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Motor Cortex Stimulation for the  treatment of neuropathic and central pain

DEPARTMENT OF NEUROSURGERY HOSPITAL ITALIANO DE BUENOS AIRES ARGENTINA Chairman :  Claudio Yampolsky, M.D.

XXIII
CONGRESO DE LA
SOCIEDAD ESPANOLA
DE SENEC
Oeciamos ayer, diremos mahana
SALAMANCA
14-17 MAYO
2019
JOINT MEETING I REUNIdN CONJUNTA

https://www.congresoneurocirugia.com/images/cabecera_web_es.jpg

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Herewith  I  confirm   that  I do NOT  have   any   relevant   financial   relationships   with   commercial   interests

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Unpleasant feeling Depression Anxiety Anger

Unpleasant sensation P ins Needles Torsion Pressure Crushing Electric shock

Physiologic Pathologic nociceptive neuropathic psychogenic unknown physiopathology mixed

An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.   IASP

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Persistent pain Nociceptive pain Pain   signaling Pain pathways intact Neuropathic pain C entral or peripheral lesion or dyfunction of pain signaling pathway permits perception of pain in the absence of tissue damage

CONGRESO DE LA XXIII
SOCIEDAD ESPANOLA
DE NEUROClRUGiA SENEC
Oeciamos ayer, diremos manana
SALAMANCA
14-17 MAYO
2019
JOINT MEETING / REUNION CONJUNU

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Multidimensional Experience: neurophysiological, biochemistry, psychological, ethnic, cultural, religious, cognitive, afective and sociological. Multidisciplinary treatment

CONGRESO DE LA XXIII
SOCIEDAD ESPANOLA
DE NEUROCIRUGiA SENEC
Oeciamos ayer, diremos manana
SALAMANCA
14-17 MAYO
2019
JOINT MEETING / REUNION CONJUNTA

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Nociceptive Pain Processing*
Transduction to Perception
Transduction
Perception
Modulation
Withdrawal
pain
Avoidance
Emotional
reaction
•The stimulus •s well localized. its durabon. intensity. and quality are cW.
Image courtesy of MedCom
Adapted from Schou J, Wood CJ, Nat Neurosci 1062-1067. Reprinted by perrnission from Macrnillan Publishers Ltd.

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Glutamate Aspartate Substance P  Cholecistokinine Calcitonine  VIP Galanine Neuropeptide

bombesin somatostatine neurokinin A e  B dinorphin enkephalines vasopressine cortrophine releasing factor oxitocin gastrin serotonin dopamine tirosine adenosine substance k

Central       IL-1b        COX-2  Prostaglandines Central sensitization

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Algogenic substances Bradikinin Protons 5-HT Histamine PGs, TBXs Adenosine, AMP, ADM, ATP Citokines  (IL-1β, TNFα, IL-6) NGF Endotelin 1 Opioids (endoteline ET B )

Receptors  Vaniloid (TRPV1)  Cholinergic  GABA-A  10-14% (↑) Somatostatine 10% (SSTR2A)

Stimuli   Thermal (hot or cold)  Mechanic  Chemical (inflammation, ischemia, drugs)

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CNS sensitization and synaptic reorganization

Sensitization Synaptic reorganization Desihibition

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Synaptic reoganization Synapsis reinforcement

P eripheral sensitization Central sensitization Neuronal desinhibition Synaptic reorganization

Continuous burning pain Sensitization of  nociceptors  Inhibitory control deficit   Ectopic activity in C fiber Synaptic reorganization

Paroxystic lancinating pain Ectopic activity    Allodynea

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Discrimination Temporospatial Intensity Localization Supression

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Brain regions related to the sensorial, cognitive and emocional aspects of pain

Apkarian AV et al. Eur J Pain. 2005;9:463-484.

