Imaging Pain: From Research to Clinical Application

M. CATHERINE BUSHNELLMCGILL UNIVERSITY

Brain imaging allows us to measure

neural basis of pain perception

Important technique for examining neural changes related to chronic pain

Brain imaging techniques used to study pain mechanisms

MRI: provides functional and anatomical information

PET: provides neurochemical information

Evoked Potentials: provides temporal information

ACC: Anterior cingulate cortex; IC: Insular

cortex. Apkarian A, et al. Eur J Pain.

2005;9:463–485.

S1 S2

ACC IC

Imaging reveals sensory and limbic regions activated by pain

Pain affect without “pain sensation” in patient with postcentral lesion

Sensory and limbic regions have different roles in pain processing

Ploner et al. 1999

Imaging shows that the pain network activated by many types of

pain

Frida Kahlo

Chronic pain can be associated with changes in pain processing.

Post-herpetic neuralgia

Diabetic neuropathy

Back pain

In chronic pain patients the pain network can be activated by tactile stimuli

(allodynia)

Tactile allodynia related to neuropathic pain reflected in the brain

Hofbauer RK, et al. Clin J Pain. 2006;22:104–108.

DMN = Default mode network.Cauda F. PLoS ONE. 2009;4:e4542.

Control DMN Patient DMN

DMN Patient-Control

Chronic pain can alter brain resting state activity

diabetic neuropathic pain

Hypersensitivity in “functional” pain syndromes

Pukall et al 2005

Vulvar vestibulitis

Increased stimulus-evoked brain activation to light touch in vulvar

vestibulitis

Pukall CF, et al. Pain. 2005;115:118–127.

Hypersensitivity in fibromyalgia

Wood et al, Eur. J. Pain 2007

Increased activation to pressure in fibromyalgia

Gracely et al 2002

Pain intensity = 0/10

Pain intensity = 10/10

Measuring ongoing chronic pain in MRI

scanner

MRI: Magnetic resonance imaging. Baliki MN, et al. J Neurosci. 2006;21:12165–12173.

Baliki MN, et al. J Neurosci. 2006;21:12165–12173.

Chronic back pain has transient and sustained

components

Baliki MN, et al. J Neurosci. 2006;21:12165–12173.

Correlates of increasing pain are similar to acute pain processing

Correlates of high sustained pain involve emotional and cognitive regions

Chronic back pain activates two brain circuits

Imaging shows that some cortical regions are involved in descending pain modulation

Descending modulation of pain

Information from cortex ultimately received in spinal cord

Schweinhardt and Bushnell, J. Clin. Investigation, in press

Psychological factors modulate pain via these descending modulatory pathways

Emotions Attention

Attention to pain

Distraction from pain

Bushnell et al. 1999

Attention Modulates Pain

Emotions alters pain

Mood alters pain-evoked activity in limbic brain regions

Villemure & Bushnell 2009

Bad mood + Pain Good mood + Pain

Anterior cingulate cortex

Attention and emotion activate different modulatory circuitry in brain

Villemure & Schweinhart 2010

Attentional focussing and/or negative emotional states can

contribute to chronic pain states

Strigo I et al, Arch Gen Psychiatry 65: 1275-1284, 2008.

Major depressive disorder associated with altered descending inhibition

during pain

Imaging has revealed that chronic pain patients have changes in brain grey matter that might reflect changes in pain modulation

Tracey and Bushnell J. Pain 2008 (review)

Gray matter decreased first shown by Apkarian in back pain patients

Apkarian AV, et al. J Neurosci. 2004;24:10410–10415.

Similar findings with multiple chronic pain conditions

Gray matter decreases in chronic tension-type

headache

Schmidt-Wilcke T, et al. Neurology. 2005;66:1483–1486.

Gray matter decreases in fibromyalgia

Kuchinad A, et al. J Neurosci. 2007;404:1104–1107.

Davis KD, et al. Neurology. 2008;70:153‒154. Epub 2007 Oct 24.

