Advertisement

Alterations in Resting-State Functional Connectivity Link Mindfulness Meditation With Reduced Interleukin-6: A Randomized Controlled Trial

      Abstract

      Background

      Mindfulness meditation training interventions have been shown to improve markers of health, but the underlying neurobiological mechanisms are not known. Building on initial cross-sectional research showing that mindfulness meditation may increase default mode network (DMN) resting-state functional connectivity (rsFC) with regions important in top-down executive control (dorsolateral prefrontal cortex [dlPFC]), here we test whether mindfulness meditation training increases DMN-dlPFC rsFC and whether these rsFC alterations prospectively explain improvements in interleukin (IL)-6 in a randomized controlled trial.

      Methods

      Stressed job-seeking unemployed community adults (n = 35) were randomized to either a 3-day intensive residential mindfulness meditation or relaxation training program. Participants completed a 5-minute resting-state scan before and after the intervention program. Participants also provided blood samples at preintervention and at 4-month follow-up, which were assayed for circulating IL-6, a biomarker of systemic inflammation.

      Results

      We tested for alterations in DMN rsFC using a posterior cingulate cortex seed-based analysis and found that mindfulness meditation training, and not relaxation training, increased posterior cingulate cortex rsFC with left dlPFC (p < .05, corrected). These pretraining to posttraining alterations in posterior cingulate cortex-dlPFC rsFC statistically mediated mindfulness meditation training improvements in IL-6 at 4-month follow-up. Specifically, these alterations in rsFC statistically explained 30% of the overall mindfulness meditation training effects on IL-6 at follow-up.

