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Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation

Published:January 19, 2018DOI:https://doi.org/10.1016/j.jpain.2018.01.001

      Highlights

      • Smaller periaqueducal gray (PAG) volume was observed in fibromyalgia (FM) patients.
      • Conditioned pain modulation (CPM) facilitation was observed in FM patients.
      • PAG resting connectivity with cortical areas was associated with CPM inhibition.
      • Aberrant PAG-to-brainstem connectivity helps explain CPM facilitation in FM.
      • The results are consistent with animal models of descending pain facilitation.

      Abstract

      Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients.

      Perspective

      These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system.

      Key words

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      References

        • Ashburner J.
        A fast diffeomorphic image registration algorithm.
        Neuroimage. 2007; 38: 95-113
        • Bingel U.
        • Lorenz J.
        • Schoell E.
        • Weiller C.
        • Buchel C.
        Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network.
        Pain. 2006; 120: 8-15
        • Bingel U.
        • Schoell E.
        • Herken W.
        • Buchel C.
        • May A.
        Habituation to painful stimulation involves the antinociceptive system.
        Pain. 2007; 131: 21-30
        • Bjorkedal E.
        • Flaten M.A.
        Expectations of increased and decreased pain explain the effect of conditioned pain modulation in females.
        J Pain Res. 2012; 5: 289-300
        • Bogdanov V.B.
        • Vigano A.
        • Noirhomme Q.
        • Bogdanova O.V.
        • Guy N.
        • Laureys S.
        • Renshaw P.F.
        • Dallel R.
        • Phillips C.
        • Schoenen J.
        Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: An fMRI study in healthy subjects.
        Behav Brain Res. 2015; 281: 187-198
        • Bouhassira D.
        • Bing Z.
        • Le Bars D.
        Studies of the brain structures involved in diffuse noxious inhibitory controls: The mesencephalon.
        J Neurophysiol. 1990; 64: 1712-1723
        • Bouhassira D.
        • Villanueva L.
        • Bing Z.
        • Le Bars D.
        Involvement of the subnucleus reticularis dorsalis in diffuse noxious inhibitory controls in the rat.
        Brain Res. 1992; 595: 353-357
        • Bouhassira D.
        • Villanueva L.
        • Le Bars D.
        Intracerebroventricular morphine decreases descending inhibitions acting on lumbar dorsal horn neuronal activities related to pain in the rat.
        J Pharmacol Exp Ther. 1988; 247: 332-342
        • Clauw D.J.
        Fibromyalgia: A clinical review.
        JAMA. 2014; 311: 1547-1555
        • Cleeland C.S.
        • Ryan K.M.
        Pain assessment: Global use of the Brief Pain Inventory.
        Ann Acad Med Singapore. 1994; 23: 129-138
        • Coulombe M.A.
        • Erpelding N.
        • Kucyi A.
        • Davis K.D.
        Intrinsic functional connectivity of periaqueductal gray subregions in humans.
        Hum Brain Mapp. 2016; 37: 1514-1530
        • Dunckley P.
        • Wise R.G.
        • Fairhurst M.
        • Hobden P.
        • Aziz Q.
        • Chang L.
        • Tracey I.
        A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging.
        J Neurosci. 2005; 25: 7333-7341
        • Edwards R.R.
        • Dolman A.J.
        • Michna E.
        • Katz J.N.
        • Nedeljkovic S.S.
        • Janfaza D.
        • Isaac Z.
        • Martel M.O.
        • Jamison R.N.
        • Wasan A.D.
        Changes in pain sensitivity and pain modulation during oral opioid treatment: The impact of negative affect.
        Pain Med. 2016; 17: 1882-1891
        • Edwards R.R.
        • Fillingim R.B.
        • Ness T.J.
