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Motor Cortex Stimulation Activates the Incertothalamic Pathway in an Animal Model of Spinal Cord Injury

  • Myeounghoon Cha
    Affiliations
    Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Baltimore, School of Dentistry, Baltimore, Maryland
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  • Yadong Ji
    Affiliations
    Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Baltimore, School of Dentistry, Baltimore, Maryland
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  • Radi Masri
    Correspondence
    Address reprint requests to Radi Masri, University of Maryland Baltimore, School of Dentistry, Department of Endodontics, Prosthodontics and Operative Dentistry, 650 West Baltimore St, 4th floor, Baltimore, MD 21201.
    Affiliations
    Department of Endodontics, Prosthodontics and Operative Dentistry, University of Maryland Baltimore, School of Dentistry, Baltimore, Maryland

    Department of Anatomy and Neurobiology, University of Maryland Medical School, Baltimore, Maryland
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Published:January 18, 2013DOI:https://doi.org/10.1016/j.jpain.2012.11.007

      Abstract

      We have shown previously that electrical stimulation of the motor cortex reduces spontaneous painlike behaviors in animals with spinal cord injury (SCI). Because SCI pain behaviors are associated with abnormal inhibition in the inhibitory nucleus zona incerta (ZI) and because inactivation of the ZI blocks motor cortex stimulation (MCS) effects, we hypothesized that the antinociceptive effects of MCS are due to enhanced inhibitory inputs from ZI to the posterior thalamus (Po)—an area heavily implicated in nociceptive processing. To test this hypothesis, we used a rodent model of SCI pain and performed in vivo extracellular electrophysiological recordings in single well-isolated neurons in anesthetized rats. We recorded spontaneous activity in ZI and Po from 48 rats before, during, and after MCS (50 μA, 50 Hz; 300-ms pulses). We found that MCS enhanced spontaneous activity in 35% of ZI neurons and suppressed spontaneous activity in 58% of Po neurons. The majority of MCS-enhanced ZI neurons (81%) were located in the ventrorateral subdivision of ZI—the area containing Po-projecting ZI neurons. In addition, we found that inactivation of ZI using muscimol (GABAA receptor agonist) blocked the effects of MCS in 73% of Po neurons. Although we cannot eliminate the possibility that muscimol spread to areas adjacent to ZI, these findings support our hypothesis and suggest that MCS produces antinociception by activating the incertothalamic pathway.

      Perspective

      This article describes a novel brain circuit that can be manipulated, in rats, to produce antinociception. These results have the potential to significantly impact the standard of care currently in place for the treatment of patients with intractable pain.

