Journal of Affective Disorders 150 (2013) 1152–1157

Contents lists available at ScienceDirect

Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Preliminary communication

The effects of mindfulness-based cognitive therapy in patients with

bipolar disorder: A controlled functional MRI investigation
Victoria L Ives-Deliperi a,n, Fleur Howells b, Dan J. Stein b, Ernesta M. Meintjes a, Neil Horn b
a
Department of Human Biology, University of Cape Town, Western Cape 7800, South Africa
b
Department of Psychiatry, University of Cape Town, Western Cape 7800, South Africa

art ic l e i nf o a b s t r a c t

Article history: Background: Preliminary research findings have shown that mindfulness-based cognitive therapy
Received 10 May 2013 improves anxiety and depressive symptoms in bipolar disorder. In this study, we further investigated
Accepted 24 May 2013 the effects of MBCT in bipolar disorder, in a controlled fMRI study.
Available online 20 June 2013
Method: Twenty three patients with bipolar disorder underwent neuropsychological testing and
Keywords: functional MRI. Sixteen of these patients were tested before and after an eight-week MBCT intervention,
Bipolar disorder and seven were wait listed for training and tested at the same intervals. The results were compared with
Mindfulness 10 healthy controls.
fMRI Results: Prior to MBCT, bipolar patients reported significantly higher levels of anxiety and symptoms of
MBCT
stress, scored significantly lower on a test of working memory, and showed significant BOLD signal
decrease in the medial PFC during a mindfulness task, compared to healthy controls. Following MBCT,
there were significant improvements in the bipolar treatment group, in measures of mindfulness, anxiety
and emotion regulation, and in tests of working memory, spatial memory and verbal fluency compared to
the bipolar wait list group. BOLD signal increases were noted in the medial PFC and posterior parietal
lobe, in a repeat mindfulness task. A region of interest analysis revealed strong correlation between
signal changes in medial PFC and increases in mindfulness.
Limitations: The small control group is a limitation in the study.
Conclusion: These data suggest that MBCT improves mindfulness and emotion regulation and reduces
anxiety in bipolar disorder, corresponding to increased activations in the medial PFC, a region associated
with cognitive flexibility and previously proposed as a key area of pathophysiology in the disorder.
& 2013 Elsevier B.V. All rights reserved.

1. Introduction and possibly family therapy may be beneficial as adjuncts to

Bipolar disorder is a chronic disorder of mood affecting 2% of
the population (Kessler et al., 2005). The condition is characterized
by cyclical states of mania and depression. Manic states are
marked by persistently elevated mood and may include high
levels of irritability, while depression states are periods of persis-
tent feelings of sadness, futility and worthlessness (DSM-IV-TR).
Bipolar disorder is characterized by emotional dysregulation and
patients therefore demonstrate impairments in emotional control
and executive functioning, even during euthymic states (Green
et al., 2007; Phillips et al., 2008).
Pharmacological management is considered the treatment of
choice for bipolar disorder and there is some evidence that
cognitive-behavioural therapy (CBT), group psycho-education
n
Corresponding author. Tel.: +27 83 2859743; fax: +27 21 7979960.
E-mail address: vives@mweb.co.za (V. Ives-Deliperi).
pharmacological maintenance treatments for the prevention of
relapse in stable patients (Beyon et al., 2008;. Scott et al., 2007;
Vieta and Colom, 2004). CBT in bipolar disorder focuses on
recognizing early promodal symptoms and using behavioural
regulation strategies to prevent relapse. The related technique of
noticing and observing mood fluctuations and changes in symp-
tomatology, and responding in a regulated way to these signals, is
one of the primary skills taught in mindfulness-based interven-
tions. Acquiring mindfulness through training, which focuses on
increasing awareness and reevaluating mental processes, has been
shown to increase positive affect and reduce cognitive vulner-
ability to stress and emotional distress in clinical and non-clinical
populations (Grossman et al., 2004). Mindfulness-based cognitive
therapy (MBCT) combines mindfulness training and CBT techni-
ques, and has been reported to reduce relapse in major depression
(Teasdale et al., 1995).
The effects of mindfulness training in bipolar disorder patients
have yet to be fully explored. A preliminary evaluation of the
effects of MBCT in bipolar disorder has been conducted with a

