Functional role of exercise-induced cortical organization of sensorimotor cortex after spinal transection.

Spinal cord transection silences neuronal activity in the deafferented cortex to cutaneous stimulation of the body and untreated animals show no improvement in functional outcome (weight-supported stepping) with time after lesion. However, adult rats spinalized since neonates that receive exercise therapy exhibit greater functional recovery and exhibit more cortical reorganization. This suggests that the change in the somatotopic organization of the cortex may be functionally relevant. To address this issue, we chronically implanted arrays of microwire electrodes into the infragranular layers of the hindlimb somatosensory cortex of adult rats neonatally transected at T8/T9 that received exercise training (spinalized rats) and of normal adult rats. Multiple, single neuron activity was recorded during passive sensory stimulation, when the animals were anesthetized, and during active sensorimotor stimulation during treadmill-induced locomotion when the animal was awake and free to move. Our results demonstrate that cortical neurons recorded from the spinalized rats that received exercise 1) had higher spontaneous firing rates, 2) were more likely to respond to both sensory and sensorimotor stimulations of the forelimbs, and also 3) responded with more spikes per stimulus than those recorded from normal rats, suggesting expansion of the forelimb map into the hindlimb map. During treadmill locomotion the activity of neurons recorded from neonatally spinalized rats was greater during weight-supported steps on the treadmill compared with the neuronal activity during nonweight supported steps. We hypothesize that this increased activity is related to the ability of the animal to take weight supported steps and that, therefore, these changes in cortical organization after spinal cord injury are relevant for functional recovery.

[1]  Jon H. Kaas,et al.  Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord , 2008, Experimental Neurology.

[2]  G. Gerstein,et al.  Trial-to-Trial Variability and State-Dependent Modulation of Auditory-Evoked Responses in Cortex , 1999, The Journal of Neuroscience.

[3]  Markus Rudin,et al.  Functional and Anatomical Reorganization of the Sensory-Motor Cortex after Incomplete Spinal Cord Injury in Adult Rats , 2009, The Journal of Neuroscience.

[4]  S. Giszter,et al.  Fetal Transplants Alter the Development of Function after Spinal Cord Transection in Newborn Rats , 1997, The Journal of Neuroscience.

[5]  P. Mckinley,et al.  Chronological observations of primary somatosensory cortical maps in kittens following low thoracic (T12) spinal cord transection at 2 weeks of age. , 1991, Somatosensory & motor research.

[6]  V. Dietz,et al.  Differential effect of spinal cord injury and functional impairment on human brain activation. , 2002, Journal of neurotrauma.

[7]  M. Murray,et al.  Role of the 5-HT2C receptor in improving weight-supported stepping in adult rats spinalized as neonates , 2006, Brain Research.

[8]  M. Murray,et al.  Exercise Induces Cortical Plasticity after Neonatal Spinal Cord Injury in the Rat , 2009, The Journal of Neuroscience.

[9]  H. Topka,et al.  Combination of TMS and fMRI reveals a specific pattern of reorganization in M1 in patients after complete spinal cord injury. , 2006, Restorative neurology and neuroscience.

[10]  C. Gray,et al.  Cellular Mechanisms Contributing to Response Variability of Cortical Neurons In Vivo , 1999, The Journal of Neuroscience.

[11]  Grigori N. Orlovsky,et al.  Activity of Different Classes of Neurons of the Motor Cortex during Postural Corrections , 2003, The Journal of Neuroscience.

[12]  J P Donoghue,et al.  Organization of adult motor cortex representation patterns following neonatal forelimb nerve injury in rats , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  W J Kargo,et al.  Fetal transplants rescue axial muscle representations in M1 cortex of neonatally transected rats that develop weight support. , 1998, Journal of neurophysiology.

[14]  Jon H. Kaas,et al.  Deactivation and reactivation of somatosensory cortex after dorsal spinal cord injury , 1997, Nature.

[15]  Bradley C. Wheeler,et al.  Automatic Discrimination of Single Units , 1998 .

[16]  G. Foffani,et al.  Responses of infragranular neurons in the rat primary somatosensory cortex to forepaw and hindpaw tactile stimuli , 2008, Neuroscience.