Decreased cortical thickness in IBS patients

Gray matter decreases in regions related to pain modulation may lead to

increased pain

M1

S1

Adapted from Price DD. Science. 2000;288:1769–1772.

IS THERE A RELATIONSHIP BETWEEN CHANGES IN GRAY MATTER AND PERCEPTUAL AND/OR

BEHAVIORAL MEASURES?

Correlations with behavior

Neuropathic painGray matter changes in trigeminal neuropathic pain correlated with allodynia

Borsook et al PloS One 3:e3396, 2008

Disruption of working memory correlates with frontal cortex thinning in fibromyalgia

ACT score

Cor

tica

l thi

ckne

ss

Ceko et al 2010

Life-style related differences in cortical thickness

Villemure, Cotton, Čeko & Bushnell, IASP 2010

Long-term yoga practitioners have increased pain tolerance and increased gray matter

Are gray matter changes cause or effect?

Longitudinal studies

Correlation with pain duration in cross-sectional studies

Back pain patientsBack pain patients Fibromyalgia patientsFibromyalgia patients

Gray matter reduction related to duration of symptoms

Apkarian AV, et al. J Neurosci. 2004;24:10410–10415. Kuchinad A, et al. J Neurosci. 2007;404:1104–1107.

DAVID A. SEMINOWICZ, TIMOTHY H. WIDEMAN, LINA NASO, ZEINAB HATAMI-KHOROUSHAHI,

SUMMAYA FALLATAH, MARK WARE, PETER JARZEM, YORAM SHIR,

JEAN A. OUELLET, M. CATHERINE BUSHNELL, AND LAURA S. STONE

Treating Chronic Low Back Pain Reverses Structural Brain Changes

Longitudinal Studies

Cortical thinning in back pain reversed by treatment

pre-treatment post-treatment

Seminowicz et al 2010

Thicker DLPFC post-treatment

Seminowicz et al 2010

Less pain thicker DLPFC

Seminowicz et al 2010

Rodent imaging longitudinal studies

EPM: Elevated plus-maze; MRI: Magnetic resonance imaging; SNI: Spared nerve injury.Seminowicz DA, et al., Neuroimage, 2009.

Neuropathic rats followed for five months

Anxiety increases later than hyperalgesia

Seminowicz DA, et al., Neuroimage, 2009.

von Frey test

Log

(50%

von

Fre

y th

resh

old

(g))

Time post-surgery (weeks)

Sham

SNI

Mechanical hyperalgesia

Elevated plus maze

Num

ber

of

exits

fro

m

clos

ed a

rms

Sham SNI

Time post-surgery (weeks)

**

Anxiety behavior

Reduced PFC thickness in SNI rat

Seminowicz DA, et al., Neuroimage 2009.

Mea

n re

lativ

e vo

xel s

ize

Time post-surgery (weeks)

Sham

SNI*

*

PET imaging shows that some chronic pain patients have

disruptions offorebrain neurotransmitter systems

Tracey and Bushnell J. Pain 2008 (review)

Fibromyalgia patients have

reduced µ-opioid binding potential in pain-

related brain regions

NACC

AMYG

dACC

AMYG = Amygdala; dACC = Dorsal anterior cingulate; NACC = Nucleus accumbens.Harris RE, et al. J Neurosci. 2007;27:1000–1006.

35-

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Left

Post Put Left

Post CN Left

V Striatum

Ant GP Left

Ant CN LeftC

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Pote

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(%)

Adapted from: Wood PB, et al. Eur J Neurosci. 2007;25:3576–3582.

Ant=Anterior; CN=Caudate nucleus; GP=Globus pallidus; Post=Posterior; Put: Putamen.

Fibromyalgia patients have reduced basal ganglia dopamine release in response to

muscle pain

Healthy controls Fibromyalgia patients

*p<0.001

*

**

***

Brain imaging has revealed:

Distinct neural signature for pain that includes sensory and limbic regions of the brain

Chronic patients can have altered pain transmission and modulation

Chronic pain involves more emotional and cognitive processing than does acute pain

Long-term pain can alter brain anatomy and chemistry and associated emotions and cognitive function