surgery. Additionally, this topic is rarely mentioned in standard neurosurgical textbooks. In our experience, most neurosurgical residents and trainees are not acquainted with the concept of plasticity and its role in peripheral nerve regeneration. This review attempts to fill this gap in knowledge and provide a broad overview of this topic for practitioners, trainees, and residents who are interested in peripheral nerve surgery. The review also aims to inspire the exploration of the role of central nervous system plasticity in improving clinical outcomes after nerve injury. Improving our understanding of central plasticity is also useful for studying the role of physiotherapy and synkinetic exercises in the early phase of rehabilitation for patients undergoing nerve transfers. The subsequent discussion is restricted to the role of central reorganization. Although, some of the studies that are referenced in this review are not directly related to nerve injury, they improve our understanding of the brain plasticity and its possible applications in nerve injury.
ABBREVIATIONS: BDNF, brain-derived neurotrophic factor; GABA, Gamma amino-butyric acid; ICN-MCN, intercosto-musculocutaneous nerve; LTD, long-term depression; LTP, long-term potentiation; NGF, nerve growth factor; NT-4, neurotrophin; TMS, transcranial magnetic stimulation
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CENTRAL NERVOUS SYSTEM PLASTICITY AND PERIPHERAL NERVE REGENERATION Currently, despite the improved microsurgical techniques coupled with the use of various types of grafts, immunomodulators, and growth factors, the results of peripheral nerve surgery are far from satisfactory. The surgical refinements for nerve repair have plateaued, and it is imperative to seek newer targets for improving nerve regeneration; this requires a better understanding of the role of the central nervous system. Cortical plasticity is defined as a change in the property of cortical neurons.1 Cortical synapses respond to neural input activity by modulating their function. Changes in the synaptic function may be activity-dependent, and thus central plasticity can be caused by changes in the neural activity input from the periphery.2 A common misconception related to plasticity is that it only occurs in a developing brain and at the cerebral cortical level. It is important to highlight at the outset that brain plasticity is also seen in adults after nerve injury. Furthermore, infants and children demonstrate better recovery from nerve injury compared with adults, and it is postulated that they have a greater regeneration potential and shorter distances to be crossed by regenerating axons after nerve injury.2 Based on a fetal primate experimental study, it has also been suggested that the superior recovery of hand perception in children, compared with adults, may be due to better restoration of the cortical sensory maps after nerve transection and repair.3 Importantly, plasticity after nerve injury
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CENTRAL PLASTICITY IN PERIPHERAL NERVE REGENERATION
can occur at all levels of the central nervous system, including the spinal cord, brainstem, and thalamus.4-6 Some of the experimental findings in support of this fact are as follows: 1. Mismatched sensory reconnection between the sensory receptors and dorsal horn neurons after nerve injury leads to an altered somatotopic representation in the spinal cord, which gives rise to a loss of tactile discrimination and tactile acuity as well as positive symptoms, such as neuropathic pain.7 2. Anesthetic blockade of sensory nerves has been shown to induce the reorganization of the ventral posteromedial nucleus of the thalamus in a rodent model.4 3. Xu and Wall6 in 1997 showed that after median and ulnar nerve section in a primate model, the post injury mapping of the brainstem cuneate nucleus has increased input from the intact radial nerve input (dorsal hand). Interestingly, this increase in the brainstem (66%) is almost twice the size of the cortical increase (37%) recorded from somatosensory area 3b.6 Despite this evidence, the role of thalamic and brainstem plasticity is somewhat poorly understood because most of the data supporting this are from animal studies that require invasive monitoring techniques. Cortical plasticity, on the other hand, is better understood because of its easy accessibility and larger area and the better understanding of the somatotopic maps in the cortex. The outcome after nerve repair depends on the functional central reorganizational processes, which are caused by misdirected axonal outgrowth.6-10 Misdirected axonal growth leads to errors in both the peripheral inputs and cortical representation of the reinnervated area.