0165-0327/$ - see front matter & 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jad.2013.05.074
 V.L Ives-Deliperi et al. / Journal of Affective Disorders 150 (2013) 1152–1157 1153

specific focus on between-episode anxiety and depressive symp- Table 1

toms (Williams et al., 2008). Using data from a randomized wait list Participant demographics and neuropsychology data.
trail of MBCT for people with bipolar disorder in remission, these
Variable BP group (n¼ 23) HC group (n¼10)
authors reported improved anxiety and depressive symptoms
following MBCT. Reductions in anxiety, but not in relapse rate, Demographics
were reported in a controlled study of bipolar patients 12 months Age (years) 37.6 (9.3)n 30.2 (5.3)
after MBCT (Perich et al., 2012). Improvements in cognitive Gender (male: female) 4:6 4:22
Completed high school (%) 87.00% 100%
functioning in bipolar patients have also been reported following
Employed (%) 94% 98%
MBCT (Stange et al., 2011). Deficits in early information processing Self-report questionnaires
and emotional dysregulation, reported by EEG and HRV measures, Depression (HADS) 5.9 (4.3) 2.9 (2.6)
were reportedly attenuated following MBCT (Howells et al., 2011). Mania (YMRS) 3 (2.9) 0
We are not aware of reports of neuroimaging studies of the effects Anxiety (BAI) 19.3 (11.6)nnn 7.6 (5.4)
Mindfulness (FFMQ) 24.7 (4.1) 27.5 (3.1)
of MBCT in people with bipolar disorder. Emotion regulation (DERS) 95.7 (23.2) 97.9 (19.6)
Although a diverse range of activation patterns have been Symptoms of stress (SOSI) 1.18 (0.696)nn 0.58 (0.39)
reported in functional neuroimaging studies of mindfulness med- Edinburgh handedness inventory (EHS 0.78 (0.11) 0.76 (0.13)
itation, several studies report signal increases in the dorsolateral Neuropsychology
Digit span forward 6.5 (1.1) 6.9 (0.3)
PFC and the anterior cingulate cortex (Baerentsen, 2001; Creswell
Digit span backward 4.7 (1.1)nnn 6 (0.7)
et al., 2007; Farb et al., 2007; Lazar et al., 2005; Ritskes et al., Rey Complex Figure—copy 32.3 (3.7) 32 (1.6)
2003). In novice meditators the early stages of mindfulness Rey Complex Figure—recall 17.5 (7.7)n 23.6 (5.3)
meditation are associated with activations in attentional control Babcock Story Recall 6.9 (2) 8.3 (2.6)
networks including the medial PFC, anterior and posterior cingu- Stroop-inhibition 0.33 (0.64)n 0
Stroop-switching 1 (1.56) 0.1 (0.32)
late cortices (Chiesa and Serretti, 2010; Hölzel, 2007). Informed by COWAT 38.4 (10.3) 46.4 (14.3)
the findings of these studies, we expected to find comparable
n
activation patterns in midline cortical regions, during a mind- p o .05.
nn
fulness meditation task, in healthy participants with altered po .01.
nnn
po .001.
activation patterns in bipolar patients. We hypothesized improve-
ments in cognitive function, clinical measures of mindfulness, and
mood and anxiety symptoms, and increased activations in midline completed self-report measures of mindfulness, emotion dysregu-
cortical regions in bipolar disorder patients, following an eight- lation, stress and anxiety and underwent neuropsychological
week MBCT intervention. assessment. Neuroimaging was conducted in individual sessions
lasting approximately 2-h. These sessions commenced with an
MRI safety screening and an explanation of the experimental
2. Method procedure. Participants were also required to complete mood
questionnaires again to evaluate symptom severity.
2.1. Participants