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Glutamate   Aspartate  Acetilcholine  Histamine  Neurotensin  Adenosine  Vasopressine  Glicine

Frontal lobe Amygdala   Brain GABA Acetilcholine Dopamine Serotonine Noradrenaline Enkephalins 	 Thalamus Endorphins Brain stem   Enkephalins Noradrenaline  Substance P  Calcitonine D orsal horn Enkephalins GABA Serotonine Noradrenaline Somastostatine CGRP

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Emotional Cognitive Behavioral Spiritual Social Sensorial

Acute/ chronic    Nociceptive / neuropathic    Evoked by stimuli/ independent of stimuli  Hyperalgesia and allodynia

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Ativaqäo encefålica: capsaicina edor
Sl, SII, cingulado, insula, cortex frontal
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ladarola et al. 1998

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Peripheral mechanisms Abnormal nociceptor sensitivity Spontaneous neuronal activity Sprouting Altered growth factor/peptide expression Abnormal ion-channel expression  TRPs Na+ Ca++ Catecholamine sensitivity Axonal sprouting

Consequences of Peripheral Nerve Injury Relevant to Aetiology of Neuropathic Pain

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CNS impact of the denervaton
Synaptic reorganinöon
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CNS consequences of peripheral painful neuropathies

Continuous burning pain Se nsitization of  nociceptors  Inhibitory control deficit   Ectopic activity in C fiber

Paroxisms of pain Ectopic activity in C fiber Ectopic activity of CNS neurons Deficit of the inhibitory control

Allodynia Se nsitization of  nociceptors  Inhibitory control deficit   Synaptic reorganisation

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Reticularis
Thalamic n
Reticular
Nuclei
Parietal
cortex
Thalamic
transmission n.
Thalamic
Intralaminaris n.
Dorsal horn

VB thalamus 16.7%   Bogousslavky et al., 1988 Lateral medulla  25.0%   McGowan et al., 1997 Parietal lobe (subcortical) caudal insula / operculum) Schamahmann; Leifer, 1992   Lesion of spinothalamic cortical (thermal) pathways  Adas et al. 2001 Multiple   Bowsher, 1998

Loss of neo-spine-thalamic supression / paleo-spino-reticulo-thalamic    Leijon et al.,1989 Denervation hipersensibility  Loeser et al., 1968; Tasker, 1990 Neuroplasticity  Up regulation of excitatory receptors in spino-thalamo-cortical pathways   Bowsher et al, 1997 Imbalance glutamatergic/gabaergic activity   Canavero & Bonicalzi, 1998

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Clinical history, previous medical history and psychosocial history  Physical, muscleskeletal, psychological and functional evaluation Pain inventories: undimensional (numeric, VAS, physiological) , improvement, psychological impact, functional impacts, DLAs.... Intruments for evaluation of pain: QST, cold pressor test, laser evoked potential

Evaluation of the pain process Eletrophisiology Image: X-rays, fCT Scan, fNMR, fRadioisotope Laboratory: blood, urine, CSF, synovial fluid, abnormal collections, skin and nerve biópsies......

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Carbamazepine Phenitoin Lamotrigine Topiramate TCAs Mexiletine Lidocaine

Nadr and 5-HT  reuptake Na and 5HT blockers Endogenous opioids

Ca ++   	 Pregabalin 	Gabapentin 	Oxcarbazepine  	Topiramate  NMDA antagonists 	 	 Ketamine 	Dextrometorphan                                      Methadone

Analgesics and adjuvants used in treatment of neuropathic pain

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Functional neurosurgical treatment of pain

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Nucleus Nucleus Tract Tract  Tract  Tract

Cancer  pain   10% Nociceptive noncancer related pain ? Neuropathic pain  PNS pains idiopathic craniofacial pain (V, VII, IX neuralgias) 85% peripheral neuropathic pain (PHN)  ? Central pain myelopatic pain 10% enkephalic lesions pain  ? phanton limb pain 25% pain due to avulsion of plexus roots 25% Psychiatric abnormalities in pain patients

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Ablative neurosurgical procedures for treatment of pain

