INTERNATIONAL NEUROMODULATION SOCIETY 9TH WORLD CONGRESS
SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
Robert D. Foreman University of Oklahoma Health Sciences Center Department of Physiology Oklahoma City, Oklahoma USA
11-15 SEPTEMBER 2009 SEOUL, SOUTH KOREA
SF Hobbs, Uhtaek Oh, TJ Professor Emeritus Brennan, MJ Chandler, Hanyang University Kee Soon Kim, and RD College of Medicine Foreman. Urinary bladder and hindlimb stimuli inhibit Department of Physiology T1-T6 spinal and spino- Seoul reticular cells. Am. J. Physiol. 258: R10-R20, 1990 Uhtaek Oh, Ph.D. 1987 University of Oklahoma Health Sciences Center Department of Physiology SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary HEART PAIN CAN RADIATE TO THE JAW, TEETH, AND NECK UPPER CERVICAL SPINAL CORD STIMULATION (SCS) UNSTABLE ANGINA PECTORIS IN HUMANS
Stimulation Parameters: intensity
• “migration of pain” particularly to the neck, jaws, and temples C5/C6
• pain appears on exertion
• disappears after nitroglycerin C7/C8
• pain relieved by injecting mandibular nerve with procaine Foreman T1-T5 • most likely pathway-vagus Ann. Rev. Physiol.61, 1999 SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary NEURAL MECHANISMS UNDERLYING ANGINA PECTORIS Does Cardiac Input Excite C1/C2 STT Cells Via the Vagus?
Thalamus CL VPLc CM-Pf VPM VPMpcVPI ??? NTS
Medulla
Vagus C1/C2
C5/C6
C7/C8
Foreman Ann. Rev. Physiol.61, 1999 T1-T5 VAGAL INNERVATION OF THE C1/C2 SPINAL CORD
Nucleus < Tractus Solitarius
< < C1/C2 EFFECTS OF VAGAL STIMULATION ON ACTIVITY OF STT CELLS AT DIFFERENT SPINAL SEGMENTS
Intact Ipsilateral Vagus Vagotomy 40 Thalamus CL VPLc 20 CM-Pf
NTS Rate (imp/s) 0 Medulla IC Saline Algesic Algesic Heart Chemicals Chemicals C1/C2 Heart Heart
C5/C6
C7/C8
T1-T5
Foreman Ann. Rev. Physiol.61, 1999 NEURAL MECHANISMS UNDERLYING ANGINA PECTORIS Cardiac Input Excites C1/C2 STT Cells Via the Vagus
Thalamus CL VPLc CM-Pf VPM VPMpcVPI NTS
Medulla
Vagus C1/C2
C5/C6
C7/C8
Foreman Ann. Rev. Physiol.61, 1999 T1-T5 SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary DO NEURAL NETWORKS OF C1/C2 SEGMENTS MODULATE NOXIOUS CARDIAC INPUT?
C1/C2 ??
T3/T4 Spinal integration
Cardiac afferents EXPERIMENTAL SETUP RECORDINGS FROM T3/T4 SPINAL NEURONS CHEMICAL STIMULATION OF C1/C2
Spike 3 Data acquisition and Oscilloscope & analysis Audio amplifier
Microelectrode A B
C
A, Glutamate (activates cell bodies but not axons) pledget on C1/C2 segments; B, cell recording at T3/T4 segments; C, pericardial sac EFFECTS OF C1/C2 GLUTAMATE ON T3 SPINAL NEURON RESPONSES INTRAPERICARDIAL BRADYKININ BEFORE ROSTRAL C1 TRANSECTION
SpontaneousSpontaneous Activity Activity (imp/s) (imp/s) TotalTotal Response Response (imp) (imp) DurationDuration of of Response Response (s) (s)
1414 18001800 160160 1600 140 1212 1600 140 14001400 10 120120 10 1200 1200 100 8 100 8 10001000 s 80 s 80
imps 800 imps imps/s 6 800
imps/s 6 6060 600600 44 40 400400 40 2 20 2 200200 20 00 00 00
Before Glutamate After Glutamate 60 MINUTES AFTER ROSTRAL C1 TRANSECTION
SpontaneousSpontaneous Activity Activity (imp/s) (imp/s) TotalTotal Response Response (imp) (imp) DurationDuration of of Response Response (s) (s)
2000 1616 2000 200200 18001800 180 1414 180 16001600 160160 1212 14001400 140140 10 10 12001200 120120
1000 s 100 88 1000 s 100 imps imps imps/s
imps/s 800 80 66 800 80 600 6060 4 600 4 40 400400 40 2 20 2 200200 20 0 00 00 0
Qin et al. Auton Neurosci 114: 11-116, 2004 NEURAL HIERARCHY ORIGINATES FROM C1-C2 SEGMENTS
Glutamate effects are preserved after rostral C1 spinal transections C1/C2 !
