Psychiatry Research: Neuroimaging 319 (2022) 111418

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Psychiatry Research: Neuroimaging

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

Action-based cognitive remediation in bipolar disorder improved verbal

memory but had no effect on the neural response during episodic
memory encoding
Julian Macoveanu a, 1, Viktoria Damgaard a, b, 1, Caroline V. Ott a, b, Gitte M. Knudsen c, d,
Lars V Kessing a, c, Kamilla W Miskowiak a, b, *
a
Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
b
Department of Psychology, University of Copenhagen, Copenhagen, Denmark
c
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Institute of Clinical Medicine, University of Copenhagen, Copenhagen,
Denmark
d
Neurobiology Research Unit and The Center for Experimental Medicine Neuropharmacology, Rigshospitalet, Copenhagen, Denmark

A R T I C L E I N F O A B S T R A C T

Keywords: Verbal memory and executive function impairments are common in remitted patients with bipolar disorder (BD).
Picture encoding We recently found that Action-Based Cognitive Remediation (ABCR) may improve executive function and verbal
Verbal memory memory in BD. Here, we investigated neuronal changes associated with ABCR treatment-related memory
Fmri
improvement in a longitudinal functional MRI (fMRI) study. Forty-five patients with remitted BD (ABCR: n = 26,
control treatment: n = 19) completed a picture-encoding task during fMRI and tests of verbal memory and ex­
ecutive function outside the scanner before and after two weeks of ABCR/control treatment. The cognitive
assessment was performed again following ten weeks of treatment. Thirty-four healthy controls underwent the
same test protocol once for baseline comparisons. Patients showed a moderate improvement in a domain
composite of verbal learning and memory both after two weeks and ten weeks of ABCR treatment, which
correlated with improved executive function. At baseline, patients showed encoding-related hypoactivity in
dorsal prefrontal cortex compared to healthy controls. However, treatment was not associated with significant
task-related neuronal activity changes. Improved verbal learning and memory may have occurred through
strengthened strategic processing targeted by ABCR. However, picture-encoding paradigms may be suboptimal to
capture the neural correlates of this improvement, possibly by failing to engage strategic encoding processes.

1. Introduction BD has shown replicable and enduring pro-cognitive efficacy (Kamilla

Objective cognitive impairments across several domains are present
in bipolar disorder (BD), even in remitted or subsyndromal patients
(Bourne et al., 2013). Cognitive impairments in BD impede psychosocial
function, occupational status, and quality of life (Baune and Malhi,
2015; Brissos et al., 2008; Tse et al., 2014). Specifically, verbal learning
and memory has been identified as a robust indicator of neuropsycho­
logical impairment in BD and is associated with a significant impact on
daily functioning and occupational outcome (Bonnín et al., 2012, 2010;
Tse et al., 2014). Currently, no treatment for cognitive impairments in
W. Miskowiak et al., 2016a), although emerging evidence points to
beneficial effects of cognitive remediation interventions (Lewandowski
et al., 2017; Strawbridge et al., 2021). A study of functional remediation
in BD revealed a selective improvement in verbal memory, which was
associated with improved functioning at six months (Bonnín et al.,
2016) and two years after treatment completion (Solé et al., 2020).
Verbal memory thus seems particularly important for patients’ daily life
functioning.
In line with the recommendations from the International Society for
Bipolar Disorder (ISBD) Cognition Task Force (Miskowiak et al., 2017),

* Corresponding author at: Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research center, Psychiatric center
Copenhagen, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, and Department of Psychology, University of Copenhagen,
Øster Farimagsgade 2A, DK-1353 Copenhagen, Denmark.
E-mail address: kamilla.miskowiak@regionh.dk (K.W. Miskowiak).
1
Contributed equally as first authors