      Conclusions

      These findings provide the first evidence that mindfulness meditation training functionally couples the DMN with a region known to be important in top-down executive control at rest (left dlPFC), which, in turn, is associated with improvements in a marker of inflammatory disease risk.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ludwig D.S.
        • Kabat-Zinn J.
        Mindfulness in medicine.
        JAMA. 2008; 300: 1350-1352
        • Brown K.W.
        • Ryan R.M.
        • Creswell J.D.
        Mindfulness: Theoretical foundations and evidence for its salutary effects.
        Psychol Inq. 2007; 18: 211-237
        • Goyal M.
        • Singh S.
        • Sibinga E.M.
        • Gould N.F.
        • Rowland-Seymour A.
        • Sharma R.
        • et al.
        Meditation programs for psychological stress and well-being: A systematic review and meta-analysis.
        JAMA Intern Med. 2014; 174: 357-368
        • Segal Z.V.
        • Bieling P.
        • Young T.
        • MacQueen G.
        • Cooke R.
        • Martin L.
        • et al.
        Antidepressant monotherapy vs sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression.
        Arch Gen Psychiatry. 2010; 67: 1256-1264
        • Teasdale J.D.
        • Segal Z.V.
        • Mark J.
        • Ridgeway V.A.
        • Soulsby J.M.
        • Lau M.A.
        Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy.
        J Consult Clin Psychol. 2000; 68: 615-623
        • Creswell J.D.
        • Myers H.F.
        • Cole S.W.
        • Irwin M.R.
        Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected adults: A small randomized controlled trial.
        Brain Behav Immun. 2009; 23: 184-188
        • Goldin P.R.
        • Gross J.J.
        Effects of mindfulness-based stress reduction (MBSR) on emotion regulation in social anxiety disorder.
        Emotion. 2010; 10: 83-91
        • Creswell J.D.
        • Irwin M.R.
        • Burklund L.J.
        • Lieberman M.D.
        • Arevalo J.M.
        • Ma J.
        • et al.
        Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: A small randomized controlled trial.
        Brain Behav Immun. 2012; 26: 1095-1101
        • Malarkey W.B.
        • Jarjoura D.
        • Klatt M.
        Workplace based mindfulness practice and inflammation: A randomized trial.
        Brain Behav Immun. 2013; 27: 145-154
        • Rosenkranz M.A.
        • Davidson R.J.
        • MacCoon D.G.
        • Sheridan J.F.
        • Kalin N.H.
        • Lutz A.
        A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation.
        Brain Behav Immun. 2013; 27C: 174-184
        • Lengacher C.A.
        • Kip K.E.
        • Barta M.K.
        • Post-White J.
        • Jacobsen P.
        • Groer M.
        • et al.
        A pilot study evaluating the effect of mindfulness-based stress reduction on psychological status, physical status, salivary cortisol, and interleukin-6 among advanced-stage cancer patients and their caregivers.
        J Holist Nurs. 2012; 30: 170-185
        • Hölzel B.K.
        • Lazar S.W.
        • Gard T.
        • Schuman-Olivier Z.
        • Vago D.R.
        • Ott U.
        How does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective.
        Perspect Psychol Sci. 2011; 6: 537-559
        • Tang Y.-Y.
        • Hölzel B.K.
        • Posner M.I.
        The neuroscience of mindfulness meditation.
        Nat Rev Neurosci. 2015; 16: 213-225
        • Creswell J.D.
        • Lindsay E.K.
        How does mindfulness training affect health? A mindfulness stress buffering account.
        Curr Dir Psychol Sci. 2014; 23: 401-407
        • Mrazek M.D.
        • Smallwood J.
        • Schooler J.W.
        Mindfulness and mind-wandering: Finding convergence through opposing constructs.
        Emotion. 2012; 12: 442-448
        • Christoff K.
        • Gordon A.M.
        • Smallwood J.
        • Smith R.
        • Schooler J.W.
        Experience sampling during fMRI reveals default network and executive system contributions to mind wandering.
        Proc Natl Acad Sci U S A. 2009; 106: 8719-8724
        • Brewer J.A.
        • Worhunsky P.D.
        • Gray J.R.
        • Tang Y.-Y.
        • Weber J.
        • Kober H.
        Meditation experience is associated with differences in default mode network activity and connectivity.
