Chapter 11--novel mechanism for hyperreflexia and spasticity.

We established that hyperreflexia is delayed after spinal transection in the adult rat and that passive exercise could normalize low frequency-dependent depression of the H-reflex. We were also able to show that such passive exercise will normalize hyperreflexia in patients with spinal cord injury (SCI). Recent results demonstrate that spinal transection results in changes in the neuronal gap junction protein connexin 36 below the level of the lesion. Moreover, a drug known to increase electrical coupling was found to normalize hyperreflexia in the absence of passive exercise, suggesting that changes in electrical coupling may be involved in hyperreflexia. We also present results showing that a measure of spasticity, the stretch reflex, is rendered abnormal by transection and normalized by the same drug. These data suggest that electrical coupling may be dysregulated in SCI, leading to some of the symptoms observed. A novel therapy for hyperreflexia and spasticity may require modulation of electrical coupling.

[1]  E. Garcia-Rill,et al.  Restoration of frequency-dependent depression of the H-reflex by passive exercise in spinal rats , 2006, Spinal Cord.

[2]  E. Garcia-Rill,et al.  Modulation of rhythmic function in the posterior midbrain , 1988, Neuroscience.

[3]  Michael A Long,et al.  Rhythmicity without Synchrony in the Electrically Uncoupled Inferior Olive , 2002, The Journal of Neuroscience.

[4]  M. Clare,et al.  Fusimotor Function: Part VI. H Reflex, Tendon Jerk, and Reinforcement in Hemiplegia , 1964 .

[5]  J. Nielsen,et al.  Interaction between peripheral afferent activity and presynaptic inhibition of ia afferents in the cat. , 2002, Journal of neurophysiology.

[6]  R. Kuhn,et al.  FUNCTITONAL CAPACITY OF THE ISOLATED HUMAN SPINAL CORD , 1950 .

[7]  D. Friedman,et al.  Both electrical and chemical synapses mediate fast network oscillations in the olfactory bulb. , 2003, Journal of neurophysiology.

[8]  S. Andreassen,et al.  Non–reflex and reflex mediated ankle joint stiffness in multiple sclerosis patients with spasticity , 1993, Muscle & nerve.

[9]  M. Tresch,et al.  Gap junctions and motor behavior , 2002, Trends in Neurosciences.

[10]  A. J. Berger,et al.  Gap junctions and inhibitory synapses modulate inspiratory motoneuron synchronization. , 2001, Journal of neurophysiology.

[11]  E. Garcia-Rill,et al.  Electrically induced locomotion in the in vitro brainstem-spinal cord preparation. , 1988, Brain research.

[12]  Yasin Dhaher,et al.  Reflex Torque Response to Movement of the Spastic Elbow: Theoretical Analyses and Implications for Quantification of Spasticity , 1999, Annals of Biomedical Engineering.

[13]  J Quintern,et al.  Electrophysiological studies of gait in spasticity and rigidity. Evidence that altered mechanical properties of muscle contribute to hypertonia. , 1981, Brain : a journal of neurology.

[14]  Induction of synchronous oscillatory activity in the rat lateral amygdala in vitro is dependent on gap junction activity , 2006, The European journal of neuroscience.

[15]  Modafinil normalized hyperreflexia after spinal transection in adult rats , 2008, Spinal Cord.

[16]  M. Whittington,et al.  A Novel Network of Multipolar Bursting Interneurons Generates Theta Frequency Oscillations in Neocortex , 2003, Neuron.

[17]  R. A. Hensbroek,et al.  Analysis of Cx36 Knockout Does Not Support Tenet That Olivary Gap Junctions Are Required for Complex Spike Synchronization and Normal Motor Performance , 2002, Annals of the New York Academy of Sciences.

[18]  N. S. Bradley,et al.  Animal models offer the opportunity to acquire a new perspective on motor development. , 1990, Physical therapy.

[19]  K. Klose,et al.  Evidence that alterations in presynaptic inhibition contribute to segmental hypo- and hyperexcitability after spinal cord injury in man. , 1993, Electroencephalography and clinical neurophysiology.

