Carnegie Mellon University
Research Showcase @ CMU
Department of Psychology
Dietrich College of Humanities and Social Sciences
1-29-2016
Alterations in Resting-State Functional
Connectivity Link Mindfulness Meditation With
Reduced Interleukin-6: A Randomized Controlled
Trial.
J. David Creswell
Carnegie Mellon University, creswell@cmu.edu
Adrienne A. Taren
University of Pittsburgh
Emily K. Lindsay
Carnegie Mellon University
Carol M. Greco
University of Pittsburgh
Peter J. Gianaros
University of Pittsburgh
See next page for additional authors
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Published In
Biological psychiatry, forthcoming.
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Authors
J. David Creswell, Adrienne A. Taren, Emily K. Lindsay, Carol M. Greco, Peter J. Gianaros, April Fairgrieve,
Anna L. Marsland, Kirk Warren Brown, Baldwin M. Way, Rhonda K. Rosen, and Jennifer Ferris
This article is available at Research Showcase @ CMU: http://repository.cmu.edu/psychology/1401
J.D.
Creswell
SHORT TITLE: MEDITATION, BRAIN, IL-6
WORD COUNT: 3,860 (249 abstract)
TABLES: 2
FIGURES: 3
SUPPLEMENTAL TEXT: 1
Alterations in Resting State Functional Connectivity link Mindfulness Meditation
with Reduced Interleukin-6: A Randomized Controlled Trial
In press, Biological Psychiatry
J. David Creswell, PhD1§, Adrienne A. Taren, MD2, Emily K. Lindsay, MA1, Carol M.
Greco, PhD3, Peter J. Gianaros, PhD4, April Fairgrieve, BS1, Anna L. Marsland, PhD4,
Kirk Warren Brown, PhD5, Baldwin M. Way, PhD6, Rhonda K. Rosen, LCSW4, Jennifer
L. Ferris, MA1
1
Department of Psychology and Center for the Neural Basis of Cognition, Carnegie
Mellon University, 5000 Forbes Ave, Pittsburgh, PA, 15213
2
Department of Neuroscience and Center for the Neural Basis of Cognition, University of
Pittsburgh, A210 Langley Hall, Pittsburgh, PA, 15260
3
Department of Psychiatry, University of Pittsburgh, 580 S. Aiken Ave, Pittsburgh, PA,
15232
4
Department of Psychology and Center for the Neural Basis of Cognition, University of
Pittsburgh, 210 South Bouquet St, Pittsburgh, PA, 15260
5
Department of Psychology, Virginia Commonwealth University, 806 W Franklin St,
Richmond, VA, 23284
6
Department of Psychology, Ohio State University, 1827 Neil Ave, Columbus, OH,
43210
§
Corresponding Author: J. David Creswell, Associate Professor in Psychology and
Center for the Neural Basis of Cognition, Carnegie Mellon University, 5000 Forbes Ave,
Pittsburgh, PA, 15213, creswell@cmu.edu. (phone: 412-268-9182)
Keywords: mindfulness meditation; functional connectivity; IL-6; unemployment; fMRI;
stress
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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-6 (IL6) in a randomized controlled trial.
Method: 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 five-minute resting state scan before and after the
intervention program. Participants also provided blood samples at pre-intervention 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 (PCC)
seed-based analysis, and found that mindfulness meditation training, and not relaxation
training, increased PCC rsFC with left dlPFC (p<.05, corrected). These pre-post training
alterations in PCC-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.
Abstract word count: 249
Trial Registration: The RCT is registered on clinicaltrials.gov (#NCT01628809)
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Alterations in Resting State Functional Connectivity link Mindfulness Meditation
with Reduced Interleukin-6: A Randomized Controlled Trial
Mindfulness meditation training programs, which train receptive attention and
awareness to one’s present moment experience, have been shown to improve a broad
range of stress-related psychiatric and physical health outcomes in initial randomized
controlled trials (e.g., depression relapse, anxiety, HIV-progression) (1–7). For example,
recent well-controlled studies indicate that mindfulness meditation training may reduce
markers of inflammation (C Reactive Protein, Interleukin-6 (IL-6), neurogenic
inflammation) in stressed individuals (8–11). However, little is known about the neural
mechanisms underlying the effects of mindfulness training on health among these
individuals (12; 13).
One possibility is that mindfulness meditation training alters resting state
functional connectivity (rsFC) of brain networks implicated in mind wandering (the
Default Mode Network, DMN) and executive control (the Executive Control Network,
EC), which in turn improves emotion regulation, stress resilience, and stress-related
health outcomes in at-risk patient populations (1; 14–16). Two lines of research support
this hypothesis. First, a cross-sectional study (N=25) showed that advanced mindfulness
meditation practitioners had increased functional connectivity of a key hub in the default
mode network (DMN) (i.e., posterior cingulate cortex) with regions considered to be
important in top down executive control (EC) (dorsolateral prefrontal cortex, dorsal
ACC), both at rest and during a guided mindfulness meditation practice (17). This
coupling of one’s DMN at rest with regions of the EC network may be important for
emotion regulation and stress resilience effects, as greater activation and functional
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connectivity of EC regions, such as the dlPFC, is associated with reduced pain, negative
affect, and stress (18–21). A second line of research demonstrates initial links between
alterations in DMN rsFC and psychiatric (e.g., Alzheimer’s Disease, schizophrenia) (22;
23) and physical (e.g., obesity, diabetes) (24; 25) health risks; for example, there is
reduced rsFC of the posterior cingulate cortex and the dlPFC observed in schizophrenia
patients relative to matched controls (26).
Here we provide the first experimental test of whether an intensive 3-day
mindfulness meditation training intervention (relative to a relaxation training
intervention) alters DMN connectivity and circulating IL-6 in a high stress unemployed
job-seeking community sample. IL-6 is an established clinical health biomarker that is
elevated in high stress populations (27; 28) and is associated with elevated cardiovascular
disease and mortality risk (29–31). Moreover, unemployment is a well-known chronic
stressor that can foster a loss of control, helplessness, and financial setbacks (32)—and
unemployment is associated with elevated inflammation (33). Building on initial crosssectional evidence (17), we hypothesized that mindfulness meditation training would
increase rsFC between the DMN and regions implicated in attention and executive
control (dlPFC and dACC). Moreover, we tested whether mindfulness meditation training
(relative to relaxation training) decreased circulating IL-6 at 4-month follow up, and
whether pre-post intervention increases in DMN-dlPFC rsFC mediated IL-6
improvements at 4-month follow-up.
Method and Materials
Participants
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Thirty-five right-handed unemployed job-seeking community adults participated
(see Table S1 for inclusion/exclusion study criteria) (see Figure S1 for Consort
flowchart). Participants had moderate to high levels of job-seeking stress over the past
month, scoring >5 on an adapted 4-item Perceived Stress Scale (34) (M=9.60, SD=2.35;
for job-seeking stress measure see Table S1). After complete description of the study to
the participants, written informed consent was obtained.
Procedure
Beginning four weeks before the 3-day training intervention, participants
completed a baseline neuroimaging session, which included a 5-minute resting state scan
where they passively viewed a fixation cross. After neuroimaging, participants were
invited to a nearby residential retreat center where they provided a blood sample (for
measurement of circulating IL-6) and were then randomized (via a random number
generator by the study PI) to either a 3-day intensive mindfulness meditation training
(N=18) or a matched 3-day relaxation residential retreat intervention (N=17). Posttreatment study personnel were blind to participant study condition (including personnel
running the post-treatment MRI session and MRI data preprocessing). Participants
returned for a neuroimaging assessment within two weeks of completing the 3-day
intervention and completed an identical scanning procedure as at baseline (participants
verbally confirmed they did not engage in meditation or relaxation activities during the
resting state scan at both time points). At 4-month follow-up, participants were invited
back to the retreat center where they provided a blood sample and completed a
measurement battery. The measures described in this report are a subset of measures
collected in this trial (see Supplementary Text).