C1/C2 Propriospinal Pathway
T3/T4 Cardiac afferents
! Excitation Inhibition SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary NEURAL HIERARCHY ORIGINATING FROM C1/C2 SEGMENTS Does C1/C2 SCS Modulate Cardiac Input onto Spinal Neurons?
Spinal Cord Stimulation C1/C2 ! 90%MT, 200 us, 50 Hz ?
T3/T4 Cardiac afferents
! Excitation Inhibition
Spinal cord EXPERIMENTAL SETUP
Spike 3 Data acquisition and Oscilloscope & analysis Audio amplifier
Stimulator Microelectrode A
C1/C2 T1/T2
B
A, Cell recording at T3/T4 segments; B, Pericardial Sac
Qin et al., Neurosci Res. 2007 May;58(1):58-66. EFFECT OF C1/C2 SCS ON T3 NEURONAL RESPONSES TO BRADYKININ
A Control C1/C2 SCS on Recovery
20s 31 Keyboard 31 Keyboard 31 Keyboard 40 40 40 30 Rate 30 30 Histogra Histogra Histogra Events Events Events 20 5 20 5 20 5
10 10 10
(imp/s) 0 0 0 0 5.0 5.0 5.0 2.5 2.5 2.5 volt volt volt 4 rawtrace 0.0 4 rawtrace 0.0 4 rawtrace 0.0
-2.5 -2.5 -2.5 -5.0 IB -5.0 IB -5.0 IB
100 100 100
0 0 0 mmHg mmHg mmHg 2 UBD 2 UBD 2 UBD -100 -100 -100
-200 -200 -200
5.0 5.0 5.0
2.5 2.5 2.5 pedal pedal pedal 1 volt 0.0 1 volt 0.0 1 volt 0.0
-2.5 -2.5 -2.5
-5.0 -5.0 -5.0 B 220 240 260 280 300 320 340 360 380 400 420 440 460 480 500 520 540 560 580 600 1380 1400 1420 1440 1460 1480 1500 1520 1540 1560 1580 1600 1620 1640 1660 1680 1700 1720 1740 1760 2300 2320 2340 2360 2380 2400 2420 2440 2460 2480 2500 2520 2540 2560 2580 2600 2620 2640 2660 2680 Control s C8/T1 SCS on s Recovery s
20s 31 Keyboard 31 Keyboard 60 31 Keyboard 60 60 60 Rate 40 40 40 untitled 9 Events Histogra Events untitled 9 Events 5 20 20 20
(imp/s) 0 0 5.0 0 0 5.0 5.0 2.5 2.5 2.5 volt 4 rawtrace 0.0 rawtrace volt volt 4 rawtrace 0.0 4 0.0 -2.5 -2.5 -2.5 -5.0 IB IB -5.0 IB -5.0
200 200 200 mmHg 3 BP BP mmHg mmHg 3 BP 3 0 0 0
5.0 5.0 5.0 2.5 2.5 2.5 volt 1 pedal 0.0 volt pedal volt 1 pedal 0.0 1 0.0 -2.5 -2.5 -2.5 -5.0 -5.0 -5.0 960 980 1000 1020 1040 1060 1080 1100 1120 1140 1160 1180 1200 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 80 100 120 140 160 180 200 220 240 260 280 300 320 s IB – Intrapericardials Bradykinin—Algogenic Chemical s
Qin et al., Neurosci Res. 2007 May;58(1):58-66. NEURAL HIERARCHY ORGINATING FROM C1/C2 SEGMENTS
Spinal Cord Stimulation C1/C2 ! 90%MT, 200 us, 50 Hz
SCS depends the dorsal columns but not the propriospinal pathway
T3/T4 Cardiac afferents
! Excitation Inhibition
Spinal cord SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary NEURAL HIERARCHY ORIGINATING FROM C1/C2 SEGMENTS: DOES C1/C2 SCS MODULATE L6-S2 NEURONAL RESPONSES TO COLONIC DISTENSION?
