Gray matter changes following limb amputation with high and low intensities of phantom limb pain.

Limb amputation and chronic phantom limb pain (PLP) are both associated with neural alterations at all levels of the neuraxis. We investigated gray matter volume of 21 upper limb amputees and 14 healthy control subjects. Results demonstrate that amputation is associated with reduced gray matter in areas in the motor cortex representing the amputated limb. Additionally, patients show an increase in gray matter in brain regions that belong to the dorsal and ventral visual stream. We subdivided the patient group into patients with medium to high PLP (HPLP; N = 11) and those with slight PLP (SPLP; N = 10). HPLP patients showed reduced gray matter in brain areas involved in pain processing. SPLP patients showed a significant gray matter increase in regions of the visual stream. Results indicate that all patients may have an enhanced need for visual control to compensate the lack of sensory feedback of the missing limb. As we found these alterations primarily in the SPLP patient group, successful compensation may have an impact on PLP development. Therefore, we hypothesize that visual adaptation mechanisms may compensate for the lack of sensorimotor feedback and may therefore function as a protection mechanism against high PLP development.

[1]  Thomas Weiss,et al.  Decrease in phantom limb pain associated with prosthesis-induced increased use of an amputation stump in humans , 1999, Neuroscience Letters.

[2]  A. Dale,et al.  High‐resolution intersubject averaging and a coordinate system for the cortical surface , 1999, Human brain mapping.

[3]  Anthony K. P. Jones,et al.  The cortical representation of pain , 1999, PAIN.

[4]  J. Liepert,et al.  Abnormal motor cortex organization contralateral to early upper limb amputation in humans , 1999, Neuroscience Letters.

[5]  Anders M. Dale,et al.  Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex , 2001, IEEE Transactions on Medical Imaging.

[6]  S C Gandevia,et al.  Anatomical changes in human motor cortex and motor pathways following complete thoracic spinal cord injury. , 2009, Cerebral cortex.

[7]  Karl J. Friston,et al.  Disability, atrophy and cortical reorganization following spinal cord injury , 2011, Brain : a journal of neurology.

[8]  S. Funahashi.  Prefrontal cortex and working memory processes , 2006, Neuroscience.

[9]  Anders M. Dale,et al.  Sequence-independent segmentation of magnetic resonance images , 2004, NeuroImage.

[10]  S. Minoshima,et al.  Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. , 2003, Brain : a journal of neurology.

[11]  R. Melzack.  Evolution of the Neuromatrix Theory of Pain. The Prithvi Raj Lecture: Presented at the Third World Congress of World Institute of Pain, Barcelona 2004 , 2005, Pain practice : the official journal of World Institute of Pain.

[12]  U. Bogdahn,et al.  Subtle Grey Matter Changes Between Migraine Patients and Healthy Controls , 2008, Cephalalgia : an international journal of headache.

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

[14]  M. Mesulam.  A cortical network for directed attention and unilateral neglect , 1981, Annals of neurology.

[15]  T. Schmidt-Wilcke,et al.  Altered Regional Brain Morphology in Patients With Chronic Facial Pain , 2010, Headache.

[16]  Thomas Weiss,et al.  Brain activation upon selective stimulation of cutaneous C- and Aδ-fibers , 2008, NeuroImage.

[17]  Anders M. Dale,et al.  Cortical Surface-Based Analysis I. Segmentation and Surface Reconstruction , 1999, NeuroImage.

[18]  Melvyn A Goodale,et al.  Dual routes to action: contributions of the dorsal and ventral streams to adaptive behavior. , 2005, Progress in brain research.

[19]  J. Lagopoulos,et al.  Anatomical abnormalities of the anterior cingulate and paracingulate cortex in patients with bipolar I disorder , 2008, Psychiatry Research: Neuroimaging.

[20]  S. Kim,et al.  Mirror Therapy for Phantom Limb Pain , 2012, The Korean journal of pain.

[21]  M. Goodale,et al.  The visual brain in action , 1995 .

[22]  Alan C. Evans,et al.  A nonparametric method for automatic correction of intensity nonuniformity in MRI data , 1998, IEEE Transactions on Medical Imaging.

[23]  M. Agour,et al.  Reduction in Left Supplementary Motor Area Grey Matter in Adult Female Fibromyalgia Sufferers with Marked Fatigue and without Affective Disorder: A Pilot Controlled 3-T Magnetic Resonance Imaging Voxel-Based Morphometry Study , 2010, The Journal of international medical research.