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Interventions
We developed a 3-day residential mindfulness meditation retreat format from
activities used in the Mindfulness-Based Stress Reduction (MBSR) program (35), called
Health Enhancement through Mindfulness (HEM). Delivery of the HEM program in a
structured residential retreat format improves compliance with training and reduces
treatment attrition; greater experimental control is also afforded by offering a parallel
matched relaxation training retreat (in a separate wing of the retreat center). Briefly, the
HEM program consists of mindfulness training through body scan awareness exercises,
sitting and walking meditations, mindful eating, mindful stretching, and discussion. We
developed a structurally matched Health Enhancement through Relaxation (HER)
program that included similar behavioral training activities (e.g., walking, stretching, and
didactics) as HEM, but emphasized participation in these activities in a restful rather than
a mindful way. The use of a structurally-matched active comparison group was designed
to control for non-mindfulness specific factors such as positive treatment expectancies,
group support, teacher attention, physical activity, and mental engagement. An hour-byhour outline of interventions is provided in Table S4.
Neuroimaging Measures
Image Acquisition and Preprocessing. Structural and functional images were
acquired on a Siemens Verio 3T scanner using a 32-channel head coil. High-resolution
T1-weighted gradient-echo images were acquired (TR=1800ms, TE=2.22ms, flip
angle=9º, matrix size=256x256, number of slices=256, FOV=205mm, 0.8mm slices),
GRAPPA acceleration factor PE=2, voxel size=0.8x0.8x0.8mm). Next, four functional
echo-planar imaging runs were acquired, including a 300 second resting state scan
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(TR=2000ms, TE=30ms, flip angle=79º, matrix size=64x64, number of slices=36, FOV=
205mm, 3.2mm thick slices EPI with rate 2 GRAPPA, voxel
size=3.2mmx3.2mmx3.2mm).
Three participants were excluded from fMRI data analyses due to neuroimaging
session problems (at the baseline appointment: 1 participant reported sleeping, 1 had poor
coverage, and 1 did not understand directions; at the post-treatment appointment: 1
participant reported sleeping, 1 did not understand directions, and 1 had poor coverage).
Functional BOLD data were processed using SPM8 (Welcome Department of Cognitive
Neurology, London, UK; implemented by MATLAB, MathWorks, Inc., Natick, MA,
USA). Functional images were first realigned to the mean image of the first run and then
smoothed with a 4mm FWHM Gaussian kernel. Data were then submitted to motion
correction using the Art Repair utility (36), an interpolation-based motion correction
program. The functional data was then normalized to the standard Montreal Neurological
Institute (MNI) T1 template. Finally, the images were smoothed with a 7mm FWHM
kernel, resulting in an overall FWHM smoothing of 8mm (36).
IL-6 and Psychosocial Measures
IL-6. Blood samples were collected (between the hours of 10am-noon) and
processed (then frozen) in batch at baseline and at 4-month follow-up by technicians
blinded to treatment conditions. IL-6 levels were determined from plasma in duplicate by
high sensitivity quantitative sandwich enzyme immunoassay kit (R& D Systems,
Minneapolis, MN) run according to manufacturer’s directions. Two participants had
insufficient samples for IL-6 determination, and were excluded.
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Psychosocial Measures. In order to evaluate whether the relaxation retreat
program produced equivalent positive beliefs about its value (a placebo control)
compared to the mindfulness retreat program, participants completed a 6-item measure of
perceived positive treatment benefits at the conclusion of the 3-day retreat program using
an adapted version of the Credibility/Expectancy Questionnaire (37) (study α=.87,
sample item: “At this point, how much do you really feel that this therapy will help you
reduce your stress symptoms?” 1=not at all to 9=very much). Re-employment status was
assessed at 4-month follow-up; participants indicated whether they were unemployed,
defined as having no job for more than 20 hours per week in the 4-month post-treatment
period.
Data Analysis
Resting State Functional Connectivity Analysis. PCC-seeded resting state
BOLD fMRI images were generated in the CONN toolbox, following the recommended
CONN analysis procedures (35). Specifically, CONN implements several additional
processing and 1st level analysis routines prior to rsFC analysis: CONN estimates an
orthogonal time series using principal component analysis of the BOLD time series in
each noise ROI (subject-specific white matter and csf masks). Structural MPRAGE
images were segmented to define gray matter, white matter, and cerebrospinal fluid
areas. BOLD signal from the subject-specific white matter and CSF masks, motion
parameters (six dimensions), and the effect of rest (an average across the session) were
used as regressors to account for further temporal confounding factors. CONN uses a
component-based noise reduction (CompCor) that avoids regression of the global signal.
A covariate for each subject’s head motion was entered at the first level. A band-pass
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filter of 0.008-0.09 Hz was used. A hemodynamic response function was used to downweight the initial scans within each resting state block to minimize potential ramping
effects.
The PCC seed was anatomically defined using the Talaraich deamon database in
the Wake Forest University (WFU) Pickatlas (38) centered on MNI: -4,-50,40. Seeded
first-level maps in CONN were then submitted to a second-level full factorial analysis in
SPM8 with two factors specified, time and group. To test study predictions in the brain,
we specified a time-by-group spreading interaction contrast that tested for baseline to
post-intervention increases in rsFC in the HEM program relative to no change in the HER
program from baseline to post-intervention using contrast weights:
[-1(pre,HEM), -1(pre,HER), 3(post, HEM), -1(post,HER)]. This t-contrast models the
specific hypothesized differential group change from baseline to post-treatment. The
strength of this approach (relative to testing for significant voxels using the more
standard overall F-contrast, or just comparing the two groups at post-treatment only) is
that it tests the specific prediction the mindfulness meditation program increased rsFC
from baseline to post-treatment compared to no change in the relaxation group (as
opposed to other types of interaction patterns that might be significant with an F-contrast
analysis). Note that this approach compares the mindfulness group at post-treatment to
the average of the other cells in this 2X2 design, testing the spreading interaction
prediction (and not other interaction patterns, e.g., crossover interactions). Furthermore,
we then plotted the parameter estimates from this spreading interaction contrast to
visually confirm the specific interaction pattern (see Figure 1b and 1c).
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For purposes of testing rsFC with the PCC in this study, two ROI masks were
created using the WFU Pickatlas AAL atlas (each with dilation of 1mm): the first mask
consisted of the left and right anterior cingulate, and the second ROI mask consisted of
the left and right middle frontal cortex (based on 17). Cluster-level correction for multiple
comparisons was obtained using a Monte Carlo simulations in AlphaSim (National
Institute of Mental Health, Bethesda, MD). AlphaSim was first run on the anterior
cingulate AAL-defined mask, with significant clusters (p<.05, corrected) defined as those
involving k>49 contiguous voxels, each at p<.005. AlphaSim was then run on the middle
frontal cortex AAL-defined ROI mask, with significant clusters (p<.05, corrected)
defined as those involving k>82 contiguous voxels, each at p<.005.
IL-6 and Head Motion Analysis. IL-6 values at baseline and 4-month follow-up
were log transformed. Analyses adhered to intent-to-treat principles using mixed effect
linear models (MLMs) conducted in SPSS 21.0 (IBM, Armonk, New York). All variables
were modeled as fixed effects in models fit with a compound symmetric variancecovariance structure, using maximum likelihood estimation. These models included a
condition factor (HEM vs. HER program), a time factor (baseline, 4-month follow-up),
and their interaction, with F-statistics used to evaluate significant effects. All IL-6 MLMs
included participant age as a covariate given the significant range in participant age in
this sample (22-54 years old), as age is robustly associated with increasing IL-6 (27; 39).