        Age-related differences in endogenous pain modulation: A comparison of diffuse noxious inhibitory controls in healthy older and younger adults.
        Pain. 2003; 101: 155-165
        • Ezra M.
        • Faull O.K.
        • Jbabdi S.
        • Pattinson K.T.
        Connectivity-based segmentation of the periaqueductal gray matter in human with brainstem optimized diffusion MRI.
        Hum Brain Mapp. 2015; 36: 3459-3471
        • Fallon N.
        • Alghamdi J.
        • Chiu Y.
        • Sluming V.
        • Nurmikko T.
        • Stancak A.
        Structural alterations in brainstem of fibromyalgia syndrome patients correlate with sensitivity to mechanical pressure.
        Neuroimage Clin. 2013; 3: 163-170
        • Fanselow M.S.
        • Decola J.P.
        • Deoca B.M.
        • Landeirafernandez J.
        Ventral and dorsolateral regions of the midbrain periaqueductal gray (Pag) control different stages of defensive behavior—Dorsolateral pag lesions enhance the defensive freezing produced by massed and immediate shock.
        Aggress Behav. 1995; 21: 63-77
        • Geva N.
        • Pruessner J.
        • Defrin R.
        Acute psychosocial stress reduces pain modulation capabilities in healthy men.
        Pain. 2014; 155: 2418-2425
        • Goffaux P.
        • de Souza J.B.
        • Potvin S.
        • Marchand S.
        Pain relief through expectation supersedes descending inhibitory deficits in fibromyalgia patients.
        Pain. 2009; 145: 18-23
        • Granot M.
        • Weissman-Fogel I.
        • Crispel Y.
        • Pud D.
        • Granovsky Y.
        • Sprecher E.
        • Yarnitsky D.
        Determinants of endogenous analgesia magnitude in a diffuse noxious inhibitory control (DNIC) paradigm: Do conditioning stimulus painfulness, gender and personality variables matter?.
        Pain. 2008; 136: 142-149
        • Grashorn W.
        • Sprenger C.
        • Forkmann K.
        • Wrobel N.
        • Bingel U.
        Age-dependent decline of endogenous pain control: Exploring the effect of expectation and depression.
        PLoS One. 2013; 8: e75629
        • Gwilym S.E.
        • Keltner J.R.
        • Warnaby C.E.
        • Carr A.J.
        • Chizh B.
        • Chessell I.
        • Tracey I.
        Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.
        Arthritis Rheum. 2009; 61: 1226-1234
        • Harris R.E.
        • Clauw D.J.
        • Scott D.J.
        • McLean S.A.
        • Gracely R.H.
        • Zubieta J.K.
        Decreased central mu-opioid receptor availability in fibromyalgia.
        J Neurosci. 2007; 27: 10000-10006
        • Harte S.E.
        • Mitra M.
        • Ichesco E.A.
        • Halvorson M.E.
        • Clauw D.J.
        • Shih A.J.
        • Kruger G.H.
        Development and validation of a pressure-type automated quantitative sensory testing system for point-of-care pain assessment.
        Med Biol Eng Comput. 2013; 51: 633-644
        • Heinricher M.M.
        Pain modulation and the transition from acute to chronic pain.
        in: Ma C. Huang Y. Translational Research in Pain and Itch. Springer Netherlands, Dordrecht2016: 105-115
        • Heinricher M.M.
        • Tavares I.
        • Leith J.L.
        • Lumb B.M.
        Descending control of nociception: Specificity, recruitment and plasticity.
        Brain Res Rev. 2009; 60: 214-225
        • Henry N.L.
        • Conlon A.
        • Kidwell K.M.
        • Griffith K.
        • Smerage J.B.
        • Schott A.F.
        • Hayes D.F.
        • Williams D.A.
        • Clauw D.J.
        • Harte S.E.
        Effect of estrogen depletion on pain sensitivity in aromatase inhibitor-treated women with early-stage breast cancer.
        J Pain. 2014; 15: 468-475
        • Hsieh J.C.
        • Stahle-Backdahl M.
        • Hagermark O.
        • Stone-Elander S.
        • Rosenquist G.
        • Ingvar M.
        Traumatic nociceptive pain activates the hypothalamus and the periaqueductal gray: A positron emission tomography study.
