The anticipation of pain in patients with fibromyalgia and ...



Proposed journal section: Disorders of the Nervous SystemTitle: When the brain expects pain: Common neural responses to pain anticipation are related to clinical pain and distress in fibromyalgia and osteoarthritisAbbreviated title: Pain anticipation in fibromyalgia and osteoarthritisAuthors:(Corresponding author) Christopher A Brown, PhD. Research Associate, Human Pain Research Group, The University of Manchester, Manchester Academic Health Science Centre, Clinical Sciences Building, Salford Royal NHS Foundation Trust, Salford, M6 8HD, United KingdomEmail: christopher.brown@manchester.ac.ukTel: 0161 206 4528Wael El-Deredy, PhD. Senior Lecturer, School of Psychological Sciences, The University of Manchester, Zochonis Building, Brunswick Street, Manchester, M13 9PL, United Kingdom.Email: wael.el-deredy@manchester.ac.ukTel: 0161 275 2566Anthony KP Jones, MD. Professor of Neuro-Rheumatology, Human Pain Research Group, University of Manchester, Clinical Sciences Building, Salford Royal NHS Foundation Trust, Salford, M6 8HD, United KingdomEmail: anthony.jones@manchester.ac.ukTel: 0161 206 4266Number of pages: 33Number of figures: 2Number of tables: 3 Number of words: Abstract 239, Introduction 494, Discussion 1821, Whole manuscript 5895 (including abstract and figure legends).Keywords: Event-related potentials; electroencephalography; expectancy; chronic pain; human.AbstractSupra-spinal processes in humans can exert a top-down enhancing effect on nociceptive processing in the brain and spinal cord. Studies have begun to suggest such influences occur in conditions such as fibromyalgia (FM), but it is not clear if this is unique to FM pain or common to other forms of chronic pain, such as that associated with osteoarthritis (OA). We assessed top-down processes by measuring anticipatory evoked-potentials and their estimated sources, just prior (<500ms) to laser heat pain stimulation, between 16 patients with FM, 16 patients with OA and 15 healthy participants (HPs) using whole-brain Statistical Parametric Mapping. Clinical pain and psychological coping factors (pain catastrophizing, anxiety, and depression) were well matched between the patient groups such that these did not confound our comparisons between FM and OA patients. For the same level of heat pain, insula activity was significantly higher in FM than the other two groups during anticipation, and correlated with the intensity and extent of reported clinical pain. However, the same anticipatory insula activity also correlated with OA pain, and to the number of tender points across the two patient groups, suggesting common central mechanisms of tenderness. Activation in dorsolateral prefrontal cortex (DLPFC) was reduced during anticipation in the both patient groups, and was related to less effective psychological coping. Our findings suggest common neural correlates of pain and tenderness in FM and OA that are enhanced in FM but not unique to this condition. IntroductionFibromyalgia (FM) is characterized by chronic widespread pain and tenderness ADDIN REFMGR.CITE <Refman><Cite><Author>Wolfe</Author><Year>1990</Year><RecNum>2776</RecNum><IDText>The American College of Rheumatology 1990. Criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2776</Ref_ID><Title_Primary>The American College of Rheumatology 1990. Criteria for the classification of fibromyalgia. 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Conversely, it is often assumed that osteoarthritic (OA) pain arises solely from peripheral mechanisms in affected joints. Yet, in OA there is a poor relationship between radiographic evidence of joint damage and pain ADDIN REFMGR.CITE <Refman><Cite><Author>Bedson</Author><Year>2008</Year><RecNum>2809</RecNum><IDText>The discordance between clinical and radiographic knee osteoarthritis: A systematic search and summary of the literature</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2809</Ref_ID><Title_Primary>The discordance between clinical and radiographic knee osteoarthritis: A systematic search and summary of the literature</Title_Primary><Authors_Primary>Bedson,J.</Authors_Primary><Authors_Primary>Croft,P.R.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Osteoarthritis</Keywords><Reprint>Not in File</Reprint><Periodical>BMC Musculoskeletal Disorders</Periodical><Volume>9</Volume><Web_URL> name="System">BMC Musculoskeletal Disorders</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Bedson and Croft 2008). 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Pract. and Comm. Med., P.O. Box 1130 Blindern, 0317 Oslo, Norway</Address><Web_URL> name="System">International Journal of Rehabilitation Research</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Natvig et al 2000) and there is evidence of central sensitization ADDIN REFMGR.CITE <Refman><Cite><Author>Lee</Author><Year>2011</Year><RecNum>2876</RecNum><IDText>The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2876</Ref_ID><Title_Primary>The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia</Title_Primary><Authors_Primary>Lee,Yvonne</Authors_Primary><Authors_Primary>Nassikas,Nicholas</Authors_Primary><Authors_Primary>Clauw,Daniel</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Analgesics</Keywords><Keywords>arthritis</Keywords><Keywords>Central Nervous System</Keywords><Keywords>Central pain</Keywords><Keywords>Central sensitization</Keywords><Keywords>Chronic</Keywords><Keywords>chronic pain</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Ligands</Keywords><Keywords>Opioid</Keywords><Keywords>Opioids</Keywords><Keywords>Osteoarthritis</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Keywords>Rheumatoid</Keywords><Keywords>rheumatoid arthritis</Keywords><Keywords>Widespread</Keywords><Keywords>Widespread pain</Keywords><Reprint>Not in File</Reprint><Start_Page>211</Start_Page><Periodical>Arthritis Research &amp; Therapy</Periodical><Volume>13</Volume><Issue>2</Issue><Web_URL> name="System">Arthritis Research &amp; Therapy</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Lee et al 2011). 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Cord</Keywords><Keywords>Syndrome</Keywords><Reprint>Not in File</Reprint><Start_Page>259</Start_Page><End_Page>266</End_Page><Periodical>Curr Pain Headache Rep.</Periodical><Volume>6</Volume><Issue>4</Issue><Address>Division of Rheumatology and Clinical Immunology, University of Florida, PO Box 100221, Gainesville, FL 32610-0221, USA. staudrm@mail-cs.med.ufl.edu</Address><Web_URL>PM:12095460</Web_URL><ZZ_JournalFull><f name="System">Curr Pain Headache Rep.</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Price</Author><Year>2002</Year><RecNum>394</RecNum><IDText>Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>394</Ref_ID><Title_Primary>Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients</Title_Primary><Authors_Primary>Price,D.D.</Authors_Primary><Authors_Primary>Staud,R.</Authors_Primary><Authors_Primary>Robinson,M.E.</Authors_Primary><Authors_Primary>Mauderli,A.P.</Authors_Primary><Authors_Primary>Cannon,R.</Authors_Primary><Authors_Primary>Vierck,C.J.</Authors_Primary><Date_Primary>2002/9</Date_Primary><Keywords>administration &amp; dosage</Keywords><Keywords>Adult</Keywords><Keywords>Analgesics</Keywords><Keywords>Analgesics,Opioid</Keywords><Keywords>Cold</Keywords><Keywords>drug effects</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Fentanyl</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Heat</Keywords><Keywords>Human</Keywords><Keywords>Hyperalgesia</Keywords><Keywords>Middle Aged</Keywords><Keywords>Naloxone</Keywords><Keywords>Narcotic Antagonists</Keywords><Keywords>Nociceptors</Keywords><Keywords>Pain</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Placebos</Keywords><Keywords>Psychophysics</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Support,U.&apos;t,P.H.S.</Keywords><Keywords>surgery</Keywords><Reprint>Not in File</Reprint><Start_Page>49</Start_Page><End_Page>59</End_Page><Periodical>Pain</Periodical><Volume>99</Volume><Issue>1-2</Issue><Address>Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Box 100416, Gainesville, FL 32610-0416, USA. dprice@dental.ufl.edu</Address><Web_URL>PM:12237183</Web_URL><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Staud</Author><Year>2002</Year><RecNum>395</RecNum><IDText>Evidence of involvement of central neural mechanisms in generating fibromyalgia pain</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>395</Ref_ID><Title_Primary>Evidence of involvement of central neural mechanisms in generating fibromyalgia pain</Title_Primary><Authors_Primary>Staud,R.</Authors_Primary><Date_Primary>2002/8</Date_Primary><Keywords>Brain</Keywords><Keywords>Central Nervous System</Keywords><Keywords>Cytokines</Keywords><Keywords>Female</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Human</Keywords><Keywords>immunology</Keywords><Keywords>Male</Keywords><Keywords>metabolism</Keywords><Keywords>Neurons</Keywords><Keywords>Neuropeptides</Keywords><Keywords>Nociceptors</Keywords><Keywords>Pain</Keywords><Keywords>Pain Threshold</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>psychology</Keywords><Keywords>Sensitivity and Specificity</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>Spinal Cord</Keywords><Keywords>Synaptic Transmission</Keywords><Keywords>Syndrome</Keywords><Reprint>Not in File</Reprint><Start_Page>299</Start_Page><End_Page>305</End_Page><Periodical>Curr Rheumatol.Rep.</Periodical><Volume>4</Volume><Issue>4</Issue><Address>University of Florida, Division of Rheumatology and Clinical Immunology, PO Box 100221, Gainesville, FL 32610-0221, USA. staudrm@mail-cs.med.ufl.edu</Address><Web_URL>PM:12126581</Web_URL><ZZ_JournalFull><f name="System">Curr Rheumatol.Rep.</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Staud and Smitherman 2002;Price et al 2002;Staud 2002) and in diffuse noxious inhibitory controls ADDIN REFMGR.CITE <Refman><Cite><Author>Staud</Author><Year>2003</Year><RecNum>2781</RecNum><IDText>Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2781</Ref_ID><Title_Primary>Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients</Title_Primary><Authors_Primary>Staud,Roland</Authors_Primary><Authors_Primary>Robinson,Michael E.</Authors_Primary><Authors_Primary>Vierck Jr,Charles J.</Authors_Primary><Authors_Primary>Price,Donald D.</Authors_Primary><Date_Primary>2003/1</Date_Primary><Keywords>Diffuse noxious inhibitory controls</Keywords><Keywords>Female</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Male</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Keywords>Wind-up</Keywords><Reprint>Not in File</Reprint><Start_Page>167</Start_Page><End_Page>174</End_Page><Periodical>Pain</Periodical><Volume>101</Volume><Issue>1<f name="Symbol">G</f>&#xC7;&#xF4;2</Issue><Web_URL> name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Lautenbacher</Author><Year>1997</Year><RecNum>2782</RecNum><IDText>Possible deficiencies of pain modulation in fibromyalgia</IDText><MDL 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Brain-imaging has shown augmented responses to experimental pain stimuli compared with pain-free controls ADDIN REFMGR.CITE <Refman><Cite><Author>Gracely</Author><Year>2011</Year><RecNum>2783</RecNum><IDText>Neuroimaging of fibromyalgia</IDText><Prefix>for a review, see </Prefix><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2783</Ref_ID><Title_Primary>Neuroimaging of fibromyalgia</Title_Primary><Authors_Primary>Gracely,Richard H.</Authors_Primary><Authors_Primary>Ambrose,Kirsten R.</Authors_Primary><Date_Primary>2011/4</Date_Primary><Keywords>Basal or evoked brain activity</Keywords><Keywords>Cognitive function</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Influence of depression and catastrophising</Keywords><Keywords>neuroimaging</Keywords><Keywords>Pain augmentation</Keywords><Keywords>Pain inhibitory systems</Keywords><Reprint>Not in File</Reprint><Start_Page>271</Start_Page><End_Page>284</End_Page><Periodical>Best Practice &amp;amp; Research Clinical Rheumatology</Periodical><Volume>25</Volume><Issue>2</Issue><Web_URL> name="System">Best Practice &amp;amp; Research Clinical Rheumatology</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(for a review, see Gracely and Ambrose 2011) consistent with either central augmentation or lack of inhibition. FM is associated with psychological co-morbidities such as anxiety and depression ADDIN REFMGR.CITE <Refman><Cite><Author>Thieme</Author><Year>2004</Year><RecNum>2777</RecNum><IDText>Comorbid Depression and anxiety in fibromyalgia syndrome: Relationship to somatic and psychosocial variables</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2777</Ref_ID><Title_Primary>Comorbid Depression and anxiety in fibromyalgia syndrome: Relationship to somatic and psychosocial variables</Title_Primary><Authors_Primary>Thieme,K.</Authors_Primary><Authors_Primary>Turk,D.C.</Authors_Primary><Authors_Primary>Flor,H.</Authors_Primary><Date_Primary>2004</Date_Primary><Keywords>Anxiety</Keywords><Keywords>Depression</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Fibromyalgia syndrome</Keywords><Keywords>Psychosocial</Keywords><Keywords>Syndrome</Keywords><Reprint>Not in File</Reprint><Start_Page>837</Start_Page><End_Page>844</End_Page><Periodical>Psychosomatic Medicine</Periodical><Volume>66</Volume><Issue>6</Issue><Web_URL> name="System">Psychosomatic Medicine</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Thieme et al 2004), pain catastrophizing ADDIN REFMGR.CITE <Refman><Cite><Author>Hassett</Author><Year>2000</Year><RecNum>613</RecNum><IDText>The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>613</Ref_ID><Title_Primary>The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome</Title_Primary><Authors_Primary>Hassett,AL</Authors_Primary><Authors_Primary>Cone,JD</Authors_Primary><Authors_Primary>Patella,SJ</Authors_Primary><Authors_Primary>Sigal,LH</Authors_Primary><Date_Primary>2000</Date_Primary><Keywords>Depression</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Syndrome</Keywords><Reprint>In File</Reprint><Start_Page>2493</Start_Page><End_Page>2500</End_Page><Periodical>Arthritis.Rheum.</Periodical><Volume>43</Volume><Issue>11</Issue><ZZ_JournalStdAbbrev><f name="System">Arthritis.Rheum.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Hassett et al 2000), and cognitive impairments ADDIN REFMGR.CITE <Refman><Cite><Author>Baumstark</Author><Year>1993</Year><RecNum>2778</RecNum><IDText>Pain behavior predictors among fibromyalgia patients</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2778</Ref_ID><Title_Primary>Pain behavior predictors among fibromyalgia patients</Title_Primary><Authors_Primary>Baumstark,K.E.</Authors_Primary><Authors_Primary>Buckelew,S.P.</Authors_Primary><Authors_Primary>Sher,K.J.</Authors_Primary><Authors_Primary>Beck,N.