To test whether there were condition (and time×condition) differences in fast head
motion (defined as TR-TR head motion greater than .25mm or .25 degrees in any plane),
a hypothesis and condition-blind coder summed total high head motion TRs for each
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participant’s baseline and post-treatment resting state scan, which was then tested in a
MLM with total head motion as the outcome.
PCC Resting State Functional Connectivity Mediation Analysis. Statistical
mediation analyses were conducted following recommended procedures for testing
intervening variable effects, using MLMs (40; 41). Specifically, rsFC cluster-level
parameter estimates were extracted from the SPM8 group-level analyses and tested as
mediating variables in a series of MLMs. The MLMs consisted of (MLM #1) testing a
time×condition interaction effect on change in PCC rsFC (path a, see Figure 2); (MLM
#2) testing for a significant effect of PCC rsFC on change in IL-6 (path b), when the PCC
rsFC variable (baseline, post-training) was entered simultaneously along with the
condition, time, and time×condition interaction variables; and (MLM #3) whether the
original time×condition interactive effect on IL-6 (path c) was no longer statistically
significant when the PCC rsFC effect was entered as a simultaneous predictor variable
(path c’). Statistical mediation was defined as present when: 1) there were significant
intervening variable paths (paths a and b), and 2) when the original time×condition
interaction on IL-6 (path c’) was no longer significant when the change in rsFC variable
was entered as a simultaneous predictor variable.
Results
Preliminary Analyses—Success of randomization and treatment program
measures. There were no significant differences between the mindfulness (HEM) and
relaxation (HER) groups on study baseline characteristics, indicating successful
randomization (see Table 1). There were no significant group differences in fast head
motion during the resting state scan period (F(1,35)= .002, p=.97) and no differential fast
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head motion changes from baseline to the post-treatment fMRI resting state scan between
groups (time×condition F(1,34)= .001, p=.98). The relaxation training program was an
effective placebo control; there were no significant group differences in perceived
treatment benefits at the conclusion of the 3-day retreat (independent samples t(31)=1.06,
p=.30; HEM M=38.76, SE=2.19, HER M=42.03, SE=2.13).
97% of randomized participants completed the 3-day training programs and 97%
were retained at the 4-month follow-up assessment (see Fig. S1 for CONSORT
flowchart). These high retention rates may have reflected the high (and equivalent)
treatment satisfaction reported by participants in both the mindfulness (HEM M=4.15,
SE=.18) and relaxation (HER M=4.12, SE=.19) programs at follow-up (single item:
“Would you recommend this program to other people you know?”: 1=not at all to 5=a
great deal; independent samples t(32)=.11, p=.91). Despite our efforts to encourage home
practice after the 3-day retreats (along with sending participants home with customized
compact discs containing guided condition-specific mindfulness and relaxation
exercises), participants did not complete much formal practice in the 4-month follow-up
period. HEM participants reported using their home practice CD an average of 1.24 times
per week (SD=1.28) over the last month (at the 4-month follow-up assessment), while
HER participants reported using their home practice CD .38 times per week (SD=.86)
over the last month (t(31)= 2.27, p=.03). (We also did not collect measures of home
practice in the day(s) following the retreat program leading up to the post-treatment fMRI
session, a study limitation.)
Primary Analyses—Alterations in DMN resting state functional connectivity.
Consistent with predictions, there was a significant pre-post intervention increase in rsFC
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between the PCC (the DMN seed region) and left dlPFC (MNI: -22,52,10; k=111;
Z=3.44, p<.05, corrected) in the mindfulness meditation training group relative to the
relaxation training control group. As shown in Figure 1, there was no coupling of PCC
with the left dlPFC (panel B) at baseline in both the mindfulness and relaxation groups,
but at post-treatment the mindfulness (but not relaxation) group showed positive coupling
of PCC and left dlPFC. Although the clusters did not survive multiple comparison
correction, a homologue region of right dlPFC showed a similar effect (MNI: 26,44,34;
k=24; Z= 3.22; see Figure 1 panel C), along with another cluster in left dlPFC (MNI: 30,42,38; k=77; Z=3.11). Contrary to predictions, mindfulness meditation training did not
significantly alter rsFC of the PCC with dACC. We also observed no alterations in intraDMN rsFC; specifically, mindfulness meditation training did not decouple the PCC with
other DMN nodes (e.g., PCC with ventromedial PFC) (42). We provide exploratory
time×condition interaction results for PCC rsFC across the whole brain in Tables S2 and
S3 (thresholded at uncorrected p<.005, k>50 voxels).
Circulating IL-6. There were no significant baseline differences in log
transformed IL-6 (or raw IL-6; see Table 1) between the mindfulness meditation and
relaxation training groups (t(28)=1.04, p=.31). However, mindfulness meditation
training, relative to relaxation training, reduced circulating levels of IL-6 at 4-month
follow-up. A mixed effect linear model (controlling for participant age) indicated that
mindfulness meditation training significantly reduced circulating log-transformed IL-6
from baseline (M=.13, SE=.07) to 4-month follow-up (M=.08, SE=.08) compared to
increases in the relaxation training group (baseline M=-.06, SE=.08; 4-month follow-up
M=.08, SE=.07) (time×condition interaction F(1,29)= 4.14, p=.05, d=.71) (see Table 2).
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Changes in re-employment during the 4-month follow-up period could have explained
these changes in IL-6, but this was not the case; there were equal rates of re-employment
in the two groups at the 4-month follow-up assessment (48% of participants in both
groups were re-employed at 4-month follow-up).
Alterations in DMN rsFC mediate mindfulness meditation training improvements
in IL-6. As shown in Figure 3, increases in pre-post intervention PCC-left dlPFC rsFC
statistically mediated changes in circulating IL-6 from baseline to 4-month follow-up.
Specifically, a mediation model indicated that the strength of the time×condition
interaction effect on IL-6 (path c) was no longer significant when the change in the left
dlPFC cluster (MNI:-22,52,10; k=111) connectivity predictor variable was entered
simultaneously in a mixed effect linear model (see path c’ in Figure 2). Although the
right dlPFC cluster did not survive multiple comparison correction (MNI: 26,44,34;
k=24), it also marginally significantly mediated the IL-6 effects (also shown in Figure 3).
Mindfulness meditation training alterations in rsFC observed in the second left dlPFC
cluster (MNI:-30,42,38) did not mediate IL-6 effects. These findings in Figure 2 indicate
that change in PCC-dlPFC connectivity accounts for 30% (left dlPFC MNI:-22,52,10)
and 25% (right dlPFC MNI:26,44,34) of the overall mindfulness meditation (vs
relaxation training) effect on reductions in IL-6 at 4-month follow-up.
Conclusions
There has been considerable recent interest in characterizing resting state neural
networks such as the DMN, and understanding their role in health and disease (23). We
report that mindfulness meditation training (compared to relaxation training without a
mindfulness component) increased rsFC between the DMN (PCC) and left dlPFC. These
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findings corroborate and experimentally extend cross-sectional findings in advanced
mindfulness meditation practitioners (17), suggesting that mindfulness meditation
training may couple one’s resting state DMN with regions implicated in executive control
(dlPFC). These findings were specific to coupling of the PCC with dlPFC, and not with
dACC (cf. 17). Notably, some work has shown that dlPFC and dACC are involved with
dissociable executive control and salience processing networks, respectively (43);
furthermore, whereas increased dACC connectivity is associated with anxiety, increased
dlPFC connectivity is associated with behavioral improvements in executive task
performance (e.g., attention task switching) (43).
Although studies commonly report that the DMN is anti-correlated with regions
in the executive control network (44; 45), some studies indicate positive PCC-dlPFC
coupling during self-focused and process-oriented mental simulations (45–47) and during
guided mindfulness meditation practice (17). These findings suggest that a processoriented focus on the self during meditation may shift intra-network DMN rsFC toward
inter-network connectivity, coupling DMN with regions in the executive control network.