        Pain. 1996; 64: 303-314
        • Hu X.
        • Le T.H.
        • Parrish T.
        • Erhard P.
        Retrospective estimation and correction of physiological fluctuation in functional MRI.
        Magn Reson Med. 1995; 34: 201-212
        • Iannetti G.D.
        • Zambreanu L.
        • Wise R.G.
        • Buchanan T.J.
        • Huggins J.P.
        • Smart T.S.
        • Vennart W.
        • Tracey I.
        Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans.
        Proc Natl Acad Sci U S A. 2005; 102: 18195-18200
        • Ichesco E.
        • Schmidt-Wilcke T.
        • Bhavsar R.
        • Clauw D.J.
        • Peltier S.J.
        • Kim J.
        • Napadow V.
        • Hampson J.P.
        • Kairys A.E.
        • Williams D.A.
        • Harris R.E.
        Altered resting state connectivity of the insular cortex in individuals with fibromyalgia.
        J Pain. 2014; 15 (e1): 815-826
        • 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
        • Jensen K.B.
        • Loitoile R.
        • Kosek E.
        • Petzke F.
        • Carville S.
        • Fransson P.
        • Marcus H.
        • Williams S.C.
        • Choy E.
        • Mainguy Y.
        • Vitton O.
        • Gracely R.H.
        • Gollub R.
        • Ingvar M.
        • Kong J.
        Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network.
        Mol Pain. 2012; 8: 32
        • Julien N.
        • Goffaux P.
        • Arsenault P.
        • Marchand S.
        Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition.
        Pain. 2005; 114: 295-302
        • Kaplan H.
        • Fields H.L.
        Hyperalgesia during acute opioid abstinence: Evidence for a nociceptive facilitating function of the rostral ventromedial medulla.
        J Neurosci. 1991; 11: 1433
        • King C.D.
        • Goodin B.
        • Kindler L.L.
        • Caudle R.M.
        • Edwards R.R.
        • Gravenstein N.
        • Riley 3rd, J.L.
        • Fillingim R.B.
        Reduction of conditioned pain modulation in humans by naltrexone: An exploratory study of the effects of pain catastrophizing.
        J Behav Med. 2013; 36: 315-327
        • Kong J.
        • Tu P.C.
        • Zyloney C.
        • Su T.P.
        Intrinsic functional connectivity of the periaqueductal gray, a resting fMRI study.
        Behav Brain Res. 2010; 211: 215-219
        • Kosek E.
        • Hansson P.
        Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects.
        Pain. 1997; 70: 41-51
        • Lariviere M.
        • Goffaux P.
        • Marchand S.
        • Julien N.
        Changes in pain perception and descending inhibitory controls start at middle age in healthy adults.
        Clin J Pain. 2007; 23: 506-510
        • Lautenbacher S.
        • Kunz M.
        • Burkhardt S.
        The effects of DNIC-type inhibition on temporal summation compared to single pulse processing: Does sex matter?.
        Pain. 2008; 140: 429-435
        • Lautenbacher S.
        • Rollman G.B.
        Possible deficiencies of pain modulation in fibromyalgia.
        Clin J Pain. 1997; 13: 189-196
        • Le Bars D.
        • Dickenson A.H.
        • Besson J.M.
        Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat.
        Pain. 1979; 6: 283-304
        • Lee M.C.
        • Zambreanu L.
        • Menon D.K.
        • Tracey I.
        Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans.
        J Neurosci. 2008; 28: 11642-11649
        • Lewis G.N.
        • Rice D.A.
        • McNair P.J.
        Conditioned pain modulation in populations with chronic pain: A systematic review and meta-analysis.
        J Pain. 2012; 13: 936-944
        • Lindstedt F.
        • Berrebi J.
        • Greayer E.
        • Lonsdorf T.B.
        • Schalling M.
        • Ingvar M.
        • Kosek E.
        Conditioned pain modulation is associated with common polymorphisms in the serotonin transporter gene.