</Authors_Primary><Authors_Primary>Buescher,K.L.</Authors_Primary><Authors_Primary>Hewett,J.</Authors_Primary><Authors_Primary>Crews,T.M.</Authors_Primary><Date_Primary>1993</Date_Primary><Keywords>Behavior</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Reprint>Not in File</Reprint><Start_Page>339</Start_Page><End_Page>346</End_Page><Periodical>Pain</Periodical><Volume>55</Volume><Issue>3</Issue><Web_URL> name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Baumstark et al 1993), which are, to an extent, shared in patients with OA ADDIN REFMGR.CITE <Refman><Cite><Author>Edwards</Author><Year>2011</Year><RecNum>2805</RecNum><IDText>Pain, catastrophizing, and depression in the rheumatic diseases</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2805</Ref_ID><Title_Primary>Pain, catastrophizing, and depression in the rheumatic diseases</Title_Primary><Authors_Primary>Edwards,R.R.</Authors_Primary><Authors_Primary>Calahan,C.</Authors_Primary><Authors_Primary>Mensing,G.</Authors_Primary><Authors_Primary>Smith,M.</Authors_Primary><Authors_Primary>Haythornthwaite,J.A.</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Depression</Keywords><Keywords>Pain</Keywords><Keywords>rheumatic disease</Keywords><Keywords>Rheumatic Diseases</Keywords><Reprint>Not in File</Reprint><Start_Page>216</Start_Page><End_Page>224</End_Page><Periodical>Nature Reviews Rheumatology</Periodical><Volume>7</Volume><Issue>4</Issue><Web_URL> name="System">Nature Reviews Rheumatology</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Edwards et al 2011). Pain catastrophizing has been associated with increased activity in brain areas related to anticipation of pain ADDIN REFMGR.CITE <Refman><Cite><Author>Gracely</Author><Year>2004</Year><RecNum>392</RecNum><IDText>Pain catastrophizing and neural responses to pain among persons with fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>392</Ref_ID><Title_Primary>Pain catastrophizing and neural responses to pain among persons with fibromyalgia</Title_Primary><Authors_Primary>Gracely,R.H.</Authors_Primary><Authors_Primary>Geisser,M.E.</Authors_Primary><Authors_Primary>Giesecke,T.</Authors_Primary><Authors_Primary>Grant,M.A.</Authors_Primary><Authors_Primary>Petzke,F.</Authors_Primary><Authors_Primary>Williams,D.A.</Authors_Primary><Authors_Primary>Clauw,D.J.</Authors_Primary><Date_Primary>2004/4</Date_Primary><Keywords>Amygdala</Keywords><Keywords>analysis</Keywords><Keywords>Association</Keywords><Keywords>Attention</Keywords><Keywords>Brain</Keywords><Keywords>Cerebellum</Keywords><Keywords>Depression</Keywords><Keywords>Drive</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>Pressure</Keywords><Keywords>Somatosensory Cortex</Keywords><Keywords>Thalamus</Keywords><Reprint>Not in File</Reprint><Start_Page>835</Start_Page><End_Page>843</End_Page><Periodical>Brain</Periodical><Volume>127</Volume><Issue>Pt 4</Issue><Address>University of Michigan Health System, Department of Internal Medicine, Division of Rheumatology, Chronic Pain and Fatigue Research Center, 24 Frank Lloyd Wright Drive, PO Box 385, Ann Arbor, MI 48106, USA. dclauw@med.umich.edu</Address><Web_URL>PM:14960499</Web_URL><ZZ_JournalFull><f name="System">Brain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gracely et al 2004). Both catastrophizing ADDIN REFMGR.CITE <Refman><Cite><Author>Seminowicz</Author><Year>2006</Year><RecNum>1991</RecNum><IDText>Cortical responses to pain in healthy individuals depends on pain catastrophizing</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1991</Ref_ID><Title_Primary>Cortical responses to pain in healthy individuals depends on pain catastrophizing</Title_Primary><Authors_Primary>Seminowicz,D.A.</Authors_Primary><Authors_Primary>Davis,K.D.</Authors_Primary><Date_Primary>2006/2</Date_Primary><Keywords>Adult</Keywords><Keywords>Anxiety</Keywords><Keywords>Arousal</Keywords><Keywords>article</Keywords><Keywords>Attention</Keywords><Keywords>Behavior</Keywords><Keywords>Cerebral Cortex</Keywords><Keywords>chronic pain</Keywords><Keywords>complications</Keywords><Keywords>Cues</Keywords><Keywords>Evoked Potentials,Somatosensory</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>model</Keywords><Keywords>Ontario</Keywords><Keywords>Pain</Keywords><Keywords>Pain Threshold</Keywords><Keywords>physiopathology</Keywords><Keywords>psychology</Keywords><Keywords>Reference Values</Keywords><Keywords>Research</Keywords><Keywords>Somatosensory Cortex</Keywords><Keywords>surgery</Keywords><Reprint>Not in File</Reprint><Start_Page>297</Start_Page><End_Page>306</End_Page><Periodical>Pain</Periodical><Volume>120</Volume><Issue>3</Issue><Address>Toronto Western Research Institute, University Health Network, Institute of Medical Science and Department of Surgery, University of Toronto, Toronto, Ontario, Canada</Address><Web_URL>PM:16427738</Web_URL><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Sullivan</Author><Year>2001</Year><RecNum>320</RecNum><IDText>Catastrophizing, depression and expectancies for pain and emotional distress</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>320</Ref_ID><Title_Primary>Catastrophizing, depression and expectancies for pain and emotional distress</Title_Primary><Authors_Primary>Sullivan,M.J.</Authors_Primary><Authors_Primary>Rodgers,W.M.</Authors_Primary><Authors_Primary>Kirsch,I.</Authors_Primary><Date_Primary>2001/3</Date_Primary><Keywords>Adult</Keywords><Keywords>Attitude to Health</Keywords><Keywords>Depression</Keywords><Keywords>etiology</Keywords><Keywords>Female</Keywords><Keywords>Human</Keywords><Keywords>Male</Keywords><Keywords>Pain</Keywords><Keywords>Pain Measurement</Keywords><Keywords>physiopathology</Keywords><Keywords>psychology</Keywords><Keywords>Stress,Psychological</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Reprint>Not in File</Reprint><Start_Page>147</Start_Page><End_Page>154</End_Page><Periodical>Pain</Periodical><Volume>91</Volume><Issue>1-2</Issue><Address>Department of Psychology, Dalhousie University, Nova Scotia B3H 4J1, Halifax, Canada. sully@is.dal.ca</Address><Web_URL>PM:11240087</Web_URL><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Sullivan et al 2001;Seminowicz and Davis 2006) and anticipation ADDIN REFMGR.CITE <Refman><Cite><Author>Koyama</Author><Year>2005</Year><RecNum>1916</RecNum><IDText>The subjective experience of pain: where expectations become reality</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1916</Ref_ID><Title_Primary>The subjective experience of pain: where expectations become reality</Title_Primary><Authors_Primary>Koyama,T.</Authors_Primary><Authors_Primary>McHaffie,J.G.</Authors_Primary><Authors_Primary>Laurienti,P.J.</Authors_Primary><Authors_Primary>Coghill,R.C.</Authors_Primary><Date_Primary>2005/9/6</Date_Primary><Keywords>Adult</Keywords><Keywords>article</Keywords><Keywords>Brain</Keywords><Keywords>Chronic Disease</Keywords><Keywords>clinical trial</Keywords><Keywords>Conditioning (Psychology)</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Pain</Keywords><Keywords>Pain Measurement</Keywords><Keywords>Pain Threshold</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>psychology</Keywords><Keywords>Research Support,N.I.H.,Extramural</Keywords><Keywords>Research Support,U.&apos;t,P.H.S.</Keywords><Keywords>Somatosensory Cortex</Keywords><Keywords>technique</Keywords><Keywords>Thalamus</Keywords><Reprint>Not in File</Reprint><Start_Page>12950</Start_Page><End_Page>12955</End_Page><Periodical>Proc.Natl.Acad.Sci.U.S A</Periodical><Volume>102</Volume><Issue>36</Issue><Address>Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1010, USA</Address><Web_URL>PM:16150703</Web_URL><ZZ_JournalFull><f name="System">Proc.Natl.Acad.Sci.U.S A</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2136</RecNum><IDText>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2136</Ref_ID><Title_Primary>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>Boyle,Y.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>Uncertainty</Keywords><Reprint>Not in File</Reprint><Start_Page>240</Start_Page><End_Page>250</End_Page><Periodical>Pain</Periodical><Volume>135</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2185</RecNum><IDText>Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2185</Ref_ID><Title_Primary>Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Reprint>Not in File</Reprint><Start_Page>324</Start_Page><End_Page>332</End_Page><Periodical>Pain</Periodical><Volume>139</Volume><Issue>2</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Koyama et al 2005;Brown et al 2008a;Brown et al 2008b) have been shown to augment pain and its neural processes. However, it is not clear whether supraspinal processing abnormalities are unique to patients with FM or are just related to psychological factors that can also occur in conditions such as OA. In this study we compared central processing of pain in groups of patients with OA and FM (comparable in clinical pain levels and catastrophizing) relative to pain-free controls. We used electroencephalography (EEG) with source estimation to measure the neural generators of anticipatory and pain-evoked responses to experimental acute laser pain. The high temporal resolution of EEG provides an advantage over types of neuroimaging that are reliant on slow haemodynamic responses or blood flow. Previously, we showed in a healthy population ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2136</RecNum><IDText>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2136</Ref_ID><Title_Primary>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>Boyle,Y.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>Uncertainty</Keywords><Reprint>Not in File</Reprint><Start_Page>240</Start_Page><End_Page>250</End_Page><Periodical>Pain</Periodical><Volume>135</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown et al 2008a) and in patients with musculoskeletal pain ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2013</Year><RecNum>2726</RecNum><IDText>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2726</Ref_ID><Title_Primary>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Jones,A.K.P</Authors_Primary><Date_Primary>2013</Date_Primary><Keywords>Patients</Keywords><Keywords>Musculoskeletal</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>233</Start_Page><End_Page>244</End_Page><Periodical>Clinical Journal of Pain</Periodical><Volume>29</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Clinical Journal of Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown and Jones 2013) that ‘late’ anticipatory responses, within half a second prior to pain onset, can be reliably localized to pain processing regions. These localized responses correlate with expectancy and pain ratings ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2185</RecNum><IDText>Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2185</Ref_ID><Title_Primary>Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Reprint>Not in File</Reprint><Start_Page>324</Start_Page><End_Page>332</End_Page><Periodical>Pain</Periodical><Volume>139</Volume><Issue>2</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown et al 2008b) and provide unique picture of the brain state in preparation for pain. In the present study we hypothesized that FM and OA pain would be associated with common abnormalities in anticipatory neural networks, suggesting shared top-down influences on pain, in brain regions known to activate during pain anticipation and be modified by a psychosocial intervention (insular, mid-cingulate and dorsolateral prefrontal cortices) ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2013</Year><RecNum>2726</RecNum><IDText>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2726</Ref_ID><Title_Primary>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Jones,A.K.P</Authors_Primary><Date_Primary>2013</Date_Primary><Keywords>Patients</Keywords><Keywords>Musculoskeletal</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>233</Start_Page><End_Page>244</End_Page><Periodical>Clinical Journal of Pain</Periodical><Volume>29</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Clinical Journal of Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown and Jones 2013). Materials and MethodsThe research study was approved by Salford Local Research Ethics Committee in the United Kingdom. The study conforms with the Code of Ethics of the World Medical Association (Declaration of Helsinki). 47 right-handed participants were recruited. All subjects gave written informed consent to take part in the study. 16 patients had a diagnosis of fibromyalgia (FM, age 48.6 ± 8.6 (mean ± SD)), 16 of osteoarthritis (OA, age 54.3 ± 9.8), and 15 were pain-free healthy participants (HP, age 46.3 ± 7.3). The gender of the participants was well matched, with only one male in each of the FM and HP groups and two in the OA group. Age was significantly different between patient groups, and age was therefore used as a nuisance variable for all statistical analyses. FM and OA patients fulfilled the American College of Rheumatology (ACR) criteria for the diagnosis of FM ADDIN REFMGR.CITE <Refman><Cite><Author>Wolfe</Author><Year>1990</Year><RecNum>1385</RecNum><IDText>The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1385</Ref_ID><Title_Primary>The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee</Title_Primary><Authors_Primary>Wolfe,F.</Authors_Primary><Authors_Primary>Smythe,H.A.</Authors_Primary><Authors_Primary>Yunus,M.B.</Authors_Primary><Authors_Primary>Bennett,R.M.</Authors_Primary><Authors_Primary>Bombardier,C.</Authors_Primary><Authors_Primary>Goldenberg,D.L.</Authors_Primary><Authors_Primary>Tugwell,P.</Authors_Primary><Authors_Primary>Campbell,S.M.</Authors_Primary><Authors_Primary>Abeles,M.</Authors_Primary><Authors_Primary>Clark,P.</Authors_Primary><Authors_Primary>Fam,A.G.</Authors_Primary><Authors_Primary>Farber,S.J.</Authors_Primary><Authors_Primary>Fiechtner,J.J.</Authors_Primary><Authors_Primary>Franklin,C.M.</Authors_Primary><Authors_Primary>Gatter,R.A.</Authors_Primary><Authors_Primary>Hamaty,D.</Authors_Primary><Authors_Primary>Lessard,J.</Authors_Primary><Authors_Primary>Lichtbroun,A.S.</Authors_Primary><Authors_Primary>Masi,A.T.</Authors_Primary><Authors_Primary>McCain,G.A.</Authors_Primary><Authors_Primary>Reynolds,W.J.</Authors_Primary><Authors_Primary>Romano,T.J.</Authors_Primary><Authors_Primary>Russel,I.J.</Authors_Primary><Authors_Primary>Sheon,R.P.</Authors_Primary><Date_Primary>1990</Date_Primary><Keywords>FIBROMYALGIA</Keywords><Reprint>Not in File</Reprint><Start_Page>160</Start_Page><End_Page>172</End_Page><Periodical>Arthritis Rheum.</Periodical><Volume>33</Volume><Web_URL_Link4><f name="System">Arthritis and Rheumatism</f></Web_URL_Link4><ZZ_JournalStdAbbrev><f name="System">Arthritis Rheum.