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

[25]  Thomas Weiss,et al.  Rapid functional plasticity in the primary somatomotor cortex and perceptual changes after nerve block , 2004, The European journal of neuroscience.

[26]  David A Seminowicz,et al.  Accelerated Brain Gray Matter Loss in Fibromyalgia Patients: Premature Aging of the Brain? , 2007, The Journal of Neuroscience.

[27]  N Birbaumer,et al.  Extensive reorganization of the somatosensory cortex in adult humans after nervous system injury. , 1994, Neuroreport.

[28]  Alan Cowey,et al.  Differential and co-involvement of areas of the temporal and parietal streams in visual tasks , 2009, Neuropsychologia.

[29]  R. Peyron,et al.  Functional imaging of brain responses to pain. A review and meta-analysis (2000) , 2000, Neurophysiologie Clinique/Clinical Neurophysiology.

[30]  W. Miltner,et al.  Gray matter volume loss after upper limb amputation , 2004 .

[31]  Jody C. Culham,et al.  Orientation sensitivity to graspable objects: An fMRI adaptation study , 2007, NeuroImage.

[32]  J. Liepert,et al.  Treatment-induced cortical reorganization after stroke in humans. , 2000, Stroke.

[33]  Anders M. Dale,et al.  Reliability in multi-site structural MRI studies: Effects of gradient non-linearity correction on phantom and human data , 2006, NeuroImage.

[34]  Michel Magnin,et al.  Emotional Modulation of Pain: Is It the Sensation or What We Recall? , 2006, The Journal of Neuroscience.

[35]  A. Gorea,et al.  On the perceptual/motor dissociation: a review of concepts, theory, experimental paradigms and data interpretations. , 2010, Seeing and perceiving.

[36]  H. Diener,et al.  Hypothalamic gray matter volume loss in hypnic headache , 2011, Annals of neurology.

[37]  A. Beck,et al.  Beck Depression Inventory–II , 2011 .

[38]  David A. Seminowicz,et al.  Cortical responses to pain in healthy individuals depends on pain catastrophizing , 2006, Pain.

[39]  H. Alkadhi,et al.  Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. , 1997, Brain : a journal of neurology.

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

[41]  Jody C. Culham,et al.  Ventral and dorsal stream contributions to the online control of immediate and delayed grasping: A TMS approach , 2009, Neuropsychologia.

[42]  L. Merabet,et al.  The plastic human brain cortex. , 2005, Annual review of neuroscience.

[43]  Thomas E. Nichols,et al.  Validating cluster size inference: random field and permutation methods , 2003, NeuroImage.

[44]  R. Banati.  Brain plasticity and microglia: is transsynaptic glial activation in the thalamus after limb denervation linked to cortical plasticity and central sensitisation? , 2002, Journal of Physiology-Paris.

[45]  C. L. Kwan,et al.  CORTICAL THINNING IN IBS: IMPLICATIONS FOR HOMEOSTATIC, ATTENTION, AND PAIN PROCESSING , 2008, Neurology.

[46]  L. Pinessi,et al.  Voxel‐Based Morphometry Reveals Gray Matter Abnormalities in Migraine , 2007, Headache.

[47]  D. Wolpert,et al.  Maintaining internal representations: the role of the human superior parietal lobe , 1998, Nature Neuroscience.

[48]  Massimo Filippi,et al.  Brain Gray Matter Changes in Migraine Patients With T2-Visible Lesions: A 3-T MRI Study , 2006, Stroke.

[49]  Bogdan Draganski,et al.  Neuroplasticity: Changes in grey matter induced by training , 2004, Nature.

[50]  P. Downing,et al.  Selectivity for the human body in the fusiform gyrus. , 2005, Journal of neurophysiology.

[51]  C. Sorg,et al.  Patients With Pain Disorder Show Gray-Matter Loss in Pain-Processing Structures: A Voxel-Based Morphometric Study , 2009, Psychosomatic medicine.

[52]  D. Ehde,et al.  Pain site and the effects of amputation pain: further clarification of the meaning of mild, moderate, and severe pain , 2001, Pain.

[53]  A. J. Harris,et al.  Cortical origin of pathological pain , 1999, The Lancet.

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

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

[56]  F. Mauguière,et al.  Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation. , 2002, Cerebral cortex.

[57]  A. Apkarian,et al.  Chronic Back Pain Is Associated with Decreased Prefrontal and Thalamic Gray Matter Density , 2004, The Journal of Neuroscience.