Spinal Cord Stimulation C1/C2 ! 90%MT, 200 us, 50 Hz
L6-S2
Spinal cord ! Excitation Inhibition EXPERIMENTAL SETUP
Oscilloscope
Pen Discriminator writer
Stimulator Microelectrode A B
C2 L2
C
A, SCS on C1/C2 or L1/L2 segments; B, cell recording at L6-S2 segments; C, colorectal distention NEURAL HIERARCHY ORIGINATING FROM C1/C2 SEGMENTS
Spinal Cord Stimulation C1/C2 ! 90%MT, 200 us, 50 Hz
S1 Spinal Neuron Responses to SCS
31 Keyboard 31 Keyboard 31 Keyboard 31 Keyboard 20 20 20 20 20 15 Rate15 15 15 histogram Events histogram histogram Events Events Events 5 10 5 histogram 10 10 5 10 5 10 5 (imp/s)5 5 5 0 0 0 0 10 10 0 10 10
5 5 5 5 raw cell volts raw cell raw cell volts volts volts 4 4 raw cell CRD 60 4 60 4 60 60 0 0 0 0 (mmHg) -5 -5 -5 -5 5.0 5.0 5.0 5.0 2.5 2.5 2.5 SCS on C1-C2 2.5 emg volts emg emg volts volts volts 3 0.0 3 emg 0.0 3 0.0 3 0.0
-2.5 -2.5 -2.5 -2.5
-5.0 -5.0 -5.0 -5.0 300 300 300 300
200 200 200 200 torr bp bp bp torr torr bp 2 100 2 torr 100 2 100 2 100
0 0 0 0
-100 -100 -100 -100 5.0 5.0 5.0 5.0
2.5 2.5 2.5 2.5 marker volts marker marker volts volts marker 1 0.0 1 volts 0.0 1 0.0 1 0.0
-2.5 -2.5 -2.5 -2.5
-5.0 -5.0 -5.0 -5.0 1380 1400 14201660 14401680 14601700 14801720 15001740 15201760 15401780 15601800 15801820218016001840220016201860222016401880224016601900226016801920228017001940230017201960232021801740198023402200200023602220202023802240204024002260 24202280 24402300 24602320 24802340 25002360 25202380 25402400 25602420 2440 2460 2480 2500 2520 2540 2560 L6-S2 s s s s
Spinal cord ! Excitation Inhibition NEURAL HIERARCHY ORIGININATING FROM L5-S2 SEGMENTS
S1 Spinal Neuron Responses to SCS
31 Keyboard 31 Keyboard 31 Keyboard31 Keyboard 15 20 15 15 15
10 10 10 10 Events Events Events Events Rate5 histogram (imp/s) 10 5 histogram 5 histogram 5 histogram 5 5 5 5
0 0 0 0 10 0 10 10 10
5 5 5 5 raw cell raw cell raw cell raw cell CRD4 (mmHg)volts 604 volts 4 volts 604 volts 60 60 0 0 0 0
-5 -5 -5 -5 5.0 5.0 5.0 5.0
2.5 2.5 2.5 2.5 emg emg emg emg volts volts SCSvolts volts on 3 0.0 3 0.0 3 3 0.0 0.0
-2.5 -2.5 -2.5 -2.5 -5.0 -5.0 L2-L3-5.0 -5.0 300 300 300 300
200 200 200 200 bp bp bp bp 2 torr 100 2 torr 100 2 torr 2 100 torr 100
0 0 0 0
-100 -100 -100 -100 5.0 5.0 5.0 5.0
2.5 2.5 2.5 2.5 volts volts volts volts 1 marker 0.0 1 marker 0.0 1 marker 1 0.0marker 0.0
-2.5 -2.5 -2.5 -2.5
-5.0 -5.0 -5.0 -5.0 60 80 100 120 140 160 180 200 220 760240 780260 800280 820300 8402700320 86027202700340 88027402720360 90027602740380 92027802760400 94028002780420 96028202800 98028402820 100028602840 102028802860 104029002880 106029202900 108029402920 110029602940 112029802960 30002980 30203000 30403020 30603040 30803060 3080 s s s s
Spinal Cord Stimulation ! L1/L2 90%MT, 200 us, 50 Hz
L5-S2
Spinal cord ! Excitation Inhibition SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary SCS FOR TREATMENT OF CEREBRAL VASCULAR DISORDERS • Cerebral Ischemia • Ischemic Spastic Hemiparesis • Focal Cerebral Ischemia • Cerebral Vasospasm • Stroke • Ischemic Cerebral Edema • Postapoplectic Spastic Hemiplegia • Prolonged Coma • Persistent Vegetative State CERVICAL SPINAL CORD STIMULATION (cSCS) OF CEREBRAL BLOOD FLOW
Ventilator
C1-C2
Computer And A/D Converter Stimulator
Laser Doppler Stimulation Parameters: Flowmeter (50 Hz; 0.2 ms duration; 30%, 60% and 90% MT.
