Effective Connectivity Among Brain Regions Associated With Slow Temporal Summation of C-Fiber-Evoked Pain in Fibromyalgia Patients and Healthy Controls


      Temporal summation of “second pain” (TSSP) or “windup” results from the summation of C-fiber-evoked responses of dorsal-horn neurons. This phenomenon is dependent on stimulus frequency (≥.33 Hz) and relevant to central sensitization and chronic pain. Our previous neuroimaging studies characterized brain regions associated with TSSP in normal control (NC) and fibromyalgia (FM) groups. During an fMRI scan, subjects received sensitivity-adjusted repetitive heat pulses at .33 on the right foot. FM subjects required significantly lower stimulus intensities than NC to achieve similar TSSP and no significant group differences in the pain-related brain activity were detected. In our current study, we asked whether the effective connectivity among a set of TSSP-related brain regions identified in our previous work differs amongst FM and NC groups. Structural equation modeling was used to characterize the effective connectivity amongst a priori selected brain areas, including the thalamus, S1, S2, posterior insula, and the anterior midcingulate cortex (aMCC) within the left and right hemispheres. This analysis confirmed our a priori models of effective connectivity among these regions mainly confirmed those hypothesized, yet some unpredicted connections were additionally identified (thalamus to aMCC and aMCC to S1). While the models of effective connectivity were not identical in the FM and NC groups, they were very similar. Additionally, the TSSP related effective connectivity of right and left hemisphere regions was very similar. These results provide evidence for significant overlap of the fundamental brain mechanisms that process sensory and affective information related to TSSP in NC and FM groups.


      Models of effective connectivity involving pain-related processes were estimated with fMRI data from chronic pain and healthy populations. Models were estimated in both hemispheres, and although similar, fibromyalgia was associated with unique models of pain-related processes. Group differences involved the left hemisphere and S1, S2, and posterior insula.

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        • Bollen K.A.
        Structural equations with latent variables.
        Wiley, New York, NY1989
        • Browne M.W.
        • Cudeck R.
        Alternative ways of assessing model fit.
        in: Bollen K.A. Long J.S. Testing Structural Equation Models. Sage, Newbury Park, CA1993: 136-162
        • Burton H.
        • Fabri M.
        • Alloway K.
        Cortical areas within the lateral sulcus connected to cutaneous representations in areas 3b and 1: A revised interpretation of the second somatosensory area in macaque monkeys.
        J Comp Neurol. 1995; 355: 539-562
        • Casey K.L.
        Pain Imaging: Progress in Pain Research and Management. Vol 18. IASP Press, Seattle, WA2000
        • Coghill R.C.
        • Talbot J.D.
        • Evans A.C.
        • Meyer E.
        • Gjedde A.
        • Bushnell M.C.
        • Duncan G.H.
        Distributed processing of pain and vibration by the human brain.
        J Neurosci. 1994; 14: 4095-4108
        • Craggs J.G.
        • Price D.D.
        • Verne G.N.
        • Perlstein W.M.
        • Robinson M.E.
        Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia.
        Neuroimage. 2007; 38: 720-729
        • Davis K.D.
        The neural circuitry of pain as explored with functional MRI.
        Neurol Res. 2000; 22: 313-317
        • Davis K.D.
        • Kwan C.L.
        • Crawley A.P.
        • Mikulis D.J.
        Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli.
        J Neurophysiol. 1998; 80: 1533-1546
        • Davis K.D.
        • Taylor S.J.
        • Crawley A.P.
        • Wood M.L.
        • Mikulis D.J.
        Functional MRI of pain- and attention-related activations in the human cingulate cortex.
        J Neurophysiol. 1997; 77: 3370-3380
        • Disbrow E.
        • Roberts T.
        • Poeppel D.
        • Krubitzer L.
        Evidence for interhemispheric processing of inputs from the hands in human S2 and PV.
        J Neurophysiol. 2001; 85: 2236-2244
        • Eickhoff S.B.
        • Amunts K.
        • Mohlberg H.
        • Zilles K.
        The human parietal operculum. II. Stereotaxic maps and correlation with functional imaging results.
        Cereb Cortex. 2006; 16: 268-279
        • Eickhoff S.B.
        • Jbabdi S.
        • Caspers S.
        • Laird A.R.
        • Fox P.T.
        • Zilles K.
        • Behrens T.E.
        Anatomical and functional connectivity of cytoarchitectonic areas within the human parietal operculum.
