Imaging Pain: From Research to Clinical
Application
M. CATHERINE BUSHNELL
MCGILL 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
Imaging reveals sensory and limbic regions
activated by pain
S1
S2
ACC
ACC: Anterior cingulate cortex; IC: Insular cortex.
Apkarian A, et al. Eur J Pain. 2005;9:463–485.
IC
Sensory and limbic regions have different
roles in pain processing
Pain affect without “pain sensation” in
patient with postcentral lesion
Ploner et al. 1999
Imaging shows that the pain network
activated by many types of pain
Chronic pain
can be
associated
with changes
in pain
processing.
Frida Kahlo
In chronic pain patients the pain network can
be activated by tactile stimuli (allodynia)
Post-herpetic
neuralgia
Diabetic
neuropathy
Back pain
Tactile allodynia related to neuropathic pain reflected in the brain
Hofbauer RK, et al. Clin J Pain. 2006;22:104–108.
Chronic pain can alter brain resting state activity
Control DMN
Patient DMN
DMN Patient-Control
DMN = Default mode network.
Cauda F. PLoS ONE. 2009;4:e4542.
diabetic neuropathic pain
Hypersensitivity in “functional” pain syndromes
Vulvar vestibulitis
Pukall et al 2005
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
Measuring ongoing
chronic pain in MRI
scanner
Pain intensity = 10/10
Pain intensity = 0/10
MRI: Magnetic resonance imaging.
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.
Chronic back pain activates two brain circuits
Correlates of
increasing pain are
similar to acute pain
processing
Correlates of high
sustained pain
involve emotional
and cognitive regions
Baliki MN, et al. J Neurosci. 2006;21:12165–12173.
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
Modulates
Pain
Attention to pain
Distraction from pain
Bushnell et al. 1999
Emotions
alters pain
Mood alters pain-evoked activity in
limbic brain regions
Bad mood + Pain
Good mood + Pain
Anterior cingulate cortex
Villemure & Bushnell 2009
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
Major depressive disorder associated with
altered descending inhibition during pain
Strigo I et al, Arch Gen Psychiatry 65: 1275-1284, 2008.
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.
Decreased cortical thickness in IBS patients
Davis KD, et al. Neurology. 2008;70:153‒154. Epub 2007 Oct 24.
Gray matter decreases in regions
related to pain modulation may
lead to increased pain
M
1
Adapted from Price DD. Science. 2000;288:1769–1772.
S
1
Correlations with behavior
IS THERE A RELATIONSHIP BETWEEN
CHANGES IN GRAY MATTER AND
PERCEPTUAL AND/OR BEHAVIORAL
MEASURES?
Neuropathic
pain
Gray matter changes in
trigeminal neuropathic
pain correlated with
allodynia
Borsook et al PloS One 3:e3396, 2008
Cortical thickness
Disruption of working memory correlates with frontal
cortex thinning in fibromyalgia
ACT score
Ceko et al 2010
Life-style related differences in cortical thickness
Long-term yoga practitioners have increased pain tolerance and increased gray matter
Villemure, Cotton, Čeko & Bushnell, IASP 2010
Are gray matter changes cause
or effect?
Correlation with pain duration in crosssectional studies
Longitudinal studies
Gray matter reduction related to duration of
symptoms
Back pain patients
Apkarian AV, et al. J Neurosci. 2004;24:10410–10415.
Fibromyalgia patients
Kuchinad A, et al. J Neurosci. 2007;404:1104–1107.
Longitudinal Studies
Treating Chronic Low Back Pain Reverses
Structural Brain Changes
DAVID A. SEMINOWICZ, TIMOTHY H.
WIDEMAN, LINA NASO, ZEINAB HATAMIKHOROUSHAHI, SUMMAYA FALLATAH,
MARK WARE, PETER JARZEM, YORAM SHIR,
JEAN A. OUELLET, M. CATHERINE
BUSHNELL, AND LAURA S. STONE
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
Neuropathic
rats
followed for
five months
EPM: Elevated plus-maze; MRI: Magnetic resonance imaging; SNI: Spared nerve injury.
Seminowicz DA, et al., Neuroimage, 2009.
Anxiety increases later than hyperalgesia
Mechanical
hyperalgesia
Anxiety behavior
von Frey test
Elevated plus maze
Log(50% von Frey
threshold (g))
SNI
Time post-surgery (weeks)
Seminowicz DA, et al., Neuroimage, 2009.
Number of exits from
closed arms
Sham
Sham
SNI
*
Time post-surgery (weeks)
*
Reduced PFC thickness in SNI rat
Mean relative voxel size
Sham
SNI
*
*
Time post-surgery (weeks)
Seminowicz DA, et al., Neuroimage 2009.
PET imaging shows that some chronic
pain patients have disruptions of
forebrain neurotransmitter systems
Tracey and Bushnell J. Pain 2008 (review)
NACC
AMYG
dACC
Fibromyalgia patients
have reduced
µ-opioid binding
potential in pain-related
brain regions
AMYG = Amygdala; dACC = Dorsal anterior cingulate; NACC = Nucleus accumbens.
Harris RE, et al. J Neurosci. 2007;27:1000–1006.
Fibromyalgia patients have reduced basal ganglia
dopamine release in response to muscle pain
Change in Binding Potential (%)
3525-
Healthy controls
*
*
*
Fibromyalgia patients
*
*
*
1555-
*p<0.001
-15-25-35-
Ant CN
Left
V Striatum
Ant GP
Left
Post CN
Left
Post Put
Left
Ant=Anterior; CN=Caudate nucleus; GP=Globus pallidus; Post=Posterior; Put: Putamen.
Adapted from: Wood PB, et al. Eur J Neurosci. 2007;25:3576–3582.
Post GP
Left
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