MECHANISM OF CENTRAL REORGANIZATION AFTER NERVE INJURY Cortical Reorganization After Nerve Injury Consists of 2 Stages Stage 1 This occurs during denervation and involves the expansion of the surrounding cortical areas that occupy the area represented by the damaged nerve. This change may be apparent within a few minutes to a few months after denervation11 and occurs due to the unmasking of the latent excitatory synaptic connections, leading to the rapid expansion of the adjacent motor and sensory cortical areas,7 which in turn is caused by a reduction in Gamma aminobutyric acid (GABAergic) inhibition.12 GABA is the predominant inhibitory neurotransmitter in the brain and GABA interneurons are located in the intracortical regions. The projections of these neurons can extend to 6 mm. Therefore, the inhibition of GABA can unmask the projections of these interneurons.13 In humans, a rapid decline in GABA and glutamic acid decarboxylase (which helps in the synthesis of GABA) has been noted in the sensorimotor cortex after deafferentation.14 These findings are further confirmed by the fact that GABA receptor antagonists cause the expansion of the somatosensory neuron projections and increased evoked potential responses.15
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Stage 2 This occurs during reinnervation and once again involves cortical reorganization, which parallels the axonal misorientation at the site of peripheral nerve injury. Therefore, the damaged area is not innervated by the original axons. These long-term changes occur due to a combination of long-term potentiation (LTP), long-term depression (LTD), synaptogenesis, and axonal sprouting.16 Neurotrophins, such as nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), and neurotrophin (NT-4), modulate electrical activity, synaptic transmission, and intracortical inhibition.17 LTP and LTD, which are critical in stage II cortical reorganization, require a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor activation with high intracellular calcium.18 It has also been shown that the systemic administration of an NMDA antagonist within 1 month of median injury reduced the expansion of the area 3b map of hand in a primate model.19,20 Therefore, the well-organized cortical area prior to injury is transformed into an ill-defined, mosaic-like area.2 The role of rehabilitation in altering cortical reorganization is well documented in stroke models.21,22 The alteration of motor maps by skill acquisition and repetitive use has been shown in primate models.21 Therefore, based on these data, we hypothesize that it may be possible to exploit the concept of brain plasticity in preventing the transformation of the well-organized cortical area into an ill-defined mosaic-like area with the goal of improving the outcomes of nerve injuries. This may be achieved by restricting the encroachment of the surrounding cortical areas during stage 1 of cortical reorganization, which can be achieved by initiating rehabilitation at the earliest time point after nerve injury. It may also be important to simultaneously keep the cortical area of the damaged nerve intact during stage 1 of cortical reorganization by ensuring a full range of motion of the lost movement. Therefore, mentally simulated movement may play a crucial role in planning the rehabilitative program after peripheral nerve injury. The main role of synkinetic exercises after nerve transfer is to maintain the original cortical map of an injured nerve. As our understanding of the roles of receptors and neurotransmitters in cortical reorganization improves, these can be medically manipulated to improve the outcomes after nerve injury. Nerve injury in humans results in enlarged cortical representation and increased motor-evoked potentials of the myotome innervated by the nerve proximal to the injured nerve. This occurs in conjunction with a decrease in the cortical map of the muscles supplied by the injured nerve.12 Experimental studies involving primates, who have undergone forelimb amputation, have shown that the stimulation of motor cortex originally subserving the hand function results in contractions of the proximal muscles in the stump and shoulder.23,24 It is worth noting that for a bilateral hand amputee, bilateral hand transplantation 4 years after amputation was associated with the expansion of the cortical hand areas on functional magnetic
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resonance imaging (fMRI).25 This example suggests that there is potential for functional reorganization, which is also possible in cases with long-standing deafferentation.
ROLE OF CENTRAL PLASTICITY AFTER NERVE TRANSFER Successful intercosto-musculocutaneous nerve (ICN-MCN) transfer for patients with brachial plexus injuries showed an initial synkinetic movement of elbow flexion during inspiration, which subsequently becomes independent of the respiratory effort.26 Transcranial magnetic stimulation (TMS) has shown that cortical control of the biceps muscle is initially transferred to the neurons controlling the intercostal muscle, which is followed by the original biceps cortical area regaining access to the biceps muscle over a period of time through the intercostal nerve.26 This transposition of elbow flexion on the motor cortex from the chest to the elbow area has also been demonstrated with fMRI and diffusion tensor imaging (DTI).27 Malessy et al26 have elegantly shown the role of brain plasticity in regaining biceps function with fMRI of patients undergoing ICN-MCN transfer. TMS has demonstrated that the intercostal cortical area is located in the midline, whereas the biceps area is located a few centimeters off the midline.27 The motor neurons for the biceps are located at the C5-C6 level, whereas the motor neurons of the intercostal muscles are located in the thoracic region. Therefore, theoretically, the new pathways can develop either at the level of the cortex or in the spinal cord between the 2 motor neurons after ICN-MCN transfer. However, the absence of spinal plasticity has been shown in 2 human studies and 1 primate study.28 Therefore, the authors hypothesized that there is a latent interneuronal network between the ICN and MCN corticospinal neurons, which is clinically reflected as simultaneous intercostal contraction (for posture control and rib stabilization) during elbow flexion. The presence of interneurons may explain the return of volitional control of biceps contraction after ICN-MCN transfer (Figure).27-29 Similarly, the absence of volitional control of biceps contraction after hypoglossal-MCN transfer may be due to the lack of interneurons between the tongue and biceps, considering that the actions by these muscles are not synergistic. Interestingly, interhemispheric cortical reorganization, independent of the corpus callosum, has also been proven in rodent models where a brachial plexus avulsion injury was treated with the transfer of a C7 root from the healthy to injured side.30 At 5 months after repair, the ipsilateral motor cortex was able to move the injured limb. At 8 to 10 months, the injured limb could be moved by stimulating the motor cortex on either hemisphere, representing the bilateral cortical representation of the injured limb. At 16 months, the injured limb could be moved by stimulating the contralateral motor cortex. This experiment demonstrates the transference of functional plasticity between the 2 hemispheres. Hua et al31 evaluated 5 patients who underwent contralateral C7 repair and 9 healthy controls with fMRI. The fMRI showed that cortical reorganization continues