        PLoS One. 2011; 6: e18252
        • Linnman C.
        • Moulton E.A.
        • Barmettler G.
        • Becerra L.
        • Borsook D.
        Neuroimaging of the periaqueductal gray: State of the field.
        Neuroimage. 2012; 60: 505-522
        • Nahman-Averbuch H.
        • Martucci K.T.
        • Granovsky Y.
        • Weissman-Fogel I.
        • Yarnitsky D.
        • Coghill R.C.
        Distinct brain mechanisms support spatial vs temporal filtering of nociceptive information.
        Pain. 2014; 155: 2491-2501
        • Nahman-Averbuch H.
        • Nir R.R.
        • Sprecher E.
        • Yarnitsky D.
        Psychological factors and conditioned pain modulation: A meta-analysis.
        Clin J Pain. 2016; 32: 541-554
        • Nahman-Averbuch H.
        • Yarnitsky D.
        • Sprecher E.
        • Granovsky Y.
        • Granot M.
        Relationship between personality traits and endogenous analgesia: The role of harm avoidance.
        Pain Pract. 2016; 16: 38-45
        • 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
        • Normand E.
        • Potvin S.
        • Gaumond I.
        • Cloutier G.
        • Corbin J.F.
        • Marchand S.
        Pain inhibition is deficient in chronic widespread pain but normal in major depressive disorder.
        J Clin Psychiatry. 2011; 72: 219-224
        • Pfeuffer J.
        • Van de Moortele P.F.
        • Ugurbil K.
        • Hu X.
        • Glover G.H.
        Correction of physiologically induced global off-resonance effects in dynamic echo-planar and spiral functional imaging.
        Magn Reson Med. 2002; 47: 344-353
        • Piche M.
        • Arsenault M.
        • Rainville P.
        Cerebral and cerebrospinal processes underlying counterirritation analgesia.
        J Neurosci. 2009; 29: 14236-14246
        • Porreca F.
        • Ossipov M.H.
        • Gebhart G.F.
        Chronic pain and medullary descending facilitation.
        Trends Neurosci. 2002; 25: 319-325
        • Potvin S.
        • Marchand S.
        Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls.
        Pain. 2016; 157: 1704-1710
        • Schmidt-Wilcke T.
        • Ichesco E.
        • Hampson J.P.
        • Kairys A.
        • Peltier S.
        • Harte S.
        • Clauw D.J.
        • Harris R.E.
        Resting state connectivity correlates with drug and placebo response in fibromyalgia patients.
        Neuroimage Clin. 2014; 6: 252-261
        • Schmidt-Wilcke T.
        • Kairys A.
        • Ichesco E.
        • Fernandez-Sanchez M.L.
        • Barjola P.
        • Heitzeg M.
        • Harris R.E.
        • Clauw D.J.
        • Glass J.
        • Williams D.A.
        Changes in clinical pain in fibromyalgia patients correlate with changes in brain activation in the cingulate cortex in a response inhibition task.
        Pain Med. 2014; 15: 1346-1358
        • Schmidt-Wilcke T.
        • Leinisch E.
        • Ganssbauer S.
        • Draganski B.
        • Bogdahn U.
        • Altmeppen J.
        • May A.
        Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients.
        Pain. 2006; 125: 89-97
        • Schmidt-Wilcke T.
        • Leinisch E.
        • Straube A.
        • Kampfe N.
        • Draganski B.
        • Diener H.C.
        • Bogdahn U.
        • May A.
        Gray matter decrease in patients with chronic tension type headache.
        Neurology. 2005; 65: 1483-1486
        • Schoen C.J.
        • Ablin J.N.
        • Ichesco E.
        • Bhavsar R.J.
        • Kochlefl L.
        • Harris R.E.
        • Clauw D.J.
        • Gracely R.H.
        • Harte S.E.
        A novel paradigm to evaluate conditioned pain modulation in fibromyalgia.
        J Pain Res. 2016; 9: 711-719
        • Schrepf A.
        • Harper D.E.
        • Harte S.E.
        • Wang H.
        • Ichesco E.
        • Hampson J.P.
        • Zubieta J.K.
        • Clauw D.J.