[58]  N. Diemer,et al.  Glutamate receptor transmission and ischemic nerve cell damage: evidence for involvement of excitotoxic mechanisms. , 1993, Progress in brain research.

[59]  Matthias M. Müller,et al.  Perceptual Correlates of Changes in Cortical Representation of Fingers in Blind Multifinger Braille Readers , 1998, The Journal of Neuroscience.

[60]  D. Turk,et al.  The West Haven-Yale Multidimensional Pain Inventory (WHYMPI) , 1985, Pain.

[61]  Anders M. Dale,et al.  Improved Localization of Cortical Activity By Combining EEG and MEG with MRI Cortical Surface Reconstruction , 2002 .

[62]  Todd B. Parrish,et al.  The Brain in Chronic CRPS Pain: Abnormal Gray-White Matter Interactions in Emotional and Autonomic Regions , 2008, Neuron.

[63]  David A. Williams,et al.  No consistent difference in gray matter volume between individuals with fibromyalgia and age-matched healthy subjects when controlling for affective disorder , 2009, PAIN®.

[64]  Justin L. Vincent,et al.  Precuneus shares intrinsic functional architecture in humans and monkeys , 2009, Proceedings of the National Academy of Sciences.

[65]  T. Jensen,et al.  Immediate and long-term phantom limb pain in amputees: Incidence, clinical characteristics and relationship to pre-amputation limb pain , 1985, Pain.

[66]  Alan Cowey,et al.  TMS can reveal contrasting functions of the dorsal and ventral visual processing streams , 2006, Experimental Brain Research.

[67]  Bruce Fischl,et al.  Geometrically Accurate Topology-Correction of Cortical Surfaces Using Nonseparating Loops , 2007, IEEE Transactions on Medical Imaging.

[68]  Roland Peyron,et al.  Operculo-insular pain (parasylvian pain): a distinct central pain syndrome. , 2010, Brain : a journal of neurology.

[69]  M. Goodale,et al.  Two distinct modes of control for object-directed action. , 2004, Progress in brain research.

[70]  M. Goodale,et al.  FMRI Reveals a Dissociation between Grasping and Perceiving the Size of Real 3D Objects , 2007, PloS one.

[71]  Anders M. Dale,et al.  Reliability of MRI-derived measurements of human cerebral cortical thickness: The effects of field strength, scanner upgrade and manufacturer , 2006, NeuroImage.

[72]  Y. Rossetti,et al.  Optic ataxia revisited: visually guided action versus immediate visuomotor control. , 2003, Experimental brain research.

[73]  M. Hallett,et al.  Modulation of motor cortical outputs to the reading hand of braille readers , 1993, Annals of neurology.

[74]  Y. Rossetti,et al.  No double-dissociation between optic ataxia and visual agnosia: Multiple sub-streams for multiple visuo-manual integrations , 2006, Neuropsychologia.

[75]  P. Churchland,et al.  The Mind-Brain Continuum: Sensory Processes , 1996 .

[76]  Ayse Pinar Saygin,et al.  Smoothing and cluster thresholding for cortical surface-based group analysis of fMRI data , 2006, NeuroImage.

[77]  Alan Cowey,et al.  Time course of the involvement of the ventral and dorsal visual processing streams in a visuospatial task , 2007, Neuropsychologia.

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

[79]  J. Marshall,et al.  The neural consequences of conflict between intention and the senses. , 1999, Brain : a journal of neurology.

[80]  B. Wand,et al.  Chronic non-specific low back pain – sub-groups or a single mechanism? , 2008, BMC musculoskeletal disorders.

[81]  Simon B. Eickhoff,et al.  Coordinate-based meta-analysis of experimentally induced and chronic persistent neuropathic pain , 2011, NeuroImage.

[82]  O. Witte,et al.  Sensory feedback prosthesis reduces phantom limb pain: Proof of a principle , 2012, Neuroscience Letters.

[83]  E. Silberman,et al.  Hemispheric lateralization of functions related to emotion , 1986, Brain and Cognition.

[84]  J L Lancaster,et al.  Automated Talairach Atlas labels for functional brain mapping , 2000, Human brain mapping.

[85]  N. Szeverenyi,et al.  Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study , 2003, Journal of Neural Transmission.

[86]  A. May.  Structural Brain Imaging: A Window into Chronic Pain , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[87]  A. May,et al.  Chronischer Schmerz verändert die Struktur des Gehirns , 2009, Der Schmerz.