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for approximately 5 years after surgery. They noted a transfer of the motor control from the contralateral to ipsilateral side. The authors concluded that this cortical transfer is key to independent motor recovery.31 This finding can be explained by the fact that approximately 15% of the descending corticospinal tract does not decussate and remains ipsilateral, which may be unmasked during the recovery stage. Ipsilateral control can also be explained by the presence of interhemispheric cortical connections through the corpus callosum.32,33 Interhemispheric plasticity has also been demonstrated after stroke.34,35 In fact, the pathophysiological mechanism of sustained mirror movements in stroke patients may be secondary to contralateral motor cortex activation.35
PLASTICITY IN SOMATOSENSORY CORTEX AND ITS ROLE IN SENSORY RELEARNING It is well known that changes in the human cortical representation can be due to peripheral sensory input. In string musical instrument players, the left hand, which contacts the strings, has a larger cortical representation than the right hand.36 Similarly, there is a larger cortical representation for the index finger (reading finger) compared with other nonreading fingers in blind Braille readers.37 Sensory relearning techniques after peripheral nerve injury are designed to remodel and normalize the distorted cortical map after misdirected axonal regrowth. The use of a sensor glove system, which stereophonically transposes the friction sound elicited by touch, has shown better restoration of tactile discrimination in a hand with a damaged nerve.38 The underlying principle of this technique is to substitute the tactile inputs with auditory inputs. Therefore, the sensory cortex receives an alternate auditory stimulus, which maintains the cortical sensory map of the territory of the injured nerve, resulting in better recovery of tactile sensation 6 months after nerve repair when compared with controls.38 Rehabilitation programs include sensory training in which an enriched sensory experience improves sensory function. Current sensory relearning programs include training the patient to touch and recognize familiar patterns and objects under visual guidance.39 Alternately, the encroachment of the adjacent intact cortical areas into the nerve-injured cortical area can be prevented, improving sensory recovery.40 This can be achieved by using a local anesthetic agent over the intact adjacent skin areas to eliminate the sensory input from the intact skin. The use of EMLA, a surface anesthetic agent, over the forearm in a nerveinjured hand with sensory re-education showed improved hand sensation after nerve repair. In a study of 14 patients with nerve injury at the wrist, transient contralateral deafferentation of the forearm and hand led to the significantly improved tactile discrimination and grip strength in the nerve-injured hand.41 It should be noted that in cases of mismatched end organ reinnervation, central plasticity has a limited role and may even hamper the recovery of motor function and fine sensory functions.
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FIGURE. Postoperative fMRI showing: A, grade zero power. Activity is not recorded on the motor cortex (which has not recovered; on virtual elbow flexion). Left upper limb healthy arm, right upper limb affected arm. B, grade 4 power without the assistance of respiration. Activity is recorded on the motor cortex, representing elbow area. Left upper limb affected arm, right upper limb healthy arm. Reproduced with permission from Sokki AM, Bhat DI, Devi BI. Cortical reorganization following neurotization: a diffusion tensor imaging and functional magnetic resonance imaging study. Neurosurgery 2012;70:1305-1311.
Defective somatosensory reorganization is the basis of neuropathic pain, phantom pain, dystonia, and hyperreflexia.7,42,43 An fMRI study involving 14 upper limb amputees and 7 controls showed that patients with phantom limb pain had a shift in the lip representation into the primary motor and somatosensory areas that were deafferented.44 The degree of displacement of the lip area also correlated with the level of phantom pain. The authors concluded that this reorganizational change was a neural correlate of the phantom limb pain.44 Taylor et al10 showed, in
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a comparative study of 14 patients with surgical repair of completely transected peripheral nerve and 14 healthy volunteers, that reduced thickness of the cortical matter was associated with poorer sensory recovery (mechanical and vibration). fMRI maps of the surgically treated patients also had significantly lower activation in the somatosensory cortex compared with healthy controls. Therefore, these authors observed both structural and functional alterations in the somatosensory cortex after nerve injury.10 A recent article based on a rodent model showed that the
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firing pattern of cortical layer V pyramidal neurons could adversely affect other circuitry involving the cortical, subcortical, and interhemispheric connections.45 The authors suggested that future rehabilitative strategy after nerve injury should focus on preventing this maladaptive plasticity of layer V. Rosenkranz et al46 showed that paired associative stimulation increased the motor-evoked potential; semicontinuous muscle vibration caused changes in sensorimotor organization; and repetitive motor movement achieved improvement in motorevoked potentials and changes in sensorimotor organization of the cortex. They proposed that these protocols could be tailored for the individual patient. Therefore, in summary, some of the possible strategies that use the principle of central plasticity are the following: 1) TMS of the affected motor areas, 2) electrical stimulation of the injured nerve, 3) deprivation of sensory input from adjacent areas with intact nerves, 4) sensory relearning techniques and substitution of sensory inputs, and 5) paired associative stimulation (combines the use of electrical stimulation of the peripheral nerve and transcranial magnetic stimulation) to increase the excitability of muscles supplied by the stimulated cortical area.
REVERSIBILITY OF BRAIN PLASTICITY Recently, a few studies have shown that brain plasticity may be reversible. In one of the studies, patients with chronic hip pain due to osteoarthritis had decreased grey matter in multiple sites of the brain, including the cingulate gyrus, prefrontal cortex, and insular cortex, compared with controls.47 The authors found that when the pain resolved after surgery, repeat MRI 6 weeks and 4 months after pain resolution showed an increase in the grey matter at the same sites.47 Another group showed reversal of thalamic atrophy after successful treatment of painful osteoarthritis of the hip.48 These findings demonstrate the possibility to reverse some of the maladaptive central reorganization. However, it remains to be seen whether this will translate into reversal of maladaptive symptoms, such as neuropathic pain, phantom limb syndrome, etc.
