Functional Expansion of Sensorimotor Representation and Structural Reorganization of Callosal Connections in Lower Limb Amputees

Previous studies have indicated that amputation or deafferentation of a limb induces functional changes in sensory (S1) and motor (M1) cortices, related to phantom limb pain. However, the extent of cortical reorganization after lower limb amputation in patients with nonpainful phantom phenomena remains uncertain. In this study, we combined functional magnetic resonance (fMRI) and diffusion tensor imaging (DTI) to investigate the existence and extent of cortical and callosal plasticity in these subjects. Nine “painless” patients with lower limb amputation and nine control subjects (sex- and age-matched) underwent a 3-T MRI protocol, including fMRI with somatosensory stimulation. In amputees, we observed an expansion of activation maps of the stump in S1 and M1 of the deafferented hemisphere, spreading to neighboring regions that represent the trunk and upper limbs. We also observed that tactile stimulation of the intact foot in amputees induced a greater activation of ipsilateral S1, when compared with controls. These results demonstrate a functional remapping of S1 in lower limb amputees. However, in contrast to previous studies, these neuroplastic changes do not appear to be dependent on phantom pain but do also occur in those who reported only the presence of phantom sensation without pain. In addition, our findings indicate that amputation of a limb also induces changes in the cortical representation of the intact limb. Finally, DTI analysis showed structural changes in the corpus callosum of amputees, compatible with the hypothesis that phantom sensations may depend on inhibitory release in the sensorimotor cortex.

[1]  T. Dorpat Phantom sensations of internal organs , 1971 .

[2]  Phantom sensation of internal organs. , 1971, Comprehensive psychiatry.

[3]  J. Arcadi "Phantom bladder": is this an unusual entity? , 1977, The Journal of urology.

[4]  J. Kaas,et al.  What, if anything, is SI? Organization of first somatosensory area of cortex. , 1983, Physiological reviews.

[5]  M. Cynader,et al.  Somatosensory cortical map changes following digit amputation in adult monkeys , 1984, The Journal of comparative neurology.

[6]  T. Wobbes,et al.  Phantom breast sensations following mastectomy , 1985, Cancer.

[7]  M. Mishkin,et al.  Lesion-induced plasticity in the second somatosensory cortex of adult macaques. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Melzack Pain and the neuromatrix in the brain. , 2001, Journal of dental education.

[9]  S. Bandinelli,et al.  Motor reorganization after upper limb amputation in man. A study with focal magnetic stimulation. , 1991, Brain : a journal of neurology.

[10]  J. Kaas,et al.  Injury-induced reorganization of somatosensory cortex is accompanied by reductions in GABA staining. , 1991, Somatosensory & motor research.

[11]  J. Kaas Plasticity of sensory and motor maps in adult mammals. , 1991, Annual review of neuroscience.

[12]  S. Juliano,et al.  Cholinergic depletion prevents expansion of topographic maps in somatosensory cortex. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[13]  P. Ovesen,et al.  Phantom-related phenomena after rectal amputation: prevalence and clinical characteristics , 1991, Pain.

[14]  M. Mishkin,et al.  Massive cortical reorganization after sensory deafferentation in adult macaques. , 1991, Science.

[15]  V. Ramachandran,et al.  Perceptual correlates of massive cortical reorganization. , 1992, Science.

[16]  M. Merzenich,et al.  Reorganization of cortical representations of the hand following alterations of skin inputs induced by nerve injury, skin island transfers, and experience. , 1993, Journal of hand therapy : official journal of the American Society of Hand Therapists.

[17]  M. Nicolelis,et al.  Induction of immediate spatiotemporal changes in thalamic networks by peripheral block of ascending cutaneous information , 1993, Nature.

[18]  V. Ramachandran,et al.  Behavioral and magnetoencephalographic correlates of plasticity in the adult human brain. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Karl J. Friston,et al.  Analysis of fMRI Time-Series Revisited , 1995, NeuroImage.

