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Mindfulness: Behavioral Outcomes, Neural Substrates, and Inflammation

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A presentation I gave on the emerging science of mindfulness meditation.

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Mindfulness: Behavioral Outcomes, Neural Substrates, and Inflammation

  1. 1. Mindfulness Behavioral benefits, neural substrates, and inflammation.
  2. 2. Meditation/Mindfulness Techniques Changes in rsFC Improved Behavioral and Health Outcomes Reduction of Inflammatory Response Traits States
  3. 3. What is mindfulness and why should I care?
  4. 4. What is mindfulness? Why should I care? Monitoring, detecting, disengaging, and redirecting/reorienting attention. Many different forms of meditation: ● FA (focused attention) ● OM (open monitoring) MBSR (Kabat-Zinn) incorporates elements of FA and OM into a secular, 8-week program. Not about staying in one mental state.
  5. 5. RCT: Delineate Different Components of MBI’s
  6. 6. Beliefs About Meditation Pre vs. Post
  7. 7. Behavioral and Health Outcomes Associated with Mindfulness
  8. 8. Improve working memory capacity and (modified) GRE scores N = 48 (26 mindfulness class, 22 nutrition) 2 weeks: 1 class/week + meditate 10 min./log food intake daily OSPAN task and GRE verbal with task- unrelated thought probes (self-report, during, and post-test). Average improvement analogous to 16
  9. 9. Moore et al 2012: Attentional Blink and improved conflict monitoring Longitudinal RCT, N = 40 meditation naive individuals, randomized to meditation or waitlist group EEG and Stroop task at T1=0, T2= 8 weeks, T3=16 weeks. Look for differences in ERP’s (error monitoring, Stroop interference effect).
  10. 10. ● Possibly no behavioral improvements on Stroop task (longitudinal vs. cross sectional). ● Increased n200 irrespective of congruence → vigilance (as opposed to habituation)? ● Reduced p300 ERP for incongruent stimuli → less resources marshalled in conflict monitoring because of increased n2?
  11. 11. Improved emotional regulation n=83 undergrads reporting distress, randomized to 1-month MBSR-like program vs. somatic relaxation control program vs. control Dependent variables: GSI (Global Severity Index), a measure of general psychological distress, and Positive States of Mind Scale (PSOM) No difference between groups (MBSR v. relax): GSI: d=1.36, .91. Medium difference: PSOM: d=.71, .25 Big difference: rumination (p <0.04, d=.57) and distraction (p<0.04, d=.25)
  12. 12. Cherkin 2017: RCT of MBSR vs. CBT for pain N = 342 adults with chronic low-back pain; 3 groups, follow-up 4 wks, 8 wks...2-years Takeaway: CBT and MBSR are equivalent for treating back pain.
  13. 13. Goyal 2014: Meta-analysis of effects sizes ● Only look at studies with a proper control group, 47 made the cut ● “Over the course of 2–6 months, mindfulness meditation program effect size estimates ranged from 0.22–0.38 for anxiety symptoms and 0.23–0.30 for depressive symptoms. These small effects are comparable with what would be expected from the use of an antidepressant in a primary care population, without the associated toxicities” ● Caution: publication bias, small N’s, etc.