Notably, the present results show that these alterations in DMN-EC rsFC can be
maintained in the weeks following brief, intensive mindfulness meditation training.
We also provide an initial indication in this RCT sample (N=35) that mindfulness
meditation training reduces IL-6 from baseline to 4-month follow-up, compared to
increases in IL-6 in the relaxation training control group. This finding suggests that
mindfulness meditation training may decrease biomarkers of inflammatory disease risk in
populations whom have elevated inflammation (such as stressed unemployed adults),
although we note this was a small sample and this IL-6 finding should be treated with
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some caution. But like this study finding, several studies show that mindfulness
meditation training interventions reduce markers of inflammation in stressed populations
(8–11). Moreover, the present work shows that pre-post training changes in PCC-dlPFC
rsFC mediate these effects on IL-6. Currently very little is known about top-down neural
modulation of peripheral inflammation in humans, despite a large number of
epidemiologic studies linking peripheral circulating pro-inflammatory cytokines with
cardiovascular morbidity and all-cause mortality (29–31; 48). Some initial studies in
humans highlight reciprocal brain-peripheral inflammation links (49; 50), although the
present study offers a novel top-down regulatory pathway for the modulation of
circulating IL-6 in humans. Notably, studies have implicated activation and functional
connectivity of dlPFC with improved executive control resources, and reduced pain,
negative affect and stress (18–21; 43). We speculate that mindfulness meditation training
coupled the brain’s DMN with regulatory areas of prefrontal cortex (dlPFC), which
facilitated more effective emotion regulation and stress resilience in this high stress
unemployed job-seeking sample, reducing circulating IL-6. Specifically, efferent
projections from dlPFC might modulate medial PFC and subcortical cell groups known to
trigger peripheral stress and inflammatory response cascades (51; 52). A small
experimental literature provides initial support for this neural stress-buffering account of
mindfulness meditation training (14), although more research is needed to evaluate these
stress reduction mediated pathways.
An important question going forward will be to evaluate whether these observed
PCC-dlPFC rsFC changes reflect neuroplasticity in white matter connectivity after
mindfulness meditation training. Several lines of evidence provide suggestive support:
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anatomic studies in primate models have shown that measures of rsFC have high
correspondence to underlying white matter architecture (53), and there are established
white matter tracts linking PCC with dlPFC (54). Notably, an initial experimental study
demonstrates that even brief meditation training (~11 hours) fosters neuroplasticity by
increasing white matter connectivity (as measured by fractional anisotropy) of the
anterior corona radiata (55).
Unlike a previous study (17), mindfulness meditation training did not increase
PCC-dACC rsFC in this sample. We speculate that one possibility for these divergent
effects may be due to differences in study methodology. The previous study measured
rsFC using 2-minute resting state periods at the beginning of each run, followed by 4.5
minute meditation practice periods (17). By contrast, the present study collected rsFC at
the beginning of the fMRI session (immediately following the collection of the structural
scans). Some neuroimaging evidence indicating that acute meditation practice activates
the ACC (56; 57), and it may be that ACC activity during these 4.5 minute meditation
practice periods had some residual carry-over into the rsFC scans in the previous study.
Indeed, there is research showing that cognitive tasks have carry-over effects on PCCACC functional connectivity during subsequent rsFC periods (58). The present study
design is less susceptible to potential task-based carry over effects, and provides an initial
indication for non-task based PCC-dlPFC rsFC effects in the weeks following a 3-day
mindfulness meditation training intervention.
Conclusions
Little is known about how behavioral interventions, such as mindfulness
meditation training, can impact the brain and physical health. We provide the first well-
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controlled evidence that 3-days of mindfulness meditation training increases rsFC of the
DMN with neural regions important in executive control (left dlPFC), and that these rsFC
changes statistically mediate improvements in circulating levels of IL-6 at follow-up.
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Acknowledgements and Financial Disclosures
The authors declare no conflicts of interest. J.D. Creswell and A.A. Taren had full
access to the data and take responsibility for the integrity of the data and the accuracy of
the data analysis. We would like to thank the research assistants in the Health and Human
Performance laboratory, the blood draw nurses (Karen Foley, Diana Ross) and lab
technician (Katarina Krajina), the Sisters at Kearns Spirituality Center for hosting the
retreats, and the Scientific Imaging and Brain Research (SIBR) center. We also thank
Erica Julson, Laura Pacilio, and Shinzen Young for help and feedback.
The authors report no financial interests or potential conflicts of interest regarding
this research. This research was supported by funding from the Pittsburgh Life Sciences
Greenhouse Opportunity Fund, who played no role in the design and conduct of the
study; collection management, analysis, and interpretation of the data; and preparation,
review, or approval of the manuscript; and the decision to submit the manuscript for
publication.
19
J.D.
Creswell
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J.D.
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28
Figure
Legend
Figure
1.
Baseline
to
Post-‐Treatment
Resting
State
Functional
Connectivity
in
the
Mindfulness
and
Relaxation
Training
Groups.
(A)
Left
dlPFC
cluster
(MNI:
-‐22,52,10;
k=111,
p<.05
corrected).
that
showed
increased
rsFC
with
PCC
from
before
to
after
mindfulness
meditation
training
(HEM)
relative
to
relaxation
training
(HER).
Specifically,
a
time×condition
spreading
interaction
analysis
revealed
a
significant
cluster
in
left
dlPFC
(panels
A
and
B).
A
cluster
in
right
dlPFC
(MNI:
26,42,38;
k=24)
showed
the
same
pattern
of
effects
as
the
left
dlPFC
cluster
but
it
did
not
survive
correction,
thus
the
(panel
C)
right
dlPFC
rsFC
results
should
be
interpreted
with
caution.
.The
spreading
interaction
effects
that
mediate
IL-‐6
effects
are
depicted
for
left
(B)
and
right
(C)
dlPFC.
Specifically,
mean
connectivity
strength
is
shown
for
the
mindfulness
(HEM)
and
relaxation
(HER)
training
groups
at
baseline
and
post-‐
treatment.
Error
bars
depict
+/-‐
1
standard
error.
Figure
2.
IL-‐6
Mediation
analyses.
Increases
in
left
dlPFC
connectivity
(MNI:
-‐
22,52,10)
significantly
mediate
(panel
A)
the
time
× treatment
interaction
on
circulating
(log
transformed)
IL-‐6.
Increases
in
right
dlPFC
(MNI:
26,42,38)
marginally
significantly
mediate
(panel
B)
IL-‐6
effects.
Numbers
represent
b
coefficients
from
mixed
effect
linear
models,
with
parentheses
representing
b
coefficients
when
the
main
effect
and
time
× treatment
condition
interaction
terms
and
dlPFC
connectivity
parameter
estimates
are
entered
in
a
mixed
effect
linear
model
simultaneously.
***p<.05;
**p=.05;
*p=.06
J.D.
Creswell
Table
I.
Baseline
Characteristics
of
Randomized
Participants.
Characteristic
Age
[mean
years
(SD)]
Gender
Male
Female
Ethnicity
Caucasian
African
American
Asian
American
Latino(a)
Native
American
Biracial
Other
Months
Unemployed
Education
No
high
school
degree
GED
High
school
degree
Technical
training
Some
college
Associate
degree
Bachelor’s
degree
Master’s
degree
MD/PhD/JD/PharmD
Body
Mass
Index
Cognitive
Impairment
(MMSE)
IL-‐6
pg/mL
Post-‐fMRI
Days
Elapsed
HEM
HER
Difference
Statistic
37.94
(10.96)
11
7
10
6
1
0
0
1
0
8.17(12.48)
1
1
1
3
4
2
2
3
1
27.15
(4.30)
29.39
(.70)
41.00
(9.55)
t(33)=
-‐.48,
p=
0.64
1.81
(2.03)
5.06
(3.29)
χ2(1)=.24,
p=
0.63
9
8
χ2(5)=
6.37,
p=
0.27
13
2
0
1
0
0
1
10.58(20.31)
t(33)=
-‐.43,
p=
0.67
χ2(8)=
8.43,
p=
0.39
0
0
2
2
3
0
7
3
0
26.44
(5.50)
t(32)=
.423,
p=
0.68
28.88
(1.15)
t(32)=
1.60,
p=
0.12
1.21
(.76)
5.29
(4.52)
t(28)=
1.03,
p=
0.31
t(32)=
-‐.17,
p=.86
Notes:
Standard
deviation
values
are
provided
in
parentheses.