A total of 56 patients with bipolar disorder (type 1 or 2) were
identified as suitable candidates for the study and recruited
through psychiatrists working in public and private healthcare in
the Western Cape. In addition, 10 healthy control subjects were
recruited to undergo the same testing. Diagnoses in the bipolar
group were confirmed using the Structured Clinical Interview for
DSM IV Axis 1 Disorders (SCID; First et al., 1996). Current mood
symptoms were evaluated with the Young Mania Rating Scale
(YMRS; Young et al., 1978) and Hospital Anxiety and Depression
Scale (HADS; Zigmond and Snaith, 1983). Subjects with mild or sub
threshold symptoms (o 14 on YMRS and HADS) were entered into
the study. Full data sets prior to the intervention were acquired for
the 10 healthy control subjects (HC) and 23 bipolar patients (BP).
All bipolar patients underwent testing on two occasions, 16 before
and after an eight-week MBCT intervention (BPT group), and the
remaining seven were wait listed for training and tested at the
same intervals (BPW group). Participant demographics are out-
lined in Table 1.
The aims and procedure of the study were explained to
participants and written informed consent was obtained. MBCT
training and its potential benefits were also outlined. Ethical
approval to conduct the study was granted by the University of
Cape Town, Faculty of Health Sciences Research Ethics Committee
and the Committee for Human Research at Tygerberg Hospital.
2.2. Procedure
All participants underwent SCID interviews and screening
symptom assessments using the YMRS and the HADS. Participants
2.2.1. Self-report questionnaires
Five-Facet Mindfulness Questionnaire (FFMQ; Baer et al., 2006,
2008). This is a 39-item questionnaire that measures mindfulness
according to a 5-factor model of the construct. The five factors are
‘observe’, ‘describe’, ‘act with awareness’, ‘non-judgment’ and
‘non-reaction’ and these subscales were summed to produce a
total mindfulness score.
Symptoms of Stress Inventory (SOSI; Leckie and Thompson,
1979). The questionnaire is divided into 12 subscales: peripheral
manifestations, cardiopulmonary symptoms of arousal, upper
respiratory symptoms, central-neurological symptoms, gastroin-
testinal symptoms, muscle tension, habitual patterns, depression,
anxiety and fear, emotional irritability (anger) and cognitive
disorganisation. The subscales were summed to report only the
total symptoms of stress (SOS) score and the measure was used to
assess the effects of MBSR training on the experience of stress.
Difficulties in Emotion Regulation Scale (DERS; Gratz and Roemer,
2004). This is a 36-item self-report measure of difficulties with
various dimensions of emotional regulation.
Becks Anxiety Index (BAI). This is a 21-item multiple choice self-
report inventory used to measure severity of anxiety. The BAI asks
how the participant has been feeling in the last week, expressed as
common symptoms of anxiety and required to respond by select-
ing a level of severity on a 4-point Likert-type scale.
Edinburgh Handedness Inventory (EHI; Olfield, 1971). This mea-
surement scale is used to assess the dominance of a person's right
or left hand in everyday activities. The inventory consists of eight
items describing activities like throwing, writing and using instru-
ments, and the participant in required to indicate which hand they
either always or usually use, or whether they have no preference.
1154 V.L Ives-Deliperi et al. / Journal of Affective Disorders 150 (2013) 1152–1157