  14. 14. Takeaway: mindfulness training has many salutary effects
  15. 15. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Improved Behavioral and Health Outcomes Reduction of Inflammatory Response Traits States Attention Working Memory Pain Management Emotion Regulation
  16. 16. Neural Changes and the Phenomenal Correlates of Mindfulness
  17. 17. Resting State fMRI
  18. 18. Functional Networks That Emerge from rsfMRI
  19. 19. For our purposes: DMN, SEN, & CEN DMN/Task-Negative Network: ● Social thinking ● Mind-wandering ● Mental time travel (MTT) Salience Network: ● Bottom-up awareness of salient stimuli ● Error-monitoring Central Executive Network: ● Top-down control ● Attention ● Task-switching and executive function
  20. 20. Tang 2015: Meta-analysis of mindfulness
  21. 21. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Improved Behavioral and Health Outcomes Reduction of Inflammatory Response Traits States Volitionally change activity Reduction of DMN Theta frequency (EEG)
  22. 22. Functional Network Activity During Meditation
  23. 23. Marusak 2018: dFC in children & adolescents ● N = 42 children (ages 6-17, mean = 10.3) ● Complete measure of trait mindfulness in children, and index of anxiety and depression symptoms. → 62% exceeded thresholds for anxiety and/or depression. ● Dynamic rsFC approach (4 networks, 5 states)
  24. 24. ● More mindful kids spent less time in state 2 (positive DMN-CEN coupling, negative SEN-CEN, negative DMN- SEN.) → FC pattern linked to mind- wandering in adults. ● SEN-left CEN connectivity in state 4 → negative association with mindfulness ● The seductive allure of post-hoc, reverse inferences and functional ascriptions.
  25. 25. Hasenkamp 2012: Neural correlates of mind- wandering and attention ● n=14 meditators, some high practice time, others low ● Focused attention (FA) meditation stages/seeds: FOCUS -- MW -- AWARE -- SHIFT ● Button press when mind wanders. Seeds: ● DMN: vmPFC, PCC. ● SEN: dACC, anterior insula ● CEN: right dlPFC.
  26. 26. ● Practice time effects of vmPFC during SHIFT phase (evaluative processing) ● Other practice time effects: ● Seed 1 (right dlPFC) → right insula, l dlPFC ● Seed 2 (PCC) → increased connection with left OFC; reduced connection with ACC → processing viscero-motor states?
  27. 27. Berkovich-Ohana 2016: task-induced spontaneous fluctuations ● N = 18 LTM’s, 18 med-naive controls ● Visual recognition memory task (basically a one-back memory task). ● In LTM’s, spontaneous fMRI fluctuations (i.e. variance in amplitude) in the DMN are decreased; in the visual cortex they’re increased. ● LTM’s also had shorter reaction times.
  28. 28. Functional Connectivity of DMN & visual cortex ● Inter-network DMN-Vis functional connectivity higher in LTM’s (more extrinsic awareness), while intra- network (e.g. DMN-DMN) functional connectivity was higher in controls ● Strong negative correlation between years of meditation practice and DMN-DMN fc (r=-.340) ● Caution: small N’s, possible a priori personality effects
  29. 29. Young 2018: Meta-analysis of fMRI studies ● Regions listed in order of robustness of findings. ● Only 7 articles qualified for the meta-analysis? ● Long term practitioners (>10,000 hours) vs. novices
  30. 30. Garrison 2013a: rtfMRI, meditator v. controls ● PCC = DMN hub, implicated in self-related processing, social cognition, response error on flankers task. ● 1a: n = 22 meditators (Theravada), 22 controls ● FA task: focus on breath, graph in background (displayed PCC activity for runs 1-4, randomized [PPC or PCC] for runs 5-6).
  31. 31. ● 1b: n=9 meditators, 11 controls ● Real-time feedback. Object of attention → Volitional manipulation of PCC graph.
  32. 32. Garrison 2013b: blinded neurofeedback ● N = 10 experienced meditators; meditation with rtfMRI (PCC seed), then self-report. ● 4 runs: no feedback → offline feedback → real time feedback → volitional change ● “Undistracted awareness” and “effortless doing” elicit PCC deactivation ● Volitionally able to reduce PCC response ● Obviate the problem of reverse inference (Poldrack 2006)?
  33. 33. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Improved Behavioral and Health Outcomes Reduction of Inflammatory Response Traits States Increased ACC activity (novice v. LTM) Amygdala (reduced in novices) Reduced PCC, mPFC Reduced DMN-DMN rsFC Increased SEN-CEN coupling Increased insula, dlPFC activity
  34. 34. White Matter Changes Associated with Meditation
  35. 35. Karapanagiotidis et al. 2017: MTT (FA and rs) ● n=86 (non-meditators), two cohorts (A & B); 15 min. choice reaction time task (induces mind-wandering) ● “multidimensional experience-sampling” (MDES) throughout the task ● Measured outcomes: structural connectivity analysis (fractional anisotropy), rsFC.