LIMITATIONS AND FUTURE DIRECTIONS The current knowledge of central plasticity is based on experimental studies, animal studies, and brain mapping in amputees. Because this knowledge cannot be directly extrapolated to patients with nerve injury, it has limited implementation in improving nerve injury outcomes. Substantial data are based on fMRI. The physiological changes of respiration, cardiac pulsation, possible hyperperfusion, and poor spatial and temporal localization limit the utility of fMRI in patients with nerve injury.49 It is worth re-emphasizing that not all types of central reorganization may be beneficial. Neuropathic pain in the phantom limb is a classic example of a maladaptive response. In our opinion, the concept of sensory relearning techniques is relatively straightforward and can be applied to clinical practice pending additional information from a well-designed, randomized controlled trial.
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Improving our understanding of the plasticity in the spinal cord and subcortical structures after nerve injury, albeit more difficult to exploit for clinical benefit, is expected to provide new opportunities for improving clinical outcomes. The use of fMRI, DTI, TMS, and future refinements in these fields presents a unique and noninvasive method for understanding the anatomic and physiological basis of brain plasticity in both humans and animals. The therapeutic application of central plasticity in the setting of nerve injury will be based on the principal of preventing abnormal increase or decrease of central areas by modulating sensory inputs and motor outputs.
CONCLUSION The optimal refinement in nerve repair techniques has plateaued, making it imperative to continually explore newer areas targeted at improving the clinical outcome of peripheral nerve regeneration. Nerve injury and regeneration affect the brain in a structural and functional manner. Strategies for exploiting brain plasticity provide us with substantial potential to further improve the outcomes after nerve repair in the near future. Efforts to improve the outcomes after nerve repair should address the peripheral, as well as central, nervous system. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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15. Chowdhury SA, Rasmusson DD. Comparison of receptive field expansion produced by GABA(B) and GABA(A) receptor antagonists in raccoon primary somatosensory cortex. Exp Brain Res. 2002;144(1):114-211. 16. Kaas JH. Plasticity of sensory and motor maps in adult mammals. Annu Rev Neurosci. 1991;14:137-167. 17. Berardi N, Lodovichi C, Caleo M, Pizzorusso T, Maffei L. Role of neurotrophins in neural plasticity: what we learn from the visual cortex. Restor Neurol Neurosci. 1999;15(2-3):125-136. 18. Hess G, Donoghue JP. Long-term potentiation of horizontal connections provides a mechanism to reorganize cortical maps. J Neurophysiol. 1994;71:2543-2547. 19. Garraghty PE, Muja N. NMDA receptors and plasticity in adult primate somatosensory cortex. J Comp Neurol. 1996;367(2):319-326. 20. Myers WA, Churchill JD, Muja N, Garraghty PE. Role of NMDA receptors in adult primate cortical somatosensory plasticity. J Comp Neurol. 2000;418(4): 373-382. 21. Nudo RJ. Remodeling of cortical motor representations after stroke: implications for recovery from brain damage. Mol Psychiatry. 1997;2(3):188-191. 22. Takeuchi N, Izumi S. Rehabilitation with poststroke motor recovery: a review with a focus on neural plasticity. Stroke Res Treat. 2013;2013:128641. 23. Qi HX, Stepniewska I, Kaas JH. Reorganization of primary motor cortex in adult macaque monkeys with long-standing amputations. J Neurophysiol. 2000;84(4): 2133-2147. 24. Wu CW, Kaas JH. Reorganization in primary motor cortex of primates with longstanding therapeutic amputations. J Neurosci. 1999;19(17):7679-7697. 25. Giraux P, Sirigu A, Schneider F, Dubernard JM. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci. 2001;4(7):691-692. 26. Mano Y, Nakamuro T, Tamura R, et al. Central motor reorganization after anastomosis of the musculocutaneous and intercostal nerves following cervical root avulsion. Ann Neurol. 1995;38(1):15-20. 27. Sokki AM, Bhat DI, Devi BI. Cortical reorganization following neurotization: a diffusion tensor imaging and functional magnetic resonance imaging study. Neurosurgery. 2012;70(5):1305-1311; discussion 11. 28. Malessy MJ, Bakker D, Dekker AJ, Van Duk JG, Thomeer RT. Functional magnetic resonance imaging and control over the biceps muscle after intercostalmusculocutaneous nerve transfer. J Neurosurg. 2003;98(2):261-268. 29. Malessy MJ, van der Kamp W, Thomeer RT, van Dijk JG. Cortical excitability of the biceps muscle after intercostal-to-musculocutaneous nerve transfer. Neurosurgery. 1998;42(4):787-794. 30. Lou L, Shou T, Li Z, Li W, Gu Y. Transhemispheric functional reorganization of the motor cortex induced by the peripheral contralateral nerve transfer to the injured arm. Neuroscience. 2006;138(4):1225-1231. 31. Hua XY, Liu B, Qiu YQ, et al. Long-term ongoing cortical remodeling after contralateral C-7 nerve transfer. J Neurosurg. 2013;118(4):725-729. 32. Beaulieu JY, Blustajn J, Teboul F, et al. Cerebral plasticity in crossed C7 grafts of the brachial plexus: an fMRI study. Microsurgery. 2006;26(4):303-310.