HEM=
3-‐Day
Health
Enhancement
thru
Mindfulness
group;
HER=
3-‐Day
Health
Enhancement
thru
Relaxation
group;
MMSE=
Mini-‐Mental
State
Exam;
IL-‐6=
Interleukin-‐6;
Participants
indicated
their
ethnicity/gender
via
self-‐report;
Post-‐fMRI
Days
Elapsed=
number
of
days
elapsed
at
post-‐MRI
session
from
the
conclusion
of
the
retreat
program.
29
J.D.
Creswell
Table
2.
Circulating
IL-‐6,
by
Treatment
Group
and
Time
Mean HEM
SE
Mean HER
SE
Log-Transformed IL-6
Baseline
.13
.07
-.06
.08
4-Month Follow-Up
.08
.08
.08
.07
Baseline
1.87
.31
1.17
.32
4-Month Follow-Up
1.45
.32
1.41
.30
Raw IL-6
Notes:
Means
and
Standard
Errors
(SE)
from
IL-‐6
MLMs,
with
Baseline
Age
as
a
covariate.
IL-‐6=
Circulating
Interleukin-‐6;
SE=
standard
error;
HEM=
Health
Enhancement
thru
Mindfulness
program;
HER=
Health
Enhancement
thru
Relaxation
program;
All
IL-‐6
values
are
in
pg/mL.
30
J.D.
Creswell
31
Figure
1
A)
B)
Left
dlPFC
(MNI:
-‐22,52,10)
C)
Right
dlPFC
(MNI:26,44,34)
J.D.
Creswell
Figure
2
(A)
Left
dlPFC
Connectivity
Path
a:
-‐.20***
Path
b:
(-‐.43***)
Mindfulness
vs.
Relaxation
Training
Baseline-‐4
Month
IL-‐6
Path
c:
.190**
Path
c’:
(.133)
(B)
Right
dlPFC
Connectivity
Path
a:
-‐.20***
Path
b:
(-‐.34*)
Mindfulness
vs.
Relaxation
Training
Baseline-‐4
Month
IL-‐6
Path
c:
.190**
Path
c’:
(.143)
32
J.D.
Creswell
33
Supplementary
Online
Information
Supplementary
Text
Detailed
Description
of
Mindfulness
(HEM)
and
Relaxation
(HER)
Programs
The
present
study
utilizes
two
strategies
for
increasing
the
scientific
rigor
of
meditation
research.
First,
we
have
developed
a
3-‐day
condensed
retreat
format
for
teaching
mindfulness
meditation
training
entitled
the
Health
Enhancement
thru
Mindfulness
(HEM)
program
(which
is
based
on
exercises
and
didactics
taught
in
the
Mindfulness-‐Based
Stress
Reduction
(MBSR)
program).
Delivery
of
the
HEM
program
in
a
retreat
format
ensures
a
consistent
and
strong
dose
of
mindful
awareness
practice
across
participants,
provides
a
relatively
controlled
external
environment
away
from
the
variety
of
stresses
and
supports
of
participants’
lives,
and
has
the
potential
to
minimize
drop-‐outs.
Second,
we
have
designed
an
active
control
or
comparison
program,
Health
Enhancement
through
Relaxation
(HER)
that
is
structurally
similar
to
HEM,
but
avoids
cultivation
of
mindfulness
and
body
awareness.
The
use
of
a
structurally-‐matched
active
comparison
group
helps
to
control
for
non-‐specific
factors
such
as
group
support,
teacher
attention,
physical
activity,
and
mental
engagement.
Both
HEM
and
HER
consist
of
similar
behavioral
activities,
scheduled
on
an
hourly
basis
throughout
each
retreat
day,
such
as
sitting
quietly,
stretching,
slow
walking,
eating,
and
discussion.
However,
the
instructions
and
guidance
for
how
to
engage
in
the
activities
differ
in
systematic
ways.
In
the
HEM
program,
participants
are
instructed
to
train
their
attention
and
awareness
to
be
fully
present
to
each
of
these
activities,
learning
the
skill
of
mindful
awareness.
In
contrast,
HER
participants
engage
in
similar
guided
activities,
but
are
instructed
to
participate
in
these
activities
in
a
relaxed
and
restful
way,
to
let
their
minds
wander,
or
even
to
rest
or
sleep.
Common
features
of
the
HEM
and
HER
retreats
included:
individual
10
minute
interviews
with
the
teacher
on
Day
1
and
Day
3
in
order
to
build
rapport
and
also
assess
progress,
instructions
to
avoid
discussion
with
members
of
the
other
group
in
order
to
avoid
cross-‐contamination
of
groups,
and
instructions
to
keep
up
with
practice.
CD’s
with
meditation
(HEM
group)
or
relaxation
exercises
(HER
group)
were
provided
for
home
use
following
the
retreat.
HEM
Program.
The
HEM
retreat
program
was
designed
as
an
adapted
and
condensed
version
of
the
8-‐week
MBSR
program.
The
specific
content
of
the
HEM
program
was
developed
in
consultation
with
a
senior
teacher
at
the
UMass
Medical
School’s
Center
for
Mindfulness
(Melissa
Blacker,
MA).
On
retreat
day
1,
HEM
participants
were
welcomed
and
introduced
to
the
topic
of
mindfulness
meditation
for
stress
reduction,
and
oriented
to
the
program.
Following
participant
introductions,
the
group
engaged
in
a
mindful
eating
exercise,
and
the
body
scan
meditation
was
introduced
after
a
period
of
gentle
stretching.
Participants
were
encouraged
to
practice
mindful
awareness
of
eating
during
lunch.
Sitting
meditation,
walking
meditation,
and
mindful
movement
(gentle
hatha
yoga
postures)
were
also
introduced
on
retreat
Day
1.
After
each
formal
meditation
J.D.
Creswell
34
period,
participants
engaged
in
discussion
of
their
observations
about
themselves
and
the
practices.
During
all
interactions,
from
guided
meditations
to
discussions,
the
instructor
modeled
and
encouraged
attitudes
of
mindfulness
such
as
letting
go
of
judgment
and
expectations,
cultivating
self-‐care,
patience,
and
friendly
curiosity
regarding
present
moment
experience.
In
the
evening
of
Day
1,
participants
were
asked
to
notice
pleasant
and
unpleasant
events
and
record
their
physical
sensations,
moods
or
emotions,
and
thoughts
in
their
retreat
notebook,
to
be
discussed
on
Day
2.
Participants
were
asked
to
continue
their
awareness
practice
by
remaining
relatively
quiet
after
the
group
sessions
ended
at
9PM.
During
Day
2,
which
began
at
7:30AM,
formal
mindfulness
meditation
practices
were
continued,
consisting
of
mindful
movement
(yoga),
sitting
meditation,
guided
and
unguided
walking
meditation,
and
meditation
on
various
objects
of
attention,
such
as
breath
sensations,
body
sensations,
sounds,
moods
or
emotions,
and
thoughts
and
the
spaces
between
thoughts.
Discussions
during
Day
2
included
exploration
of
pleasant
and
unpleasant
events,
stress
and
stress
physiology,
and
reacting
and
responding
to
stress.