[20]  J. Kaas,et al.  Large-scale reorganization at multiple levels of the somatosensory pathway follows therapeutic amputation of the hand in monkeys , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  Karl J. Friston,et al.  Analysis of fMRI Time-Series Revisited—Again , 1995, NeuroImage.

[22]  P. Basser Inferring microstructural features and the physiological state of tissues from diffusion‐weighted images , 1995, NMR in biomedicine.

[23]  T. Elbert,et al.  Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation , 1995, Nature.

[24]  P. Basser,et al.  Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. , 1996, Journal of magnetic resonance. Series B.

[25]  P. Basser,et al.  Toward a quantitative assessment of diffusion anisotropy , 1996, Magnetic resonance in medicine.

[26]  Á. Pascual-Leone,et al.  Reorganization of human cortical motor output maps following traumatic forearm amputation , 1996, Neuroreport.

[27]  N Birbaumer,et al.  Effects of Regional Anesthesia on Phantom Limb Pain Are Mirrored in Changes in Cortical Reorganization , 1997, The Journal of Neuroscience.

[28]  H. Flor,et al.  The relationship of phantom limb pain to other phantom limb phenomena in upper extremity amputees 1 This work was supported by the Deutsche Forschungsgemeinschaft (Research Group `Clinical Psychophysiology of Pain', Bi 195/24). 1 , 1997, PAIN.

[29]  G. Doetsch Progressive changes in cutaneous trigger zones for sensation referred to a phantom hand: a case report and review with implications for cortical reorganization. , 1997, Somatosensory & motor research.

[30]  M Hallett,et al.  Mechanisms of Cortical Reorganization in Lower-Limb Amputees , 1998, The Journal of Neuroscience.

[31]  V. Ramachandran,et al.  Acute plasticity in the human somatosensory cortex following amputation , 1998, Neuroreport.

[32]  D. Buonomano,et al.  Cortical plasticity: from synapses to maps. , 1998, Annual review of neuroscience.

[33]  C. Braun,et al.  The cortical somatotopic map and phantom phenomena in subjects with congenital limb atrophy and traumatic amputees with phantom limb pain , 1998, The European journal of neuroscience.

[34]  T. Elbert,et al.  Plasticity of plasticity? Changes in the pattern of perceptual correlates of reorganization after amputation. , 1998, Brain : a journal of neurology.

[35]  T. Elbert,et al.  Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees , 1998, Experimental Brain Research.

[36]  V. Ramachandran,et al.  The perception of phantom limbs , 1998 .

[37]  V. Ramachandran,et al.  The perception of phantom limbs. The D. O. Hebb lecture. , 1998, Brain : a journal of neurology.

[38]  Daniel Rueckert,et al.  Nonrigid registration using free-form deformations: application to breast MR images , 1999, IEEE Transactions on Medical Imaging.

[39]  M. Merzenich,et al.  Representational plasticity in cortical area 3b paralleling tactual-motor skill acquisition in adult monkeys. , 1999, Cerebral cortex.

[40]  Ronald Melzack,et al.  From the gate to the neuromatrix , 1999, Pain.

[41]  N. Birbaumer,et al.  Does use of a myoelectric prosthesis prevent cortical reorganization and phantom limb pain? , 1999, Nature Neuroscience.

[42]  B U Meyer,et al.  Long-term reorganization of motor cortex outputs after arm amputation , 1999, Neurology.

[43]  J. Kaas,et al.  Spinal Cord Atrophy and Reorganization of Motoneuron Connections Following Long-Standing Limb Loss in Primates , 2000, Neuron.

[44]  R. Vickers,et al.  Phantom Tooth Pain , 2000 .

[45]  F. Barrios,et al.  Brain somatic representation of phantom and intact limb: a fMRI study case report , 2000, European journal of pain.

[46]  C. Darian‐Smith,et al.  Functional changes at periphery and cortex following dorsal root lesions in adult monkeys , 2000, Nature Neuroscience.