      Key words

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      References

        • Andersen P.
        • Eccles J.C.
        • Sears T.A.
        Presynaptic inhibitory action of cerebral cortex on the spinal cord.
        Nature. 1962; 194: 740-741
        • Baastrup C.
        • Finnerup N.B.
        Pharmacological management of neuropathic pain following spinal cord injury.
        CNS Drugs. 2008; 22: 455-475
        • Bartho P.
        • Freund T.F.
        • Acsady L.
        Selective gabaergic innervation of thalamic nuclei from zona incerta.
        Eur J Neurosci. 2002; 16: 999-1014
        • Bokor H.
        • Frere S.G.
        • Eyre M.D.
        • Slezia A.
        • Ulbert I.
        • Luthi A.
        • Acsady L.
        Selective gabaergic control of higher-order thalamic relays.
        Neuron. 2005; 45: 929-940
        • Cadusseau J.
        • Roger M.
        Cortical and subcortical connections of the pars compacta of the anterior pretectal nucleus in the rat.
        Neurosci Res. 1991; 12: 83-100
        • Canavero S.
        • Bonicalzi V.
        Cortical stimulation for central pain.
        J Neurosurg. 1995; 83: 1117
        • Canavero S.
        • Bonicalzi V.
        Therapeutic extradural cortical stimulation for central and neuropathic pain: A review.
        Clin J Pain. 2002; 18: 48-55
        • Canavero S.
        • Bonicalzi V.
        • Paolotti R.
        • Castellano G.
        • Greco-Crasto S.
        • Rizzo L.
        • Davini O.
        • Maina R.
        Therapeutic extradural cortical stimulation for movement disorders: A review.
        Neurol Res. 2003; 25: 118-122
        • Canavero S.
        • Bonicalzi V.
        Extradural cortical stimulation for central pain.
        Acta Neurochir Suppl. 2007; 97: 27-36
        • Cruccu G.
        • Aziz T.Z.
        • Garcia-Larrea L.
        • Hansson P.
        • Jensen T.S.
        • Lefaucheur J.P.
        • Simpson B.A.
        • Taylor R.S.
        Efns guidelines on neurostimulation therapy for neuropathic pain.
        Eur J Neurol. 2007; 14: 952-970
        • Davoody L.
        • Quiton R.L.
        • Lucas J.M.
        • Ji Y.
        • Keller A.
        • Masri R.
        Conditioned place preference reveals tonic pain in an animal model of central pain.
        J Pain. 2011; 12: 868-874
        • Finnerup N.B.
        • Johannesen I.L.
        • Bach F.W.
        • Jensen T.S.
        Sensory function above lesion level in spinal cord injury patients with and without pain.
        Somatosens Mot Res. 2003; 20: 71-76
        • Finnerup N.B.
        • Johannesen I.L.
        • Fuglsang-Frederiksen A.
        • Bach F.W.
        • Jensen T.S.
        Sensory function in spinal cord injury patients with and without central pain.
        Brain. 2003; 126: 57-70
        • Finnerup N.B.
        • Baastrup C.
        Spinal cord injury pain: Mechanisms and management.
        Curr Pain Headache Rep. 2012; 16: 207-216
        • Fonoff E.T.
        • Dale C.S.
        • Pagano R.L.
        • Paccola C.C.
        • Ballester G.
        • Teixeira M.J.
        • Giorgi R.
        Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system.
        Behav Brain Res. 2009; 196: 63-70
        • Friedberg M.H.
        • Lee S.M.
        • Ebner F.F.
        Modulation of receptive field properties of thalamic somatosensory neurons by the depth of anesthesia.
        J Neurophysiol. 1999; 81: 2243-2252
        • Garcia-Larrea L.
        • Peyron R.
        • Mertens P.
        • Gregoire M.C.
        • Lavenne F.
        • Bonnefoi F.
        • Mauguiere F.
        • Laurent B.
        • Sindou M.
        Positron emission tomography during motor cortex stimulation for pain control.
        Stereotact Funct Neurosurg. 1997; 68: 141-148
        • Garcia-Larrea L.
        • Peyron R.
        • Mertens P.
        • Gregoire M.C.
        • Lavenne F.
        • Le Bars D.
        • Convers P.
        • Mauguiere F.
        • Sindou M.
        • Laurent B.
        Electrical stimulation of motor cortex for pain control: A combined pet-scan and electrophysiological study.
        Pain. 1999; 83: 259-273
        • Garcia-Larrea L.
        • Maarrawi J.
        • Peyron R.
        Thalamocingulate mechanisms of precentral cortex stimulation for central pain.
        in: Vogt B. Cingulate Neurobiology and Disease. Oxford University Press, New York, NY2009: 437-465
        • Gybels J.
        • Kupers R.
        Deep brain stimulation in the treatment of chronic pain in man: Where and why?.
        Neurophysiol Clin. 1990; 20: 389-398
        • Khedr E.M.
        • Kotb H.
        • Kamel N.F.
        • Ahmed M.A.
        • Sadek R.
        • Rothwell J.C.
        Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain.
        J Neurol Neurosurg Psychiatry. 2005; 76: 833-838
        • Lefaucheur J.P.
        • Drouot X.
        • Menard-Lefaucheur I.
        • Nguyen J.P.
        Neuropathic pain controlled for more than a year by monthly sessions of repetitive transcranial magnetic stimulation of the motor cortex.
        Neurophysiol Clin. 2004; 34: 91-95
        • Lefaucheur J.P.
        Use of repetitive transcranial magnetic stimulation in pain relief.
