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Why Brain Science is Essential to the Success of Hand Allotransplantation

  • Scott H. FreyEmail author
Chapter
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Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

The capacity of the brain to reorganize in response to changes in stimulation plays a critical, yet poorly understood, role in the successful outcome of allogeneic hand transplants. Here, I begin by reviewing evidence on intra and interhemispheric changes in functional organizations that follow upper extremity amputation. The absence of data prior to limb loss makes it impossible to determine whether these changes are fully reversed following hand transplantation. However, accumulating data suggest that areas of the sensory and motor cortex that likely were devoted to representing the hand prior to amputation do come to represent the transplanted hand, even after years or decades of complete loss of afferent and efferent communication. Nevertheless, at least some amputation-related cortical changes may persist even long after a transplant. These results are consistent with a model in which restoration of afferent and efferent signals between hand and brain enables gross recovery of cortical organization through reactivation of existing networks. However, recovery of finer-grained details of the cortical maps requires experience-dependent changes, due to peripheral reinnervation errors and lower-level structural reorganization, recovering finer-grained details of cortical maps requires experience-dependent changes. These latter changes evolve slowly, are essential to achieve optimal sensory and motor functions, and stand to benefit from advances in evidence-based neurorehabilitation.

Keywords

Hand transplantation Sensory and motor cortex Brain Cortical mapping Structural reorganization Neurorehabilitation Amputation Nerve regeneration 

Notes

Acknowledgments

In alphabetical order, the author wishes to acknowledge the essential contributions of Drs. Sergei Bogdanov, Warren Breidenbach III, Christina Kaufman, Joseph Kutz, and Jolinda Smith to the research described. Preparation of this chapter was supported by the USAMRMC (W81XWH-10-1-1020), and the NIH (NS083377) to S.H.F.