The
structure
of
these
discussions
included
reflections
in
dyads
or
triads
as
well
as
the
entire
group.
Participants
were
asked
to
remain
quiet
during
the
evening
session
until
after
breakfast
on
Day
3.
The
intention
of
the
quiet
period
was
to
foster
self-‐care
and
deepen
the
mindful
awareness
experienced
during
the
day’s
group
sessions.
On
retreat
Day
3,
formal
meditation
practices
continued,
with
the
addition
of
Choiceless
Awareness
and
Lovingkindness
or
Metta
meditation.
Building
from
the
previous
day’s
discussions
of
stress
reactivity
and
the
possibility
of
responding
to
stress
with
greater
flexibility
and
presence,
Day
3
discussions
focused
more
closely
upon
participants’
own
life
challenges,
and
their
plans
for
meeting
their
unemployment
and
job-‐seeking
stress
with
mindfulness.
Participants
worked
individually,
in
dyads,
and
with
the
entire
group
to
develop
their
intentions
for
continuing
their
meditation
practice
and
for
applying
what
they
had
learned
at
the
retreat
to
their
daily
lives.
Closure
exercises
included
yoga
postures
or
favorite
stretches
taught
by
the
group
members,
and
sharing
of
good-‐byes.
HER
Program.
The
HER
program
was
designed
to
maximize
similarity
in
activity
to
the
HEM
program
but
without
mindfulness
skill
development.
On
Day
1,
participants
were
oriented
to
the
HER
program
as
an
opportunity
to
rest
and
rejuvenate
and
gain
information
about
healthy
living.
They
had
the
opportunity
to
introduce
themselves
to
the
group
and
to
share
their
ways
of
managing
stress.
To
parallel
the
HEM
meditation
without
mindfulness
or
specific
instructions
about
awareness
of
body
sensations,
the
HER
instructor
led
imagery
exercises
focused
on
visualizing
a
stream
and
later
on
a
comfortable
and
safe
place.
To
parallel
the
dyadic
work
in
the
HEM
group,
the
HER
participants
worked
in
pairs
to
develop
scripts
for
pleasant,
relaxing
place
imagery,
and
guided
one
another
in
this
relaxation
exercise.
Discussions
throughout
Day
1
and
Day
2
included
topics
such
as
exercise
for
stress
management,
nutrition,
using
Michael
Pollan’s
Food
Rules,
and
Sleep
Hygeine.
To
match
the
mindful
yoga
of
the
HEM
group,
HER
participants
engaged
in
stretches
led
using
counting
or
joke-‐telling
in
order
to
avoid
the
development
of
body
awareness
and
acceptance.
On
Day
2,
HER
retreatants
continued
to
engage
in
light
stretching,
took
walks,
engaged
in
drawing
and
imagery
exercises
involving
exploration
of
their
own
strengths
and
values.
Stress
and
Health
J.D.
Creswell
35
was
a
topic
for
discussion,
with
participants
working
in
dyads
as
well
as
the
whole
group
to
explore
what
they
experience
when
they
are
stressed.
Hobbies
and
interests
was
an
additional
topic
for
discussion.
On
Day
3,
HER
participants
continued
gentle
calisthenics
and
engaged
in
writing
about
what
they
were
learning
at
the
retreat.
Discussions
centered
on
stress
and
social
support,
and
participants
used
drawing
to
explore
their
own
social
circles
of
support,
and
discussed
this
in
dyads
and
the
entire
group.
Imagery
exercises
included
reflecting
on
the
future
and
where
participants
imagined
themselves
being
in
five
years.
The
group
closed
with
creation
of
and
sharing
of
personal
plans
for
a
healthy
daily
routine,
and
sharing
of
good-‐byes.
Overview
of
Parent
Study
Measurement
Approach
The
present
report
focuses
on
testing
hypotheses
about
mindfulness
training
alterations
in
Default
Mode
Network
(DMN)
resting
state
functional
connectivity
(rsFC),
and
whether
these
training
neural
alterations
prospectively
predict
changes
in
the
health
biomarker
IL-‐6
at
follow-‐up.
These
neural
and
circulating
IL-‐6
measures
are
part
of
a
broader
measurement
battery
in
this
study,
the
other
measures
we
aim
to
describe
in
other
published
reports.
Here
we
provide
an
overview
of
the
additional
measures
collected
in
this
study:
Baseline
Assessment:
psychosocial
and
individual
difference
self-‐report
questionnaire
packet
(e.g.,
SF-‐36,
Perceived
Stress
Scale,
Life
Experiences
Survey,
UCLA
Loneliness).
Baseline
MRI:
1
hour
functional
and
structural
neuroimaging
session
(high
resolution
structural
scan,
four
functional
scans:
resting
state
BOLD,
Multi-‐Source
Interference
Task,
Affect
labeling,
and
Unemployment
Stress
Task).
At
the
end
of
the
fMRI
session
participants
completed
an
audio-‐guided
mindfulness
meditation
task
(during
arterial
spin
labeling
perfusion
MRI).
Retreat
Assessment:
blood
sample
(pre-‐retreat
prior
to
randomization),
palm
pilot
assessments
(5
times
per
day
during
all
retreat
days),
instructor
interviews
(during
Day
1
and
during
Day
3),
and
retreat
behavioral
tasks
(e.g.,
walking
speed,
implicit
tasks).
Post-‐Treatment
MRI:
[same
measures
as
baseline
MRI]
4-‐Month
Follow-‐Up
Assessment
session
at
Retreat
Center:
blood
sample,
hair
sample,
psychosocial
self-‐report
questionnaire
packet
[same
as
at
baseline,
plus
additional
program/study
evaluation
measures,
assessment
of
job
status
and
job-‐
seeking
behaviors],
behavioral
task
measures
(implicit
tasks).
J.D.
Creswell
36
Table
S1.
Study
inclusion/exclusion
criteria.
Participants
were
required
to
meet
all
study
criteria
at
screening
to
be
enrolled
in
the
trial.
General
Inclusion:
• 24-‐54
years
• Fluent
in
English
• Nonsmoker
(smoking
prohibited
at
retreat
center)
Exclusion:
• Cognitive
impairment
(<23
on
MMSE)
• Serious
mind-‐body
practice
(>2x/week)
• Alcohol
Consumption
(>15
drinks/week)
• Recreational
Drug
Use
(past
month)
• Pregnancy
or
Breastfeeding
Health
&
Immune-‐Related
Exclusion:
• Hospitalization
for
mental
or
physical
health
problem
(past
6
months)
• Chronic
disease
(e.g.,
cancer,
HIV,
diabetes,
heart
disease,
arthritis)
•
Medication
use:
o Mental
health
problems
o Cholesterol-‐lowering
meds
(Crestor,
statins)
o Immune-‐related
treatment
(corticosteroids,
chemotherapy,
transplantation
medication)
fMRI
Criteria
Exclusion:
• Left-‐handed
• Presence
of
metal
in
body
• Weight
>350
pounds
•
•
Claustrophobia
Neurological
disorders
(epilepsy,
spina
bifida,
stroke,
traumatic
brain
injury)
Stress
&
Unemployment
Inclusion:
• Unemployed
(working
<20
hours/week)
• Seeking
employment
• Having
trouble
finding
a
job
• Stressed:
total
score
>5
on
job-‐seeking
PSS
(4
items
listed
at
right)
o 5-‐point
Likert
scale
(0
–
never
to
4
–
very
often)
Adapted Job Seeking Stress Screening Items
1. In the last month, how often have you felt that
you were unable to control the important things
in your life?
2. In the last month, how often have you felt
confident about your ability to handle your jobrelated problems? This could include your efforts
at finding a job, or paying your bills. (reverse
scored)
3. In the last month, how often have you felt that
things were going your way in finding a job?