        J Neurosci. 2010; 30: 6409-6421
        • Eickhoff S.B.
        • Schleicher A.
        • Zilles K.
        • Amunts K.
        The human parietal operculum. I. Cytoarchitectonic mapping of subdivisions.
        Cereb Cortex. 2006; 16: 254-267
        • Fields H.
        State-dependent opioid control of pain.
        Nat Rev Neurosci. 2004; 5: 565-575
        • Forman S.D.
        • Cohen J.D.
        • Fitzgerald M.
        • Eddy W.F.
        • Mintun M.A.
        • Noll D.C.
        Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): Use of a cluster-size threshold.
        Magn Reson Med. 1995; 33: 636-647
        • Hargrove J.B.
        • Bennett R.M.
        • Simons D.G.
        • Smith S.J.
        • Nagpal S.
        • Deering D.E.
        Quantitative electroencephalographic abnormalities in fibromyalgia patients.
        Clin EEG Neurosci. 2010; 41: 132-139
        • Jensen K.B.
        • Kosek E.
        • Petzke F.
        • Carville S.
        • Fransson P.
        • Marcus H.
        • Williams S.C.
        • Choy E.
        • Giesecke T.
        • Mainguy Y.
        • Gracely R.
        • Ingvar M.
        Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain.
        Pain. 2009; 144: 95-100
        • Jöreskog K.G.
        • Sörbom D.
        LISREL8: User’s Reference Guide.
        Scientific Software International, Inc., Chicago, IL1996
        • Kong J.
        • White N.S.
        • Kwong K.K.
        • Vangel M.G.
        • Rosman I.S.
        • Gracely R.H.
        • Gollub R.L.
        Using fMRI to dissociate sensory encoding from cognitive evaluation of heat pain intensity.
        Hum Brain Mapp. 2006; 27: 715-721
        • Koyama Y.
        • Koyama T.
        • Kroncke A.P.
        • Coghill R.C.
        Effects of stimulus duration on heat induced pain: The relationship between real-time and post-stimulus pain ratings.
        Pain. 2004; 107: 256-266
        • Mendell L.
        • Wall P.
        Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres.
        Nature. 1965; 206: 97-99
        • Moulton E.A.
        • Keaser M.L.
        • Gullapalli R.P.
        • Greenspan J.D.
        Regional intensive and temporal patterns of functional MRI activation distinguishing noxious and innocuous contact heat.
        J Neurophysiol. 2005; 93: 2183-2193
        • Napadow V.
        • LaCount L.
        • Park K.
        • As-Sanie S.
        • Clauw D.J.
        • Harris R.E.
        Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
        Arthritis Rheum. 2010; 62: 2545-2555
        • Ogino Y.
        • Nemoto H.
        • Inui K.
        • Saito S.
        • Kakigi R.
        • Goto F.
        Inner experience of pain: Imagination of pain while viewing images showing painful events forms subjective pain representation in human brain.
        Cereb Cortex. 2007; 17: 1139-1146
        • Perlstein W.M.
        • Elbert T.
        • Stenger V.A.
        Dissociation in human prefrontal cortex of affective influences on working memory-related activity.
        Proc Natl Acad Sci U S A. 2002; 99: 1736-1741
        • Petersel D.L.
        • Dror V.
        • Cheung R.
        Central amplification and fibromyalgia: Disorder of pain processing.
        J Neurosci Res. 2011; 89: 29-34
        • Peyron R.
        • Laurent B.
        • Garcia-Larrea L.
        Functional imaging of brain responses to pain. A review and meta-analysis (2000).
        Neurophysiol Clin. 2000; 30: 263-288
        • Ploner M.
        • Lee M.C.
        • Wiech K.
        • Bingel U.
        • Tracey I.
        Flexible cerebral connectivity patterns subserve contextual modulations of pain.
        Cereb Cortex. 2011; 21: 719-726
        • Price D.D.
        Psychological and neural mechanisms of the affective dimension of pain.
        Science. 2000; 288: 1769-1772
        • Price D.D.
        Central neural mechanisms that interrelate sensory and affective dimensions of pain.
        Mol Interv. 2002; 2: 392-403, 339
        • Price D.D.
        • Dubner R.
        Mechanisms of first and second pain in the peripheral and central nervous systems.
        J Invest Dermatol. 1977; 69: 167-171
        • Price D.D.
        • Hayes R.L.