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euromo
u atlon
Cörtex motor
TsUb6kowa et al. 1991
Cåpsula interna
Mazars, Meriene e Cioloca 1973
Mazars etal. 1960, Whitek Sweet 1969
VPL-VPM
CM
oden et al. 1979—
Substäncia cinzenta periventricular
HosobuChi, Adams eunchitz 1977
Hipotålamo PM
Substäncia cinzenta periqüedutal mesencefålica
Richardson e Akil 19
Medula espinal
Shealey et al. 1967
Sistema nervoso periférico
Wall e Sweet 1967
A lesäo do trato de Lissauer e do corno posterior da substäncja cjnzenta da medula espinal e a estimulaqäo do Sistema nervoso central para o tratamento da dor por
desaferentaqäo. Tejxejra MJ 1990.

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Cases Immediate (%) Long term (%)   Plexus avulsion             50-75 0 -36 Thalamus (VPL-VPM) 33 - Phantom limb pain Thalamus - 25-50 Leminiscus medialis - 75 Capsula Interna - 50 Myelopaty  50 Cluster headache PM hypothalamus 60 40           Post-herpetic neuralgia  Thalamus (VPL-VPM) 33 - Thalamus (VPLVPM) 75 50

Motor cortex stimulation  Tsubokawa et al. 1991 Capsula interna   Mazars, Meriene e Cioloca 1973 VPL-VPM  Mazars et al. 1960, White e Sweet 1969 CM    Thoden et al. 1979 Periventricular gray    Hosobuchi, Adams e Linchitz 1977 PM hypothalamus Franzini et al. 2002           PGM            Richardson e Akil 1977

Deep brain stimulation improves less than 1/3 of central pain patients

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1800
-1810
-1820
-1830
1840
1850
1860
1870
-1880
-1890
-1900
1910
1920
-1930
-1940
950
1960
-1970
-1980
-1990
-2000

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Tsubokawa and Katayama (1988) : they started to study the effect of cortex stimulation in patients who suffered from thalamic pain They achieved better results with stimulation of the motor cortex than stimulation of the somatosensory one Their initial results were published in 1991 and 1993 (11 patients)

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Tasker (1992) and Meyerson (1993) reported their experience with motor cortex stimulation (MCS) Meyerson concluded that MCS was more useful for neuropathic trigeminal pain, principally those cases due to peripheral nerve injury

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Mechanism of action: Cortico-thalamic inhibition Cortico-cortical inhibition Placebo effect?

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2009 Jan 3; d0i: 10.1016/j.tor.2CU.07.027. Epub 2008 Jul 31.
Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid
system.
ELLE-II , Qal.e-CS, Eagang-B.L, Paccp!a cc, Teixeira MO, Giorqi R.
Author information
Abstract
Epidural motor codex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches.
Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying
mechanisms of pain control have not been clarified yet_ The aim of this study was to investigate the effects of epidural electrical MCS on the
nociceptive threshold of nawe rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping
accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were
evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated coltex, but no changes were
noticed in the ipsilateral paw. When the nociceptive test was repeated 15 min after cessation of electrical stimulation, the nociceptive threshold
returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally,
no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or
somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished
the increase in nociceptive threshold induced by MCS Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective
antinociceptive effect, which is mediated by opioids.