        Proc Natl Acad Sci U S A. 2011; 108: 20254-20259
        • Wager T.D.
        • Rilling J.K.
        • Smith E.E.
        • Sokolik A.
        • Casey K.L.
        • Davidson R.J.
        • et al.
        Placebo-induced changes in fMRI in the anticipation and experience of pain.
        Science. 2004; 303: 1162-1167
        • Lorenz J.
        • Minoshima S.
        • Casey K.L.
        Keeping pain out of mind: The role of the dorsolateral prefrontal cortex in pain modulation.
        Brain. 2003; 126: 1079-1091
        • Goldin P.R.
        • McRae K.
        • Ramel W.
        • Gross J.J.
        The neural bases of emotion regulation: Reappraisal and suppression of negative emotion.
        Biol Psychiatry. 2008; 63: 577-586
        • Cisler J.M.
        • James G.A.
        • Tripathi S.
        • Mletzko T.
        • Heim C.
        • Hu X.P.
        • et al.
        Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress.
        Psychol Med. 2013; 43: 507-518
        • Greicius M.
        Resting-state functional connectivity in neuropsychiatric disorders.
        Curr Opin Neurol. 2008; 24: 424-430
        • Anticevic A.
        • Cole M.W.
        • Murray J.D.
        • Corlett P.R.
        • Wang X.-J.
        • Krystal J.H.
        The role of default network deactivation in cognition and disease.
        Trends Cogn Sci. 2012; 16: 584-592
        • Tregellas J.R.
        • Wylie K.P.
        • Rojas D.C.
        • Tanabe J.
        • Martin J.
        • Kronberg E.
        • et al.
        Altered default network activity in obesity.
        Obesity (Silver Spring). 2011; 19: 2316-2321
        • Musen G.
        • Jacobson A.M.
        • Bolo N.R.
        • Simonson D.C.
        • Shenton M.E.
        • McCartney R.L.
        • et al.
        Resting-state brain functional connectivity is altered in type 2 diabetes.
        Diabetes. 2012; 61: 2375-2379
        • Zhou Y.
        • Liang M.
        • Jiang T.
        • Tian L.
        • Liu Y.
        • Liu Z.
        • et al.
        Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI.
        Neurosci Lett. 2007; 417: 297-302
        • Kiecolt-Glaser J.K.
        • Preacher K.J.
        • MacCallum R.C.
        • Atkinson C.
        • Malarkey W.B.
        • Glaser R.
        Chronic stress and age-related increases in the proinflammatory cytokine IL-6.
        Proc Natl Acad Sci U S A. 2003; 100: 9090-9095
        • Steptoe A.
        • Hamer M.
        • Chida Y.
        The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis.
        Brain Behav Immun. 2007; 21: 901-912
        • Harris T.B.
        • Ferrucci L.
        • Tracy R.P.
        • Corti M.C.
        • Wacholder S.
        • Ettinger Jr, W.H.
        • et al.
        Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.
        Am J Med. 1999; 106: 506-512
        • Pal M.
        • Febbraio M.A.
        • Whitham M.
        From cytokine to myokine: The emerging role of interleukin-6 in metabolic regulation.
        Immunol Cell Biol. 2014; 92: 331-339
        • Danesh J.
        • Kaptoge S.
        • Mann A.G.
        • Sarwar N.
        • Wood A.
        • Angleman S.B.
        • et al.
        Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review.
        PLoS Med. 2008; 5: e78
        • Baum A.
        • Fleming R.
        • Reddy D.M.
        Unemployment stress: Loss of control, reactance and learned helplessness.
        Soc Sci Med. 1986; 22: 509-516
        • Hintikka J.
        • Lehto S.
        • Niskanen L.
        • Huotari A.
        • Herzig K.-H.
        • Koivumaa-Honkanen H.
        • et al.
        Unemployment and ill health: A connection through inflammation?.
        BMC Public Health. 2009; 9: 410
        • Warttig S.L.
        • Forshaw M.J.
        • South J.
        • White A.K.
        New, normative, English-sample data for the Short Form Perceived Stress Scale (PSS-4).
        J Health Psychol. 2013; 18: 1617-1628
        • Kabat-Zinn J.
        Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.
        Delta, New York1990
      1. Mazaika P, Whitfield-Gabrieli S, Reiss A (2007): Artifact repair for fMRI data from motion clinical subjects. Presented at the Organization for Human Brain Mapping Annual Conference, June 10–14, Chicago, Illinois.