2.2.2. fMRI experimental protocol
A block paradigm was used, consisting of a 6-min mindfulness
active block between two 2-min control blocks. In the 6-min active
block, participants were asked to perform a resting/ meditative
exercise, modeled on a mindfulness meditation. Signaled by the
display of the word Meditate, participants were requested to open
awareness to the breath and bodily sensations, thoughts and
emotions without judging or reacting to these mental and physical
events. This exercise was repeated in the second round of
neuroimaging, following mindfulness training. During a control
blocks, participants performed a distracter task in which they
generated random numbers, to induce focused-attention. The
distracter task was used to contrast with the meditation state,
which is characterised by open awareness.
2.2.3. fMRI data acquisition
Scans were acquired using a 3T Allegra MRI scanner (Siemens
Medical Systems, Erlangen, Germany). High-resolution anatomical
images were acquired in the sagittal plane using a three-
dimensional inversion recovery gradient echo sequence (160
slices, TR ¼2300 ms, TE ¼3.93 ms, TI ¼1100 ms, resolution
1.3  1  1 mm3, 256 mm FOV). During the fMRI protocol 360
functional volumes sensitive to blood oxygen level dependent
contrast were acquired in the rest/meditation task with a T2n-
weighted gradient echo, echo planar imaging sequence
(TR ¼2000 ms, TE ¼ 30 ms, 34 interleaved slices, 3 mm thick, gap
0.9 mm, matrix size 64  64, resolution 3.125  3.125  3 mm3).
2.2.4. fMRI data analysis
All fMRI analyses were performed using Brain Voyager QX
(Brain Innovation, Maastricht, The Netherlands). Nine dummy
images were excluded from analysis in the meditation run. Images
were motion corrected relative to the first volume with trilinear
estimation and interpolation. Images were corrected for different
slice acquisition times and linear trends, spatially smoothed using
a Gaussian filter (FWHM 4 mm), and temporally smoothed with a
high pass filter of three cycles/point. Data sets exceeding move-
ment criteria of 3 mm displacement and 3.01 rotation within a
functional run were rejected. Each subject's functional data were
co-registered to his/her high-resolution anatomical MRI, rotated
into the AC–PC plane and normalized to Talaraich space using a
linear transform calculated on the anatomical images. The 3.125 
3.125  3 mm3 fMRI voxels were interpolated during Talaraich
normalization to 3  3  3 mm3.
Whole-brain group analysis: For the meditation task, a random-
effect analysis of variance was performed using the general linear
model with one predictor for mindfulness meditation convolved
by the standard hemodynamic function. The six motion correction
parameters were added as predictors of no interest. Activations
during the meditation were examined by comparing activations
during the meditation block with the control task (generating
random numbers) before and after meditation. The voxel-wise
threshold was set to po 0.001 (voxel-wise Bonferroni corrected
for whole-brain multiple comparisons, min t statistic 7.6). Clusters
were reported if their extent was greater than 50 contiguous
voxels, where the voxel size refers to the 1  1  1 mm3 resolution
of the iso-voxeled structural images.
Region of interest analysis: The medial PFC, a region showing
greatest signal change in the whole brain comparison between the
BP group and HC group prior to MBCT, was further interrogated
through region of interest analysis. The region was defined in a
volume of interest analysis and beta values for the BPT patients
were derived from the resulting time course. Beta values were also
derived for the BPT patients from the time course in this region of
interest post MBCT. The difference between these beta values was
correlated with the change scores in mindfulness, as measured by
the FFMQ, to determine the strength of the association between
the two.
3. Results
3.1. Self-report measures
Table 2 reports self-rated measures. Significant increases were
noted in the BPT group following MBCT, compared to the BPW
group in measures of mindfulness (t(15) ¼−2.9, p ¼.010), and
significant decreases were noted in anxiety (t(15) ¼2.3, p¼ .05)
and emotion dysregulation (t(15) ¼ 4.1, p¼ .001). In addition sig-
nificantly improved performance was noted in BPT group in
neuropsychological tasks measuring working memory (digit span
backward) (t(15) ¼−2.8, p ¼.01) spatial memory (Rey Complex
Figure recall) (t(15) ¼−3.4, p ¼004) and verbal fluency, measured
using the COWAT task following MBCT (t(15) ¼−2.6, p¼ .02).
3.2. fMRI results
In the whole-brain analysis of the meditation condition, one
single cluster of signal decrease was identified in the medial PFC in

Table 2
Changes in self-report measures in the bipolar treatment and control groups.

Variable Time I BPT group (n¼16) Time I BPW group (n¼7) Time II BPT group (n¼ 16) Time II BPW group (n¼ 7)