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Wolfe et al 1990b) and OA ADDIN REFMGR.CITE <Refman><Cite><Author>Altman</Author><Year>1986</Year><RecNum>1441</RecNum><IDText>The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1441</Ref_ID><Title_Primary>The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the knee</Title_Primary><Authors_Primary>Altman,R.</Authors_Primary><Authors_Primary>Asch,E.</Authors_Primary><Authors_Primary>Bloch,D.</Authors_Primary><Authors_Primary>Bole,G.</Authors_Primary><Authors_Primary>Borenstein,K.</Authors_Primary><Authors_Primary>Brandt,K.</Authors_Primary><Date_Primary>1986</Date_Primary><Reprint>In File</Reprint><Start_Page>1039</Start_Page><End_Page>1049</End_Page><Periodical>Arthritis Rheum.</Periodical><Volume>29</Volume><Web_URL_Link4><f name="System">Arthritis and Rheumatism</f></Web_URL_Link4><ZZ_JournalStdAbbrev><f name="System">Arthritis Rheum.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Arnett</Author><Year>1988</Year><RecNum>1442</RecNum><IDText>The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1442</Ref_ID><Title_Primary>The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.</Title_Primary><Authors_Primary>Arnett,F.C.</Authors_Primary><Authors_Primary>Edworthy,S.M.</Authors_Primary><Authors_Primary>Bloch,D.A.</Authors_Primary><Authors_Primary>McShane,D.J.</Authors_Primary><Authors_Primary>Fries,J.F.</Authors_Primary><Authors_Primary>Cooper,N.S.</Authors_Primary><Date_Primary>1988</Date_Primary><Keywords>RHEUMATOID ARTHRITIS</Keywords><Reprint>In File</Reprint><Start_Page>315</Start_Page><End_Page>324</End_Page><Periodical>Arthritis Rheum.</Periodical><Volume>31</Volume><Web_URL_Link4><f name="System">Arthritis and Rheumatism</f></Web_URL_Link4><ZZ_JournalStdAbbrev><f name="System">Arthritis Rheum.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Altman et al 1986;Arnett et al 1988). While new criteria for FM currently exist ADDIN REFMGR.CITE <Refman><Cite><Author>Wolfe</Author><Year>2011</Year><RecNum>2833</RecNum><IDText>Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2833</Ref_ID><Title_Primary>Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR preliminary diagnostic criteria for fibromyalgia</Title_Primary><Authors_Primary>Wolfe,F.</Authors_Primary><Authors_Primary>Clauw,D.J.</Authors_Primary><Authors_Primary>Fitzcharles,M.A.</Authors_Primary><Authors_Primary>Goldenberg,D.L.</Authors_Primary><Authors_Primary>H+&#xF1;user,W.</Authors_Primary><Authors_Primary>Katz,R.S.</Authors_Primary><Authors_Primary>Mease,P.</Authors_Primary><Authors_Primary>Russell,A.S.</Authors_Primary><Authors_Primary>Russell,I.J.</Authors_Primary><Authors_Primary>Winfield,J.B.</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Diagnostic criteria</Keywords><Keywords>Epidemiological study</Keywords><Keywords>Fibromyalgia</Keywords><Reprint>Not in File</Reprint><Start_Page>1113</Start_Page><End_Page>1122</End_Page><Periodical>Journal of Rheumatology</Periodical><Volume>38</Volume><Issue>6</Issue><Web_URL> name="System">Journal of Rheumatology</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Wolfe et al 2011), data collection for this study began prior the new criteria being available and so these were not used. Participants were excluded from the study if their medical records showed a history of neurological disorder, morbid psychiatric disorder (including major depression and anxiety-related disorders confirmed by a psychiatrist) or cardiovascular disease. It was expected that patients would be recruited with sub-clinical levels of anxiety and depression that are normal for chronic pain populations. All participants were non-medicating at the time of the study, having been requested to withdraw from any analgesic medication for the purpose of the study.Experimental protocolQuestionnaires were posted to participants to fill out two weeks prior to the experimental session. The Hospital Anxiety and Depression Scale (HADS, ADDIN REFMGR.CITE <Refman><Cite><Author>Zigmond</Author><Year>1983</Year><RecNum>2787</RecNum><IDText>The Hospital Anxiety and Depression Scale</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2787</Ref_ID><Title_Primary>The Hospital Anxiety and Depression Scale</Title_Primary><Authors_Primary>Zigmond,A.S.</Authors_Primary><Authors_Primary>Snaith,R.P.</Authors_Primary><Date_Primary>1983</Date_Primary><Keywords>Anxiety</Keywords><Keywords>Anxiety Disorders</Keywords><Keywords>Depression</Keywords><Keywords>depressive disorders</Keywords><Keywords>Psychiatric Status Rating Scales</Keywords><Reprint>Not in File</Reprint><Start_Page>361</Start_Page><End_Page>370</End_Page><Periodical>Acta Psychiatrica Scandinavica</Periodical><Volume>67</Volume><Issue>6</Issue><Web_URL> name="System">Acta Psychiatrica Scandinavica</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Zigmond and Snaith 1983)) was used to assess mood symptoms. It is composed of statements relating to anxiety or depression. The Pain Catastrophising Scale (PCS, ADDIN REFMGR.CITE <Refman><Cite><Author>Sullivan</Author><Year>1995</Year><RecNum>1782</RecNum><IDText>The Pain Catastrophizing Scale: Development and Validation</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1782</Ref_ID><Title_Primary>The Pain Catastrophizing Scale: Development and Validation</Title_Primary><Authors_Primary>Sullivan,M.J.L.</Authors_Primary><Authors_Primary>Bishop,S.R.</Authors_Primary><Authors_Primary>Pivik,J.</Authors_Primary><Date_Primary>1995/12</Date_Primary><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>524</Start_Page><End_Page>532</End_Page><Periodical>Psychological Assessment</Periodical><Volume>7</Volume><Issue>4</Issue><ZZ_JournalFull><f name="System">Psychological Assessment</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Sullivan et al 1995)) was used as a measure of pain-related psychological coping. On the day of the experiment, tender point (TP) examinations were first carried out by a trained research nurse, and scored using the Manual Tender Point Survey according to a published methodology ADDIN REFMGR.CITE <Refman><Cite><Author>Okifuji</Author><Year>1997</Year><RecNum>2788</RecNum><IDText>A standardized Manual Tender Point Survey. I. Development and determination of a threshold point for the identification of positive tender points in fibromyalgia syndrome</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2788</Ref_ID><Title_Primary>A standardized Manual Tender Point Survey. I. Development and determination of a threshold point for the identification of positive tender points in fibromyalgia syndrome</Title_Primary><Authors_Primary>Okifuji,A.</Authors_Primary><Authors_Primary>Turk,D.C.</Authors_Primary><Authors_Primary>Sinclair,J.D.</Authors_Primary><Authors_Primary>Starz,T.W.</Authors_Primary><Authors_Primary>Marcus,D.A.</Authors_Primary><Date_Primary>1997</Date_Primary><Keywords>Fibromyalgia</Keywords><Keywords>Fibromyalgia syndrome</Keywords><Keywords>Syndrome</Keywords><Reprint>Not in File</Reprint><Start_Page>377</Start_Page><End_Page>383</End_Page><Periodical>Journal of Rheumatology</Periodical><Volume>24</Volume><Issue>2</Issue><Web_URL> name="System">Journal of Rheumatology</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Okifuji et al 1997). Due to the lack of availability of a research nurse on the day, tender points were examined in only 8 out of the 15 healthy volunteers and 14 out of the 16 OA patients, while all 16 FM patients were examined.Clinical pain levels (“In general, how severe is your pain?”) was measured using a 0 – 10 visual analogue scale (VAS) ranging from “no pain” to “very severe”. Pain interference (“How much does the pain interfere with your life?”) was also assessed using a VAS ranging from “not at all” to “completely”. Healthy volunteers completed these scales as well as patients. Neural responses to acute painAcute pain was induced using a CO2 laser that specifically activates nociceptors in the skin ADDIN REFMGR.CITE <Refman><Cite><Author>Meyer</Author><Year>1976</Year><RecNum>1975</RecNum><IDText>A laser stimulator for the study of cutaneous thermal and pain sensations</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1975</Ref_ID><Title_Primary>A laser stimulator for the study of cutaneous thermal and pain sensations</Title_Primary><Authors_Primary>Meyer,R.A.</Authors_Primary><Authors_Primary>Walker,R.E.</Authors_Primary><Authors_Primary>Mountcastle,V.B.,Jr.</Authors_Primary><Date_Primary>1976/1</Date_Primary><Keywords>article</Keywords><Keywords>Humans</Keywords><Keywords>laser</Keywords><Keywords>Lasers</Keywords><Keywords>Pain</Keywords><Keywords>Research Support,U.&apos;t,P.H.S.</Keywords><Keywords>Sensation</Keywords><Keywords>Skin Physiology</Keywords><Keywords>Temperature</Keywords><Keywords>Thermodynamics</Keywords><Reprint>Not in File</Reprint><Start_Page>54</Start_Page><End_Page>60</End_Page><Periodical>IEEE Trans.Biomed.Eng</Periodical><Volume>23</Volume><Issue>1</Issue><Web_URL>PM:1244317</Web_URL><ZZ_JournalFull><f name="System">IEEE Trans.Biomed.Eng</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Meyer et al 1976). Heat stimuli of 150ms duration and a beam diameter of 15mm were applied to the dorsal surface of the subjects’ right forearm. Between stimuli, the laser was moved randomly over an area 3cm x 5cm to avoid habituation, sensitization or skin damage. Subjects wore protective laser safety goggles during the experiment. An initial psychophysics procedure was performed using a 0-10 numerical rating scale, which was anchored such that a level 4 indicated pain threshold, 7 indicated moderate pain, and 10 indicated unbearable pain. A ramping procedure was repeated three times to determine an intensity of laser stimulus for each subject at level 7, corresponding to a moderately painful heat level, as done previously ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2136</RecNum><IDText>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2136</Ref_ID><Title_Primary>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>Boyle,Y.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>Uncertainty</Keywords><Reprint>Not in File</Reprint><Start_Page>240</Start_Page><End_Page>250</End_Page><Periodical>Pain</Periodical><Volume>135</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown et al 2008a). The main experiment consisted of the delivery of 40 moderately painful (level 7) laser pulses, occurring ten seconds apart. Each laser stimulus occurred after three preceding auditory anticipation cues spaced one second apart, to ‘count-down’ the onset of the laser stimulus so that participants could accurately predict it. The first of the auditory cues was concurrent with a visual cue indicating that the laser stimulus could be expected in three seconds time (Fig. 1), which was to act as a visual fixation point to discourage eye movements. Participants were instructed to attend to the intensity of the pain and to rate it using the same 0-10 numerical scale as used in the psychophysics testing procedure as detailed above. Electroencephalographic recordings of anticipatory and pain-evoked responsesEEG recordings were taken from 61 scalp electrodes placed according to an extended 10-20 system (Quik-Cap system, Neuroscan, Inc.). Bandpass filters were set at DC - 70Hz, with a sampling rate of 500Hz and gain of 500. A notch filter was set to 50Hz to reduce electrical interference. Electrodes were referenced to common average across all electrodes. The vertical and horizontal electro-oculograms (EOG) were measured for off-line reduction of blink and eye-movement artifacts. Analysis of self-report measuresDifferences were analyzed between groups in self-reported pain and the different measures of psychological coping. A series of univariate ANOVAs were conducted on each measure with two-tailed tests, with group (FM, OA, HP) as a fixed factor and age as a covariate. Pain ratings and the laser energy required to induce a level 7 pain were also compared in this way. VAS measures of clinical pain, and tender point scores, were subjected to a non-parametric test (Kruskal Wallis) due to non-normality of the data in the OA group. P-values were corrected for multiple comparisons using the False Discovery Rate (FDR) statistic set at q = 0.05 (using Matlab code by Nichols available at ). The resulting p-value threshold at this level was p < 0.012. For dependent variables showing significant group effects in the ANOVA, post-hoc tests were performed on each group pair. For the parametric ANOVAs, we used the Scheffe test, while for the non-parametric data (VAS scores and tender points) we used the Mann-Whitney U test.Pre-processing of EEG dataEEG data were analyzed using the EEGLAB toolbox (v4.515) running on MATLAB version 7.8. Averaged Event-Related Potentials (ERPs) covering the anticipation and pain phases of neural activity were created for each participant and each session, after the removal of linear trends in the data and ocular artifacts (by removing artifactual components after performing Independent Components Analysis), and filtering at 20 Hz low pass. ERPs were baseline-corrected to either the 500ms interval preceding the visual anticipation cue (for the measurement of anticipatory-evoked responses) or the 500ms preceding the laser stimulus (for measurement of the pain-evoked response). Three 500ms temporal periods of the anticipatory brain response were extracted for analysis: a ‘baseline’ period, at -3500ms to -3000ms preceding the laser stimulus and occurring just prior to the anticipation cue (used for baseline correction of the EEG data), an ‘early’ period, at -2500ms to -2000ms preceding the laser stimulus and occurring soon after the anticipation cue, and a ‘late’ period, at –500ms to 0ms preceding the laser stimulus, as detailed and justified elsewhere ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2010</Year><RecNum>2439</RecNum><IDText>Meditation experience predicts less negative appraisal of pain: Electrophysiological evidence for the involvement of anticipatory neural responses</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2439</Ref_ID><Title_Primary>Meditation experience predicts less negative appraisal of pain: Electrophysiological evidence for the involvement of anticipatory neural responses</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>Anticipation</Keywords><Keywords>Attention</Keywords><Keywords>EEG</Keywords><Keywords>LORETA</Keywords><Keywords>Meditation</Keywords><Keywords>Mindfulness</Keywords><Keywords>nociception</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>428</Start_Page><End_Page>433</End_Page><Periodical>Pain</Periodical><Volume>150</Volume><Issue>3</Issue><Web_URL> name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown and Jones 2010). The P2 peak of the Laser-Evoked Potential (LEP) was analyzed, as this was the largest amplitude potential generated post-laser stimulus and the only potential to be robustly produced across subjects with our laser stimulation parameters. For each subject and