Paul Wacnik PhD

paul.w.wacnik@medtronic.com

Principal Scientist

Medtronic Neuromodulation Research

Boston, MA paul.w.wacnik@medtronic.com

June 14, 2013

Spinal Cord Stimulation: Basic Science Highlights

3rd international conference on interventional pain

medicine & neuromodulation

Warsaw, 14-16 June 2013

B. Linderoth and B.A.

Meyerson; Anesthesiology,

2010

Activation of descending

inhibition

Effect on higher brain areas

Local Spinal Segment Peripheral

Nerve Effects 1 2

3

4

Activation of large diameter sensory fibers

• Increased vasodilation via VR-1 containing (C-fiber) afferents (Wu et al., 2006)

• Reduces vascular tone via increased peripheral CGRP (Tanaka et al., 2004 and Croom et al., 1996)

• Activate descending inhibition: releasing inhibitory neurotransmitters (for example, serotonin) into the spinal cord and mediated by spinal serotonin 5HT 2A, 3, and 4 receptors (Song et al., 2011)

• Increasing spinal Ach and mediated by M(4) receptors (Schechtmann et al., 2008)

• Opioid involvement in spinal cord (Sato et al., 2012)

• Activating interneurons (GABA) and decreasing glutamate (Cui et al., 1997)

• Inhibition of spinal neurons SCS (WDR) (Yakhnitsa et al., 1999, Guan et al., 2010)

• SCS alters cortical excitability (Schlaier et al.,

2007)

• SCS increases activation of sensorimotor

cortex and insula. Paralimbic activation with

heat pain. (Stancak et al., 2007)

• Deactivation on bilateral medial thalamus and

its connections to the rostral and caudal

cingulate cortex (Moens et al., 2012)

Agenda • SCS Mechanisms and Parameters

Goal: identify mechanisms linked to frequency.

• SCS intensity-response

Goal: Is there an intensity-dependent inhibition of the dorsal horn neuron activity

• Targeting: dorsal column vs. dorsal root stim

Goal: Is there an target-dependent inhibition

SCS Frequency (Rate)

• There is no specific SCS frequency

• Patients programmed to “feeling” of paresthesia and report of pain relief

• Usually around 60 Hz (+/- 40 Hz) for back pain

• Available range in devices 2 – 1.2kHz and 10kHz

• What is the research around frequency and SCS?

Frequency Impact on Mechanism

Hypothesize that different rates engage preferred neural mechanisms. Depending on the pain mechanism or patient’s physiology, one rate may be better than another.

• Frequency 1 Mechanism 1 –pain type Outcome

• Frequency 2 Mechanism 2 –pain type Outcome

• Frequency 3 Mechanism 3 –pain type Outcome

• Frequency 4 Mechanism 4 –pain type Outcome

Engage Preferred Neural Mechanisms

Depending on the pain mechanism or patient’s physiology, one rate may be better than another.

SCS Examples:

• 4 Hz Opioids (Sato et al, 2012) Pain relief

• 50 Hz Spinal GABA (Cui et al., 1997, 1998) Pain relief

• 500 Hz Peripheral Blood Flow (Goa et al, 2010) Pain relief

• 1000 Hz Conduction changes (Yang et al, 2013) Pain relief

Mechanism 1 + 2 + 3 + 4 > Analgesia

Low frequencies, but not high frequencies of bi-polar spinal cord stimulation reduce cutaneous and muscle hyperalgesia induced by nerve injury. Maeda et.al., Pain 2008

Spinal cord stimulation reduces hypersensitivity through activation of opioid receptors in a frequency-dependent manner K.L. Sato et.al., European Journal of Pain 2012

Effects of spinal cord stimulation with "standard clinical" and higher frequencies on peripheral blood flow in rats. Gao et al., Brain Research 2010

Data Examples: Frequency Research

High Frequency: Neuromodulation vs. Block Neuromodulation

• SCS and PNS relies primarily on activation of large Aβ-

afferent fibers in the dorsal column (DC) • Aβ-afferent fibers activate- spinal, supra spinal and

peripheral mechanisms

HF Blocking Stim Literature:

• Peripheral Nervous system • High amplitude stimulation

Guan et al., 2012

Bhadra, 2005

1. Neurons fire before being blocked

2. If the amplitude is not high enough,

neurons fire asynchronously

3. When the amplitude is high enough,

neurons are blocked

Neuropathic Injury Model (SNL):

The spinal nerve ligation model

SCS Conditioning stimulation (CS): ~0.2 mA

Spinal dorsal horn recording (CS off):

In vivo extracellular single unit recordings of wide-dynamic-range (WDR) neurons in spinal segment L4.