        • Harris R.E.
        Endogenous opioidergic dysregulation of pain in fibromyalgia: A PET and fMRI study.
        Pain. 2016; 157: 2217-2225
        • Smallwood R.F.
        • Laird A.R.
        • Ramage A.E.
        • Parkinson A.L.
        • Lewis J.
        • Clauw D.J.
        • Williams D.A.
        • Schmidt-Wilcke T.
        • Farrell M.J.
        • Eickhoff S.B.
        • Robin D.A.
        Structural brain anomalies and chronic pain: A quantitative meta-analysis of gray matter volume.
        J Pain. 2013; 14: 663-675
        • Sprenger C.
        • Bingel U.
        • Buchel C.
        Treating pain with pain: Supraspinal mechanisms of endogenous analgesia elicited by heterotopic noxious conditioning stimulation.
        Pain. 2011; 152: 428-439
        • Taylor B.K.
        • Westlund K.N.
        The noradrenergic locus coeruleus as a chronic pain generator.
        J Neurosci Res. 2017; 95: 1336-1346
        • Tracey I.
        Neuroimaging mechanisms in pain: From discovery to translation.
        Pain. 2017; 158: S115-S122
        • Urban M.O.
        • Gebhart G.F.
        Supraspinal contributions to hyperalgesia.
        Proc Natl Acad Sci U S A. 1999; 96: 7687-7692
        • Villanueva L.
        • Le Bars D.
        The activation of bulbo-spinal controls by peripheral nociceptive inputs: Diffuse noxious inhibitory controls.
        Biol Res. 1995; 28: 113-125
        • Wanigasekera V.
        • Lee M.C.
        • Rogers R.
        • Hu P.
        • Tracey I.
        Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.
        J Neurosci. 2011; 31: 2835-2842
        • Willer J.C.
        • Le Bars D.
        • De Broucker T.
        Diffuse noxious inhibitory controls in man: Involvement of an opioidergic link.
        Eur J Pharmacol. 1990; 182: 347-355
        • Wolfe F.
        • Smythe H.A.
        • Yunus M.B.
        • Bennett R.M.
        • Bombardier C.
        • Goldenberg D.L.
        • Tugwell P.
        • Campbell S.M.
        • Abeles M.
        • Clark P.
        • Fam A.G.
        • Farber S.J.
        • Fiechtner J.J.
        • Franklin C.M.
        • Gatter R.A.
        • Hamaty D.
        • Lessard J.
        • Lichtbroun A.S.
        • Masi A.T.
        • McCain G.A.
        • Reynolds W.J.
        • Romano T.J.
        • Russell I.J.
        • Sheon R.P.
        The American College of Rheumatology 1990 Criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee.
        Arthritis Rheum. 1990; 33: 160-172
        • Yarnitsky D.
        • Bouhassira D.
        • Drewes A.M.
        • Fillingim R.B.
        • Granot M.
        • Hansson P.
        • Landau R.
        • Marchand S.
        • Matre D.
        • Nilsen K.B.
        • Stubhaug A.
        • Treede R.D.
        • Wilder-Smith O.H.
        Recommendations on practice of conditioned pain modulation (CPM) testing.
        Eur J Pain. 2015; 19: 805-806
        • Yarnitsky D.
        • Crispel Y.
        • Eisenberg E.
        • Granovsky Y.
        • Ben-Nun A.
        • Sprecher E.
        • Best L.A.
        • Granot M.
        Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk.
        Pain. 2008; 138: 22-28
        • Youssef A.M.
        • Macefield V.G.
        • Henderson L.A.
        Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans.
        Hum Brain Mapp. 2016; 37: 2630-2644
        • Youssef A.M.
        • Macefield V.G.
        • Henderson L.A.
        Pain inhibits pain; human brainstem mechanisms.
        Neuroimage. 2016; 124: 54-62
        • Zambreanu L.
        • Wise R.G.
        • Brooks J.C.
        • Iannetti G.D.
        • Tracey I.
        A role for the brainstem in central sensitisation in humans. Evidence from functional magnetic resonance imaging.
        Pain. 2005; 114: 397-407
        • Zigmond A.S.
        • Snaith R.P.
        The hospital anxiety and depression scale.
        Acta Psychiatr Scand. 1983; 67: 361-370