        Expert Rev Neurother. 2008; 8: 799-808
        • Lima M.C.
        • Fregni F.
        Motor cortex stimulation for chronic pain: Systematic review and meta-analysis of the literature.
        Neurology. 2008; 70: 2329-2337
        • Lindblom U.F.
        • Ottosson J.O.
        Influence of pyramidal stimulation upon the relay of coarse cutaneous afferents in the dorsal horn.
        Acta Physiol Scand. 1957; 38: 309-318
        • Liu X.B.
        • Jones E.G.
        Predominance of corticothalamic synaptic inputs to thalamic reticular nucleus neurons in the rat.
        J Comp Neurol. 1999; 414: 67-79
        • Lucas J.M.
        • Ji Y.
        • Masri R.
        Motor cortex stimulation reduces hyperalgesia in an animal model of central pain.
        Pain. 2011; 152: 1398-1407
        • Luedtke K.
        • Rushton A.
        • Wright C.
        • Geiss B.
        • Juergens T.P.
        • May A.
        Transcranial direct current stimulation for the reduction of clinical and experimentally induced pain: A systematic review and meta-analysis.
        Clin J Pain. 2012; 28: 452-461
        • Maarrawi J.
        • Peyron R.
        • Mertens P.
        • Costes N.
        • Magnin M.
        • Sindou M.
        • Laurent B.
        • Garcia-Larrea L.
        Motor cortex stimulation for pain control induces changes in the endogenous opioid system.
        Neurology. 2007; 69: 827-834
        • Masri R.
        • Bezdudnaya T.
        • Trageser J.C.
        • Keller A.
        Encoding of stimulus frequency and sensor motion in the posterior medial thalamic nucleus.
        J Neurophysiol. 2008; 100: 681-689
        • Masri R.
        • Quiton R.L.
        • Lucas J.M.
        • Murray P.D.
        • Thompson S.M.
        • Keller A.
        Zona incerta: A role in central pain.
        J Neurophysiol. 2009; 102: 181-191
        • Masri R.M.
        • Trageser J.C.
        • Bezdudnaya T.
        • Li Y.
        • Keller A.
        Cholinergic regulation of the posterior medial thalamic nucleus.
        J Neurophysiol. 2006; 96: 2265-2273
        • Mitrofanis J.
        Some certainty for the “zone of uncertainty”? Exploring the function of the zona incerta.
        Neuroscience. 2005; 130: 1-15
        • Mitrofanis J.
        • Mikuletic L.
        Organisation of the cortical projection to the zona incerta of the thalamus.
        J Comp Neurol. 1999; 412: 173-185
        • Murray P.D.
        • Masri R.
        • Keller A.
        Abnormal anterior pretectal nucleus activity contributes to central pain syndrome.
        J Neurophysiol. 2010; 103: 3044-3053
        • Pagano R.L.
        • Assis D.V.
        • Clara J.A.
        • Alves A.S.
        • Dale C.S.
        • Teixeira M.J.
        • Fonoff E.T.
        • Britto L.R.
        Transdural motor cortex stimulation reverses neuropathic pain in rats: A profile of neuronal activation.
        Eur J Pain. 2011; 15: 268.e1-268.e14
        • Pagano R.L.
        • Fonoff E.T.
        • Dale C.S.
        • Ballester G.
        • Teixeira M.J.
        • Britto L.R.
        Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity of pag neurons: Possible pathways for antinociception.
        Pain. 2012; 153: 2359-2369
        • Paxinos G.
        • Watson C.
        The rat brain in stereotaxic coordinates.
        Academic Press, San Diego, CA2005
        • Peyron R.
        • Garcia-Larrea L.
        • Deiber M.P.
        • Cinotti L.
        • Convers P.
        • Sindou M.
        • Mauguiere F.
        • Laurent B.
        Electrical stimulation of precentral cortical area in the treatment of central pain: Electrophysiological and pet study.
        Pain. 1995; 62: 275-286
        • Peyron R.
        • Garcia-Larrea L.
        • Gregoire M.C.
        • Costes N.
        • Convers P.
        • Lavenne F.
        • Mauguiere F.
        • Michel D.
        • Laurent B.
        Haemodynamic brain responses to acute pain in humans: Sensory and attentional networks.
        Brain. 1999; 122: 1765-1780
        • Peyron R.
        • Garcia-Larrea L.
        • Gregoire M.C.
        • Convers P.
        • Richard A.
        • Lavenne F.
        • Barral F.G.
        • Mauguiere F.
        • Michel D.
        • Laurent B.
        Parietal and cingulate processes in central pain: A combined positron emission tomography (pet) and functional magnetic resonance imaging (fmri) study of an unusual case.
        Pain. 2000; 84: 77-87
        • Power B.D.
        • Mitrofanis J.
        Specificity of projection among cells of the zona incerta.
        J Neurocytol. 1999; 28: 481-493
        • Quiton R.L.
        • Masri R.
        • Thompson S.M.
        • Keller A.
        Abnormal activity of primary somatosensory cortex in central pain syndrome.
        J Neurophysiol. 2010; 104: 1717-1725
        • Sceniak M.P.
        • Maciver M.B.
        Cellular actions of urethane on rat visual cortical neurons in vitro.
        J Neurophysiol. 2006; 95: 3865-3874
      1. Seminowicz DA, Jiang L, Ji Y, Xu S, Gullapalli RP, Masri R: Thalamocortical asynchrony in conditions of spinal cord injury pain in rats. J Neurosci 32:15843-15848.