condition, P2 peak latencies were determined at the electrode for which the P2 peak showed maximum amplitude (Cz). An averaged 20ms window of LEP data was then extracted, centered on this latency. Analysis of Event-Related Potential (ERP) dataFor each temporal period (early anticipation, late anticipation, P2 peak), we performed a “scalp-region-of-interest” analysis to avoid the multiple comparisons problem of individually testing groups effects at every electrode. The voltage at nine electrodes were extracted and averaged for analysis of ERP amplitudes. The nine electrodes used included the electrode showing the maximum amplitude over the whole scalp for that time window when a grand average was created across subjects, plus the surrounding eight adjacent electrodes. This number of electrodes was regarded as reasonably broad enough to capture the peak of activity in most subjects (which wasn’t necessarily at the same electrode as in the grand average), while maintaining a reasonable degree of spatial specificity. For early anticipation the nine electrodes were centered on FCz, while for late anticipation at the P2 peak the nine electrodes were centered on Cz. We used a univariate ANOVA (fixed factor: group; covariate: age) to identify group differences in the anticipatory and pain-evoked potentials. The ANOVA was performed once for each of the three time periods, and so results were judged to be statistically significant after correcting for multiple comparisons using False Discovery Rate (FDR), with a q value of 0.05 and two-tailed statistics. The resulting p value threshold was p < 0.01.Source analysis of Event-Related Potential (ERP) dataSources of anticipatory and pain-evoked potentials were estimated using the imaging approach to source reconstruction as implemented in SPM8 for MEG/EEG, combined with custom MATLAB code for batch processing. For each participant, a forward model was constructed, using an 8196 vertex template cortical mesh, coregistered to the electrode positions of the standard 10-20 system via three fiducial markers. This produced ‘voxels’ (equivalent current dipoles) of 2mm x 2mm x 2mm. The lead-field of the forward model was computed using the three-shell BEM EEG head model available in SPM8. Source estimates were computed on the canonical mesh using 256 multiple sparse priors per hemisphere including subcortical structures ADDIN REFMGR.CITE <Refman><Cite><Author>Friston</Author><Year>2008</Year><RecNum>2458</RecNum><IDText>Multiple sparse priors for the M/EEG inverse problem</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2458</Ref_ID><Title_Primary>Multiple sparse priors for the M/EEG inverse problem</Title_Primary><Authors_Primary>Friston,K.</Authors_Primary><Authors_Primary>Harrison,L.</Authors_Primary><Authors_Primary>Daunizeau,J.</Authors_Primary><Authors_Primary>Kiebel,S.</Authors_Primary><Authors_Primary>Phillips,C.</Authors_Primary><Authors_Primary>Trujillo-Barreto,N.</Authors_Primary><Authors_Primary>Henson,R.</Authors_Primary><Authors_Primary>Flandin,G.</Authors_Primary><Authors_Primary>Mattout,J.</Authors_Primary><Date_Primary>2008</Date_Primary><Reprint>Not in File</Reprint><Start_Page>1104</Start_Page><End_Page>1120</End_Page><Periodical>Neuroimage</Periodical><Volume>39</Volume><Issue>3</Issue><Web_URL> name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Friston et al 2008), under group constraints ADDIN REFMGR.CITE <Refman><Cite><Author>Litvak</Author><Year>2008</Year><RecNum>2459</RecNum><IDText>Electromagnetic source reconstruction for group studies</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2459</Ref_ID><Title_Primary>Electromagnetic source reconstruction for group studies</Title_Primary><Authors_Primary>Litvak,V.</Authors_Primary><Authors_Primary>Friston,K.</Authors_Primary><Date_Primary>2008/10/1</Date_Primary><Keywords>Algorithms</Keywords><Keywords>article</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Computer Simulation</Keywords><Keywords>EEG</Keywords><Keywords>Electroencephalography</Keywords><Keywords>MEG</Keywords><Keywords>methods</Keywords><Keywords>model</Keywords><Keywords>Models,Neurological</Keywords><Keywords>Pattern Recognition,Automated</Keywords><Keywords>physiology</Keywords><Keywords>Reproducibility of Results</Keywords><Keywords>Research</Keywords><Keywords>Sensitivity and Specificity</Keywords><Keywords>technique</Keywords><Reprint>Not in File</Reprint><Start_Page>1490</Start_Page><End_Page>1498</End_Page><Periodical>Neuroimage</Periodical><Volume>42</Volume><Issue>4</Issue><Address>The Wellcome Trust Centre for Neuroimaging, University College London, UK. v.litvak@ion.ucl.ac.uk</Address><Web_URL>PM:18639641</Web_URL><ZZ_JournalFull><f name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Litvak and Friston 2008). Source prior smoothness was set at 1mm. Source estimates were created based on windows of the ERP data of 500ms for pre-anticipation baseline, early and late anticipation (using the time windows described in the pre-processing section above), and 80ms for the P2 peak centered on the maximum amplitude of the peak for each individual participant. The resulting images were smoothed at 10mm FWHM, and log-transformed prior to statistical analysis to improve the normality in the distribution of the data.Statistical analysis at the group level was performed using conventional SPM t tests. Statistical tests were performed over all voxels in the brain to enable exploratory analyses outside of our hypothesized regions of interest. To control for type I errors over the whole brain, results are reported that were significant at the voxel level after FDR correction (whole-brain) at pvoxel < 0.05, and only considering cluster sizes greater than 100 voxels. To view the images and extract clusters as volumes of interest, statistical parametrical maps were thresholded at pvoxel < 0.001 (uncorrected). We compared the groups at each of the three time periods individually. The names of regions of activity were identified using the Automated Anatomical Labeling (AAL) system ADDIN REFMGR.CITE <Refman><Cite><Author>Tzourio-Mazoyer</Author><Year>2002</Year><RecNum>2859</RecNum><IDText>Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2859</Ref_ID><Title_Primary>Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain</Title_Primary><Authors_Primary>Tzourio-Mazoyer,N.</Authors_Primary><Authors_Primary>Landeau,B.</Authors_Primary><Authors_Primary>Papathanassiou,D.</Authors_Primary><Authors_Primary>Crivello,F.</Authors_Primary><Authors_Primary>Etard,O.</Authors_Primary><Authors_Primary>Delcroix,N.</Authors_Primary><Authors_Primary>Mazoyer,B.</Authors_Primary><Authors_Primary>Joliot,M.</Authors_Primary><Date_Primary>2002</Date_Primary><Keywords>Brain</Keywords><Reprint>Not in File</Reprint><Start_Page>273</Start_Page><End_Page>289</End_Page><Periodical>Neuroimage</Periodical><Volume>15</Volume><Issue>1</Issue><Web_URL> name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Tzourio-Mazoyer et al 2002).To test if there were any differences between patients in general and the HP group, analyses were conducted for each time period as follows. The two paired contrasts comparing HP patients with the FM group (“FM > HP” and “HP > FM”), were used, in addition to a further two contrasts comparing the HP group to the OA group (“HP > OA” and “OA > HP”). Age was added as a covariate for each contrast. These four contrasts were used to construct two separate conjunction analyses, for the purpose of identifying the main effect of chronic pain, i.e. common differences in both patient groups compared to the HP group. Specifically, activations were identified that were greater in the HP group than in the other two groups (i.e. [HP > FM] + [HP > OA]), and that were greater in the patient groups compared to the HP group (i.e. [FM > HP] + [OA > HP]). To test for differences between the FM group and the other two groups, for each time period two paired contrasts were defined comparing FM patients with the HP group (“FM > HP” and “HP > FM”), and a further two contrasts comparing the FM group to the OA group (“FM > OA” and “OA > FM”), with age as a covariate. These four contrasts were then used to construct two separate conjunction analyses to test for the main effects of FM, i.e. common differences in the FM group compared to both OA and HP groups. The first test was for activations that were greater in the FM group than in the other two groups (i.e. [FM > HP] + [FM > OA]), while the second was for for activations that were lesser in the FM group (i.e. [HP > FM] + [OA > FM]).A final analysis was performed to explain the discrepancy between the FM and OA groups in the overall size of the anticipatory-evoked potential during late anticipation. The OA group were contrasted to the FM group [OA > FM] in a single SPM t-test, with age as a covariate.Analyses of volumes of interest (VOIs)We extracted data from VOIs identified in the previous analyses (from the conjunctive group comparisons) as possible correlates of self-report variables. We also correlated anticipatory activity across patient groups between different clusters of brain regions that appeared functionally important. Linear regression was used on the data pooled across the patient groups. For each VOI, brain activity was initially adjusted for age by regressing age with VOI activity and calculating the residuals of VOI activity for further regressions. There were five statistical tests per VOI (table 3) and to control for multiple comparisons the False Discovery Rate (FDR) statistic was set at q = 0.05. The standardized residuals of the variables tested were tested for normality to check that the assumptions of linear regression were not violated. ResultsPatient characteristicsThe ages of patients in each group were significantly different after applying a univariate ANOVA (p < 0.04). Because of these differences, age was used as a covariate in all statistical analyses to remove any variance attributed to this variable from the results. Self-report measuresGroup comparisons of self-report measures showed that a number of variables (clinical pain, pain catastrophizing, and anxiety) showed no difference between the two patient groups, but were significantly greater in these groups compared to the HP group (table 1). Scores for depression were no different between the two patient groups, but only the FM group showed significantly higher scores than the HP group. The number of tender points was significantly higher in the FM group compared to the HP group, and there was a trend towards a greater number in the OA group compared to the HP group, and the FM group compared to the OA group. Laser energies, pain scores and evoked potentialsRegarding the acute pain experiment, the levels of laser energy used were no different between groups, nor were there any significant differences in the resulting pain ratings (table 1). In comparing the amplitudes of the anticipatory (early, late phases) and the pain-evoked potential (P2 peak), group effects were only found during late anticipation (p < 0.01, figure 1). Statistical significance was found in a post-hoc paired test comparing the FM and OA groups (p < 0.01). The anticipatory response was of highest amplitude in the OA group, and lowest in the FM group, with HP group amplitudes being in-between but nearer to the OA group. Neural sources of evoked potentialsThe group effects on source activity during each anticipatory and pain-evoked ERP are shown in figure 2 and listed in table 2. Significant results were only found during late anticipation, as follows. In the comparison of the FM group with the other two groups (figure 2a), the conjunction analysis showed greater activations in the FM group during late anticipation in the bilateral insula cortices, and the right inferior temporal gyrus. The conjunction analyses of the two patient groups compared to the HP group (figure 2b) showed areas with significantly reduced activations in the patients during late anticipation, including frontal and parietal brain regions consisting of the left (contralateral) postcentral gyrus, left superior frontal gyrus (supplementary motor area), and the left middle frontal gyrus (dorsolateral prefrontal cortex). Smaller clusters were found in the right superior and middle frontal gyrus, right precentral gyrus, bilateral occipito-temporal gyrus, the left (contralateral) insula and neighboring parietal operculum, and the thalamus. The contrast [OA > FM] during late anticipation revealed a source in the precuneus bilaterally (figure 2c and table 2).Regression of VOI clusters and self-report variablesThe results of the regression analyses of volume of interest (VOIs) on clinical and psychological variables (clinical pain, tender point count, anxiety, depression and pain catastrophising) are shown in table 3 and as scatter plots in figures 2a and 2b. VOI clusters extracted were the left insula and right insula (more active in FM group compared to HP and OA groups), a left middle frontal gyrus / superior frontal gyrus / postcentral gyrus cluster and a right middle frontal gyrus cluster (more active in the HP group than the two patient groups), and a precuneus cluster (more active in the OA group than FM group). For all of the following regressions, the standardized residuals were normally distributed.Anticipatory activity in the left insula showed significant positive relationships with clinical pain and the number of tender points when data was pooled across patient groups (table 3). For average clinical pain scores, these regressions were also significant within the FM group (r = 0.49, p = 0.02) and the OA group (r = 0.63, p = 0.004) individually. In the regression of the left insula on clinical pain over the patient groups, controlling for anxiety and catastrophizing by including them as covariates did not reduce the significance of the relationship. This implies that coping factors were not responsible for the relationship between anticipatory insula activity and clinical pain. Conversely, negative correlations were found when regressing the left frontal and parietal cluster of regions, which were negatively correlated with anxiety and pain catastrophizing across the patient groups. These correlated within the OA group when considered separately, although not enough to survive correlation for multiple comparisons, for anxiety (r = - 0.60, p = 0.03) and pain catastrophizing (r = - 0.57, p = 0.03). These correlations where not significant within the FM group individually. The greater correlation in OA patients compared to FM patients is likely a result of greater variance in predictor variables in the OA group. We also correlated anticipatory activity across patient groups between two key clusters of brain regions, the left insula and the left frontal/parietal cluster, but this was not significant (r = 0.15, p = 0.43).DiscussionIn this study, we utilized the high temporal resolution of EEG with source localization to resolve spatial patterns of activity within pain processing regions in the few hundred milliseconds prior to experiencing acute pain. While a fMRI study ADDIN REFMGR.CITE <Refman><Cite><Author>Burgmer</Author><Year>2011</Year><RecNum>2789</RecNum><IDText>Cerebral activation and catastrophizing during pain anticipation in patients with fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2789</Ref_ID><Title_Primary>Cerebral activation and catastrophizing during pain anticipation in patients with fibromyalgia</Title_Primary><Authors_Primary>Burgmer,M.