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33. Stancak A, Luncking CH, Kristeva-Feige R. The size of corpus callosum and functional connectivities of cortical regions in finger and shoulder movements. Brain Res Cogn Brain Res. 2002;13(1):61-74. 34. Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol. 2006;16(3):258-264. 35. Kim YH, Jang SH, Chang Y, Byun WM, Son S, Ahn SH. Bilateral primary sensori-motor cortex activation of post-stroke mirror movements: an fMRI study. Neuroreport. 2003;14(10):1329-1332. 36. Elbert T, Pantev C, Wienbruch C, Rockstroh B, Taub E. Increased cortical representation of the fingers of the left hand in string players. Science. 1995;270 (5234):305-307. 37. Pascual-Leone A, Torres F. Plasticity of the sensorimotor cortex representation of the reading finger in Braille readers. Brain. 1993;116(pt 1):39-52. 38. Rosen B, Lundborg G. Early use of artificial sensibility to improve sensory recovery after repair of the median and ulnar nerve. Scand J Plast Reconstr Surg Hand Surg. 2003;37(1):54-57. 39. Schmidhammer R, Hausner T, Kropfl A, et al. Enhanced sensory re-learning after nerve repair using 3D audio-visual signals and kinaesthesia—preliminary results. Acta Neurochir Suppl. 2007;100:127-129. 40. Rosen B, Bjorkman A, Lundborg G. Improved sensory relearning after nerve repair induced by selective temporary anaesthesia—a new concept in hand rehabilitation. J Hand Surg Br. 2006;31(2):126-132. 41. Bjorkman A, Rosen B, Lundborg G. Enhanced function in nerve-injured hands after contralateral deafferentation. Neuroreport. 2005;16(5):517-519. 42. Quartarone A, Siebner HR, Rothwell JC. Task-specific hand dystonia: can too much plasticity be bad for you? Trends Neurosci. 2006;29(4):192-199. 43. Ramachandran VS, Hirstein W. The perception of phantom limbs. The D. O. Hebb lecture. Brain. 1998;121(pt 9):1603-1630. 44. Lotze M, Flor H, Grodd W, Larbig W, Birbaumer N. Phantom movements and pain. An fMRI study in upper limb amputees. Brain. 2001;124(pt 11):2268-2277. 45. Han Y, Li N, Zeiler SR, Pelled G. Peripheral nerve injury induces immediate increases in layer v neuronal activity. Neurorehabil Neural Repair. 2013;27(7): 664-672. 46. Rosenkranz K, Rothwell JC. Differences between the effects of three plasticity inducing protocols on the organization of the human motor cortex. Eur J Neurosci. 2006;23(3):822-829. 47. Rodriguez-Raecke R, Niemeier A, Ihle K, Ruether W, May A. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29(44):13746-13750. 48. Gwilym SE, Filippini N, Douaud G, Carr AJ, Tracey I. Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study. Arthritis Rheum. 2010;62(10): 2930-2940. 49. Constable RT. Challenges in FMRI and its Limitations. In: Faro SH, Mohamed FB, eds. Functional MRI. New York, NY: Springer; 2006:75-98.
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Role of Central Plasticity in the Outcome of Peripheral Nerve Regeneration Chandan B. Mohanty, MCh Dhananjaya Bhat, MCh Bhagavatula Indira Devi, MCh Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India Correspondence: Bhagavatula Indira Devi, MCh, Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, India, 560029. E-mail: [email protected], [email protected] Received, July 16, 2014. Accepted, April 22, 2015. Published Online, June 18, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.
The optimal refinement in nerve repair techniques has reached a plateau, making it imperative to continually explore newer avenues for improving the clinical outcome of peripheral nerve regeneration. The aim of this short review is to discuss the role and mechanism of brain plasticity in nerve regeneration, as well as to explore the possible application of this knowledge for improving the clinical outcome following nerve repair. KEY WORDS: Central reorganization, Nerve injury, Nerve transfer, Plasticity, Regeneration Neurosurgery 77:418–423, 2015
DOI: 10.1227/NEU.0000000000000851
T
he role of central nervous system plasticity in peripheral nerve regeneration is seldom covered in textbooks that are exclusively devoted to peripheral nerve surgery. Additionally, this topic is rarely mentioned in standard neurosurgical textbooks. In our experience, most neurosurgical residents and trainees are not acquainted with the concept of plasticity and its role in peripheral nerve regeneration. This review attempts to fill this gap in knowledge and provide a broad overview of this topic for practitioners, trainees, and residents who are interested in peripheral nerve surgery. The review also aims to inspire the exploration of the role of central nervous system plasticity in improving clinical outcomes after nerve injury. Improving our understanding of central plasticity is also useful for studying the role of physiotherapy and synkinetic exercises in the early phase of rehabilitation for patients undergoing nerve transfers. The subsequent discussion is restricted to the role of central reorganization. Although, some of the studies that are referenced in this review are not directly related to nerve injury, they improve our understanding of the brain plasticity and its possible applications in nerve injury.