[20]  Magladery Jw,et al.  Electrophysiological studies of reflex activity in patients with lesions of the nervous system. I. A comparison of spinal motoneurone excitability following afferent nerve volleys in normal persons and patients with upper motor neurone lesions. , 1952 .

[21]  E. Garcia-Rill,et al.  The effects of passive exercise therapy initiated prior to or after the development of hyperreflexia following spinal transection , 2008, Experimental Neurology.

[22]  E. Garcia-Rill,et al.  The onset of hyperreflexia in the rat following complete spinal cord transection , 2008, Spinal Cord.

[23]  M. Christie,et al.  Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  Ole Kiehn,et al.  Motor coordination without action potentials in the mammalian spinal cord , 2000, Nature Neuroscience.

[25]  Little Jw,et al.  H-reflex changes following spinal cord injury. , 1985 .

[26]  E. Garcia-Rill,et al.  Bias in magnitude estimation following left hemisphere injury , 2006, Neuropsychologia.

[27]  D. Bennett,et al.  Persistent sodium and calcium currents cause plateau potentials in motoneurons of chronic spinal rats. , 2003, Journal of neurophysiology.

[28]  W. Lajara-Nanson,et al.  Walking With Modafinil and Its Use in Diplegic Cerebral Palsy , 2006, Journal of child neurology.

[29]  E. Garcia-Rill,et al.  Chemical activation of the mesecephalic locomotor region , 1985, Brain Research.

[30]  D. Stuart,et al.  Low frequency depression of the H wave in normal and spinal man. , 1966, Experimental neurology.

[31]  R. Angel,et al.  THE H REFLEX IN NORMAL, SPASTIC, AND RIGID SUBJECTS. , 1963, Archives of neurology.

[32]  W. Rymer,et al.  Windup of flexion reflexes in chronic human spinal cord injury: a marker for neuronal plateau potentials? , 2003, Journal of neurophysiology.

[33]  H. Wigström,et al.  Maintained changes in motoneuronal excitability by short‐lasting synaptic inputs in the decerebrate cat. , 1988, The Journal of physiology.

[34]  J. Ballon,et al.  A systematic review of modafinil: Potential clinical uses and mechanisms of action. , 2006, The Journal of clinical psychiatry.

[35]  D. Hurst,et al.  Modafinil for Drooling in Cerebral Palsy , 2006, Journal of child neurology.

[36]  W. Ershler,et al.  Effects of spinal transection in neonatal and weanling rats: Survival of function , 1975, Experimental Neurology.

[37]  J R Wolpaw,et al.  Short-Term and medium-term effects of spinal cord tract transections on soleus H-reflex in freely moving rats. , 2001, Journal of neurotrauma.

[38]  E. Garcia-Rill,et al.  Control of locomotion in vitro: II. Chemical stimulation. , 1991, Somatosensory & motor research.

[39]  R. Llinás,et al.  Role of gap junctions in synchronized neuronal oscillations in the inferior olive. , 2005, Journal of neurophysiology.

[40]  F. Thompson,et al.  Velocity-dependent ankle torque in the normal rat. , 1996, Neuroreport.

[41]  J. P. Lund,et al.  Synaptic inputs to trigeminal primary afferent neurons cause firing and modulate intrinsic oscillatory activity. , 2004, Journal of neurophysiology.

[42]  G L Soderberg,et al.  A guide for use and interpretation of kinesiologic electromyographic data. , 2000, Physical therapy.

[43]  Meijun Ye,et al.  Electrical coupling: novel mechanism for sleep-wake control. , 2007, Sleep.

[44]  Chou-Ching K. Lin,et al.  Time-course analysis of stretch reflexes in hemiparetic subjects using an on-line spasticity measurement system. , 2000, Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology.

[45]  J. Leiter,et al.  Ventilatory effects of gap junction blockade in the RTN in awake rats. , 2004, American journal of physiology. Regulatory, integrative and comparative physiology.

[46]  M. Gorassini,et al.  Spasticity in rats with sacral spinal cord injury. , 1999, Journal of neurotrauma.