</Authors_Primary><Authors_Primary>Petzke,F.</Authors_Primary><Authors_Primary>Giesecke,T.</Authors_Primary><Authors_Primary>Gaubitz,M.</Authors_Primary><Authors_Primary>Heuft,G.</Authors_Primary><Authors_Primary>Pfleiderer,B.</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Anticipation</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Reprint>Not in File</Reprint><Start_Page>751</Start_Page><End_Page>759</End_Page><Periodical>Psychosomatic Medicine</Periodical><Volume>73</Volume><Issue>9</Issue><Web_URL> name="System">Psychosomatic Medicine</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Burgmer et al 2011) has investigated differences in pain anticipation between FM patients and healthy controls, our methodology provides a unique window into possible abnormalities in pain anticipation by enabling resolution of neural processing immediately prior to pain experience (not possible with fMRI), and by comparing with a psychologically well-matched OA group to enable assessment of abnormalities that may be unique to FM. We identified anticipatory neural substrates of pain and tenderness that are common in FM and OA, albeit exaggerated in FM, which provide potential common brain contributors to the mechanisms of chronic pain. Patients with FM had significantly augmented responses during anticipation of pain in insula cortices compared to both the OA and HP groups, but this was a difference of extent rather than type: left (contralateral) insula activity correlated with clinical pain scores and tender points (but not psychological coping factors) across the patient groups (and within each patient group for clinical pain scores), suggesting common mechanisms of pain and tenderness in the insula cortex across patient conditions. Both patient groups, compared to HPs, had less neural processing during pain anticipation in a left-lateral frontal/parietal cluster, including dorsolateral prefrontal, superior frontal, and postcentral (primary somatosensory) cortical regions, which were related to poorer coping across patient groups.Group effects in the insula corticesThe increased responses in the insula in FM patients compared to both OA and HP groups were correlated to symptoms normally associated with FM (clinical pain and number of tender points) across all patients in the study, regardless of diagnosis, and in particular within the OA group when considering clinical pain scores. We speculate that abnormal insula responses represent part of a common mechanism for pain and tenderness in chronic pain rather than being specific to FM. This reflects the view of some researchers and clinicians ADDIN REFMGR.CITE <Refman><Cite><Author>Croft</Author><Year>1996</Year><RecNum>2875</RecNum><IDText>More pain, more tender points: is fibromyalgia just one end of a continuous spectrum?</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2875</Ref_ID><Title_Primary>More pain, more tender points: is fibromyalgia just one end of a continuous spectrum?</Title_Primary><Authors_Primary>Croft,P.</Authors_Primary><Authors_Primary>Burt,J.</Authors_Primary><Authors_Primary>Schollum,J.</Authors_Primary><Authors_Primary>Thomas,E.</Authors_Primary><Authors_Primary>Macfarlane,G.</Authors_Primary><Authors_Primary>Silman,A.</Authors_Primary><Date_Primary>1996/7/1</Date_Primary><Keywords>Association</Keywords><Keywords>Chronic</Keywords><Keywords>Chronic widespread pain</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>methods</Keywords><Keywords>Musculoskeletal</Keywords><Keywords>Odds Ratio</Keywords><Keywords>Pain</Keywords><Keywords>SITE</Keywords><Keywords>Widespread</Keywords><Keywords>Widespread pain</Keywords><Reprint>Not in File</Reprint><Start_Page>482</Start_Page><End_Page>485</End_Page><Periodical>Annals of the Rheumatic Diseases</Periodical><Volume>55</Volume><Issue>7</Issue><Web_URL> name="System">Annals of the Rheumatic Diseases</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Croft et al 1996), that FM pain represents one end of a spectrum chronic pain conditions that is driven by mechanisms that can potentially affect patients with any form of chronic pain, rather than viewing FM as have an entirely distinct etiology.There is already support in the literature for the hypothesis of a key involvement of the insula cortices both at rest and in response to acute pain stimuli in the symptoms of FM ADDIN REFMGR.CITE <Refman><Cite><Author>Cook</Author><Year>2004</Year><RecNum>2784</RecNum><IDText>Functional imaging of pain in patients with primary fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2784</Ref_ID><Title_Primary>Functional imaging of pain in patients with primary fibromyalgia</Title_Primary><Authors_Primary>Cook,Dane B.</Authors_Primary><Authors_Primary>Lange,Gudrun</Authors_Primary><Authors_Primary>Ciccone,Donald S.</Authors_Primary><Authors_Primary>Liu,Wen Ching</Authors_Primary><Authors_Primary>Steffener,Jason</Authors_Primary><Authors_Primary>Natelson,Benjamin H.</Authors_Primary><Date_Primary>2004/2/1</Date_Primary><Keywords>Brain</Keywords><Keywords>Cingulate</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>fMRI</Keywords><Keywords>Function</Keywords><Keywords>Heat</Keywords><Keywords>imaging</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>methods</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Reprint>Not in File</Reprint><Start_Page>364</Start_Page><End_Page>378</End_Page><Periodical>The Journal of Rheumatology</Periodical><Volume>31</Volume><Issue>2</Issue><Web_URL> name="System">The Journal of Rheumatology</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Kim</Author><Year>2011</Year><RecNum>2785</RecNum><IDText>Insular cortex is a trait marker for pain processing in fibromyalgia syndrome--blood oxygenation level-dependent functional magnetic resonance imaging study in Korea</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2785</Ref_ID><Title_Primary>Insular cortex is a trait marker for pain processing in fibromyalgia syndrome--blood oxygenation level-dependent functional magnetic resonance imaging study in Korea</Title_Primary><Authors_Primary>Kim,S.H.</Authors_Primary><Authors_Primary>Chang,Y.</Authors_Primary><Authors_Primary>Kim,J.H.</Authors_Primary><Authors_Primary>Song,H.J.</Authors_Primary><Authors_Primary>Seo,J.</Authors_Primary><Authors_Primary>Kim,S.H.</Authors_Primary><Authors_Primary>Han,S.W.</Authors_Primary><Authors_Primary>Nam,E.J.</Authors_Primary><Authors_Primary>Choi,T.Y.</Authors_Primary><Authors_Primary>Lee,S.J.</Authors_Primary><Authors_Primary>Kim,S.K.</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Fibromyalgia</Keywords><Keywords>imaging</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>S19</Start_Page><End_Page>S27</End_Page><Periodical>Clinical and experimental rheumatology</Periodical><Volume>29</Volume><Issue>6 Suppl 69</Issue><Web_URL> name="System">Clinical and experimental rheumatology</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Harris</Author><Year>2009</Year><RecNum>2796</RecNum><IDText>Elevated insular glutamate in fibromyalgia is associated with experimental pain</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2796</Ref_ID><Title_Primary>Elevated insular glutamate in fibromyalgia is associated with experimental pain</Title_Primary><Authors_Primary>Harris,Richard E.</Authors_Primary><Authors_Primary>Sundgren,Pia C.</Authors_Primary><Authors_Primary>Craig,A.D.</Authors_Primary><Authors_Primary>Kirshenbaum,Eric</Authors_Primary><Authors_Primary>Sen,Ananda</Authors_Primary><Authors_Primary>Napadow,Vitaly</Authors_Primary><Authors_Primary>Clauw,Daniel J.</Authors_Primary><Date_Primary>2009</Date_Primary><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>3146</Start_Page><End_Page>3152</End_Page><Periodical>Arthritis &amp; Rheumatism</Periodical><Volume>60</Volume><Issue>10</Issue><Web_URL> name="System">Arthritis &amp; Rheumatism</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Napadow</Author><Year>2010</Year><RecNum>2797</RecNum><IDText>Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2797</Ref_ID><Title_Primary>Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity</Title_Primary><Authors_Primary>Napadow,Vitaly</Authors_Primary><Authors_Primary>LaCount,Lauren</Authors_Primary><Authors_Primary>Park,Kyungmo</Authors_Primary><Authors_Primary>As-Sanie,Sawsan</Authors_Primary><Authors_Primary>Clauw,Daniel J.</Authors_Primary><Authors_Primary>Harris,Richard E.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>Brain</Keywords><Keywords>Chronic</Keywords><Keywords>chronic pain</Keywords><Keywords>CONNECTIVITY</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Pain intensity</Keywords><Reprint>Not in File</Reprint><Start_Page>2545</Start_Page><End_Page>2555</End_Page><Periodical>Arthritis &amp; Rheumatism</Periodical><Volume>62</Volume><Issue>8</Issue><Web_URL> name="System">Arthritis &amp; Rheumatism</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Cook et al 2004;Harris et al 2009;Napadow et al 2010;Kim et al 2011). The results of the current study add to this growing body of literature by suggesting that increases in anticipatory responses in insula cortex may be functionally important. Anticipatory responses represent top-down processes such as expectancy that can influence subsequent pain, and are distinct from resting-state activity that is controlled for by removal of baseline processing in the analysis. The insula is important in aversive conditioning, a process that augments pain and fear responses to stimuli through interactions with the medial temporal lobes ADDIN REFMGR.CITE <Refman><Cite><Author>Sehlmeyer</Author><Year>2009</Year><RecNum>2483</RecNum><IDText>Human fear conditioning and extinction in neuroimaging: A systematic review</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2483</Ref_ID><Title_Primary>Human fear conditioning and extinction in neuroimaging: A systematic review</Title_Primary><Authors_Primary>Sehlmeyer,C.</Authors_Primary><Authors_Primary>Sch+&#xA6;ning,S.</Authors_Primary><Authors_Primary>Zwitserlood,P.</Authors_Primary><Authors_Primary>Pfleiderer,B.</Authors_Primary><Authors_Primary>Kircher,T.</Authors_Primary><Authors_Primary>Arolt,V.</Authors_Primary><Authors_Primary>Konrad,C.</Authors_Primary><Date_Primary>2009</Date_Primary><Keywords>Fear</Keywords><Keywords>Human</Keywords><Keywords>review</Keywords><Reprint>Not in File</Reprint><Periodical>PLoS ONE</Periodical><Volume>4</Volume><Issue>6</Issue><Web_URL> name="System">PLoS ONE</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Buchel</Author><Year>2000</Year><RecNum>1967</RecNum><IDText>Classical fear conditioning in functional neuroimaging</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1967</Ref_ID><Title_Primary>Classical fear conditioning in functional neuroimaging</Title_Primary><Authors_Primary>Buchel,C.</Authors_Primary><Authors_Primary>Dolan,R.J.</Authors_Primary><Date_Primary>2000/4</Date_Primary><Keywords>Acoustic Stimulation</Keywords><Keywords>Amygdala</Keywords><Keywords>anatomy &amp; histology</Keywords><Keywords>Animal</Keywords><Keywords>Animals</Keywords><Keywords>article</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Conditioning,Classical</Keywords><Keywords>Diagnostic Imaging</Keywords><Keywords>Electric Stimulation</Keywords><Keywords>Fear</Keywords><Keywords>Human</Keywords><Keywords>Humans</Keywords><Keywords>imaging</Keywords><Keywords>Learning</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>methods</Keywords><Keywords>Photic Stimulation</Keywords><Keywords>physiology</Keywords><Keywords>positron</Keywords><Keywords>positron emission tomography</Keywords><Keywords>psychology</Keywords><Keywords>radionuclide imaging</Keywords><Keywords>Research Support,Non-U.&apos;t</Keywords><Keywords>review</Keywords><Keywords>technique</Keywords><Keywords>Tomography</Keywords><Keywords>Tomography,Emission-Computed</Keywords><Reprint>Not in File</Reprint><Start_Page>219</Start_Page><End_Page>223</End_Page><Periodical>Curr Opin.Neurobiol.</Periodical><Volume>10</Volume><Issue>2</Issue><Address>The Wellcome Department of Cognitive Neurology, Institute of Neurology, London, UK. buechel@uke.uni-hamburg.de</Address><Web_URL>PM:10753800</Web_URL><ZZ_JournalFull><f name="System">Curr Opin.Neurobiol.</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Fendt</Author><Year>1999</Year><RecNum>2015</RecNum><IDText>The neuroanatomical and neurochemical basis of conditioned fear</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2015</Ref_ID><Title_Primary>The neuroanatomical and neurochemical basis of conditioned fear</Title_Primary><Authors_Primary>Fendt,M.</Authors_Primary><Authors_Primary>Fanselow,M.S.</Authors_Primary><Date_Primary>1999/5</Date_Primary><Keywords>anatomy &amp; histology</Keywords><Keywords>Animal</Keywords><Keywords>Animals</Keywords><Keywords>Anxiety</Keywords><Keywords>Anxiety Disorders</Keywords><Keywords>article</Keywords><Keywords>Behavior</Keywords><Keywords>Brain</Keywords><Keywords>Brain Chemistry</Keywords><Keywords>Conditioning (Psychology)</Keywords><Keywords>Face</Keywords><Keywords>Fear</Keywords><Keywords>Human</Keywords><Keywords>Humans</Keywords><Keywords>model</Keywords><Keywords>physiology</Keywords><Keywords>Rats</Keywords><Keywords>Research</Keywords><Keywords>review</Keywords><Reprint>Not in File</Reprint><Start_Page>743</Start_Page><End_Page>760</End_Page><Periodical>Neurosci Biobehav.Rev</Periodical><Volume>23</Volume><Issue>5</Issue><Address>Tierphysiologie, Universitat Tubingen, Germany. markus.fendt@uni-tuebingen.de</Address><Web_URL>PM:10392663</Web_URL><ZZ_JournalFull><f name="System">Neurosci Biobehav.Rev</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Fendt and Fanselow 1999;Buchel and Dolan 2000;Sehlmeyer et al 2009), and contributes to negative expectancy effects on pain and other aversive stimuli ADDIN REFMGR.CITE <Refman><Cite><Author>Franciotti</Author><Year>2009</Year><RecNum>2661</RecNum><IDText>Modulation of alpha oscillations in insular cortex reflects the threat of painful stimuli</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2661</Ref_ID><Title_Primary>Modulation of alpha oscillations in insular cortex reflects the threat of painful stimuli</Title_Primary><Authors_Primary>Franciotti,Raffaella</Authors_Primary><Authors_Primary>Ciancetta,Luca</Authors_Primary><Authors_Primary>la Penna,Stefania</Authors_Primary><Authors_Primary>Belardinelli,Paolo</Authors_Primary><Authors_Primary>Pizzella,Vittorio</Authors_Primary><Authors_Primary>Romani,Gian Luca</Authors_Primary><Date_Primary>2009</Date_Primary><Keywords>Affect</Keywords><Keywords>Alpha Rhythm</Keywords><Keywords>Arousal</Keywords><Keywords>Brain</Keywords><Keywords>Expectation</Keywords><Keywords>Fear</Keywords><Keywords>insula</Keywords><Keywords>Pain</Keywords><Keywords>Threat</Keywords><Keywords>Time</Keywords><Reprint>Not in File</Reprint><Start_Page>1082</Start_Page><End_Page>1090</End_Page><Periodical>Neuroimage</Periodical><Volume>46</Volume><Issue>4</Issue><Web_URL>WOS:000266975600021</Web_URL><ZZ_JournalFull><f name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Sarinopoulos</Author><Year>2006</Year><RecNum>2410</RecNum><IDText>Brain mechanisms of expectation associated with insula and amygdala response to aversive taste: implications for placebo</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2410</Ref_ID><Title_Primary>Brain mechanisms of expectation associated with insula and amygdala response to aversive taste: implications for placebo</Title_Primary><Authors_Primary>Sarinopoulos,I.