        • Ruda M.
        • Dubner R.
        Neural representation of cutaneous aftersensations by spinothalamic tract neurons.
        Fed Proc. 1978; 37: 2237-2239
        • Price D.D.
        • Hu J.W.
        • Dubner R.
        • Gracely R.H.
        Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses.
        Pain. 1977; 3: 57-68
        • Price D.D.
        • Long S.
        • Huitt C.
        Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy.
        Pain. 1992; 49: 163-173
        • Price D.D.
        • Staud R.
        • Robinson M.E.
        • Mauderli A.P.
        • Cannon R.
        • Vierck C.J.
        Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients.
        Pain. 2002; 99: 49-59
        • Price D.D.
        • Zhou Q.
        • Moshiree B.
        • Robinson M.E.
        • Verne G.N.
        Peripheral and central contributions to hyperalgesia in irritable bowel syndrome.
        J Pain. 2006; 7: 529-535
        • Rainville P.
        • Doucet J.C.
        • Fortin M.C.
        • Duncan G.H.
        Rapid deterioration of pain sensory-discriminative information in short-term memory.
        Pain. 2004; 110: 605-615
        • Rainville P.
        • Duncan G.H.
        • Price D.D.
        • Carrier B.
        • Bushnell M.C.
        Pain affect encoded in human anterior cingulate but not somatosensory cortex.
        Science. 1997; 277: 968-971
        • Robinson M.E.
        • Craggs J.G.
        • Price D.D.
        • Perlstein W.M.
        • Staud R.
        Gray matter volumes of pain-related brain areas are decreased in fibromyalgia syndrome.
        J Pain. 2011; 12: 436-443
        • Shackman A.J.
        • Salomons T.V.
        • Slagter H.A.
        • Fox A.S.
        • Winter J.J.
        • Davidson R.J.
        The integration of negative affect, pain and cognitive control in the cingulate cortex.
        Nat Rev Neurosci. 2011; 12: 154-167
        • Smith S.M.
        Overview of fMRI analysis.
        Br J Radiol 77 Spec No. 2004; 2: S167-S175
        • Staud R.
        • Cannon R.C.
        • Mauderli A.P.
        • Robinson M.E.
        • Price D.D.
        • Vierck Jr., C.J.
        Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome.
        Pain. 2003; 102: 87-95
        • Staud R.
        • Craggs J.G.
        • Perlstein W.M.
        • Robinson M.E.
        • Price D.D.
        Brain activity associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls.
        Eur J Pain. 2008; 12: 1078-1089
        • Staud R.
        • Craggs J.G.
        • Robinson M.E.
        • Perlstein W.M.
        • Price D.D.
        Brain activity related to temporal summation of C-fiber evoked pain.
        Pain. 2007; 129: 130-142
        • Staud R.
        • Domingo M.
        Evidence for abnormal pain processing in fibromyalgia syndrome.
        Pain Med. 2001; 2: 208-215
        • Staud R.
        • Price D.D.
        • Fillingim R.B.
        Advanced continuous-contact heat pulse design for efficient temporal summation of second pain (windup).
        J Pain. 2006; 7: 575-582
        • Staud R.
        • Price D.D.
        • Robinson M.E.
        • Vierck Jr., C.J.
        Body pain area and pain-related negative affect predict clinical pain intensity in patients with fibromyalgia.
        J Pain. 2004; 5: 338-343
        • Staud R.
        • Robinson M.E.
        • Price D.D.
        Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients.
        J Pain. 2007; 8: 893-901
        • Staud R.
        • Robinson M.E.
        • Vierck Jr., C.J.
        • Cannon R.C.
        • Mauderli A.P.
        • Price D.D.
        Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome.
        Pain. 2003; 105: 215-222
        • Staud R.
        • Vierck C.J.
        • Cannon R.L.
        • Mauderli A.P.
        • Price D.D.
        Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome.
        Pain. 2001; 91: 165-175
        • Talairach J.
        • Tournoux P.
        Co-Planar stereotaxic atlas of the human brain.
        Thieme Publishers Inc, New York, NY1988
      1. Tantorski E.: Functional Neuroanatomy: Web textbook: Available at Accessed August 1, 2011

        • Vierck Jr., C.J.
        • Cannon R.L.
        • Fry G.
        • Maixner W.
        • Whitsel B.L.
        Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode.
        J Neurophysiol. 1997; 78: 992-1002