ABBREVIATIONS: BDNF, brain-derived neurotrophic factor; GABA, Gamma amino-butyric acid; ICN-MCN, intercosto-musculocutaneous nerve; LTD, long-term depression; LTP, long-term potentiation; NGF, nerve growth factor; NT-4, neurotrophin; TMS, transcranial magnetic stimulation
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CENTRAL NERVOUS SYSTEM PLASTICITY AND PERIPHERAL NERVE REGENERATION Currently, despite the improved microsurgical techniques coupled with the use of various types of grafts, immunomodulators, and growth factors, the results of peripheral nerve surgery are far from satisfactory. The surgical refinements for nerve repair have plateaued, and it is imperative to seek newer targets for improving nerve regeneration; this requires a better understanding of the role of the central nervous system. Cortical plasticity is defined as a change in the property of cortical neurons.1 Cortical synapses respond to neural input activity by modulating their function. Changes in the synaptic function may be activity-dependent, and thus central plasticity can be caused by changes in the neural activity input from the periphery.2 A common misconception related to plasticity is that it only occurs in a developing brain and at the cerebral cortical level. It is important to highlight at the outset that brain plasticity is also seen in adults after nerve injury. Furthermore, infants and children demonstrate better recovery from nerve injury compared with adults, and it is postulated that they have a greater regeneration potential and shorter distances to be crossed by regenerating axons after nerve injury.2 Based on a fetal primate experimental study, it has also been suggested that the superior recovery of hand perception in children, compared with adults, may be due to better restoration of the cortical sensory maps after nerve transection and repair.3 Importantly, plasticity after nerve injury
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CENTRAL PLASTICITY IN PERIPHERAL NERVE REGENERATION
can occur at all levels of the central nervous system, including the spinal cord, brainstem, and thalamus.4-6 Some of the experimental findings in support of this fact are as follows: 1. Mismatched sensory reconnection between the sensory receptors and dorsal horn neurons after nerve injury leads to an altered somatotopic representation in the spinal cord, which gives rise to a loss of tactile discrimination and tactile acuity as well as positive symptoms, such as neuropathic pain.7 2. Anesthetic blockade of sensory nerves has been shown to induce the reorganization of the ventral posteromedial nucleus of the thalamus in a rodent model.4 3. Xu and Wall6 in 1997 showed that after median and ulnar nerve section in a primate model, the post injury mapping of the brainstem cuneate nucleus has increased input from the intact radial nerve input (dorsal hand). Interestingly, this increase in the brainstem (66%) is almost twice the size of the cortical increase (37%) recorded from somatosensory area 3b.6 Despite this evidence, the role of thalamic and brainstem plasticity is somewhat poorly understood because most of the data supporting this are from animal studies that require invasive monitoring techniques. Cortical plasticity, on the other hand, is better understood because of its easy accessibility and larger area and the better understanding of the somatotopic maps in the cortex. The outcome after nerve repair depends on the functional central reorganizational processes, which are caused by misdirected axonal outgrowth.6-10 Misdirected axonal growth leads to errors in both the peripheral inputs and cortical representation of the reinnervated area.
MECHANISM OF CENTRAL REORGANIZATION AFTER NERVE INJURY Cortical Reorganization After Nerve Injury Consists of 2 Stages Stage 1 This occurs during denervation and involves the expansion of the surrounding cortical areas that occupy the area represented by the damaged nerve. This change may be apparent within a few minutes to a few months after denervation11 and occurs due to the unmasking of the latent excitatory synaptic connections, leading to the rapid expansion of the adjacent motor and sensory cortical areas,7 which in turn is caused by a reduction in Gamma aminobutyric acid (GABAergic) inhibition.12 GABA is the predominant inhibitory neurotransmitter in the brain and GABA interneurons are located in the intracortical regions. The projections of these neurons can extend to 6 mm. Therefore, the inhibition of GABA can unmask the projections of these interneurons.13 In humans, a rapid decline in GABA and glutamic acid decarboxylase (which helps in the synthesis of GABA) has been noted in the sensorimotor cortex after deafferentation.14 These findings are further confirmed by the fact that GABA receptor antagonists cause the expansion of the somatosensory neuron projections and increased evoked potential responses.15
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Stage 2 This occurs during reinnervation and once again involves cortical reorganization, which parallels the axonal misorientation at the site of peripheral nerve injury. Therefore, the damaged area is not innervated by the original axons. These long-term changes occur due to a combination of long-term potentiation (LTP), long-term depression (LTD), synaptogenesis, and axonal sprouting.16 Neurotrophins, such as nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), and neurotrophin (NT-4), modulate electrical activity, synaptic transmission, and intracortical inhibition.17 LTP and LTD, which are critical in stage II cortical reorganization, require a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor activation with high intracellular calcium.18 It has also been shown that the systemic administration of an NMDA antagonist within 1 month of median injury reduced the expansion of the area 3b map of hand in a primate model.19,20 Therefore, the well-organized cortical area prior to injury is transformed into an ill-defined, mosaic-like area.2 The role of rehabilitation in altering cortical reorganization is well documented in stroke models.21,22 The alteration of motor maps by skill acquisition and repetitive use has been shown in primate models.21 Therefore, based on these data, we hypothesize that it may be possible to exploit the concept of brain plasticity in preventing the transformation of the well-organized cortical area into an ill-defined mosaic-like area with the goal of improving the outcomes of nerve injuries. This may be achieved by restricting the encroachment of the surrounding cortical areas during stage 1 of cortical reorganization, which can be achieved by initiating rehabilitation at the earliest time point after nerve injury. It may also be important to simultaneously keep the cortical area of the damaged nerve intact during stage 1 of cortical reorganization by ensuring a full range of motion of the lost movement. Therefore, mentally simulated movement may play a crucial role in planning the rehabilitative program after peripheral nerve injury. The main role of synkinetic exercises after nerve transfer is to maintain the original cortical map of an injured nerve. As our understanding of the roles of receptors and neurotransmitters in cortical reorganization improves, these can be medically manipulated to improve the outcomes after nerve injury. Nerve injury in humans results in enlarged cortical representation and increased motor-evoked potentials of the myotome innervated by the nerve proximal to the injured nerve. This occurs in conjunction with a decrease in the cortical map of the muscles supplied by the injured nerve.12 Experimental studies involving primates, who have undergone forelimb amputation, have shown that the stimulation of motor cortex originally subserving the hand function results in contractions of the proximal muscles in the stump and shoulder.23,24 It is worth noting that for a bilateral hand amputee, bilateral hand transplantation 4 years after amputation was associated with the expansion of the cortical hand areas on functional magnetic
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resonance imaging (fMRI).25 This example suggests that there is potential for functional reorganization, which is also possible in cases with long-standing deafferentation.