(reverse scored)
4. In the last month, how often have you felt
difficulties were piling up so high that you could
not overcome them?
J.D.
Creswell
Table
S2.
Whole-‐brain
analyses
of
regions
displaying
increased
PCC-‐seeded
resting
state
functional
connectivity
in
the
mindfulness
relative
to
the
relaxation
treatment
program
in
a
spreading
interaction
analysis
using
contrast
weights:
[-‐1(pre,HEM),
-‐1(pre,HER),
3(post,
HEM),
-‐1(post,HER)]
(
(p<
0.005,
k>50).
Specifically,
regions
that
are
more
coupled
with
PCC
after
the
HEM
training
(relative
to
HER
training).
Region
Cluster
Size
Peak
MNI
Coordinates
Z
Right
Superior
Frontal
Gyrus
147
20
62
-‐6
3.97
Left
Pallidum
72
-‐20
-‐4
2
3.68
Left
Insula
57
-‐26
18
-‐8
3.98
Left
Pallidum
62
-‐6
0
-‐6
4.09
Left
Thalamus
54
-‐28
-‐26
8
3.58
Left
Middle
Frontal
Gyrus
117
-‐22
52
10
3.44
Left
Superior
Frontal
Gyrus
79
-‐30
42
38
3.11
Right
Supramarginal
Gyrus
66
60
-‐44
38
3.35
37
J.D.
Creswell
38
Table
S3.
Whole-‐brain
analyses
of
regions
displaying
decreased
PCC-‐seeded
resting
state
functional
connectivity
in
the
mindfulness
relative
to
the
relaxation
treatment
program
in
a
spreading
interaction
analysis
using
contrast
weights:
[1(pre,HEM),
1(pre,HER),
-‐3(post,
HEM),
1(post,HER)]
(
(p<0.005,
k>50).
Specifically,
regions
that
are
less
coupled
with
PCC
after
the
HEM
training
(relative
to
HER
training).
Region
Cluster
Size
Peak
MNI
Coordinates
Z
Right
Inferior
Temporal
Cortex
54
46
2
-‐44
3.23
Right
Fusiform
Gyrus
56
36
-‐62
-‐14
3.96
Left
Lingual
Gyrus
353
-‐12
-‐78
-‐4
4.09
Left
Inferior
Frontal
Gyrus
55
-‐46
32
0
3.33
Right
Insula
57
32
-‐26
20
3.57
Right
Postcentral
Gyrus
235
48
-‐4
28
4.55
Left
Precentral
Gyrus
91
-‐52
-‐12
36
3.34
Right
Paracentral
Lobule
82
4
-‐34
64
3.43
Right
Precentral
Gyrus
464
10
-‐6
80
4.36
J.D.
Creswell
39
Table
S4. A detailed overview of the 3-day Health Enhancement thru Mindfulness
(HEM) and Health Enhancement thru Relaxation (HER) intervention programs.
Health Enhancement thru Mindfulness
Welcome and orientation to the
guidelines for participation in the
program; introduce the concept of
mindfulness; centering exercise and
individual introductions; mindful raisineating exercise; 45-minute body scan
exercise (show alternative postures, and
start with some stretching).
Depending on when program starts,
raisin and body scan may be after lunch.
12:15- Mindful lunch (not silent) (1/2 hr in
1:45
cafeteria, 1 hr break) (3 student
interviews)
1:45Continue intros, raisin exercise, body
3:15
scan as needed, depending on progress
prior to lunch.
Discussion of body scan/morning, weave
Conf
in relevant ‘attitudes of mindfulness’
area
(non-striving, patience, don’t know
mind) intro to sitting and postures,
sitting meditation with AOB. Review
definitions of mindfulness as indicated.
Use Mountain meditation or other
stabilizing imagery as indicated.
3:15Snack /tea (2 student interviews)
4:15
4:15Standing and walking
5:45
Mindful movement yoga, Intro
awareness of pleasant events assignment
Chapel
(to discuss tomorrow)
10:0012:00
Conf area
5:457:30
7:30-9
Conf
area
5:30-7:30
Day 1
10 12:15
chapel
Mindful dinner (2 student interviews)
Sit (~15 min). Walking. Seated body
scan, followed by stretching. Use
Mountain imagery as indicated.
Reflection and discussion of 1st today’s
experiences, integrating attitudes of
Health Enhancement thru Relaxation
Orientation, guidelines*, and introductions
(pairs first, then big group)
How do you manage stress? (keep it somewhat
light) (this may generate a list of diverse coping
methods, and can be referred back to as the
weekend goes on).
End session with stream imagery for relaxation.
12:00-1:30
Lunch (3 student interviews)
1:30-3:00
chapel
Brief disc of physical activity as method for
stress reduction.
Stretching / exercise.
Discussion what keeps you from exercising, if
you don’t--list
3:00-4:00
Snack / tea (2 student interviews)
Intro to safe place.
Demonstration of dyadic work--development of
an image of being safe and at ease. Work in
pairs, writing down, then guiding each other.
(comfort and ease imagery)
Share feedback in large group
Dinner (2 student interviews)
Sleep Hygiene: talk about the connection
between sleep and health.
Ask them how they sleep (this could take a long
time!)
Give Sleep Hygiene handout and go over it
4:00-5:30
Conf area
7:30 – 9
chapel
J.D.
Creswell
mindfulness.
Orientation and instructions for
continuing mindfulness practice during
the later evening and bedtime, noting
pleasant and also unpleasant events,
(give calendars) returning wandering
mind to present moment awareness.
Lying down Body Scan.
40
briefly.
Nutrition (using Pollen material)
What is true; what is helpful here?
Reminder: maintain quiet this evening and in
early morning (if you talk, keep it fairly quiet)
Relaxation exercise for sleep.
9:00-10:30
Quiet time (4-5 interviews)
10:30pm
Lights out
910:30
10:30
pm
Day 2
7am
7:308:15
Chapel
Quiet time (4-5 interviews)
Lights out
8:159:15
9:1510:45
Conf
area
Mindful Breakfast (silence optional)
8:30-9:30
Brief sit (~15 minutes). Discussion of
last evening and this morning’s
mindfulness practice, including silence;
dyads and then group disc/ mindful
listening re: pleasant and unpleasant
events. Begin disc of what makes an
event pleasant/ unpleasant; topic of
‘stress/ stress physiology’
Walking meditation (unguided)
9:30-11
Chapel
Physical Exercise
‘non-mindfulness’ version of yoga
stretch/strengthening exercises.
Incorporate some HEP exercise activities.
Something to think about on your walk: what
are your personal strengths?
11-11:30
Take a walk
Mindful stretch followed by sit.
Continue disc of anatomy of stress, stress
reactivity /automatic pilot and possibility
of responding mindfully to stressful
events. Use metaphors as indicated (e.g,
4 story building, waterfall and barrel,
etc.)
Mindful lunch
11:3012:15
Chapel
Discussion of strengths and values. Who are
your role models and what do you admire re:
them?
Exercise: draw your personal ‘values and
strengths’ coat of arms. Share ‘coat of arms’ in
dyads and then large groups.
10:4511:15
11:1512
Conf
area
12-1
Wake up (maintain silence)
Mindful stretch – on floor, followed by
sit with AOB, AO body sensations. Prep
for mindful breakfast.
Day 2
7am
7:30-8:30
Conf .
Wake up (maintain quiet)
Movement – gentle calesthenics
Reflective writing re: ideas sparked by
yesterday’s and last night’s disc (what do they
want to explore, what do they want to
remember.)
Breakfast
12:15-1:15
Lunch
1-2:30
Sit with AOB, Body, AOSound, AO
1:15-3
Demonstration of development of imagery for
Chapel
Thought (internal image/talk). Disc of
feeling competent and effective, or strong.
participants own stress reactivity patterns Conf area
They break into dyads to do this.