  36. 36. ● FA increase in temporo-limbic white matter region for those engaging in MTT more. ● Right hippocampus was the most well- connected GM region with the temporo- limbic WM pathway ● Right Hipp-dACC/mPFC functional connectivity (i & ii) positively correlated with MTT scores
  37. 37. Laneri 2016: White Matter Changes and Age ● n=33 meditators, n=31 non-meditators ● Fractional anisotropy (white matter imaging) of ROI’s: ACC, insula, amygdala, thalamus, and hippocampus. ● In all ROI’s besides right Insula & left ACC, non- meditators demonstrate age-related FA decline ● higher FA in left insula, right thalamus, right amygdala (p <0.05) and left thalamus and right hippocampus (p <0.1). Issues with cross-sectional study design.
  38. 38. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Changes in WM/GM Structures Improved Behavioral and Health Outcomes Regulation of Stress Response Reduction of Inflammatory Response Traits States Reduced atrophying of: Insula Amygdala Thalamus
  39. 39. Biological changes associated with meditation
  40. 40. Inflammation and the brain (Marsland 2015) Inflammation is linked to cognitive decline in midlife N = 408 (ages 30-54), measure IL-6 and CRP, cognitive function and MRI Inflammation inversely associated with total GM and WM volumes, and cognitive function Possible mediation effects but… correlation != causation.
  41. 41. Rosenkranz 2016: Inflammatory response ● N = 37 healthy controls, 31 long-term meditators ● Add topical capsaicin to forearm; then take Trier Social Stress Test (speech + math). ● Measure cortisol (HPA) and alpha amylase (SNS), flare size, self-report measures. ● After controlling for age, sex and flare peak, significant intergroup differences in cortisol AUC (a summary indicator)
  42. 42. ● Meditators had smaller flare response peak than healthy controls (p=0.19) ● Flare response highly correlated with cortisol response to TSST but not AA response. ● Meditators perceived level of stress correlated with cortisol max % change (r=.5, p=.009); HC’s (r=.24, p=.21). Differences not significant across groups.
  43. 43. So why do meditators: a) present an attenuated inflammatory response? b) subjectively rate this response more accurately than healthy controls? Are people who are more stress-resistant more likely to meditate; is there a selection effect for who sticks with meditation; or does meditation have a salutary effect in and of itself?
  44. 44. Rosenkranz 2013: MBSR vs. active control ● 8 week RCT, n = 49 mindfulness-naive individuals ● Randomized to MBSR or HEP; TSST and capsaicin skin flare ● Results: MBSR and HEP comparable for cortisol response ● Daily cortisol release negatively correlated with MBSR and HEP practice times! MBSR group showed smaller flare AUC post- intervention.
  45. 45. Creswell (2012): MBSR RCT for lonely old folks ● N = 40 individuals (M=65, SD=7) → 20 MBSR program, 20 waitlist ● NF-kB transcription factor: controls DNA transcription and cytokine production ● Mindfulness, loneliness, gene expression (NF-kB target genes that code for WBC’s) and pro-inflam. protein (C-reactive protein and IL-6, implicated in cardiovasc. disease) analysis
  46. 46. ● MBSR reduces loneliness as compared to control ● Reduction in activity of NF-kB target genes in MBSR group relative to controls ● CRP (p = 0.075) condition x time interaction was marginally significant between groups. ● IL-6 was not significant.
  47. 47. Creswell 2016: Randomized trial + inflammation ● IL-6: pro-inflammatory cytokine, important biomarker ● Experimental test of if mindfulness training (MBSR) can alter DMN rsFC and IL-6 ● N = 35 unemployed (i.e. stressed) → 18 meditation training, 17 relaxation retreat (3 days long) ● Measure IL-6 and rsFC at baseline and 4- months post treatment.