MT = Increase SCS current until neck muscles Yang, Farber, Wu & Foreman; Neuroscience (2008) 152: 950-958 clearly contract. LOCATION OF DOPPLER FLOW PROBES
30%,60%,90%MT SCS
bregma
3.0 mm posterior
Laser 3mm Doppler 4.0 mm Flow Probe lateral SUMMARY OF THE EFFECTS OF DORSAL COLUMN OR SPINAL TRANSECTIONS ON C1/C2 SCS-INDUCED CEREBRAL VASODILATION
A Before After 80 80 __ 60 60 __
40 CBF 40 °˜
20 % 20
0 0 C6/C7 cut C1/C2 IA i.t C1 DC cut C1 cut
B C6/C7 cut C1/C2 IA i.t C1 DC cut C1 cut 0 0 + -10 -10 +
-20 -20 CVR °˜
-30 % -30 __ _ -40 -40 IA it = Ibotenic Aciid intrathecal = disrupts cell bodies BUT not axons ARE CAPSAICIN-SENSITIVE (TRPV-1 Receptors) SENSORY NERVES INVOLVED IN SCS-INDUCED VASODILATION? ARE CAPSAICIN-SENSITIVE (TRPV-1 Receptors) SENSORY NERVES INVOLVED IN SCS-INDUCED VASODILATION? Experimental Setup
Resinferatoxin (RTX) (2 _g/kg i.v.) Vanilloid Receptor 20’-30’
RTX
SCS 30% 60% 90% 300% 30% 60% 90% 300% % MT
Resinferatoxin = Ultrapotent Capsaicin Agonist—desensitizes TRPV-1 containing sensory afferents in 15 minutes Fig. 4 SCS INDUCED CEREBRAL VASODILATION BEFORE AND AFTER C1/C2 INTRATHECAL (i.t.) OR INTRAVENOUS (i.v.) INJECTIONS OF RTX
A Before After
100
80 _
60
CBF 40 !
% 20
0 RTX i.t. RTX i.v.
B RTX i.t. RTX i.v. 0
-10
-20 CVR ! -30 % -40 _ Before After CONCLUSIONS
°Ò SCS-induced cortical vasodilation did not depend on C1/C2 cell bodies, but did depend on the dorsal columns.
°Ò SCS-induced cortical vasodilation or augmentation of cerebral blood flow involved transient receptor potential vanilloid type1 (TRPV1). SPINAL CORD MECHANISMS— VISCERAL: THE C1/C2 CONNECTION
• Introduction—Why C1/C2
• C1/C2 Spinothalamic Tract Cells, Vagus and the Heart
• C1/C2 Propriospinal Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Nociceptive Cardiac Input
• C1/C2 SCS Modulation of Colonic Input
• C1/C2 SCS Augmentation of Cerebral Blood Flow
• Summary SUMMARY
• Nociceptive Cardiac Input Excites C1/C2 STT Cells Via the Vagus • C1/C2 Neural Networks via a Propriospinal Pathway Modulate Noxious Cardiac Input to T3/T4 Spinal Neurons • C1/C2 SCS Modulates T3/T4 Neuronal Responses to Nociceptive Cardiac Input via dorsal columns • C1/C2 SCS Modulates L6-S2 Neuronal Responses to Nociceptive Colonic Input via dorsal columns • SCS-induced Cortical Vasodilation involved the dorsal columns and the transient receptor potential vanilloid type1 (TRPV1).