Self-report questionnaires
Depression (HAD-Depression)) 5.8 (4.2) 6 (4.8) 4 (3.1) 6.4 (4.8)
Anxiety (BAI) 19.8 (12.7) 23 (9.4) 14.1 (12.1)n 20.6 (9.9)
Mindfulness (FFMQ) 24.7 (4.3) 24.9 (4.4) 28.9 (3.3)nn 24.9 (4.4)
Emotion regulation (DERS) 100.9 (24.5) 86.7 (21.8) 73.2 (23)nnn 96.3 (21.6)
Symptoms of stress (SOSI) 1.11 (0.73) 1.47 (0.77) 0.93 (0.75) 1.44 (0.6)
Neuropsychology
Digit span forward 6.4 (0.8) 6.3 (0.5) 6.5 (1.3) 6.6 (0.5)
Digit span backward 4.5 (0.9) 5 (1.67) 5 (1.2)n 5.5 (1.6)
Rey Complex Figure—copy 30.7 (3.9) 33 (3.7) 33.7 (3.2) 35 (2.5)
Rey Complex Figure—recall 17.4 (8.1) 15.4 (7.9) 24 (7.5)nnn 19.5 (7.3)
Babcock Story Recall 6.6 (1.7) 6.7 (2.3) 7.8 (3) 8.5 (2.4)
Stroop-inhibition 0.3 (0.6) 0.7 (1.4) 0.2 (0.4) 1.2 (2.4)
Stroop-switching 1 (1.8) 1.1 (2.1) 1.2 (2.8) 1 (1.4)
Verbal fluency—COWAT 37.8 (10.8) 37.1 (12.1) 42.7 (13.7)n 38.3 (9.3)

n
po .05.
nn
p o.01.
nnnn
p o .001.
 V.L Ives-Deliperi et al. / Journal of Affective Disorders 150 (2013) 1152–1157 1155

the BP group compared to the HC group (Talaraich coordinates:
medial PFC 12, 44, 16; 3691 voxels) t(35) ¼ −2.8, p ¼.008 (Fig. 1).
After the eight-week mindfulness intervention the BPT group was
again scanned and the comparison with the HC group was repeated.
Significant signal increases were observed in the post MBCT analysis
in the left anterior cingulate cortex (ACC) (Talaraich coordinates: left
ACC-18, 23, 19; 1281 voxels) t(25)¼2.6, p¼.014 (Fig. 2).
Significant signal increases were noted in the medial PFC and
posterior cingulated cortex of the RH in the BPT group compared
to the BPW group after the BPT group completed the MBCT
intervention (Talaraich coordinates: medial PFC 5, 46, 24; 1606
voxels) t(22) ¼3.28, p ¼.001, posterior CC 17, −62, 27; 1167 voxels) t
(22) ¼4.15, p ¼.0005 (Fig. 3). All BOLD signal changes are detailed
in Table 3.
In the region of interest analysis the difference between the
beta values extracted from the activations in the medial PFC time
course in BPT patients before and after MBCT, were correlated with
their change scores in mindfulness, as measured by the FFMQ,

Fig. 1. BP groupo HC group prior to MBCT.

Fig. 2. BPT group4HC group post MBCT.

Fig. 3. Bipolar treatment group (n¼16) o bipolar waitlist group (n¼7) post MBCT.
1156 V.L Ives-Deliperi et al. / Journal of Affective Disorders 150 (2013) 1152–1157