[17]  K. Moxon,et al.  Responses of Trigeminal Ganglion Neurons during Natural Whisking Behaviors in the Awake Rat , 2007, Neuron.

[18]  J. Gregg,et al.  Somatotopic organization of the trigeminal ganglion in the rat. , 1973, Archives of oral biology.

[19]  Niranjan Kambi,et al.  Large-Scale Expansion of the Face Representation in Somatosensory Areas of the Lateral Sulcus after Spinal Cord Injuries in Monkeys , 2009, The Journal of Neuroscience.

[20]  Jon H. Kaas,et al.  Patterned Activity via Spinal Dorsal Quadrant Inputs Is Necessary for the Formation of Organized Somatosensory Maps , 2003, The Journal of Neuroscience.

[21]  Antonio Oliviero,et al.  Spinal Cord Injury Immediately Changes the State of the Brain , 2010, The Journal of Neuroscience.

[22]  M Hallett,et al.  Reorganization of corticospinal pathways following spinal cord injury , 1991, Neurology.

[23]  A. Grinvald,et al.  Linking spontaneous activity of single cortical neurons and the underlying functional architecture. , 1999, Science.

[24]  Dawn L. Merrett,et al.  Reaching training in rats with spinal cord injury promotes plasticity and task specific recovery. , 2007, Brain : a journal of neurology.

[25]  A. Grinvald,et al.  Dynamics of Ongoing Activity: Explanation of the Large Variability in Evoked Cortical Responses , 1996, Science.

[26]  P. Mckinley,et al.  Age-dependent differences in reorganization of primary somatosensory cortex following low thoracic (T12) spinal cord transection in cats , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[27]  P. Mckinley,et al.  Progressive changes in somatosensory cortical maps in 6-week-old kittens cord-transected at T12 , 1989, Brain Research.

[28]  Ian Q. Whishaw,et al.  Arpeggio and fractionated digit movements used in prehension by rats , 1994, Behavioural Brain Research.

[29]  J. Mcdonald,et al.  Spinal-cord injury , 2002, The Lancet.

[30]  Guglielmo Foffani,et al.  Structure of the excitatory receptive fields of infragranular forelimb neurons in the rat primary somatosensory cortex responding to touch. , 2006, Cerebral cortex.

[31]  Toshiki Endo,et al.  Cortical sensory map rearrangement after spinal cord injury: fMRI responses linked to Nogo signalling. , 2007, Brain : a journal of neurology.

[32]  M. Bear,et al.  Metaplasticity: the plasticity of synaptic plasticity , 1996, Trends in Neurosciences.

[33]  H. Killackey,et al.  Source of inappropriate receptive fields in cortical somatotopic maps from rats that sustained neonatal forelimb removal. , 1999, Journal of neurophysiology.

[34]  C. Rivadulla,et al.  New corticocuneate cellular mechanisms underlying the modulation of cutaneous ascending transmission in anesthetized cats. , 2003, Journal of neurophysiology.

[35]  L G Cohen,et al.  Mechanisms, functional relevance and modulation of plasticity in the human central nervous system. , 1999, Electroencephalography and clinical neurophysiology. Supplement.

[36]  E. Field-Fote,et al.  Cortical Reorganization Following Bimanual Training and Somatosensory Stimulation in Cervical Spinal Cord Injury: A Case Report , 2007, Physical Therapy.

[37]  J. Wall,et al.  Cutaneous responsiveness in primary somatosensory (S-I) hindpaw cortex before and after partial hindpaw deafferentation in adult rats , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[38]  Ian Q. Whishaw,et al.  The structure of skilled forelimb reaching in the rat: A proximally driven movement with a single distal rotatory component , 1990, Behavioural Brain Research.

[39]  D. Rasmusson,et al.  Non-overlapping thalamocortical projections for separate forepaw digits before and after cortical reorganization in the raccoon , 1986, Brain Research Bulletin.

[40]  D. J. Felleman,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 , 1983, Neuroscience.

[41]  C. Gilbert,et al.  Brain States: Top-Down Influences in Sensory Processing , 2007, Neuron.