References

  1. 1.
    Florence SL, Kaas JH. Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys. J Neurosci. 1995;15(12):8083–95.PubMedGoogle Scholar
  2. 2.
    Jones EG. Cortical and subcortical contributions to activity-dependent plasticity in primate somatosensory cortex. Annu Rev Neurosci. 2000;23:1–37.CrossRefPubMedGoogle Scholar
  3. 3.
    Kaas JH. Plasticity of sensory and motor maps in adult mammals. Annu Rev Neurosci. 1991;14:137–67.CrossRefPubMedGoogle Scholar
  4. 4.
    Kaas JH, Merzenich MM, Killackey HP. The reorganization of somatosensory cortex following peripheral nerve damage in adult and developing mammals. Annu Rev Neurosci. 1983;6:325–56.CrossRefPubMedGoogle Scholar
  5. 5.
    Wu CW, Kaas JH. The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord. Somatosens Mot Res. 2002;19(2):153–63.CrossRefPubMedGoogle Scholar
  6. 6.
    Pons TP, et al. Massive cortical reorganization after sensory deafferentation in adult macaques. Science. 1991;252(5014):1857–60.CrossRefPubMedGoogle Scholar
  7. 7.
    Ramachandran VS, Rogers-Ramachandran D, Stewart M. Perceptual correlates of massive cortical reorganization. Science. 1992;258(5085):1159–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Merzenich MM, et al. Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. Neuroscience. 1983;8(1):33–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Merzenich MM, et al. Progression of change following median nerve section in the cortical representation of the hand in areas 3b and 1 in adult owl and squirrel monkeys. Neuroscience. 1983;10(3):639–65.CrossRefPubMedGoogle Scholar
  10. 10.
    Wall JT, Felleman DJ, Kaas JH. Recovery of normal topography in the somatosensory cortex of monkeys after nerve crush and regeneration. Science. 1983;221(4612):771–3.CrossRefPubMedGoogle Scholar
  11. 11.
    Sperry RW. The problem of central nervous reorganization after nerve regeneration and muscle transposition. Q Rev Biol. 1945;20:311–69.CrossRefPubMedGoogle Scholar
  12. 12.
    Penfield W, Boldrey E. Somatotopic motor and sesnory representation in the cerebral cortex of man as studied by electrical stimulation. Brain. 1937;60:389–443.CrossRefGoogle Scholar
  13. 13.
    Sanes JN, Donoghue JP. Plasticity and primary motor cortex. Annu Rev Neurosci. 2000;23:393–415.CrossRefPubMedGoogle Scholar
  14. 14.
    Kaas JH. The reorganization of somatosensory and motor cortex after peripheral nerve or spinal cord injury in primates. Prog Brain Res. 2000;128:173–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Garraghty PE, Kaas JH. Large-scale functional reorganization in adult monkey cortex after peripheral nerve injury. Proc Natl Acad Sci U S A 1991;88(16):6976–80.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Merzenich MM, et al. Somatosensory cortical map changes following digit amputation in adult monkeys. J Comp Neurol. 1984;224(4):591–605.CrossRefPubMedGoogle Scholar
  17. 17.
    Merzenich MM, Jenkins WM. Reorganization of cortical representations of the hand following alterations of skin inputs induced by nerve injury, skin island transfers, and experience. J Hand Ther. 1993;6(2):89–104.CrossRefPubMedGoogle Scholar
  18. 18.
    Buonomano DV, Merzenich MM. Cortical plasticity: from synapses to maps. Annu Rev Neurosci. 1998;21:149–86.CrossRefPubMedGoogle Scholar
  19. 19.
    Qi HX, Stepniewska I, Kaas JH. Reorganization of primary motor cortex in adult macaque monkeys with long-standing amputations. J Neurophysiol. 2000;84(4):2133–47.PubMedGoogle Scholar
  20. 20.
    Florence SL, Taub HB, Kaas JH. Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science. 1998;282(5391):1117–21.CrossRefPubMedGoogle Scholar
  21. 21.
    Cohen LG, et al. Topographic maps of human motor cortex in normal and pathological conditions: mirror movements, amputations and spinal cord injuries. Electroencephalogr Clin Neurophysiol Suppl. 1991;43:36–50.PubMedGoogle Scholar
  22. 22.
    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):2268–77.CrossRefPubMedGoogle Scholar
  23. 23.
    Karl A, Birbaumer N, Lutzenberger W, Cohen LG, Flor H. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. J Neurosci. 2001;21(10):3609–18.PubMedGoogle Scholar
  24. 24.
    Kew JJ, et al. Abnormal access of axial vibrotactile input to deafferented somatosensory cortex in human upper limb amputees. J Neurophysiol. 1997;77(5):2753–64.PubMedGoogle Scholar
  25. 25.
    Elbert T, et al. Extensive reorganization of the somatosensory cortex in adult humans after nervous system injury. Neuroreport. 1994;5(18):2593–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Flor H, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995;375(6531):482–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Yang TT, et al. Noninvasive detection of cerebral plasticity in adult human somatosensory cortex. Neuroreport. 1994;5(6):701–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Schwenkreis P, et al. Changes of cortical excitability in patients with upper limb amputation. Neurosci Lett. 2000;293(2):143–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Schwenkreis P, et al. Assessment of reorganization in the sensorimotor cortex after upper limb amputation. Clin Neurophysiol. 2001;112(4):627–35.CrossRefPubMedGoogle Scholar