ROLE OF CENTRAL PLASTICITY AFTER NERVE TRANSFER Successful intercosto-musculocutaneous nerve (ICN-MCN) transfer for patients with brachial plexus injuries showed an initial synkinetic movement of elbow flexion during inspiration, which subsequently becomes independent of the respiratory effort.26 Transcranial magnetic stimulation (TMS) has shown that cortical control of the biceps muscle is initially transferred to the neurons controlling the intercostal muscle, which is followed by the original biceps cortical area regaining access to the biceps muscle over a period of time through the intercostal nerve.26 This transposition of elbow flexion on the motor cortex from the chest to the elbow area has also been demonstrated with fMRI and diffusion tensor imaging (DTI).27 Malessy et al26 have elegantly shown the role of brain plasticity in regaining biceps function with fMRI of patients undergoing ICN-MCN transfer. TMS has demonstrated that the intercostal cortical area is located in the midline, whereas the biceps area is located a few centimeters off the midline.27 The motor neurons for the biceps are located at the C5-C6 level, whereas the motor neurons of the intercostal muscles are located in the thoracic region. Therefore, theoretically, the new pathways can develop either at the level of the cortex or in the spinal cord between the 2 motor neurons after ICN-MCN transfer. However, the absence of spinal plasticity has been shown in 2 human studies and 1 primate study.28 Therefore, the authors hypothesized that there is a latent interneuronal network between the ICN and MCN corticospinal neurons, which is clinically reflected as simultaneous intercostal contraction (for posture control and rib stabilization) during elbow flexion. The presence of interneurons may explain the return of volitional control of biceps contraction after ICN-MCN transfer (Figure).27-29 Similarly, the absence of volitional control of biceps contraction after hypoglossal-MCN transfer may be due to the lack of interneurons between the tongue and biceps, considering that the actions by these muscles are not synergistic. Interestingly, interhemispheric cortical reorganization, independent of the corpus callosum, has also been proven in rodent models where a brachial plexus avulsion injury was treated with the transfer of a C7 root from the healthy to injured side.30 At 5 months after repair, the ipsilateral motor cortex was able to move the injured limb. At 8 to 10 months, the injured limb could be moved by stimulating the motor cortex on either hemisphere, representing the bilateral cortical representation of the injured limb. At 16 months, the injured limb could be moved by stimulating the contralateral motor cortex. This experiment demonstrates the transference of functional plasticity between the 2 hemispheres. Hua et al31 evaluated 5 patients who underwent contralateral C7 repair and 9 healthy controls with fMRI. The fMRI showed that cortical reorganization continues
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for approximately 5 years after surgery. They noted a transfer of the motor control from the contralateral to ipsilateral side. The authors concluded that this cortical transfer is key to independent motor recovery.31 This finding can be explained by the fact that approximately 15% of the descending corticospinal tract does not decussate and remains ipsilateral, which may be unmasked during the recovery stage. Ipsilateral control can also be explained by the presence of interhemispheric cortical connections through the corpus callosum.32,33 Interhemispheric plasticity has also been demonstrated after stroke.34,35 In fact, the pathophysiological mechanism of sustained mirror movements in stroke patients may be secondary to contralateral motor cortex activation.35
PLASTICITY IN SOMATOSENSORY CORTEX AND ITS ROLE IN SENSORY RELEARNING It is well known that changes in the human cortical representation can be due to peripheral sensory input. In string musical instrument players, the left hand, which contacts the strings, has a larger cortical representation than the right hand.36 Similarly, there is a larger cortical representation for the index finger (reading finger) compared with other nonreading fingers in blind Braille readers.37 Sensory relearning techniques after peripheral nerve injury are designed to remodel and normalize the distorted cortical map after misdirected axonal regrowth. The use of a sensor glove system, which stereophonically transposes the friction sound elicited by touch, has shown better restoration of tactile discrimination in a hand with a damaged nerve.38 The underlying principle of this technique is to substitute the tactile inputs with auditory inputs. Therefore, the sensory cortex receives an alternate auditory stimulus, which maintains the cortical sensory map of the territory of the injured nerve, resulting in better recovery of tactile sensation 6 months after nerve repair when compared with controls.38 Rehabilitation programs include sensory training in which an enriched sensory experience improves sensory function. Current sensory relearning programs include training the patient to touch and recognize familiar patterns and objects under visual guidance.39 Alternately, the encroachment of the adjacent intact cortical areas into the nerve-injured cortical area can be prevented, improving sensory recovery.40 This can be achieved by using a local anesthetic agent over the intact adjacent skin areas to eliminate the sensory input from the intact skin. The use of EMLA, a surface anesthetic agent, over the forearm in a nerveinjured hand with sensory re-education showed improved hand sensation after nerve repair. In a study of 14 patients with nerve injury at the wrist, transient contralateral deafferentation of the forearm and hand led to the significantly improved tactile discrimination and grip strength in the nerve-injured hand.41 It should be noted that in cases of mismatched end organ reinnervation, central plasticity has a limited role and may even hamper the recovery of motor function and fine sensory functions.