[42]  A. Grinvald,et al.  Spontaneously emerging cortical representations of visual attributes , 2003, Nature.

[43]  J. Chapin,et al.  Mapping the body representation in the SI cortex of anesthetized and awake rats , 1984, The Journal of comparative neurology.

[44]  A. Canedo,et al.  Spatial and cortical influences exerted on cuneothalamic and thalamocortical neurons of the cat , 2000, The European journal of neuroscience.

[45]  R. S. Waters,et al.  Digit removal leads to discrepancies between the structural and functional organization of the forepaw barrel subfield in layer IV of rat primary somatosensory cortex , 1996, Experimental Brain Research.

[46]  Karen A Moxon,et al.  Relationship between physiological response type (RA and SA) and vibrissal receptive field of neurons within the rat trigeminal ganglion. , 2006, Journal of neurophysiology.

[47]  Nicolas J. Kerscher,et al.  State-dependent receptive-field restructuring in the visual cortex , 1998, Nature.

[48]  E. Manjarrez,et al.  Cortical neuronal ensembles driven by dorsal horn spinal neurones with spontaneous activity in the cat , 2002, Neuroscience Letters.

[49]  A. Nuñez,et al.  Sensory‐interference in rat primary somatosensory cortical neurons , 2004, The European journal of neuroscience.

[50]  F. Ebner,et al.  Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia. , 1999, Journal of neurophysiology.

[51]  Cortico-subcortical synchronization in the chloralose-anesthetized cat , 1999, Neuroscience.

[52]  M. Nicolelis,et al.  Principal component analysis of neuronal ensemble activity reveals multidimensional somatosensory representations , 1999, Journal of Neuroscience Methods.

[53]  J B Green,et al.  Cortical sensorimotor reorganization after spinal cord injury , 1998, Neurology.

[54]  J. Chapin,et al.  Distribution of somatic sensory and active-movement neuronal discharge properties in the MI-SI cortical border area in the rat , 1986, Experimental Neurology.

[55]  J. Williamson,et al.  Changes in Supraspinal Activation Patterns following Robotic Locomotor Therapy in Motor-Incomplete Spinal Cord Injury , 2005, Neurorehabilitation and neural repair.

[56]  J. Kalaska,et al.  Chronic paw denervation causes an age-dependent appearance of novel responses from forearm in "paw cortex" of kittens and adult cats. , 1979, Journal of neurophysiology.

[57]  J. Levitt,et al.  Sensory hind-limb representation in the SmI cortex of the cat after spinal tractotomies. , 1968, Experimental neurology.

[58]  R. Dykes,et al.  Neuronal response properties within subregions of raccoon somatosensory cortex 1 week after digit amputation. , 1992, Somatosensory & motor research.

[59]  E. Field-Fote,et al.  Massed Practice versus Massed Practice with Stimulation: Effects on Upper Extremity Function and Cortical Plasticity in Individuals with Incomplete Cervical Spinal Cord Injury , 2005, Neurorehabilitation and neural repair.

[60]  Jon H. Kaas,et al.  Large-Scale Reorganization in the Somatosensory Cortex and Thalamus after Sensory Loss in Macaque Monkeys , 2008, The Journal of Neuroscience.

[61]  Michael M Merzenich,et al.  Local circuit properties underlying cortical reorganization. , 2002, Journal of neurophysiology.

[62]  Guglielmo Foffani,et al.  Role of Spike Timing in the Forelimb Somatosensory Cortex of the Rat , 2004, The Journal of Neuroscience.

[63]  A Curt,et al.  How does the human brain deal with a spinal cord injury? , 1998, The European journal of neuroscience.

[64]  Markus Rudin,et al.  Rewiring of hindlimb corticospinal neurons after spinal cord injury , 2010, Nature Neuroscience.

[65]  Hatem Alkadhi,et al.  Changes of non-affected upper limb cortical representation in paraplegic patients as assessed by fMRI. , 2002, Brain : a journal of neurology.

[66]  J. Chapin,et al.  Laminar differences in sizes, shapes, and response profiles of cutaneous receptive fields in the rat SI cortex , 2004, Experimental Brain Research.