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Res_ 2012 Jun Epub 2012 Apr 21.
Epidural motor cortex stimulation suppresses somatosensory evoked potentials in the primary
somatosensory cortex of the rat.
R.J Lee HY, ct-,anq CW, KH, CC.
Department Of Anatomy. SCh001 Of Medicine, college of Medicine, Taipei Medical university, 250 wu-Hsing Street, Taipei City 10031 , Taiwan.
Abstract
Motor cortex stimulation (MCS) is a promising clinical procedure to help alleviate chronic pain. Animal models demonstrated that MCS is effective in
lessening nocifensive behaviors. The present study explored the effects of MCS on cortical somatosensory evoked potentials (SEPs) recorded at the
primary somatosensory cortex (Sl) of the rat. SEPs were evoked by electrical stimulation applied to the contralateral forepaws. Effects of different
intensities, frequencies, and durations of MCS were tested. MCS at 22V suppressed SEPs of the ipsilateral Sl. Suppression lasted 120 min at an
intensity of 5 V. The optimal frequency was 50 Hz, and the duration was 30s. In contrast, MCS did not affect SEPs recorded on the contralateral Sl.
Cortical stimulation out of the motor cortex did not induce a decrease in the ipsilateral SEPs. We also investigated involvement of the endogenous
opioid system in this inhibition of SEPS induced by MCS_ The opioid antagonist, naloxone (0.5 mg/kg), was administered 30 min before MCS-
Application of naloxone completely prevented the inhibitory effect of MCS on ipsilateral SEPs. These results demonstrate that MCS blocked the
transmission of somatosensory information to the primary somatosensory cortex, and this interference was mediated by the endogenous opioid
system. This inhibitory effect on sensory transmission induced by MCS may reflect its antinociceptive effect.

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Motor cortex stimulation inhibits thalamic sensory neurons and enhances activity
of PAG neurons: Possible pathways for antinociception
, Erich T. Fonoffbcl, Camila S. Dale b, Gerson Ballesterc, Manoel J. Teixeira c,
Rosana L Pagano
Luiz R.G. Brittoa
a Department of Physiology and Biophysics. Institute of Biomedical Sciences. University of .qo Paulo. SOO Paulo. Brazil
b l.atx»ratory of Neuromodulation and Experimental Pain. Hospital Sirio-l.ibanés. Såo Paulo, Brazil
Division Of Functional Neurosurgery. Institute Of Psychiatry. Hospital das Clinic-as. Department Of Neuroloo-'. University Of Såo Paulo, Sao Paulo. Brazil

ABSTRACT
Motor cortex stimulation is generally suggested as a therapy for patients with chronic and refractory neu-
ropathic pain. However, the mechanisms underlying its analgesic effects are still unknown. In a previous
study, we demonstrated that cortical stimulation increases the nociceptive threshold of naive conscious
rats with opioid participation. In the present study, we investigated the neurocircuitry involved during
the antinociception induced by transdural stimulation of motor cortex in naive rats considering that little
is known about the relation between motor cortex and analgesia. The neuronal activation patterns were
evaluated in the thalamic nuclei and midbrain periaqueductal gray. Neuronal inactivation in reslx»nse to
motor cortex stimulation was detected in thalamic sites both in terms of immunolabeling (Zif268/Fos)
and in the neuronal firing rates in ventral posterolateral nuclei and centromedian-parafascicular thalamic
complex. This effect was particularly visible for neurons responsive to nociceptive peripheral stimulation.
Furthermore. motor cortex stimulation enhanced neuronal firing rate and Fos immunoreactivity in the
ipsilateral periaqueductal gray. We have also observed a decreased Zif268, CS-aminobutyric acid (GABA).
and glutamic acid decarboxylase expression within the same region, suggesting an inhibition of GABAer-
gic interneurons of the midbrain periaqueductal gray, consequently activating neurons responsible for
the descending pain inhibitory control system. Taken together, the present findings suggest that inhibi-
tion of thalamic sensory neurons and disinhibition of the neurons in periaqueductal gray are at least in
part responsible for the motor cortex stimulation-induced antinociception.
@ 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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Thalamic pain Neuropathic trigeminal pain Brachial plexus avulsion (better for continuous than paroxysmal pain) Neuropathic pain due to spinal cord injury When less invasive neuromodulation techniques (as SCS) fail or its effects are lost over time (treatment of peripheral sources of pain)

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MRI
Axial
120
115
110
10 15
55 60 65 : 70 85. 1
10 115 120

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Transcraneal Magnetic Stimulation
(TMS)
Electrical field induction
(non invasive)
Motor areas: Motor evoked
potentials (MEP)
Speech areas

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TMS:
Brain Mapping
Language mapping
Sollmann et al. The impact of language mapping by repetitive navigated
transcranial magnetic stimulation on the clinical course of brain tumor panents. 8MC
Cancer. 1-8.

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