  48. 48. ● Mindfulness training reduced IL-6 from baseline to 4-month follow up as compared to relaxation group (not due to reemployment). ● Increased left dlPFC-PCC connection in meditation group → explains IL-6 changes?
  49. 49. Creswell (2014) Stress-Buffering Account of Mindfulness: dlPFC increased top-down regulation stress-related brain areas (HPA), prevent signal cascade throughout the peripheral nervous system (see Rosenkranz 2016).
  50. 50. Why is IL-6 significant in Creswell 2016 but not in Creswell 2012? Different samples (old people vs. distressed unemployed adults)? Old people received a longer training program (8 weeks vs. 3 days)? Creswell 2012 didn’t have an active control (would expect more pronounced effects between meditation group and control, not less?), whereas Creswell 2016 did?
  51. 51. Kaliman 2014: HDAC and inflammation ● N = 19 LTM’s and 21 HC’s; day of mindfulness vs. day of leisure (e.g. documentaries) ● Histone deacetylase: epigenetic modification enzyme (remove acetyl) → reduce gene transcription. Known to modulate inflammatory pathways. ● Post-intervention, meditation group showed decreased expression of HDAC2, 3, and 9.
  52. 52. ● Reduction correlated with HDAC expression; downregulation of COX2 (pro-inflammatory) ● HDAC3 normalized using inverse values ● RIPK2 implicated in NF-kB signalling pathway (Yin, 2010) ● Lower post-intervention levels of HDAC2 & RIPK2 gene expression → better cortisol recovery following TSST
  53. 53. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Improved Behavioral and Health Outcomes Regulation of Stress Response Reduction of Inflammatory Response Epigenetic Changes (HDAC inhibition→ IL-6 → NF-kB) Traits States Changes in /GMWM HPA Axis Top-down control (dlPFC)
  54. 54. Some conjecture: white matter changes, inflammation, and age- related decline?
  55. 55. Wang 2015: HDAC inhibition prevent WM injury in mice after TBI ● TBI is a pro-inflammatory stimulus; known to cause WMI (white matter injury); positive feedback loop of microglia (M1 = exacerbate, M2 = neurorepair). ● Some HDAC inhibitors preferentially promote transcription of neuroprotective genes (e.g. Scriptaid). ● HDAC inhibition → long, convoluted biological pathway (NF-kB) → protect oligodendrocytes → preserve/grow white matter
  56. 56. Meditation/Mindfulness Techniques Changes in rsFC (DMN) Changes in WM/GM Structures Improved Behavioral and Health Outcomes Regulation of Stress Response Reduction of Inflammatory Response Epigenetic Changes (HDAC inhibition→ IL-6 → NF-kB) Traits States Oligodendrocytes Myelin
  57. 57. Concerns with the State of Mindfulness Research Small sample sizes and survivorship bias Longitudinal vs. cross-sectional study Control for confounds (MBSR vs. HEP, see RJ Davidson most-cited study). Different techniques Different levels of practice (experienced vs. novice).
  58. 58. Epistemological Concerns w/ Neuroimaging Are our voxels too big, thus not allowing us to account for regional functional heterogeneity? (e.g. Kanwisher and the FFA) Hand-waving → Problems with forward and reverse inference (attributing a cognitive function to a brain region/network; attributing a cognitive function to a task on the basis of certain brain regions “lighting up”) Small sample sizes
  59. 59. Class Questions: ● Confounds: cross-sectional design (SES, survivorship bias, other selection effects) ● Is meditation’s influence on pain perception operating through neural or inflammatory changes? Both? Change the subjective appraisal? ● Critical period for mindfulness? Mindfulness and imagination mutually exclusive? ● Linear relationship between WM changes and practice time (see Holzel 2011)? ● Dissociation between mindfulness in kids and adults? ● M.E.D. of mindfulness to induce anti-inflammatory effects? Personality effects? ● Decay of salutary effects over time? ● Clinical applications of mindfulness to inflammation-based diseases?

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