[67]  Pattern Generators and Cortical Maps in Locomotion of Spinal Injured Rats a , 1998, Annals of the New York Academy of Sciences.

[68]  M A Nicolelis,et al.  Spatiotemporal properties of layer V neurons of the rat primary somatosensory cortex. , 1999, Cerebral cortex.

[69]  Uci Medical Brain motor system function after chronic,complete spinal cord injury , 2006 .

[70]  Simona Temereanca,et al.  Functional Topography of Corticothalamic Feedback Enhances Thalamic Spatial Response Tuning in the Somatosensory Whisker/Barrel System , 2004, Neuron.

[71]  M. Gorassini,et al.  Increases in corticospinal tract function by treadmill training after incomplete spinal cord injury. , 2005, Journal of neurophysiology.

[72]  J. Kaas,et al.  Limits on plasticity in somatosensory cortex of adult rats: hindlimb cortex is not reactivated after dorsal column section. , 1995, Journal of neurophysiology.

[73]  Afonso C. Silva,et al.  Laminar specificity of functional MRI onset times during somatosensory stimulation in rat , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Ranu Jung,et al.  Activity-dependent plasticity in spinal cord injury. , 2008, Journal of rehabilitation research and development.

[75]  S. Lalwani,et al.  Spinal cord injury. , 2011, Journal of neurosurgery. Spine.

[76]  Jerald D. Kralik,et al.  Chronic, multisite, multielectrode recordings in macaque monkeys , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[77]  H. Killackey,et al.  Organization of corticocortical connections in the parietal cortex of the rat , 1978, The Journal of comparative neurology.

[78]  Serge Rossignol,et al.  Prominent Role of the Spinal Central Pattern Generator in the Recovery of Locomotion after Partial Spinal Cord Injuries , 2008, The Journal of Neuroscience.

[79]  H. Onoe,et al.  Time-Dependent Central Compensatory Mechanisms of Finger Dexterity After Spinal Cord Injury , 2007, Science.

[80]  R. Hall,et al.  Organization of motor and somatosensory neocortex in the albino rat , 1974 .

[81]  M. Murray,et al.  Partial 5-HT1A receptor agonist activity by the 5-HT2C receptor antagonist SB 206,553 is revealed in rats spinalized as neonates , 2005, Experimental Neurology.

[82]  M. Wiesendanger,et al.  Is the hindlimb representation of the rat's cortex a ‘sensorimotor amalgam’? , 1985, Brain Research.

[83]  S. Giszter,et al.  Coordination strategies for limb forces during weight-bearing locomotion in normal rats, and in rats spinalized as neonates , 2008, Experimental Brain Research.

[84]  G. Doetsch,et al.  Time-dependent changes in the functional organization of somatosensory cerebral cortex following digit amputation in adult raccoons. , 1984, Somatosensory research.

[85]  John Cadwell,et al.  Focal magnetic coil stimulation reveals motor cortical system reorganized in humans after traumatic quadriplegia , 1990, Brain Research.

[86]  V. Reggie Edgerton,et al.  Training locomotor networks , 2008, Brain Research Reviews.

[87]  M. D. Egger,et al.  Formation of New Connexions in Adult Rat Brains after Partial Deafferentation , 1971, Nature.

[88]  Xiaoqin Wang,et al.  Remodelling of hand representation in adult cortex determined by timing of tactile stimulation , 1995, Nature.

[89]  S. Vicini,et al.  Remodeling of synaptic structures in the motor cortex following spinal cord injury , 2006, Experimental Neurology.

[90]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[91]  David J Mikulis,et al.  Sensorimotor Cortical Plasticity During Recovery Following Spinal Cord Injury: A Longitudinal fMRI Study , 2007, Neurorehabilitation and neural repair.

[92]  A. Canedo,et al.  Pyramidal tract and corticospinal neurons with branching axons to the dorsal column nuclei of the cat , 1995, Neuroscience.

[93]  G. Karmos,et al.  Entrainment of Neuronal Oscillations as a Mechanism of Attentional Selection , 2008, Science.