WDR Neurons:

• Spinal, supra spinal and peripheral C and Ab-d axons convergence

• Encode-noxious stimuli, sensitized after nerve injury

• Large receptive field input

WDR

CS:DC

Guan et al, Anesthesiology 2010; 113:1392–1405

SNL

CS:DR

Stimulation targeting and intensity

Spontaneous activity (SA) of a typical WDR neuron from a neuropathic animal; pre- and post-DC 50Hz (Ab fiber strength 0.2mA)

5

10

0

Sp

on

tan

eou

s a

ctivity (A

Ps)

15

15 min pre-CS 0-45 min post-CS

Do

rsa

l co

lum

n stim

ula

tio

n (

5 m

in)

5 min

CS

SA: Underlies spontaneous pain

Contributes to development and maintenance of central sensitization

Guan et al, Anesthesiology 2010; 113:1392–1405

Dorsal column and dorsal root conditioning stimuli inhibit the spontaneous activity of WDR neurons in neuropathic rats

Sham D14-16

Sp

on

tan

eou

s a

ctivity (

AP

s/m

in)

Pre-CS

0-15 min post-CS

30-45 min post-CS

Dorsal root stimulation

~.025 to 0.08 mA

0

100

200

300

400

*

#

0

100

200

300

400

*

#

Sp

on

tan

eou

s a

ctivity (

AP

s/m

in)

Dorsal column stimulation

(~0.15 to 0.20 mA

Sham D14-16

Guan et al, Anesthesiology 2010; 113:1392–1405

WDR neuron response to graded punctate mechanical stimuli

Mechanical sensitivity is an important expression of neuropathic pain.

0

0.6 1 2 4 8 10 15 26 Force (g)

0

10

Pre-CS

0-15 min post-CS

30-45 min post-CS

Re

sp

on

se

(A

Ps)

10

20

0 20

10

20

Guan et al, Anesthesiology 2010; 113:1392–1405

DC and DR attenuated the mechanical responses of WDR neurons

Guan et al, Anesthesiology 2010; 113:1392–1405

Extended carry-over

with Dorsal root Stim

Intensity-response

• Patients programmed to at strong but comfortable paresthesia

• Experience shows greater pain relief at higher intensities

• Is there a scientific evidence showing the effects of amplitude

-2

0

2

1 18 35 52 69 86 103 120 137 154 171 188 205 222 239 256 273 290 307 324

-2

0

2

1 18 35 52 69 86 103 120 137 154 171 188 205 222 239 256 273 290 307 324

-2

0

2

1 18 35 52 69 86 103 120 137 154 171 188 205 222 239 256 273 290 307 324

Latency 5 msec

Ab0

Threshold-

Ab1

Peak-

0.02 mA

0.10 mA

0.01 mA

Am

plit

ud

e (

mV

) A

mp

litu

de

(m

V)

Am

plit

ud

e (

mV

)

DC conditioning

stimulus intensity or

”Dose Response”

Determined by:

recording

antidromic (CAP)

at the sciatic

nerve

½ Ab0-

½ (Ab+Ab1)-

2 xAb1 -

Ab Ad

Setting the stimulation intensity

Frequencies – Amplitudes – Targets • Amplitude titration. Is there evidence to guide how far

below “sub-perception” we be and still modulate neurons?

• Frequency titration. Does any evidence exist pointing to particular frequency mechanisms for optimal SCS therapy?

• Targeting. Can we optimize mechanisms by selecting the right target?

Summary of Translational SCS Studies:

• Neurophysiology and pharmacology provides a useful paradigm to help optimize stimulation outcomes and examine the neuronal mechanisms behind the effects of SCS.

THANK YOU FOR YOUR ATTENTION Acknowledgements:

Johns Hopkins University

Dept. of Anesthesiology: Srinivasa N. Raja M.D. Ronen Shechter M.D. Fei Yang Ph.D. Chi-yang Chung M.D. Alene F. Carteret M.S.

Dept. of Neurosurgery:

Richard A. Meyer M.S.