  30. 30.
    Draganski B, et al. Decrease of thalamic gray matter following limb amputation. Neuroimage. 2006;31(3):951–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Makin TR, et al. Phantom pain is associated with preserved structure and function in the former hand area. Nat Commun. 2013;4:1570.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Calford MB, Tweedale R. Interhemispheric transfer of plasticity in the cerebral cortex. Science. 1990;249(4970):805–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Pawela CP, et al. Interhemispheric neuroplasticity following limb deafferentation detected by resting-state functional connectivity magnetic resonance imaging (fcMRI) and functional magnetic resonance imaging (fMRI). Neuroimage. 2010;49(3):2467–78.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Bogdanov S, Smith J, Frey SH. Former hand territory activity increases after amputation during intact hand movements, but is unaffected by illusory visual feedback. Neurorehabil Neural Repair. 2012;26(6):604–15.CrossRefPubMedGoogle Scholar
  35. 35.
    Kew JJ, et al. Reorganization of cortical blood flow and transcranial magnetic stimulation maps in human subjects after upper limb amputation. J Neurophysiol. 1994;72(5):2517–24.PubMedGoogle Scholar
  36. 36.
    Philip B, Bogdanov S, Frey, SH. Execution of a precision manual drawing task with the nondominant hand in amputees and controls. In Annual Meeting of the Society for Neuroscience (Washington, DC); 2011.Google Scholar
  37. 37.
    Wrigley PJ, et al. Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury. Pain. 2009;141(1/2):52–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Maihofner C, et al. The motor system shows adaptive changes in complex regional pain syndrome. Brain. 2007;130(Pt 10):2671–87.CrossRefPubMedGoogle Scholar
  39. 39.
    Maihofner C, Handwerker HO, Neundorfer B, Birklein F. Patterns of cortical reorganization in complex regional pain syndrome. Neurology. 2003;61(12):1707–15.CrossRefPubMedGoogle Scholar
  40. 40.
    Flor H. Maladaptive plasticity, memory for pain and phantom limb pain: review and suggestions for new therapies. Expert Rev Neurother. 2008;8(5):809–18.CrossRefPubMedGoogle Scholar
  41. 41.
    Simoes EL, et al. Functional expansion of sensorimotor representation and structural reorganization of callosal connections in lower limb amputees. J Neurosci. 2012;32(9):3211–20.CrossRefPubMedGoogle Scholar
  42. 42.
    Flor H, Diers M, Andoh J. The neural basis of phantom limb pain. Trends Cogn Sci. 2013;17(7):307–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Button KS, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14(5):365–76.CrossRefPubMedGoogle Scholar
  44. 44.
    Almquist E, Eeg-Olofsson O. Sensory-nerve-conduction velocity and two-point discrimination in sutured nerves. J Bone Joint Surg Am. 1970;52(4):791–96.PubMedGoogle Scholar
  45. 45.
    Wall JT, Kaas JH. Long-term cortical consequences of reinnervation errors after nerve regeneration in monkeys. Brain Res. 1986;372(2):400–4.CrossRefPubMedGoogle Scholar
  46. 46.
    Haber WB. Reactions to loss of limb: physiological and psychological aspects. Ann N Y Acad Sci. 1958;74(1):14–24.CrossRefPubMedGoogle Scholar
  47. 47.
    Katz D. Psychologische versuch mit amputierten. Z Psychol Physiol. 1920;85:83–117.Google Scholar
  48. 48.
    Teuber H-L, Krieger HP, Bender MB. Reorganization of sensory function in amputation stumps: two points discrimination. Fed Proc. 1949;8:156.Google Scholar
  49. 49.
    Moore CE, Schady W. Investigation of the functional correlates of reorganization within the human somatosensory cortex. Brain. 2000;123(Pt 9):1883–95.CrossRefPubMedGoogle Scholar
  50. 50.
    Vega-Bermudez F, Johnson KO. Spatial acuity after digit amputation. Brain. 2002;125(Pt 6):1256–64.CrossRefPubMedGoogle Scholar
  51. 51.
    Philip BA, Frey SH. Preserved grip selection planning in chronic unilateral upper extremity amputees. Exp Brain Res. 2011;214(3):437–52.CrossRefPubMedGoogle Scholar
  52. 52.
    Dhillon GS, Lawrence SM, Hutchinson DT, Horch KW. Residual function in peripheral nerve stumps of amputees: implications for neural control of artificial limbs. J Hand Surg Am. 2004;29(4):605–15; discussion 616–608.CrossRefPubMedGoogle Scholar
  53. 53.
    Dhillon GS, Kruger TB, Sandhu JS, Horch KW. Effects of short-term training on sensory and motor function in severed nerves of long-term human amputees. J Neurophysiol 93(5):2625–33.Google Scholar
  54. 54.