        • Shaw V.
        • Mitrofanis J.
        Anatomical evidence for somatotopic maps in the zona incerta of rats.
        Anat Embryol (Berl). 2002; 206: 119-130
        • Shin H.C.
        • Chapin J.K.
        Mapping the effects of motor cortex stimulation on somatosensory relay neurons in the rat thalamus: Direct responses and afferent modulation.
        Brain Res Bull. 1990; 24: 257-265
        • Sol J.C.
        • Casaux J.
        • Roux F.E.
        • Lotterie J.A.
        • Bousquet P.
        • Verdie J.C.
        • Mascott C.
        • Lazorthes Y.
        Chronic motor cortex stimulation for phantom limb pain: Correlations between pain relief and functional imaging studies.
        Stereotact Funct Neurosurg. 2001; 77: 172-176
        • Son B.C.
        • Lee S.W.
        • Choi E.S.
        • Sung J.H.
        • Hong J.T.
        Motor cortex stimulation for central pain following a traumatic brain injury.
        Pain. 2006; 123: 210-216
        • Son U.C.
        • Kim M.C.
        • Moon D.E.
        • Kang J.K.
        Motor cortex stimulation in a patient with intractable complex regional pain syndrome type II with hemibody involvement. Case report.
        J Neurosurg. 2003; 98: 175-179
        • Tani N.
        • Saitoh Y.
        • Hirata M.
        • Kato A.
        • Yoshimine T.
        Bilateral cortical stimulation for deafferentation pain after spinal cord injury. Case report.
        J Neurosurg. 2004; 101: 687-689
        • Tasker R.R.
        Microelectrode findings in the thalamus in chronic pain and other conditions.
        Stereotact Funct Neurosurg. 2001; 77: 166-168
        • Trageser J.C.
        • Keller A.
        Reducing the uncertainty: Gating of peripheral inputs by zona incerta.
        J Neurosci. 2004; 24: 8911-8915
        • Trageser J.C.
        • Burke K.A.
        • Masri R.M.
        • Li Y.
        • Sellers L.
        • Keller A.
        State-dependent gating of sensory inputs by zona incerta.
        J Neurophysiol. 2006; 96: 1456-1463
        • Tsubokawa T.
        • Katayama Y.
        • Yamamoto T.
        • Hirayama T.
        • Koyama S.
        Treatment of thalamic pain by chronic motor cortex stimulation.
        Pacing Clin Electrophysiol. 1991; 14: 131-134
        • Tsubokawa T.
        • Katayama Y.
        • Yamamoto T.
        • Hirayama T.
        • Koyama S.
        Chronic motor cortex stimulation in patients with thalamic pain.
        J Neurosurg. 1993; 78: 393-401
        • Urbain N.
        • Deschenes M.
        Motor cortex gates vibrissal responses in a thalamocortical projection pathway.
        Neuron. 2007; 56: 714-725
        • Velasco F.
        • Carrillo-Ruiz J.D.
        • Castro G.
        • Arguelles C.
        • Velasco A.L.
        • Kassian A.
        • Guevara U.
        Motor cortex electrical stimulation applied to patients with complex regional pain syndrome.
        Pain. 2009; 147: 91-98
        • Villarreal C.F.
        • Kina V.A.
        • Prado W.A.
        Antinociception induced by stimulating the anterior pretectal nucleus in two models of pain in rats.
        Clin Exp Pharmacol Physiol. 2004; 31: 608-613
        • Villarreal C.F.
        • Prado W.A.
        Modulation of persistent nociceptive inputs in the anterior pretectal nucleus of the rat.
        Pain. 2007; 132: 42-52
        • Wang G.
        • Thompson S.M.
        Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: Thalamic hyperexcitability after spinothalamic tract lesions.
        J Neurosci. 2008; 28: 11959-11969
        • Z'Graggen W.J.
        • Metz G.A.
        • Kartje G.L.
        • Thallmair M.
        • Schwab M.E.
        Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats.
        J Neurosci. 1998; 18: 4744-4757