        • Devilly G.J.
        • Borkovec T.D.
        Psychometric properties of the credibility/expectancy questionnaire.
        J Behav Ther Exp Psychiatry. 2000; 31: 73-86
        • Maldjian J.A.
        • Laurienti P.J.
        • Kraft R.A.
        • Burdette J.H.
        An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.
        Neuroimage. 2003; 19: 1233-1239
        • Wei J.
        • Xu H.
        • Davies J.L.
        • Hemmings G.P.
        Increase of plasma IL-6 concentration with age in healthy subjects.
        Life Sci. 1992; 51: 1953-1956
        • MacKinnon D.P.
        • Lockwood C.M.
        • Hoffman J.M.
        • West S.G.
        • Sheets V.
        A comparison of methods to test mediation and other intervening variable effects.
        Psychol Methods. 2002; 7: 83-104
        • Baron R.M.
        • Kenny D.A.
        The moderator–mediator variable distinction in social psychological research: Conceptual, strategic, and statistical considerations.
        J Pers Soc Psychol. 1986; 51: 1173-1182
        • Buckner R.L.
        • Andrews-Hanna J.R.
        • Schacter D.L.
        The brain’s default network.
        Ann N Y Acad Sci. 2008; 1124: 1-38
        • Seeley W.W.
        • Menon V.
        • Schatzberg A.F.
        • Keller J.
        • Glover G.H.
        • Kenna H.
        • et al.
        Dissociable intrinsic connectivity networks for salience processing and executive control.
        J Neurosci. 2007; 27: 2349-2356
        • Fox M.D.
        • Snyder A.Z.
        • Vincent J.L.
        • Corbetta M.
        • Essen D.C.V.
        • Raichle M.E.
        The human brain is intrinsically organized into dynamic, anticorrelated functional networks.
        Proc Natl Acad Sci U S A. 2005; 102: 9673-9678
        • Spreng R.N.
        The fallacy of a “task-negative” network.
        Front Psychol. 2012; 3: 145
        • Gerlach K.D.
        • Spreng R.N.
        • Madore K.P.
        • Schacter D.L.
        Future planning: Default network activity couples with frontoparietal control network and reward-processing regions during process and outcome simulations.
        Soc Cogn Affect Neurosci. 2014; 9: 1942-1951
        • Spreng R.N.
        • Stevens W.D.
        • Chamberlain J.P.
        • Gilmore A.W.
        • Schacter D.L.
        Default network activity, coupled with the frontoparietal control network, supports goal-directed cognition.
        Neuroimage. 2010; 53: 303-317
        • Cesari M.
        • Penninx BWJH
        • Newman A.B.
        • Kritchevsky S.B.
        • Nicklas B.J.
        • Sutton-Tyrrell K.
        • et al.
        Inflammatory markers and onset of cardiovascular events.
        Circulation. 2003; 108: 2317-2322
        • Harrison N.A.
        • Brydon L.
        • Walker C.
        • Gray M.A.
        • Steptoe A.
        • Critchley H.D.
        Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity.
        Biol Psychiatry. 2009; 66: 407-414
        • Gianaros P.J.
        • Marsland A.L.
        • Kuan DC-H
        • Schirda B.L.
        • Jennings J.R.
        • Sheu L.K.
        • et al.
        An inflammatory pathway links atherosclerotic cardiovascular disease risk to neural activity evoked by the cognitive regulation of emotion.
        Biol Psychiatry. 2014; 75: 738-745
        • Irwin M.R.
        • Cole S.W.
        Reciprocal regulation of the neural and innate immune systems.
        Nat Rev Immunol. 2011; 11: 625-632
        • Jankord R.
        • Zhang R.
        • Flak J.N.
        • Solomon M.B.
        • Albertz J.
        • Herman J.P.
        Stress activation of IL-6 neurons in the hypothalamus.
        Am J Physiol Regul Integr Comp Physiol. 2010; 299: R343-R351
        • Wang Z.
        • Chen L.M.
        • Négyessy L.
        • Friedman R.M.
        • Mishra A.
        • Gore J.C.
        • Roe A.W.
        The relationship of anatomical and functional connectivity to resting-state connectivity in primate somatosensory cortex.
        Neuron. 2013; 78: 1116-1126
        • Vogt B.A.
        • Rosene D.L.
        • Pandya D.N.
        Thalamic and cortical afferents differentiate anterior from posterior cingulate cortex in the monkey.
        Science. 1979; 204: 205-207
        • Tang Y.-Y.
        • Lu Q.
        • Geng X.
        • Stein E.A.
        • Yang Y.
        • Posner M.I.
        Short-term meditation induces white matter changes in the anterior cingulate.
        Proc Natl Acad Sci U S A. 2010; 107: 15649-15652
        • Zeidan F.
        • Martucci K.T.
        • Kraft R.A.
        • Gordon N.S.
        • McHaffie J.G.
        • Coghill R.C.
        Brain mechanisms supporting the modulation of pain by mindfulness meditation.
        J Neurosci. 2011; 31: 5540-5548
        • Hölzel B.K.
        • Ott U.
        • Hempel H.
        • Hackl A.
        • Wolf K.
        • Stark R.
        • Vaitl D.
        Differential engagement of anterior cingulate and adjacent medial frontal cortex in adept meditators and non-meditators.
        Neurosci Lett. 2007; 421: 16-21
        • Grigg O.
        • Grady C.L.
        Task-related effects on the temporal and spatial dynamics of resting-state functional connectivity in the default network.
        PLoS One. 2010; 5: e13311