[47]  R. Shields,et al.  Soleus H-reflex recruitment is not altered in persons with chronic spinal cord injury. , 2004, Archives of physical medicine and rehabilitation.

[48]  M. Faist,et al.  A quantitative assessment of presynaptic inhibition of Ia afferents in spastics. Differences in hemiplegics and paraplegics. , 1994, Brain : a journal of neurology.

[49]  E. Garcia-Rill,et al.  Evidence for Electrical Coupling in the SubCoeruleus (SubC) Nucleus. , 2007, Journal of neurophysiology.

[50]  D. Stokic,et al.  Neurophysiologic Evaluation of Spastic Hypertonia: Implications for Management of the Patient with the Intrathecal Baclofen Pump , 2004, American journal of physical medicine & rehabilitation.

[51]  J. Leiter,et al.  Ventilatory effects of gap junction blockade in the NTS in awake rats , 2004, Respiratory Physiology & Neurobiology.

[52]  Michael J. O'Donovan,et al.  Mechanisms that initiate spontaneous network activity in the developing chick spinal cord. , 2001, Journal of neurophysiology.

[53]  John P Welsh,et al.  Fundamental role of inferior olive connexin 36 in muscle coherence during tremor. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Alessandra Cifra,et al.  A repertoire of rhythmic bursting produced by hypoglossal motoneurons in physiological and pathological conditions , 2009, Philosophical Transactions of the Royal Society B: Biological Sciences.

[55]  J. Nielsen,et al.  Post-activation depression of Soleus stretch reflexes in healthy and spastic humans , 2008, Experimental Brain Research.

[56]  K. Walton,et al.  Postnatal changes in motoneurone electrotonic coupling studied in the in vitro rat lumbar spinal cord. , 1991, The Journal of physiology.

[57]  M. Akai,et al.  Enhanced stretch reflex excitability of the soleus muscle in persons with incomplete rather than complete chronic spinal cord injury. , 2006, Archives of Physical Medicine and Rehabilitation.

[58]  H. Meinck.  Occurrence of the H reflex and the F wave in the rat. , 1976, Electroencephalography and clinical neurophysiology.

[59]  P. Bose,et al.  Velocity-dependent ankle torque in rats after contusion injury of the midthoracic spinal cord: time course. , 2002, Journal of neurotrauma.

[60]  W Z Rymer,et al.  Effects of acute dorsal spinal hemisection on motoneuron discharge in the medial gastrocnemius of the decerebrate cat. , 1988, Journal of neurophysiology.

[61]  E. Garcia-Rill,et al.  Use of a Motorized Bicycle Exercise Trainer to Normalize Frequency-Dependent Habituation of the H-reflex in Spinal Cord Injury , 2005, The journal of spinal cord medicine.

[62]  Christopher A Hinckley,et al.  Electrical Coupling between Locomotor-Related Excitatory Interneurons in the Mammalian Spinal Cord , 2006, The Journal of Neuroscience.

[63]  W. Rymer,et al.  Afferent mechanisms for the reflex response to imposed ankle movement in chronic spinal cord injury , 2002, Experimental Brain Research.

[64]  E. Garcia-Rill,et al.  Effects of exercise and fetal spinal cord implants on the H-reflex in chronically spinalized adult rats , 1996, Brain Research.

[65]  E. Garcia-Rill.  The pedunculopontine nucleus , 1991, Progress in Neurobiology.

[66]  B. Connors,et al.  Synchronous Activity of Inhibitory Networks in Neocortex Requires Electrical Synapses Containing Connexin36 , 2001, Neuron.

[67]  P. Reier,et al.  Scientific Basis of Spasticity: Insights from a Laboratory Model , 2001, Journal of child neurology.

[68]  H Hultborn,et al.  Short-term plasticity in hindlimb motoneurons of decerebrate cats. , 1998, Journal of neurophysiology.

[69]  C. Shuler,et al.  Developmental regulation of connexins 26, 32, 36, and 43 in trigeminal neurons , 2004, Synapse.

[70]  M. Gorassini,et al.  Evidence for plateau potentials in tail motoneurons of awake chronic spinal rats with spasticity. , 2001, Journal of neurophysiology.