[47]  V S Ramachandran,et al.  Phantom limbs and neural plasticity. , 2000, Archives of neurology.

[48]  Sinisa Pajevic,et al.  Color schemes to represent the orientation of anisotropic tissues from diffusion tensor data: Application to white matter fiber tract mapping in the human brain , 1999, Magnetic resonance in medicine.

[49]  H. Flor,et al.  A neural substrate for nonpainful phantom limb phenomena , 2000, Neuroreport.

[50]  B. Pleger,et al.  Assessment of reorganization in the sensorimotor cortex after upper limb amputation , 2001, Clinical Neurophysiology.

[51]  H. Flor,et al.  The relationship of perceptual phenomena and cortical reorganization in upper extremity amputees , 2001, Neuroscience.

[52]  C. Weiller,et al.  Increased excitability in the primary motor cortex and supplementary motor area in patients with phantom limb pain after upper limb amputation , 2001, Neuroscience Letters.

[53]  H. Flor,et al.  Phantom movements and pain. An fMRI study in upper limb amputees. , 2001, Brain : a journal of neurology.

[54]  Pascal Giraux,et al.  Cortical reorganization in motor cortex after graft of both hands , 2001, Nature Neuroscience.

[55]  G J Barker,et al.  Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations , 2001, Neurology.

[56]  S. Kiebel,et al.  Structural and functional cortical abnormalities after upper limb amputation during childhood , 2001, Neuroreport.

[57]  N Birbaumer,et al.  Reorganization of Motor and Somatosensory Cortex in Upper Extremity Amputees with Phantom Limb Pain , 2001, The Journal of Neuroscience.

[58]  Herta Flor,et al.  Phantom-limb pain: characteristics, causes, and treatment , 2002, The Lancet Neurology.

[59]  L. Cohen,et al.  Cortical excitability changes induced by deafferentation of the contralateral hemisphere. , 2002, Brain : a journal of neurology.

[60]  L. G. Cohen,et al.  Nervous system reorganization following injury , 2002, Neuroscience.

[61]  Stephen M Smith,et al.  Fast robust automated brain extraction , 2002, Human brain mapping.

[62]  Thomas E. Nichols,et al.  Nonparametric permutation tests for functional neuroimaging: A primer with examples , 2002, Human brain mapping.

[63]  L. Cohen,et al.  Enhanced tactile spatial acuity and cortical processing during acute hand deafferentation , 2002, Nature Neuroscience.

[64]  H. Flor Cortical reorganisation and chronic pain: implications for rehabilitation. , 2003, Journal of rehabilitation medicine.

[65]  Martin Tegenthoff,et al.  Reorganization in the ipsilateral motor cortex of patients with lower limb amputation , 2003, Neuroscience Letters.

[66]  H. Flor,et al.  Remote activation of referred phantom sensation and cortical reorganization in human upper extremity amputees , 2003, Experimental Brain Research.

[67]  Mark W. Woolrich,et al.  Advances in functional and structural MR image analysis and implementation as FSL , 2004, NeuroImage.

[68]  J. Donoghue,et al.  Dynamic organization of primary motor cortex output to target muscles in adult rats I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions , 2004, Experimental Brain Research.

[69]  J. Donoghue,et al.  Dynamic organization of primary motor cortex output to target muscles in adult rats II. Rapid reorganization following motor nerve lesions , 2004, Experimental Brain Research.

[70]  Rajesh Kumar,et al.  A method for removal of global effects from fMRI time series , 2004, NeuroImage.

[71]  Thomas Elbert,et al.  Reorganization of Human Cerebral Cortex: The Range of Changes Following Use and Injury , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[72]  R. Carson Neural pathways mediating bilateral interactions between the upper limbs , 2005, Brain Research Reviews.

[73]  Thomas Benner,et al.  Real‐time RF pulse adjustment for B0 drift correction , 2006, Magnetic resonance in medicine.