Table 3 We found significant reductions in anxiety and concomitant

BOLD signal changes. improvements in mindfulness, emotion regulation and executive
functioning in participants with bipolar disorder following an eight-
Brain area Voxels Talaraich coordinates Voxel t p
week MBCT intervention that combined aspects of cognitive therapy
x y z and meditation. Depression scores improved but not significantly so.
Improved outcomes in anxiety and symptoms of depression were also
Before MBCT reported in a previous pilot study of the effects of MBCT in patients
Meditation
BP groupoHC group
with bipolar disorder (Williams et al., 2008). These findings suggest
Medial PFC 11,053 −4 40 42 2.93 0.006 that mindfulness training may target the key deficit of emotion
regulation in bipolar disorder. A core skill taught in mindfulness-
After MBCT based interventions is cultivating a quality of awareness in which
Meditation
thoughts and emotions are acknowledged without judgment and
BPT groupo HC group
ACC 1,281 −18 23 19 2.63 0.014 considered passing mental events. This technique of regulating emo-
BPW group4 BPT group tion has proven effective in reducing anxiety and alleviating emotional
Medial PFC 1,606 5 46 24 3.78 0.001 stress (Grossman et al., 2004).
RH posterior CC 1,167 17 −62 27 4.15 0.0005 BOLD signal decreases in the medial PFC in the bipolar group
Note: BP bipolar; HC healthy control; BPW bipolar wait list; BPT bipolar treatment.
compared to the healthy control group during the meditation task
before MBCT, is consistent with findings reported in previous
research, in which significant signal decreases have been observed
in the medial PFC, and other PFC regions in bipolar patients
(Strakowski et al., 2005). Following the MBCT intervention, sig-
nificant signal increases in the medial PFC in the bipolar patients,
compared to bipolar patients who did not undergo the training,
are consistent with findings from the Strakowski group, which
showed signal increases in midline cortical regions during a Stroop
task in medicated bipolar patients compared to untreated patients.
In addition to the functional deficits at the core of bipolar
disorder, altered brain activations have also been identified in
functional neuroimaging studies investigating the neural sub-
strates of the illness. Altered activations have been reported in
resting-state fMRI and in imaging studies applying emotion
processing tasks. In studies investigating resting-state fMRI, positive
correlations in connectivity between brain regions have been reported
Fig. 4. Correlation of changes scores in mindfulness (FFMQ) and beta values in bipolar patients between the medial PFC and the insular and
extracted from the mPFC in the BPT group before and after MBCT.
between medial PFC and ventrolateral PFC compared to healthy
controls, who have exhibited anti-correlations between these regions
using the Pearson product-moment correlation coefficient test. (Chai et al., 2011). Hypoactivity has also been reported in several
The correlation was significant (r(15) ¼0.61, p ¼.016) and graphi- regions in the PFC (Cerullo et al., 2009). The medial PFC has
cally depicted in Fig. 4. subsequently been proposed as a key area of pathophysiology in the
disorder (Anand et al., 2009; Chai et al., 2011). The medial PFC is
believed to play a critical role in generating self-referential thought
4. Discussion during conscious appraisal of threatening stimuli, as well as in
behavioural flexibility during tasks of inhibition (Strakowski et al.,
The main findings of this study were (1) at baseline, bipolar 2005). These authors propose the medial PFC, together with the ACC,
patients reported significantly increased levels of anxiety and emotion plays a key role in regulating emotional responses to engage effectively
dysregulation, compared with healthy controls, and scored lower in in executive functioning.
mindfulness and domains of executive functioning including working The findings of this study show significant improvements in
memory and inhibition. Significant BOLD signal decreases were noted executive functioning, anxiety and emotion regulation following
in the medial PFC in the bipolar group compared to the control group, MBCT. Findings also show a significant correlation between increases
in a mindfulness task. (2) MBCT resulted in significant reductions in in mindfulness and signal change in the medial PFC following the
anxiety and emotion dysregulation and improvements in mindfulness intervention. Although the study is limited by the small control group,
and executive performance in the BPT group, but not in the BPW and disparity in size of the groups, the findings support the use of
group. Significant BOLD signal increases were observed in the medial MBCT as a conjunct therapy in patients with bipolar disorder. The
PFC and posterior cingulate cortex in the BPT group, compared to the findings, together with the literature on the functional role of midline
BPW group, during the mindfulness task. These changes in BOLD cortical regions, further suggest that MBCT may bring about improve-
signal resulted in an activation pattern more closely resembling those ments in executive functioning and emotional wellbeing through
of healthy controls. Lastly (3), the region of interest analysis revealed a enhancement of emotional regulation. This insight into the mechan-
significant correlation between signal changes in the medial PFC and ism of mindfulness training is relevant to understanding the possible
increases in mindfulness in the BPT group, suggesting a mechanism efficacy of MBCT in bipolar patients.
through which MBCT may bring about improvements in cognitive
function and emotion wellbeing.
Finding 1 is consistent with the literature on cognitive impair- Funding body agreements
ment in bipolar disorder. Emotion dysregulation and executive
dysfunction are cited as two core domains of pathology in the This study was conducted using funds from a grant awarded by
disorder and represent possible endophenotypes of the condition the International Society of Affective Disorders (ISAD). We are not
(Green et al., 2007; Phillips et al., 2008). aware of an agreement between Elsevier and ISAD.
 V.L Ives-Deliperi et al. / Journal of Affective Disorders 150 (2013) 1152–1157
Conflict of interests
All authors declare that they have not conflicts of interest in
their participation in this study.
Acknowledgment
The authors would like to thank the International Society of Affective Disorders
(ISAN) for funding this research. In addition, we would like to thank Gameda
Benfeld for assisting in conducting the SCID assessments, and to all of the
contributors and participants for their time and effort.
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