[71]  J. Nielsen,et al.  Sensitivity of H-reflexes and stretch reflexes to presynaptic inhibition in humans. , 1998, Journal of neurophysiology.

[72]  R. Young,et al.  Spasticity, disordered motor control , 1980 .

[73]  J. Broton,et al.  Interlimb reflexes and synaptic plasticity become evident months after human spinal cord injury. , 2002, Brain : a journal of neurology.

[74]  R. Llinás,et al.  Modafinil enhances thalamocortical activity by increasing neuronal electrotonic coupling , 2007, Proceedings of the National Academy of Sciences.

[75]  O. Kiehn,et al.  Bistability of alpha‐motoneurones in the decerebrate cat and in the acute spinal cat after intravenous 5‐hydroxytryptophan. , 1988, The Journal of physiology.

[76]  J. Fawcett.  Overcoming inhibition in the damaged spinal cord. , 2006, Journal of neurotrauma.

[77]  E. Pierrot‐Deseilligny.  Electrophysiological assessment of the spinal mechanisms underlying spasticity. , 1990, Electroencephalography and clinical neurophysiology. Supplement.

[78]  P. Reier,et al.  Altered patterns of reflex excitability subsequent to contusion injury of the rat spinal cord. , 1992, Journal of neurophysiology.

[79]  F. Elsen,et al.  Carbenoxolone induced depression of rhythmogenesis in the pre-Bötzinger Complex , 2008, BMC Neuroscience.

[80]  Ming Wu,et al.  Temporal facilitation of spastic stretch reflexes following human spinal cord injury , 2006, The Journal of physiology.

[81]  R. Shields,et al.  Low frequency depression of H-reflexes in humans with acute and chronic spinal-cord injury , 2000, Experimental Brain Research.

[82]  J. Feldman,et al.  Bidirectional electrical coupling between inspiratory motoneurons in the newborn mouse nucleus ambiguus. , 1997, Journal of neurophysiology.

[83]  E. Diamantopoulos,et al.  Excitability of spinal motor neurones in normal subjects and patients with spasticity, Parkinsonian rigidity, and cerebellar hypotonia. , 1967, Journal of neurology, neurosurgery, and psychiatry.

[84]  D. Goodkin,et al.  Drugs Used to Treat Spasticity , 2000, Drugs.

[85]  R. Miledi,et al.  Electrical synapses between motoneurons in the spinal cord of the newborn rat , 1980, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[86]  Ole Kiehn,et al.  Chapter 21 Possible functions of transmitter-controlled plateau potentials in α motoneurones , 1989 .

[87]  B. Connors,et al.  Electrical synapses in the mammalian brain. , 2004, Annual review of neuroscience.

[88]  N. Belluardo,et al.  Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons , 1998, The European journal of neuroscience.

[89]  Alan Roberts,et al.  Locomotor rhythm maintenance: electrical coupling among premotor excitatory interneurons in the brainstem and spinal cord of young Xenopus tadpoles , 2009, The Journal of physiology.

[90]  P. Kitzman,et al.  Alteration in axial motoneuronal morphology in the spinal cord injured spastic rat , 2005, Experimental Neurology.

[91]  H. Hultborn.  Changes in neuronal properties and spinal reflexes during development of spasticity following spinal cord lesions and stroke: studies in animal models and patients. , 2003, Journal of rehabilitation medicine.

[92]  Miles A Whittington,et al.  A beta2-frequency (20–30 Hz) oscillation in nonsynaptic networks of somatosensory cortex , 2006, Proceedings of the National Academy of Sciences.

[93]  J. Ditunno,et al.  Incomplete spinal cord injury: neuronal mechanisms of motor recovery and hyperreflexia. , 1999, Archives of physical medicine and rehabilitation.

[94]  Hannah Monyer,et al.  Contrasting roles of axonal (pyramidal cell) and dendritic (interneuron) electrical coupling in the generation of neuronal network oscillations , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[95]  J. Nielsen,et al.  Changes in transmission across synapses of Ia afferents in spastic patients. , 1995, Brain : a journal of neurology.