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CENTRAL PLASTICITY IN PERIPHERAL NERVE REGENERATION
FIGURE. Postoperative fMRI showing: A, grade zero power. Activity is not recorded on the motor cortex (which has not recovered; on virtual elbow flexion). Left upper limb healthy arm, right upper limb affected arm. B, grade 4 power without the assistance of respiration. Activity is recorded on the motor cortex, representing elbow area. Left upper limb affected arm, right upper limb healthy arm. Reproduced with permission from Sokki AM, Bhat DI, Devi BI. Cortical reorganization following neurotization: a diffusion tensor imaging and functional magnetic resonance imaging study. Neurosurgery 2012;70:1305-1311.
Defective somatosensory reorganization is the basis of neuropathic pain, phantom pain, dystonia, and hyperreflexia.7,42,43 An fMRI study involving 14 upper limb amputees and 7 controls showed that patients with phantom limb pain had a shift in the lip representation into the primary motor and somatosensory areas that were deafferented.44 The degree of displacement of the lip area also correlated with the level of phantom pain. The authors concluded that this reorganizational change was a neural correlate of the phantom limb pain.44 Taylor et al10 showed, in
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a comparative study of 14 patients with surgical repair of completely transected peripheral nerve and 14 healthy volunteers, that reduced thickness of the cortical matter was associated with poorer sensory recovery (mechanical and vibration). fMRI maps of the surgically treated patients also had significantly lower activation in the somatosensory cortex compared with healthy controls. Therefore, these authors observed both structural and functional alterations in the somatosensory cortex after nerve injury.10 A recent article based on a rodent model showed that the
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firing pattern of cortical layer V pyramidal neurons could adversely affect other circuitry involving the cortical, subcortical, and interhemispheric connections.45 The authors suggested that future rehabilitative strategy after nerve injury should focus on preventing this maladaptive plasticity of layer V. Rosenkranz et al46 showed that paired associative stimulation increased the motor-evoked potential; semicontinuous muscle vibration caused changes in sensorimotor organization; and repetitive motor movement achieved improvement in motorevoked potentials and changes in sensorimotor organization of the cortex. They proposed that these protocols could be tailored for the individual patient. Therefore, in summary, some of the possible strategies that use the principle of central plasticity are the following: 1) TMS of the affected motor areas, 2) electrical stimulation of the injured nerve, 3) deprivation of sensory input from adjacent areas with intact nerves, 4) sensory relearning techniques and substitution of sensory inputs, and 5) paired associative stimulation (combines the use of electrical stimulation of the peripheral nerve and transcranial magnetic stimulation) to increase the excitability of muscles supplied by the stimulated cortical area.
REVERSIBILITY OF BRAIN PLASTICITY Recently, a few studies have shown that brain plasticity may be reversible. In one of the studies, patients with chronic hip pain due to osteoarthritis had decreased grey matter in multiple sites of the brain, including the cingulate gyrus, prefrontal cortex, and insular cortex, compared with controls.47 The authors found that when the pain resolved after surgery, repeat MRI 6 weeks and 4 months after pain resolution showed an increase in the grey matter at the same sites.47 Another group showed reversal of thalamic atrophy after successful treatment of painful osteoarthritis of the hip.48 These findings demonstrate the possibility to reverse some of the maladaptive central reorganization. However, it remains to be seen whether this will translate into reversal of maladaptive symptoms, such as neuropathic pain, phantom limb syndrome, etc.
LIMITATIONS AND FUTURE DIRECTIONS The current knowledge of central plasticity is based on experimental studies, animal studies, and brain mapping in amputees. Because this knowledge cannot be directly extrapolated to patients with nerve injury, it has limited implementation in improving nerve injury outcomes. Substantial data are based on fMRI. The physiological changes of respiration, cardiac pulsation, possible hyperperfusion, and poor spatial and temporal localization limit the utility of fMRI in patients with nerve injury.49 It is worth re-emphasizing that not all types of central reorganization may be beneficial. Neuropathic pain in the phantom limb is a classic example of a maladaptive response. In our opinion, the concept of sensory relearning techniques is relatively straightforward and can be applied to clinical practice pending additional information from a well-designed, randomized controlled trial.
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Improving our understanding of the plasticity in the spinal cord and subcortical structures after nerve injury, albeit more difficult to exploit for clinical benefit, is expected to provide new opportunities for improving clinical outcomes. The use of fMRI, DTI, TMS, and future refinements in these fields presents a unique and noninvasive method for understanding the anatomic and physiological basis of brain plasticity in both humans and animals. The therapeutic application of central plasticity in the setting of nerve injury will be based on the principal of preventing abnormal increase or decrease of central areas by modulating sensory inputs and motor outputs.
CONCLUSION The optimal refinement in nerve repair techniques has plateaued, making it imperative to continually explore newer areas targeted at improving the clinical outcome of peripheral nerve regeneration. Nerve injury and regeneration affect the brain in a structural and functional manner. Strategies for exploiting brain plasticity provide us with substantial potential to further improve the outcomes after nerve repair in the near future. Efforts to improve the outcomes after nerve repair should address the peripheral, as well as central, nervous system. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.
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