    Jia X, et al. Residual motor signal in long-term human severed peripheral nerves and feasibility of neural signal-controlled artificial limb. J Hand Surg Am. 2007;32(5):657–66.CrossRefPubMedGoogle Scholar
  55. 55.
    Reilly KT, Mercier C, Schieber MH, Sirigu A. Persistent hand motor commands in the amputees’ brain. Brain 2006;129(Pt 8):2211–23.CrossRefPubMedGoogle Scholar
  56. 56.
    Roricht S, Meyer BU. Residual function in motor cortex contralateral to amputated hand. Neurology. 2000;54(4):984–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Stoll G, Muller HW. Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol. 1999;9(2):313–25.CrossRefPubMedGoogle Scholar
  58. 58.
    Florence SL, et al. Central reorganization of sensory pathways following peripheral nerve regeneration in fetal monkeys. Nature. 1996;381(6577):69–71.CrossRefPubMedGoogle Scholar
  59. 59.
    Fox K, Glazewski S, Schulze S. Plasticity and stability of somatosensory maps in thalamus and cortex. Curr Opin Neurobiol. 2000;10(4):494–7.CrossRefPubMedGoogle Scholar
  60. 60.
    Petersen CC. The functional organization of the barrel cortex. Neuron. 2007;56(2):339–55.CrossRefPubMedGoogle Scholar
  61. 61.
    Bjorkman A, Waites A, Rosen B, Larsson EM, Lundborg G. Cortical reintegration of a replanted hand and an osseointegrated thumb prosthesis. Acta Neurochir Suppl. 2007;100:109–12.CrossRefPubMedGoogle Scholar
  62. 62.
    Bjorkman A, Waites A, Rosen B, Lundborg G, Larsson EM. Cortical sensory and motor response in a patient whose hand has been replanted: one-year follow up with functional magnetic resonance imaging. Scand J Plast Reconstr Surg Hand Surg. 2007;41(2):70–6.CrossRefPubMedGoogle Scholar
  63. 63.
    Eickhoff SB, et al. Central adaptation following heterotopic hand replantation probed by fMRI and effective connectivity analysis. Exp Neurol. 2008;212(1):132–44.CrossRefPubMedGoogle Scholar
  64. 64.
    Giraux P, Sirigu A, Schneider F, Dubernard JM. Cortical reorganization in motor cortex after graft of both hands. Nat Neurosci 2001;4(7):691–2.CrossRefPubMedGoogle Scholar
  65. 65.
    Lanzetta M, et al. Early use of artificial sensibility in hand transplantation. Scand J Plast Reconstr Surg Hand Surg. 2004;38(2):106–11.CrossRefPubMedGoogle Scholar
  66. 66.
    Brenneis C, et al. Cortical motor activation patterns following hand transplantation and replantation. J Hand Surg. 2005;30(5):530–3.CrossRefGoogle Scholar
  67. 67.
    Breidenbach WC, et al. Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant. J Hand Surg. 2008;33(7):1039–47.CrossRefGoogle Scholar
  68. 68.
    Vargas CD, et al. Re-emergence of hand-muscle representations in human motor cortex after hand allograft. Proc Natl Acad Sci U S A. 2009;106(17):7197–202.CrossRefPubMedCentralPubMedGoogle Scholar
  69. 69.
    Neugroschl C, et al. Functional MRI activation of somatosensory and motor cortices in a hand-grafted patient with early clinical sensorimotor recovery. Eur Radiol. 2005;15(9):1806–14.CrossRefPubMedGoogle Scholar
  70. 70.
    Frey SH, Bogdanov S, Smith JC, Watrous S, Breidenbach WC. Chronically deafferented sensory cortex recovers a grossly typical organization after allogenic hand transplantation. Curr Biol. 2008;18(19):1530–4.CrossRefPubMedCentralPubMedGoogle Scholar
  71. 71.
    Smith J, Bogdanov, S., Watrous, S., Frey, SH. Rapid digit mapping in the human brain at 3T in 17th Annual Meeting of the International Society for Magnet Resonance (ISMRM) in Medicine. (Honolulu); 2009.Google Scholar
  72. 72.
    Smith J, Frey, SH. Use of independent component analysis to define regions of interest for fMRI studies in 18th Annual Meeting of the International Society for Magnet Resonance (ISMRM) in Medicine. (Montreal); 2011.Google Scholar
  73. 73.
    Eickhoff SB, Grefkes C, Fink GR, Zilles K. Functional lateralization of face, hand, and trunk representation in anatomically defined human somatosensory areas. Cereb Cortex. 2008;18(12):2820–30.CrossRefPubMedCentralPubMedGoogle Scholar
  74. 74.
    Binkofski F, et al. Human anterior intraparietal area subserves prehension: a combined lesion and functional MRI activation study. Neurology. 1998;50(5):1253–9.CrossRefPubMedGoogle Scholar
  75. 75.
    Culham JC, et al. Visually guided grasping produces fMRI activation in dorsal but not ventral stream brain areas. Exp Brain Res. 2003;153(2):180–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Frey SH, Vinton D, Norlund R, Grafton ST. Cortical topography of human anterior intraparietal cortex active during visually guided grasping. Brain Res Cogn Brain Res. 2005;23(2/3):397–405.CrossRefPubMedGoogle Scholar
  77. 77.
    Schady W, Braune S, Watson S, Torebjork HE, Schmidt R. Responsiveness of the somatosensory system after nerve injury and amputation in the human hand. Ann Neurol. 1994;36(1):68–75.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Brain Imaging Center & Rehabilitation Neuroscience LaboratoryUniversity of MissouriColumbiaUSA

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