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

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 –

Baliki MN, et al. J Neurosci. 2006;21:12165 – Chronic back pain has transient and sustained components

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

Attention to pain Distraction from pain Bushnell et al 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: , 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 M1M1 S1S1 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 pain Gray 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 Cortical thickness Ceko et al 2010

Life-style related differences in cortical thickness Villemure, Cotton, Č eko & 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 patients Fibromyalgia patients Gray matter reduction related to duration of symptoms Apkarian AV, et al. J Neurosci. 2004;24:10410 – 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-treatmentpost-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, Neuropathic rats followed for five months

Anxiety increases later than hyperalgesia Seminowicz DA, et al., Neuroimage, von Frey test Log(50% von Frey threshold (g)) Time post-surgery (weeks) Sham SNI Mechanical hyperalgesia Elevated plus maze Number of exits from closed arms ShamSNI Time post-surgery (weeks) * * Anxiety behavior

Reduced PFC thickness in SNI rat Seminowicz DA, et al., Neuroimage Mean relative voxel size Time post-surgery (weeks) Sham SNI * *

PET imaging shows that some chronic pain patients have disruptions of forebrain 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.

Post GP Left Post Put Left Post CN Left V Striatum Ant GP Left Ant CN Left Change in Binding Potential (%) 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 controlsFibromyalgia 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