[88]  Anders M. Dale,et al.  An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest , 2006, NeuroImage.

[89]  Karl J. Friston,et al.  Correlation between structural and functional changes in brain in an idiopathic headache syndrome , 1999, Nature Medicine.

[90]  E. C. Huskisson,et al.  Graphic representation of pain , 1976, Pain.

[91]  Nicola Filippini,et al.  Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study. , 2010, Arthritis and rheumatism.

[92]  A. May.  Chronic pain may change the structure of the brain , 2008, PAIN®.

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

[94]  Kun-Woo Park,et al.  Regional Grey Matter Changes in Patients With Migraine: A Voxel-Based Morphometry Study , 2008, Cephalalgia : an international journal of headache.

[95]  A. Mouraux,et al.  From the neuromatrix to the pain matrix (and back) , 2010, Experimental Brain Research.

[96]  R. Melzack,et al.  Pain ‘memories’ in phantom limbs: review and clinical observations , 1990, Pain.

[97]  Kirsten Tillisch,et al.  Regional gray matter density changes in brains of patients with irritable bowel syndrome. , 2010, Gastroenterology.

[98]  William A. Cunningham,et al.  Type I and Type II error concerns in fMRI research: re-balancing the scale. , 2009, Social cognitive and affective neuroscience.

[99]  A. Craig,et al.  How do you feel — now? The anterior insula and human awareness , 2009, Nature Reviews Neuroscience.

[100]  A M Dale,et al.  Measuring the thickness of the human cerebral cortex from magnetic resonance images. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[101]  R. Kuner,et al.  Central mechanisms of pathological pain , 2010, Nature Medicine.

[102]  N. Birbaumer,et al.  Zur Anwendbarkeit des West Haven-Yale Multidimensional Pain Inventory im deutschen Sprachraum , 1990, Der Schmerz.

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

[104]  Bruce Fischl,et al.  Highly accurate inverse consistent registration: A robust approach , 2010, NeuroImage.

[105]  Bogdan Draganski,et al.  Training-induced structural changes in the adult human brain , 2008, Behavioural Brain Research.

[106]  M. Baliki,et al.  Towards a theory of chronic pain , 2009, Progress in Neurobiology.

[107]  B. Vogt,et al.  Structural and functional dichotomy of human midcingulate cortex , 2003, The European journal of neuroscience.

[108]  I. Tracey,et al.  The insula: A multidimensional integration site for pain , 2007, Pain.

[109]  G. Rizzolatti,et al.  Two different streams form the dorsal visual system: anatomy and functions , 2003, Experimental Brain Research.

[110]  Bogdan Draganski,et al.  Decrease of thalamic gray matter following limb amputation , 2006, NeuroImage.

[111]  Bogdan Draganski,et al.  Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients , 2006, Pain.

[112]  W. Miltner,et al.  Brachial plexus block in phantom limb pain: a case report. , 2011, Pain medicine.

[113]  L. Becerra,et al.  Colocalized Structural and Functional Changes in the Cortex of Patients with Trigeminal Neuropathic Pain , 2008, PloS one.

[114]  A. Dale,et al.  Cortical Surface-Based Analysis II: Inflation, Flattening, and a Surface-Based Coordinate System , 1999, NeuroImage.

[115]  Anthony K. P. Jones,et al.  Caudal cingulate cortex involvement in pain processing: an inter-individual laser evoked potential source localisation study using realistic head models , 2003, Pain.

[116]  A Straube,et al.  Gray matter decrease in patients with chronic tension type headache , 2005, Neurology.

[117]  R. Luerding,et al.  Striatal grey matter increase in patients suffering from fibromyalgia – A voxel-based morphometry study , 2007, PAIN.

[118]  David J. Miller,et al.  Diversity and Evolution of Coral Fluorescent Proteins , 2008, PloS one.

[119]  Jen-Chuen Hsieh,et al.  Brain morphological changes associated with cyclic menstrual pain , 2010, PAIN.

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

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

[122]  E. Rolls,et al.  The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology , 2004, Progress in Neurobiology.

[123]  Nikos Makris,et al.  Automatically parcellating the human cerebral cortex. , 2004, Cerebral cortex.

[124]  N. Birbaumer,et al.  [The applicability of the West Haven-Yale multidimensional pain inventory in German-speaking countries. Data on the reliability and validity of the MPI-D.]. , 1990, Schmerz.

[125]  A. M. Dale,et al.  A hybrid approach to the skull stripping problem in MRI , 2004, NeuroImage.

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