</Authors_Primary><Authors_Primary>Dixon,G.E.</Authors_Primary><Authors_Primary>Short,S.J.</Authors_Primary><Authors_Primary>Davidson,R.J.</Authors_Primary><Authors_Primary>Nitschke,J.B.</Authors_Primary><Date_Primary>2006/3</Date_Primary><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>Amygdala</Keywords><Keywords>Anterior cingulate cortex</Keywords><Keywords>article</Keywords><Keywords>Association</Keywords><Keywords>Avoidance Learning</Keywords><Keywords>Behavior</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cerebral Cortex</Keywords><Keywords>Cingulate</Keywords><Keywords>drug effects</Keywords><Keywords>Female</Keywords><Keywords>fMRI</Keywords><Keywords>Humans</Keywords><Keywords>imaging</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Perception</Keywords><Keywords>pharmacology</Keywords><Keywords>physiology</Keywords><Keywords>placebo</Keywords><Keywords>Placebo Effect</Keywords><Keywords>Placebos</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>Psychiatry</Keywords><Keywords>randomized controlled trial</Keywords><Keywords>Reference Values</Keywords><Keywords>Research</Keywords><Keywords>Set (Psychology)</Keywords><Keywords>Taste</Keywords><Reprint>Not in File</Reprint><Start_Page>120</Start_Page><End_Page>132</End_Page><Periodical>Brain Behav.Immun.</Periodical><Volume>20</Volume><Issue>2</Issue><Address>Waisman Laboratory for Brain Imaging and Behavior, Waisman Center, Department of Psychiatry, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705-2274, USA</Address><Web_URL>PM:16472720</Web_URL><ZZ_JournalFull><f name="System">Brain Behav.Immun.</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Sawamoto</Author><Year>2000</Year><RecNum>143</RecNum><IDText>Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>143</Ref_ID><Title_Primary>Expectation of pain enhances responses to nonpainful somatosensory stimulation in the anterior cingulate cortex and parietal operculum/posterior insula: an event-related functional magnetic resonance imaging study</Title_Primary><Authors_Primary>Sawamoto,N.</Authors_Primary><Authors_Primary>Honda,M.</Authors_Primary><Authors_Primary>Okada,T.</Authors_Primary><Authors_Primary>Hanakawa,T.</Authors_Primary><Authors_Primary>Kanda,M.</Authors_Primary><Authors_Primary>Fukuyama,H.</Authors_Primary><Authors_Primary>Konishi,J.</Authors_Primary><Authors_Primary>Shibasaki,H.</Authors_Primary><Date_Primary>2000/10/1</Date_Primary><Keywords>Adult</Keywords><Keywords>anatomy &amp; histology</Keywords><Keywords>Anxiety</Keywords><Keywords>Behavior</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cerebral Cortex</Keywords><Keywords>Gyrus Cinguli</Keywords><Keywords>Human</Keywords><Keywords>Lasers</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Pain</Keywords><Keywords>Pain Measurement</Keywords><Keywords>Parietal Lobe</Keywords><Keywords>Physical Stimulation</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>psychology</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Reprint>Not in File</Reprint><Start_Page>7438</Start_Page><End_Page>7445</End_Page><Periodical>J Neurosci</Periodical><Volume>20</Volume><Issue>19</Issue><Address>Department of Brain Pathophysiology, Human Brain Research Center, Kyoto, 606-8507 Japan</Address><Web_URL>PM:11007903</Web_URL><ZZ_JournalFull><f name="System">J Neurosci</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Sawamoto et al 2000;Sarinopoulos et al 2006;Franciotti et al 2009). Our data is therefore consistent with a role of the insula in mediating top-down augmentation of pain and tenderness in FM. Moreover, the augmented anticipatory insula responses in FM cannot be explained by psychological factors (catastrophizing, anxiety) that are common to FM and OA patients. This goes against our assumption that top-down effects on pain in FM would be directly related to factors such as catastrophizing. Rather, it could be that supraspinal nociceptive pathways in FM are more susceptible to being negatively conditioned for a given level of psychological distress. This would provide a unique explanation for the pain and tenderness characteristic of FM beyond that of psychological risk factors. An alternative explanation for augmentated insula responses is central sensitization, which is thought to result from facilitatory mechanisms in the brainstem and spinal cord. We were not able to image neural processes related to central sensitization using EEG in this study, but such processes are known to result in augmentation of afferent pain signals reaching the insula cortex ADDIN REFMGR.CITE <Refman><Cite><Author>Zambreanu</Author><Year>2005</Year><RecNum>2807</RecNum><IDText>A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2807</Ref_ID><Title_Primary>A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging</Title_Primary><Authors_Primary>Zambreanu,L.</Authors_Primary><Authors_Primary>Wise,R.G.</Authors_Primary><Authors_Primary>Brooks,J.C.W.</Authors_Primary><Authors_Primary>Iannetti,G.D.</Authors_Primary><Authors_Primary>Tracey,I.</Authors_Primary><Date_Primary>2005/4</Date_Primary><Keywords>Brainstem</Keywords><Keywords>Capsaicin</Keywords><Keywords>Central sensitisation</Keywords><Keywords>fMRI</Keywords><Keywords>Human</Keywords><Keywords>Humans</Keywords><Keywords>Hyperalgesia</Keywords><Keywords>imaging</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Reprint>Not in File</Reprint><Start_Page>397</Start_Page><End_Page>407</End_Page><Periodical>Pain</Periodical><Volume>114</Volume><Issue>3</Issue><Web_URL> name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Zambreanu et al 2005). If such facilitation were taking place, it would be expected that there would be a difference between FM and OA patients in the laser energy required to generate moderate pain (and possibly in the amplitude of the pain-evoked potential), which we did not find. Central sensitization therefore does not appear to explain our results.Fronto-parietal group effectsFurther abnormalities in FM patients compared to healthy volunteers were shared with OA patients. Reduced activity in a left fronto-parietal cluster was related to psychological coping factors that were common to both FM and OA groups. Previous studies have also identified differences between FM and healthy groups in similar brain regions, including negative correlations of anticipatory activity in supplementary motor area with the subsequent pain ratings ADDIN REFMGR.CITE <Refman><Cite><Author>Burgmer</Author><Year>2010</Year><RecNum>2790</RecNum><IDText>Fibromyalgia unique temporal brain activation during experimental pain: A controlled fMRI Study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2790</Ref_ID><Title_Primary>Fibromyalgia unique temporal brain activation during experimental pain: A controlled fMRI Study</Title_Primary><Authors_Primary>Burgmer,M.</Authors_Primary><Authors_Primary>Pogatzki-Zahn,E.</Authors_Primary><Authors_Primary>Gaubitz,M.</Authors_Primary><Authors_Primary>Stober,C.</Authors_Primary><Authors_Primary>Wessoleck,E.</Authors_Primary><Authors_Primary>Heuft,G.</Authors_Primary><Authors_Primary>Pfleiderer,B.</Authors_Primary><Date_Primary>2010</Date_Primary><Keywords>Brain</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>fMRI</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>123</Start_Page><End_Page>131</End_Page><Periodical>Journal of Neural Transmission</Periodical><Volume>117</Volume><Issue>1</Issue><Web_URL> name="System">Journal of Neural Transmission</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Burgmer et al 2010), although greater activity has been found in DLPFC ADDIN REFMGR.CITE <Refman><Cite><Author>Burgmer</Author><Year>2011</Year><RecNum>2789</RecNum><IDText>Cerebral activation and catastrophizing during pain anticipation in patients with fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2789</Ref_ID><Title_Primary>Cerebral activation and catastrophizing during pain anticipation in patients with fibromyalgia</Title_Primary><Authors_Primary>Burgmer,M.</Authors_Primary><Authors_Primary>Petzke,F.</Authors_Primary><Authors_Primary>Giesecke,T.</Authors_Primary><Authors_Primary>Gaubitz,M.</Authors_Primary><Authors_Primary>Heuft,G.</Authors_Primary><Authors_Primary>Pfleiderer,B.</Authors_Primary><Date_Primary>2011</Date_Primary><Keywords>Anticipation</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Pain</Keywords><Keywords>Patients</Keywords><Reprint>Not in File</Reprint><Start_Page>751</Start_Page><End_Page>759</End_Page><Periodical>Psychosomatic Medicine</Periodical><Volume>73</Volume><Issue>9</Issue><Web_URL> name="System">Psychosomatic Medicine</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Burgmer et al 2011) rather than the reductions found in this study. Methodologically our study was better able to pin-point activity within a few hundred millisecond of pain, which we have previously found ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2008</Year><RecNum>2136</RecNum><IDText>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2136</Ref_ID><Title_Primary>Modulation of pain perception by expectation and uncertainty: behavioral characteristics and anticipatory neural correlates</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Seymour,B.</Authors_Primary><Authors_Primary>Boyle,Y.</Authors_Primary><Authors_Primary>El-Deredy,W.</Authors_Primary><Authors_Primary>Jones,A.K.P.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>Uncertainty</Keywords><Reprint>Not in File</Reprint><Start_Page>240</Start_Page><End_Page>250</End_Page><Periodical>Pain</Periodical><Volume>135</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown et al 2008a) to differ from the earlier anticipatory activity likely to be resolvable with fMRI due to its poorer temporal resolution. Our results shed further light on previous data by showing that, largely, abnormalities in frontal responses are not unique to FM patients but rather generic to other forms of chronic pain. Indeed, previous work has already shown that patients with atypical facial pain have reduced DLPFC responses to pain compared to pain-free controls ADDIN REFMGR.CITE <Refman><Cite><Author>Derbyshire</Author><Year>1994</Year><RecNum>310</RecNum><IDText>Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>310</Ref_ID><Title_Primary>Cerebral responses to pain in patients with atypical facial pain measured by positron emission tomography</Title_Primary><Authors_Primary>Derbyshire,S.W.</Authors_Primary><Authors_Primary>Jones,A.K.</Authors_Primary><Authors_Primary>Devani,P.</Authors_Primary><Authors_Primary>Friston,K.J.</Authors_Primary><Authors_Primary>Feinmann,C.</Authors_Primary><Authors_Primary>Harris,M.</Authors_Primary><Authors_Primary>Pearce,S.</Authors_Primary><Authors_Primary>Watson,J.D.</Authors_Primary><Authors_Primary>Frackowiak,R.S.</Authors_Primary><Date_Primary>1994/10</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>blood</Keywords><Keywords>Brain</Keywords><Keywords>Case-Control Studies</Keywords><Keywords>Facial Pain</Keywords><Keywords>Female</Keywords><Keywords>Heat</Keywords><Keywords>Human</Keywords><Keywords>Middle Aged</Keywords><Keywords>Pain</Keywords><Keywords>physiopathology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>radionuclide imaging</Keywords><Keywords>Regional Blood Flow</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Thalamus</Keywords><Keywords>Tomography,Emission-Computed</Keywords><Reprint>Not in File</Reprint><Start_Page>1166</Start_Page><End_Page>1172</End_Page><Periodical>J Neurol.Neurosurg.Psychiatry</Periodical><Volume>57</Volume><Issue>10</Issue><Address>MRC Cyclotron Unit, Hammersmith Hospital, London, UK</Address><Web_URL>PM:7931375</Web_URL><ZZ_JournalFull><f name="System">J Neurol.Neurosurg.Psychiatry</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Derbyshire et al 1994).The correlation of the lower fronto-parietal activity during pain anticipation (found in patients) with coping factors (pain catastrophising, anxiety) lends itself to the conclusion that activation of these brain regions during anticipation of acute pain is adaptive for coping. In a recent study ADDIN REFMGR.CITE <Refman><Cite><Author>Brown</Author><Year>2013</Year><RecNum>2726</RecNum><IDText>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2726</Ref_ID><Title_Primary>Psychobiological correlates of improved mental health in patients with musculoskeletal pain after a mindfulness-based pain management program</Title_Primary><Authors_Primary>Brown,C.A.</Authors_Primary><Authors_Primary>Jones,A.K.P</Authors_Primary><Date_Primary>2013</Date_Primary><Keywords>Patients</Keywords><Keywords>Musculoskeletal</Keywords><Keywords>Pain</Keywords><Reprint>Not in File</Reprint><Start_Page>233</Start_Page><End_Page>244</End_Page><Periodical>Clinical Journal of Pain</Periodical><Volume>29</Volume><Issue>3</Issue><ZZ_JournalFull><f name="System">Clinical Journal of Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Brown and Jones 2013), we found that patients with a mixture of diagnoses (mostly FM and OA) who had participated in a non-pharmacological intervention showed less deactivation (i.e. greater activity) during pain anticipation in the left DLPFC as a result. This increase correlated with improvements in coping variables. DLPFC is considered part of an executive control network ADDIN REFMGR.CITE <Refman><Cite><Author>Buckner</Author><Year>2008</Year><RecNum>2481</RecNum><IDText>The Brain&apos;s Default Network</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2481</Ref_ID><Title_Primary>The Brain&apos;s Default Network</Title_Primary><Authors_Primary>Buckner,Randy L.</Authors_Primary><Authors_Primary>ndrews-Hanna,Jessica R.