[74]  Hangyi Jiang,et al.  DtiStudio: Resource program for diffusion tensor computation and fiber bundle tracking , 2006, Comput. Methods Programs Biomed..

[75]  K. Reilly,et al.  Mapping phantom movement representations in the motor cortex of amputees. , 2006, Brain : a journal of neurology.

[76]  P. Garraghty,et al.  Receptor autoradiographic correlates of deafferentation‐induced reorganization in adult primate somatosensory cortex , 2006, The Journal of comparative neurology.

[77]  Jens Frahm,et al.  Topography of the human corpus callosum revisited—Comprehensive fiber tractography using diffusion tensor magnetic resonance imaging , 2006, NeuroImage.

[78]  J. Thiran,et al.  Understanding diffusion MR imaging techniques: from scalar diffusion-weighted imaging to diffusion tensor imaging and beyond. , 2006, Radiographics : a review publication of the Radiological Society of North America, Inc.

[79]  Daniel Rueckert,et al.  Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data , 2006, NeuroImage.

[80]  H. Flor,et al.  Phantom limb pain: a case of maladaptive CNS plasticity? , 2006, Nature Reviews Neuroscience.

[81]  Lama Chahine,et al.  Phantom limb syndrome: a review. , 2007, Middle East journal of anaesthesiology.

[82]  John L. Bradshaw,et al.  Central mechanisms in phantom limb perception: The past, present and future , 2007, Brain Research Reviews.

[83]  S. A. Brandt,et al.  Effects of GABAA and GABAB agonists on interhemispheric inhibition in man , 2007, Clinical Neurophysiology.

[84]  Mark W. Woolrich,et al.  Probabilistic diffusion tractography with multiple fibre orientations: What can we gain? , 2007, NeuroImage.

[85]  J. Klein,et al.  Human Motor Corpus Callosum: Topography, Somatotopy, and Link between Microstructure and Function , 2007, The Journal of Neuroscience.

[86]  T. Nurmikko,et al.  Phantom limb pain, cortical reorganization and the therapeutic effect of mental imagery , 2008, Brain : a journal of neurology.

[87]  K. Hirata,et al.  PHANTOM ARM AND LEG AFTER PONTINE HEMORRHAGE , 2008, Neurology.

[88]  Mark Hallett,et al.  Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study. , 2008, Brain : a journal of neurology.

[89]  J. Bradshaw,et al.  Mechanisms underlying embodiment, disembodiment and loss of embodiment , 2008, Neuroscience & Biobehavioral Reviews.

[90]  Angela Sirigu,et al.  The Motor Cortex and Its Role in Phantom Limb Phenomena , 2008, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[91]  L. Hydén,et al.  Phantom breast and other syndromes after mastectomy: eight breast cancer patients describe their experiences over time: a 2-year follow-up study. , 2008, The journal of pain : official journal of the American Pain Society.

[92]  I. Evangelou,et al.  Thalamic Involvement and Its Impact on Clinical Disability in Patients with Multiple Sclerosis: A Diffusion Tensor Imaging Study at 3T , 2009, American Journal of Neuroradiology.

[93]  K. Reilly,et al.  Re-emergence of hand-muscle representations in human motor cortex after hand allograft , 2009, Proceedings of the National Academy of Sciences.

[94]  H Ring,et al.  Phantom limb related phenomena and their rehabilitation after lower limb amputation. , 2009, European journal of physical and rehabilitation medicine.

[95]  S. Evers,et al.  Phantom testis syndrome: prevalence, phenomenology and putative mechanisms. , 2010, International journal of andrology.

[96]  Herta Flor,et al.  Mirrored, imagined and executed movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain , 2010, PAIN®.

[97]  Jon H. Kaas,et al.  Reorganization of Somatosensory Cortical Areas 3b and 1 after Unilateral Section of Dorsal Columns of the Spinal Cord in Squirrel Monkeys , 2011, The Journal of Neuroscience.

[98]  P. Brugger,et al.  Supernumerary phantom limbs in spinal cord injury , 2011, Spinal Cord.