(start with dyads) how do they know
(if you don’t have a memory to use, can
J.D.
Creswell
2:303:30
3:305:30
Conf
area
they are stressed and how do they take
care of self. Disc mindful approach to
emotions; problem focused and emotion
focused coping. Lovingkindness
meditation if appropriate. Introduce
possibility of silent period (to start
~4:30pm).
Snack / tea
Chair yoga followed by sit. Continue
discussion of stress reactivity and
mindful responding as needed. Disc of
upcoming silent time with rationale as a
time to be with yourself, focus on
yourself in a caring way. If
group/individuals seem able to meet this,
silence begins (~4:30pm) run this
section like MBSR retreat: body scan,
mindful movement, sitting,
lovingkindness meditation (include
choiceless awareness)
41
imagine one – like you are an actor in a scene)
Share feedback in large group
3-4
4-5:45
Chapel
5:307:15
7:15-9
Chapel
Dinner
Practice in silence. Variety of formal
practices, include choiceless awareness.
Poetry reading. Mountain or Lake
meditations as indicated.
5:457:30pm
7:30-9
Conf area
910:30
10:30
Day 3
7am
7:308:15
Quiet time
Lights out
Wake up
Mindful stretching/yoga followed by
brief body scan.
9-10:30
10:30
Day 3
7am
7:30-8:30
chapel
Snack / tea
Stress physiology
Stress and Health: JKZ handout,
Charting arousal/time and symptom
development—the arousal curve and what
symptoms shows up at which level of arousal.
Do this as a group discussion. What do they
experience when they are stressed..
Do this in dyads first, and then expand to the
bigger group. This should take approximately 1
hour.
Go back to Pollen material if did not finish it
yesterday.
Earlier today we did imagery exercises around
our strengths. What personal strengths do you
have?
Hobbies and interests – have a go around about
favorite hobbies and interests that help them to
feel comfortable / good. Create a group list of
ideas.
Dinner
Disc – how do I have / make fun?
Demonstration and then guided imagery for fun,
breaking into dyads to develop them.
Humorous video
Quiet time
Lights out
Wake up
Movement – gentle calesthenics - narrative
writing – free association or free drawing
J.D.
Creswell
Conf
area
8:159:15
9:1510
chapel
10-11
11-12
chapel
121:30
1:30-3
Conf
area
3-3:45
3:455:30
chapel
5:307:30
42
What am I learning/ do I want to take with me?
Mindful breakfast (silence)
8:30-9:30
Breakfast
Continue formal practices (guided).
9:30-10:30
Disc of stress and social support. Support can
Seeing meditation. Participants remain in Conf area
come from the living or the deceased. Even just
silence.
a small thing from memory can be powerful
(Nazi example)
Draw circles of intimacy/ mandala of social
support system
Walking unguided. Mindfulness in
10:30Quiet Rest or take a walk (3 interviews)
motion (3 interviews)
11:30
Sit. Awareness Exercises for breaking
11:30Discussion of support system /mandalas in
silence (dyads, etc). Group discussion of 12:15
dyads and in big group. Brief relaxation
silence. If we have not engaged in
Conf area
focusing on feeling competent and connected,
silence, continue discussion of mindful
Supported.
approaches for self care and responding
to stress.
Mindful Lunch (optional silence) (3
12:15-2:00
Lunch (3 interviews)
interviews)
Continue formal practices. Include
2:00-3:30
Obstacles to applying who you have learned and
Mountain meditation as well as other
how you are going to work with them
formal practices already introduced.
Chapel
Mindfulness in everyday life disc.
Guided reflections for the future – where do you
Obstacles to applying what you have
imagine yourself 5 years from now? Who is
learned and how you are going to work
there? What are you doing?
with them. Formal practice – body scan.
Discuss in small and large groups
Development of personal ‘action plans’
Break / tea (2 interviews)
3:30-4:15
Break / tea (2 interviews)
Practice. group led yoga stretches if
4:15-5:30
Making a personal plan for your self: creation of
appropriate. Discussion of personal plans
daily routine, relaxation, etc. Final
for continuing practice. Final comments Conf area
comments/closing exercises.
and closure exercises. Dyads and whole
Drawing—this group and this time here.
group.
Final study procedures (5 interviews)
5:30-7:30
Final study procedures (5 interviews)
J.D.
Creswell
43
Enrollment
Figure
S1.
Consort
Flowchart
Excluded
at
screening
(n=
661)
-‐Unreachable
(n=
216)
Interested
in
program
(n=
89)
-‐-‐Not
Employed
(n=
63)
-‐Heavy
smoker
(n=
58)
health
medication
(n=
38)
-‐-‐Mental
Low
stress
score
(n=
36)
-‐Metal
concerns
(n=
20)
-‐Not
looking
for
a
job
(n=
19)
-‐Not
available
for
retreat
(n=
17)
-‐Age
(n=
16)
-‐Left-‐handed
(n=
16)
-‐Psychologist/Psychiatrist
(n=
13)
-‐Cholesterol
medication
(n=
13)
-‐Mind/body
practice
(n=
6)
-‐Chronic
Disease
(n=
5)
-‐Other
(n=
36)
Assessed
for
Eligibility
(N=
763)
Baseline
Assessment
(n=
62)
Eligible
But
Did
Not
Attend
Baseline
Assessment
(n=
40)
-‐Did
not
return
phone
calls
(n=
14)
-‐Did
not
show
up
to
appt
(n=
14)
-‐Cancelled
appointment
(n=
4)
-‐Not
available
on
retreat
dates
(n=
4)
-‐Received
job
offer
(n=
2)
-‐No
longer
interested
(n=
1)
-‐Hospitalized
(n
=
1)
Excluded
At
Baseline
(n=
7)
-‐Metal
concerns
(n=
4)
-‐Not
technically
unemployed
(n=
1)
-‐Mental
health
medication
(n=
1)
-‐Unable
to
attend
retreat
(n=
1)
Pre-‐Retreat
fMRI
(n=
50)
Did
Not
Complete
fMRI
(n=
5)
Did
Not
Attend
fMRI
(N=
5)
-‐Did
not
return
phone
calls
(n=
2)
-‐Received
job
offer
(n=
2)
-‐Did
not
show
up
(n=
1)
-‐Metal
concerns
(n=
2)
Allocation
-‐Claustrophobia
(n=
2)
-‐Unable
to
scan
(n
=1)
Randomized
(n
=
35)
Allocated
to
3-‐Day
M indfulness
Retreat
(n
=
18)
Treatment
3-‐Day
M indfulness
Retreat
sample
(n=
18)
Post-‐Test
Did
Not
Attend
R etreat
(N=
10)
-‐Did
not
return
phone
calls
(n=
1)
-‐Received
job
offer
(n=
3)
-‐Did
not
show
up
at
retreat
center
(n=
3)
-‐Sick
(n=
2)
-‐Abnormal
scan
(n=
1)
Did
not
complete
retreat
(n=
1)
Allocated
to
3-‐Day
Relaxation
Retreat
(n
=
17)
3-‐Day
Relaxation
Retreat
sample
(n=17)
Did
not
complete
retreat
(n=0)
R
etained
at
Post-‐fMRI
(n=17)
Treatment
sample
retained
(n=
17)
Treatment
sample
dropouts
(n=
1)
Retained
at
Post-‐fMRI
(n=17)
Treatment
sample
retained
(n=
17)
Treatment
sample
dropout
(n=
0)
Retained
at
4-‐Month
Follow-‐Up
(n=
17)
Treatment
sample
retained
(n=
17)
Treatment
sample
dropouts
(n=
0)
Retained
at
4-‐Month
Follow-‐Up
(n=
17)
Treatment
sample
retained
(n=
17)
Treatment
sample
dropout
(n=
0)