</Authors_Primary><Authors_Primary>Schacter,Daniel L.</Authors_Primary><Date_Primary>2008</Date_Primary><Keywords>Alzheimer</Keywords><Keywords>Brain</Keywords><Keywords>default mode</Keywords><Keywords>default network</Keywords><Keywords>default system</Keywords><Keywords>fMRI</Keywords><Keywords>Hippocampus</Keywords><Keywords>Memory</Keywords><Keywords>PET</Keywords><Keywords>Schizophrenia</Keywords><Reprint>Not in File</Reprint><Start_Page>1</Start_Page><End_Page>38</End_Page><Periodical>Annals of the New York Academy of Sciences</Periodical><Volume>1124</Volume><Issue>1</Issue><Web_URL> name="System">Annals of the New York Academy of Sciences</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Fox</Author><Year>2005</Year><RecNum>2482</RecNum><IDText>The human brain is intrinsically organized into dynamic, anticorrelated functional networks</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2482</Ref_ID><Title_Primary>The human brain is intrinsically organized into dynamic, anticorrelated functional networks</Title_Primary><Authors_Primary>Fox,M.D.</Authors_Primary><Authors_Primary>Snyder,A.Z.</Authors_Primary><Authors_Primary>Vincent,J.L.</Authors_Primary><Authors_Primary>Corbetta,M.</Authors_Primary><Authors_Primary>Van Essen,D.C.</Authors_Primary><Authors_Primary>Raichle,M.E.</Authors_Primary><Date_Primary>2005</Date_Primary><Keywords>article</Keywords><Keywords>Behavior</Keywords><Keywords>blood</Keywords><Keywords>Brain</Keywords><Keywords>CEREBRAL-CORTEX</Keywords><Keywords>Cognitive</Keywords><Keywords>CONNECTIVITY</Keywords><Keywords>CORTICAL NETWORKS</Keywords><Keywords>DEFAULT-MODE</Keywords><Keywords>EMOTION-INDUCED CHANGES</Keywords><Keywords>fMRI</Keywords><Keywords>functional connectivity</Keywords><Keywords>functional MRI</Keywords><Keywords>Human</Keywords><Keywords>INDEPENDENT COMPONENT ANALYSIS</Keywords><Keywords>Medial prefrontal cortex</Keywords><Keywords>Oxygen</Keywords><Keywords>RESTING-STATE</Keywords><Keywords>spontaneous activity</Keywords><Keywords>Washington</Keywords><Keywords>WORKING-MEMORY</Keywords><Reprint>Not in File</Reprint><Start_Page>9673</Start_Page><End_Page>9678</End_Page><Periodical>Proceedings of the National Academy of Sciences of the United States of America</Periodical><Volume>102</Volume><Issue>27</Issue><Availability>Washington Univ, Dept Radiol, St Louis, MO 63110 USA. Washington Univ, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Dept Anat &amp; Neurobiol, St Louis, MO 63110 USA. Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA.</Availability><Web_URL>ISI:000230406000042</Web_URL><ZZ_JournalFull><f name="System">Proceedings of the National Academy of Sciences of the United States of America</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Fox et al 2005;Buckner et al 2008), and has been associated with inhibitory effects on negative emotional responses, for example through cognitive re-appraisal ADDIN REFMGR.CITE <Refman><Cite><Author>Herwig</Author><Year>2007</Year><RecNum>2197</RecNum><IDText>Modulation of anticipatory emotion and perception processing by cognitive control</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2197</Ref_ID><Title_Primary>Modulation of anticipatory emotion and perception processing by cognitive control</Title_Primary><Authors_Primary>Herwig,U.</Authors_Primary><Authors_Primary>Baumgartner,T.</Authors_Primary><Authors_Primary>Kaffenberger,T.</Authors_Primary><Authors_Primary>Bruhl,A.</Authors_Primary><Authors_Primary>Kottlow,M.</Authors_Primary><Authors_Primary>Schreiter-Gasser,U.</Authors_Primary><Authors_Primary>Abler,B.</Authors_Primary><Authors_Primary>Jancke,L.</Authors_Primary><Authors_Primary>Rufer,M.</Authors_Primary><Date_Primary>2007/8/15</Date_Primary><Keywords>Adult</Keywords><Keywords>Amygdala</Keywords><Keywords>Anxiety</Keywords><Keywords>article</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cognitive Therapy</Keywords><Keywords>Emotions</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Image Processing,Computer-Assisted</Keywords><Keywords>imaging</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Perception</Keywords><Keywords>physiology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>Psychotherapy</Keywords><Keywords>questionnaire</Keywords><Reprint>Not in File</Reprint><Start_Page>652</Start_Page><End_Page>662</End_Page><Periodical>Neuroimage</Periodical><Volume>37</Volume><Issue>2</Issue><Address>Psychiatric University Hospital Zurich, Switzerland. uwe.herwig@puk.zh.ch</Address><Web_URL>PM:17588776</Web_URL><ZZ_JournalFull><f name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Goldin</Author><Year>2008</Year><RecNum>2472</RecNum><IDText>The Neural Bases of Emotion Regulation: Reappraisal and Suppression of Negative Emotion</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2472</Ref_ID><Title_Primary>The Neural Bases of Emotion Regulation: Reappraisal and Suppression of Negative Emotion</Title_Primary><Authors_Primary>Goldin,Philippe R.</Authors_Primary><Authors_Primary>McRae,Kateri</Authors_Primary><Authors_Primary>Ramel,Wiveka</Authors_Primary><Authors_Primary>Gross,James J.</Authors_Primary><Date_Primary>2008/3/15</Date_Primary><Keywords>Amygdala</Keywords><Keywords>cognitive control</Keywords><Keywords>Emotion</Keywords><Keywords>Emotion regulation</Keywords><Keywords>fMRI</Keywords><Keywords>insula</Keywords><Reprint>Not in File</Reprint><Start_Page>577</Start_Page><End_Page>586</End_Page><Periodical>Biological Psychiatry</Periodical><Volume>63</Volume><Issue>6</Issue><Web_URL> name="System">Biological Psychiatry</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Ochsner</Author><Year>2004</Year><RecNum>1841</RecNum><IDText>For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1841</Ref_ID><Title_Primary>For better or for worse: neural systems supporting the cognitive down- and up-regulation of negative emotion</Title_Primary><Authors_Primary>Ochsner,K.N.</Authors_Primary><Authors_Primary>Ray,R.D.</Authors_Primary><Authors_Primary>Cooper,J.C.</Authors_Primary><Authors_Primary>Robertson,E.R.</Authors_Primary><Authors_Primary>Chopra,S.</Authors_Primary><Authors_Primary>Gabrieli,J.D.</Authors_Primary><Authors_Primary>Gross,J.J.</Authors_Primary><Date_Primary>2004/10</Date_Primary><Keywords>Adult</Keywords><Keywords>Amygdala</Keywords><Keywords>article</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cognition</Keywords><Keywords>Cues</Keywords><Keywords>Emotions</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Image Interpretation,Computer-Assisted</Keywords><Keywords>imaging</Keywords><Keywords>Knowledge</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>physiology</Keywords><Keywords>psychology</Keywords><Keywords>Research Support,Non-U.&apos;t</Keywords><Keywords>Research Support,U.&apos;t,Non-P.H.S.</Keywords><Keywords>Research Support,U.&apos;t,P.H.S.</Keywords><Keywords>Social Perception</Keywords><Reprint>Not in File</Reprint><Start_Page>483</Start_Page><End_Page>499</End_Page><Periodical>Neuroimage</Periodical><Volume>23</Volume><Issue>2</Issue><Address>Department of Psychology, Columbia University, 369 Schermerhorn Hall, New York, NY 10027, USA. ochsner@psych.columbia.edu</Address><Web_URL>PM:15488398</Web_URL><ZZ_JournalFull><f name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Ochsner et al 2004;Herwig et al 2007;Goldin et al 2008), and on conditioned fear processing in the insula and amygdala ADDIN REFMGR.CITE <Refman><Cite><Author>Beauregard</Author><Year>2001</Year><RecNum>343</RecNum><IDText>Neural correlates of conscious self-regulation of emotion</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>343</Ref_ID><Title_Primary>Neural correlates of conscious self-regulation of emotion</Title_Primary><Authors_Primary>Beauregard,M.</Authors_Primary><Authors_Primary>Levesque,J.</Authors_Primary><Authors_Primary>Bourgouin,P.</Authors_Primary><Date_Primary>2001/9/15</Date_Primary><Keywords>Adult</Keywords><Keywords>Amygdala</Keywords><Keywords>analysis</Keywords><Keywords>anatomy &amp; histology</Keywords><Keywords>Arousal</Keywords><Keywords>Behavior</Keywords><Keywords>blood</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cognition</Keywords><Keywords>Consciousness</Keywords><Keywords>Emotions</Keywords><Keywords>Erotica</Keywords><Keywords>Human</Keywords><Keywords>Hypothalamus</Keywords><Keywords>Limbic System</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Neural Inhibition</Keywords><Keywords>Neurons</Keywords><Keywords>Oxygen</Keywords><Keywords>physiology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>psychology</Keywords><Keywords>Repression</Keywords><Keywords>Sexuality</Keywords><Keywords>Subtraction Technique</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Volition</Keywords><Reprint>Not in File</Reprint><Start_Page>RC165</Start_Page><Periodical>J Neurosci</Periodical><Volume>21</Volume><Issue>18</Issue><Address>Departement de Radiologie, Faculte de Medecine, Universite de Montreal and Centre Hospitalier de l&apos;Universite de Montreal (CHUM), Hopital Notre-Dame, Montreal, Quebec, Canada H2L 4M1. beauregm@magellan.umontreal.ca</Address><Web_URL>PM:11549754</Web_URL><ZZ_JournalFull><f name="System">J Neurosci</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Goldin</Author><Year>2008</Year><RecNum>2472</RecNum><IDText>The Neural Bases of Emotion Regulation: Reappraisal and Suppression of Negative Emotion</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2472</Ref_ID><Title_Primary>The Neural Bases of Emotion Regulation: Reappraisal and Suppression of Negative Emotion</Title_Primary><Authors_Primary>Goldin,Philippe R.</Authors_Primary><Authors_Primary>McRae,Kateri</Authors_Primary><Authors_Primary>Ramel,Wiveka</Authors_Primary><Authors_Primary>Gross,James J.</Authors_Primary><Date_Primary>2008/3/15</Date_Primary><Keywords>Amygdala</Keywords><Keywords>cognitive control</Keywords><Keywords>Emotion</Keywords><Keywords>Emotion regulation</Keywords><Keywords>fMRI</Keywords><Keywords>insula</Keywords><Reprint>Not in File</Reprint><Start_Page>577</Start_Page><End_Page>586</End_Page><Periodical>Biological Psychiatry</Periodical><Volume>63</Volume><Issue>6</Issue><Web_URL> name="System">Biological Psychiatry</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Beauregard et al 2001;Goldin et al 2008). These interactions are thought to dampen the affective response to pain ADDIN REFMGR.CITE <Refman><Cite><Author>Beauregard</Author><Year>2001</Year><RecNum>343</RecNum><IDText>Neural correlates of conscious self-regulation of emotion</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>343</Ref_ID><Title_Primary>Neural correlates of conscious self-regulation of emotion</Title_Primary><Authors_Primary>Beauregard,M.</Authors_Primary><Authors_Primary>Levesque,J.</Authors_Primary><Authors_Primary>Bourgouin,P.</Authors_Primary><Date_Primary>2001/9/15</Date_Primary><Keywords>Adult</Keywords><Keywords>Amygdala</Keywords><Keywords>analysis</Keywords><Keywords>anatomy &amp; histology</Keywords><Keywords>Arousal</Keywords><Keywords>Behavior</Keywords><Keywords>blood</Keywords><Keywords>Brain</Keywords><Keywords>Brain Mapping</Keywords><Keywords>Cognition</Keywords><Keywords>Consciousness</Keywords><Keywords>Emotions</Keywords><Keywords>Erotica</Keywords><Keywords>Human</Keywords><Keywords>Hypothalamus</Keywords><Keywords>Limbic System</Keywords><Keywords>Magnetic Resonance Imaging</Keywords><Keywords>Male</Keywords><Keywords>Neural Inhibition</Keywords><Keywords>Neurons</Keywords><Keywords>Oxygen</Keywords><Keywords>physiology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>psychology</Keywords><Keywords>Repression</Keywords><Keywords>Sexuality</Keywords><Keywords>Subtraction Technique</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Volition</Keywords><Reprint>Not in File</Reprint><Start_Page>RC165</Start_Page><Periodical>J Neurosci</Periodical><Volume>21</Volume><Issue>18</Issue><Address>Departement de Radiologie, Faculte de Medecine, Universite de Montreal and Centre Hospitalier de l&apos;Universite de Montreal (CHUM), Hopital Notre-Dame, Montreal, Quebec, Canada H2L 4M1. beauregm@magellan.umontreal.ca</Address><Web_URL>PM:11549754</Web_URL><ZZ_JournalFull><f name="System">J Neurosci</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Lorenz</Author><Year>2003</Year><RecNum>226</RecNum><IDText>Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>226</Ref_ID><Title_Primary>Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation</Title_Primary><Authors_Primary>Lorenz,J.</Authors_Primary><Authors_Primary>Minoshima,S.</Authors_Primary><Authors_Primary>Casey,K.L.</Authors_Primary><Date_Primary>2003/5</Date_Primary><Keywords>Adult</Keywords><Keywords>adverse effects</Keywords><Keywords>Affect</Keywords><Keywords>blood supply</Keywords><Keywords>Capsaicin</Keywords><Keywords>diagnostic use</Keywords><Keywords>drug effects</Keywords><Keywords>Frontal Lobe</Keywords><Keywords>Heat</Keywords><Keywords>Human</Keywords><Keywords>Hyperalgesia</Keywords><Keywords>Irritants</Keywords><Keywords>Male</Keywords><Keywords>Nociceptors</Keywords><Keywords>Pain</Keywords><Keywords>Perception</Keywords><Keywords>physiology</Keywords><Keywords>physiopathology</Keywords><Keywords>Prefrontal Cortex</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Principal Component Analysis</Keywords><Keywords>Psychophysics</Keywords><Keywords>Regional Blood Flow</Keywords><Keywords>Regression Analysis</Keywords><Keywords>Skin</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Support,U.&apos;t,Non-P.H.S.</Keywords><Keywords>Support,U.&apos;t,P.H.S.</Keywords><Keywords>Thalamus</Keywords><Keywords>Tomography,Emission-Computed</Keywords><Reprint>Not in File</Reprint><Start_Page>1079</Start_Page><End_Page>1091</End_Page><Periodical>Brain</Periodical><Volume>126</Volume><Issue>Pt 5</Issue><Address>Department of Neurology, University of Michigan, Neurology Research Laboratories, Veterans Affairs Medical Center, Ann Arbor, MI, USA. lorenz@uke.uni-hamburg.de</Address><Web_URL>PM:12690048</Web_URL><ZZ_JournalFull><f name="System">Brain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Beauregard et al 2001;Lorenz et al 2003). However, in our study, there was no statistical relationship between anticipatory response in the insula cortices and that of the DLPFC, nor was there a correlative relationship between DLPFC and clinical pain within the patient groups.Further findingsAn estimated source of the anticipatory potential in the precuneus was found to be more active in patients with osteoarthritis compared to those with fibromyalgia, explaining the difference in the evoked-potential amplitude at the scalp. This result was surprising and not related to our anatomical hypotheses. There was a lack of a relationship between activity in this region and the clinical/coping self-report measures, and so at this stage it is difficult to interpret the meaning of this result. It is interesting to note that precuneus activation is related to memory retrieval requiring visual imagery ADDIN REFMGR.CITE <Refman><Cite><Author>Fletcher</Author><Year>1995</Year><RecNum>2996</RecNum><IDText>The mind&apos;s eye - Precuneus activation in memory-related imagery</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2996</Ref_ID><Title_Primary>The mind&apos;s eye - Precuneus activation in memory-related imagery</Title_Primary><Authors_Primary>Fletcher,P.C.</Authors_Primary><Authors_Primary>Frith,C.D.</Authors_Primary><Authors_Primary>Baker,S.C.</Authors_Primary><Authors_Primary>Shallice,T.</Authors_Primary><Authors_Primary>Frackowiak,R.S.J.</Authors_Primary><Authors_Primary>Dolan,R.J.</Authors_Primary><Date_Primary>1995</Date_Primary><Reprint>Not in File</Reprint><Start_Page>195</Start_Page><End_Page>200</End_Page><Periodical>Neuroimage</Periodical><Volume>2</Volume><Issue>3</Issue><Web_URL> name="System">Neuroimage</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Fletcher et al 1995), and one possibility is that OA patients evoke more memory-related visual imagery during pain anticipation, although this cannot be verified with our data. Possible contributions of the precuneus to clinical pain symptoms warrants further investigation.Limitations and implications of the study designWhile anticipatory responses were the focus of this work, it is of interest to note that the groups in this study did not differ in their responses to the experimental laser stimulus, in terms of both the laser energy required to elicit moderate pain or the amplitude of the resulting P2 peak. This contrasts with some studies that have found allodynia to laser heat in patients with FM, and greater P2 peak amplitudes ADDIN REFMGR.CITE <Refman><Cite><Author>Gibson</Author><Year>1994</Year><RecNum>2</RecNum><IDText>Altered Heat Pain Thresholds and Cerebral Event-Related Potentials Following Painful Co2-Laser Stimulation in Subjects with Fibromyalgia Syndrome</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2</Ref_ID><Title_Primary>Altered Heat Pain Thresholds and Cerebral Event-Related Potentials Following Painful Co2-Laser Stimulation in Subjects with Fibromyalgia Syndrome</Title_Primary><Authors_Primary>Gibson,S.J.</Authors_Primary><Authors_Primary>Littlejohn,G.O.</Authors_Primary><Authors_Primary>Gorman,M.M.</Authors_Primary><Authors_Primary>Helme,R.D.</Authors_Primary><Authors_Primary>Granges,G.</Authors_Primary><Date_Primary>1994</Date_Primary><Reprint>Not in File</Reprint><Start_Page>185</Start_Page><End_Page>193</End_Page><Periodical>Pain</Periodical><Volume>58</Volume><Issue>2</Issue><Web_URL>ISI:A1994PD74900006</Web_URL><ZZ_JournalFull><f name="System">Pain</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite><Cite><Author>Lorenz</Author><Year>1998</Year><RecNum>92</RecNum><IDText>Hyperalgesia or hypervigilance? An evoked potential approach to the study of fibromyalgia syndrome</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>92</Ref_ID><Title_Primary>Hyperalgesia or hypervigilance? An evoked potential approach to the study of fibromyalgia syndrome</Title_Primary><Authors_Primary>Lorenz,J.</Authors_Primary><Date_Primary>1998</Date_Primary><Keywords>Arthritis and Rheumatism</Keywords><Keywords>Attention</Keywords><Keywords>Auditory Perception</Keywords><Keywords>carbon dioxide laser</Keywords><Keywords>clinical article</Keywords><Keywords>conference paper</Keywords><Keywords>controlled study</Keywords><Keywords>evoked auditory response</Keywords><Keywords>Evoked Potentials</Keywords><Keywords>evoked response</Keywords><Keywords>Female</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>General pathology and pathological anatomy</Keywords><Keywords>hearing</Keywords><Keywords>Human</Keywords><Keywords>Hyperalgesia</Keywords><Keywords>Internal medicine</Keywords><Keywords>laser</Keywords><Keywords>lorenz@uke.uni hamburg.de</Keywords><Keywords>neuromodulation</Keywords><Keywords>nociception</Keywords><Keywords>Pain</Keywords><Keywords>Pain Threshold</Keywords><Keywords>Perception</Keywords><Keywords>physiology</Keywords><Keywords>Sensation</Keywords><Keywords>Syndrome</Keywords><Reprint>Not in File</Reprint><Start_Page>19</Start_Page><End_Page>22</End_Page><Periodical>Z.Rheumatol.</Periodical><Volume>57</Volume><Issue>SUPPL. 2</Issue><Address>J. Lorenz, Institute of Physiology, University Hospital Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany</Address><ZZ_JournalStdAbbrev><f name="System">Z.Rheumatol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Gibson et al 1994;Lorenz 1998), although other studies have not be able to demonstrate such effects for heat stimuli ADDIN REFMGR.CITE <Refman><Cite><Author>Norregaard</Author><Year>1997</Year><RecNum>2860</RecNum><IDText>Pressure and Heat Pain Thresholds and Tolerances in Patients with Fibromyalgia</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2860</Ref_ID><Title_Primary>Pressure and Heat Pain Thresholds and Tolerances in Patients with Fibromyalgia</Title_Primary><Authors_Primary>Norregaard,Jesper</Authors_Primary><Authors_Primary>Bendtsen,Lars</Authors_Primary><Authors_Primary>Lykkegaard,Jens</Authors_Primary><Authors_Primary>Jensen,Rigmor</Authors_Primary><Date_Primary>1997/1/1</Date_Primary><Keywords>Fibromyalgia</Keywords><Keywords>Heat</Keywords><Keywords>Pain</Keywords><Keywords>Pain Threshold</Keywords><Keywords>Patients</Keywords><Keywords>Pressure</Keywords><Reprint>Not in File</Reprint><Start_Page>43</Start_Page><End_Page>53</End_Page><Periodical>J Muscoskeletal Pain</Periodical><Volume>5</Volume><Issue>2</Issue><Web_URL> name="System">Journal of Musculoskeletal Pain</f></ZZ_JournalFull><ZZ_JournalStdAbbrev><f name="System">J Muscoskeletal Pain</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>(Norregaard et al 1997) in line with the present data. Differences in methodology might explain such discrepancies: our protocol was not optimally designed to pinpoint pain thresholds, but rather laser energies eliciting moderately painful sensations. Also, unlike other studies, we adjusted the laser energy to be moderately painful for each participant rather than using fixed laser energy across all participants. Hence it may not be valid to draw comparisons between our studies and other studies assessing heat sensitivity. Another important observation in this study is that, although the anticipatory responses were related to clinical measures of pain and tenderness, the experimental pain stimulus activations were not. This can be explained by the fact that laser heat energies were tailored to each participant. The experiment was designed to avoid the potential confound of differences in brain responses being due to peripheral nociception. This involved standardization to similar levels of pain perception across participants. Hence, the size of the pain-evoked potential would also be individually adjusted, taking away any potential correlation with distress. The measurement of anticipation therefore provides a way of comparing top-down influences on pain across groups of patients and healthy volunteers in a way that is not confounded by differences in peripheral nociceptive processing. We did not control for non-specific anticipation (i.e. anticipation not related to the expected pain level) in this study, for example by providing a contrast of pain anticipation to the anticipation of non-painful stimuli. It is possible that the results of this study might arise from generic mechanisms of anticipation rather than those specific to pain anticipation. This is certainly a question that needs to be explored, and has implications for whether non-pharmacological treatments (e.g. psychological therapies) should target pain anticipation per se, negative expectancy including but not limited to pain, or general expectancy (positive or negative) mechanisms.ConclusionThis study reveals that abnormal anticipatory responses to pain in FM are largely shared with patients with regional pain (OA), suggesting that these may represent common brain mechanisms for chronic regional and widespread pain. Lower anticipatory activity in a left frontal and parietal cluster (including DLPFC) was related to coping factors (anxiety, catastrophising) rather than pain type. The greater anticipatory insula activity observed in the FM group was related to clinical pain symptoms and tenderness regardless of the pain type or psychological factors, suggesting it may play a role in enhancing pain in OA as well as FM. 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Mean (SD)Group effectPost-hoc tests (P values)HP groupFM groupOA groupStatisticP valueHP vs. FMHP vs. OAFM vs. OAn=15n=16n=16*F or **χ2Age (years)46.4 (7.3)48.6 (8.6)55.0 (8.7)4.7*0.0140.7430.0190.100Chronic pain (/10)Clinical pain0.4 (0.7)4.0 (1.7)4.1 (2.2)25.0**<0.001<0.001<0.0010.835Pain interference0.3 (0.7)4.3 (1.9)4.1 (2.5)23.9**<0.001<0.001<0.0010.952Number of tender points (/18)2.3 (2.4)14.1 (3.8)9.4 (7.3)15.2**<0.001<0.0010.0200.080Pain Catastrophizing Scale (/52)6.9 (7.6)16.3 (7.6)16.3 (2.3)5.1*0.0100.0270.0311.000Hospital Anxiety and Depression ScaleAnxiety (/21)3.6 (2.3)8.4 (4.0)7.5 (3.7)8.6*0.0010.0010.0120.766Depression (/21)1.5 (1.7)5.9 (3.8)4.3 (3.7)7.2*0.0020.0020.0780.388Laser pain ratings (/10)5.8 (0.4)6.1 (0.9)6.2 (1.3)0.3*0.747Laser energy (W cm-2)12.4 (2.2)13.6 (2.1)13.1 (3.2)0.9*0.423Table 2: Group effects on sources of anticipatory potentials. Brain regions are organized by cluster with ? denoting regions belonging to the same cluster as the previous entry.Brain Region L/RMNI coordinatesCluster levelVoxel levelxyzNo. voxelsp-ValueT-Scorep-ValueEffect of no chronic pain: [HP> FM]+[HP>OA]Late anticipation: Postcentral gyrusL-30-16563766<0.0016.35<0.001Postcentral gyrusL-8-1460??6.14<0.001Superior frontal gyrusL-63248??5.730.001Superior frontal gyrusL-106422??5.060.007Middle frontal gyrusL-36852??4.770.013Precentral gyrusR34-105815360.0025.98<0.001Superior frontal gyrusR18656??5.98<0.001Occipito-temporal gyrusR50-7046740.0165.79<0.001Occipito-temporal gyrusL-28-72247390.0115.060.007Parietal operculumL-50-26263800.0804.400.037Parietal operculumL-46-4104080.0685.190.005Middle frontal gyrusR3418549800.0044.680.018Superior temporal gyrusR-50-52122460.1865.010.007ThalamusL/R0-181213550.0034.830.018Effect of FM pain: [FM > HP]+[FM>OA]Late anticipation: InsulaL-40-823870<0.0015.830.005InsulaR36-10-82351<0.0014.650.042Inferior temporal gyrusR58-8-282830.1464.780.042Effect of OA vs. FM pain: [OA>FM]Late anticipation: PrecuneusL-6-62482748<0.0015.540.012PrecuneusR12-7650??4.620.023Table 3: Regression statistics for the comparison of volumes of interest (VOIs) relative to self-report measures across participants in the patient groups. The VOIs were selected on the basis of results from the group effects on pain anticipation. DLPFC: dorsolateral prefrontal cortex; SMA: supplementary motor area; PCG: post-central gyrus. * Covariates used in the multiple regression analyses were HADS-anxiety and pain catastrophising. Significant p values after considering multiple comparisons are italicized. Dependent variableIndependent variableAverage clinical painAverage clinical painTender pointsAnxietyDepressionPain catastro-phizingWith covariates *Left DLPFC / SMA / PCG clusterr coefficient-0.2260.057-0.434-0.385-0.485p value0.2300.7740.0190.0390.007Right DLPFCr coefficient-0.2990.234-0.086-0.108-0.164p value0.0960.2120.6470.5640.370Left Insular coefficient0.5580.6580.4230.0730.0370.110p value0.0010.0010.0200.6950.8430.549Right Insular coefficient0.4030.3140.0530.1030.158p value0.0220.0910.7760.5820.389Precuneusr coefficient-0.2300.011-0.087-0.187-0.043p value0.2060.9560.6430.3130.814-1143006553200Figure 1: ERP waveforms and topography plots. (a) Average waveforms for each group are plotted of the anticipation-evoked potential and pain-avoked potential. The data is the mean of nine electrodes including Cz and all adjacent electrodes. ERPs are corrected to the pre-anticipation baseline (-3500ms to -3000ms), with early anticipation, late anticipation, and P2 peak periods marked. (b) Topoplots displayed are the average of each group, with ERP data corrected to the pre-anticipation baseline. DLPFC: dorsolateral prefrontal cortex; SMA: supplementary motor area; PCG: post-central gyrus.00Figure 1: ERP waveforms and topography plots. (a) Average waveforms for each group are plotted of the anticipation-evoked potential and pain-avoked potential. The data is the mean of nine electrodes including Cz and all adjacent electrodes. ERPs are corrected to the pre-anticipation baseline (-3500ms to -3000ms), with early anticipation, late anticipation, and P2 peak periods marked. (b) Topoplots displayed are the average of each group, with ERP data corrected to the pre-anticipation baseline. DLPFC: dorsolateral prefrontal cortex; SMA: supplementary motor area; PCG: post-central gyrus.95255505450Figure 2: ERP source estimates and their correlates during late anticipation (average activity over -500ms to 0ms). (a) Group effects on ERP sources showing regions of greater activity in the fibromyalgia group relative to the other two groups (i.e. the conjunction of fibromyalgia patients vs. with each of the other two groups: FM>OA + FM>HP). Fixation cross shows most activated voxel. Y-axis units are the log-transformed current source density. (b) Group effects on ERP sources showing regions of reduced activity in the patient groups relative to healthy participants (i.e. the conjunction of healthy participants vs. each patient group: HP>FM + HP>OA). Coordinates of image are chosen to visualize all activated clusters, and do not denote a region of activation. Y-axis units are the log-transformed current source density. (c) Greater activity in the osteoarthritis group relative to the fibromyalgia group (OA>FM). Fixation cross shows most activated voxel.00Figure 2: ERP source estimates and their correlates during late anticipation (average activity over -500ms to 0ms). (a) Group effects on ERP sources showing regions of greater activity in the fibromyalgia group relative to the other two groups (i.e. the conjunction of fibromyalgia patients vs. with each of the other two groups: FM>OA + FM>HP). Fixation cross shows most activated voxel. Y-axis units are the log-transformed current source density. (b) Group effects on ERP sources showing regions of reduced activity in the patient groups relative to healthy participants (i.e. the conjunction of healthy participants vs. each patient group: HP>FM + HP>OA). Coordinates of image are chosen to visualize all activated clusters, and do not denote a region of activation. Y-axis units are the log-transformed current source density. (c) Greater activity in the osteoarthritis group relative to the fibromyalgia group (OA>FM). Fixation cross shows most activated voxel. ................
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