https://doi.org/10.1016/j.pscychresns.2021.111418
Received 26 May 2021; Received in revised form 24 August 2021; Accepted 16 November 2021
Available online 23 November 2021
0925-4927/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
J. Macoveanu et al.
we recently conducted a double-blinded randomized controlled study of
the effects of 10 weeks of group-based biweekly Action-Based Cognitive
Remediation (ABCR) compared with weekly unstructured group ses­
sions in remitted BD patients with cognitive impairments (for full study
protocol see Ott et al., 2018; Ott et al., 2019). Specifically, ABCR
involved a combination of strategic cognitive training and practical
exercises to promote cognitive flexibility (Bowie et al., 2017). The study
further included functional MRI (fMRI) assessments at baseline and after
two weeks of treatment to explore early neuronal underpinnings of
treatment-related changes in cognitive function. In line with the
emphasis on strategy use and planning to solve cognitive challenges in
ABCR, we found an improvement in executive function, the secondary
trial outcome, as well as on tertiary measures of verbal learning and
memory (Ott et al., 2020). The improvement of these two aspects of
cognition - in the absence of changes in other domains - is interesting in
light of evidence for an influence of executive functions on strategic
aspects of verbal encoding and recall (Chang et al., 2010; Taconnat
et al., 2010; Tremont et al., 2000). The ABCR-related executive function
improvements were accompanied and predicted by early increase in
dorsal prefrontal cortex (dPFC) activity during a spatial working mem­
ory (WM) fMRI paradigm (Ott et al., 2021). However, the neuronal
correlates of treatment-related improvements in verbal learning and
memory are unclear. There is a paucity of studies investigating the
neuronal correlates of memory impairments in mood disorders and the
findings from these studies are conflicting (Miskowiak and Petersen,
2019). Using an episodic memory encoding paradigm that probes a
network of medial temporal, parietal and prefrontal regions, we found
that cognitively impaired vs. cognitively intact BD patients display
reduced encoding-related activity in the middle temporal lobe but no
differential dPFC or hippocampal response (Petersen et al., 2021). We
also used this encoding paradigm to investigate the neuronal un­
derpinnings of verbal memory improvement following treatment with
the multifunctional growth factor erythropoietin (EPO) in patients with
mood disorders (Miskowiak et al., 2016b). This revealed
treatment-related dPFC and temporo-parietal activity increase, which
correlated with patients’ memory improvement (Miskowiak et al.,
2016b).
In the present longitudinal fMRI study, which was part of the above-
mentioned ABCR trial (Ott et al., 2018), we employed the same episodic
memory encoding paradigm to investigate whether this psychological
intervention for cognitive impairments would produce similar changes
in the neurocircuitry target engagement as following EPO intervention.
We hypothesized that improvement in verbal memory in ABCR vs.
control groups would be accompanied by early changes in neuronal
activity during episodic memory encoding after two weeks of treatment
within (i) the medial temporal region showing aberrant
encoding-related activity in cognitively impaired BD patients (Petersen
et al., 2021) and (ii) the dPFC, reflecting strengthened strategic encod­
ing processes dependent on executive functions, in line with the effects
of ABCR on strategic aspects of cognition.
2. Methods
2.1. Procedure, randomization and masking
Data were collected at the Psychiatric center Copenhagen, Rig­
shospitalet as part of the ABCR trial (Ott et al., 2018; Ott et al., 2019). An
fMRI scan and assessments of verbal memory were carried out at base­
line and week 3 following the completion of two weeks of treatment.
Verbal memory was assessed again at treatment completion (week 10).
In this outcome-assessor blind trial, participants were randomized to the
ABCR or the control treatment in a 1:1 allocation order. We used allo­
cation envelopes provided by Pharma Consulting Group (Uppsala,
Sweden), and these were kept in a locked filing cabinet to prevent
unblinding. Randomization was stratified by gender (female or male)
and age (< or ≥35 years) due to the association between age and
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Psychiatry Research: Neuroimaging 319 (2022) 111418
neuroplasticity (Park and Bischof, 2013). Upon inclusion, the primary
therapist (CO) opened the randomization envelopes in a consecutive
manner. For a power calculation for the primary outcome of the study,
see the full protocol (Ott et al., 2018). Randomization was carried out
from July 2017 to April 2019, and data collection was completed in
January 2020.
2.2. Participants
Participants were recruited from psychiatric outpatient clinics and
consultant psychiatrists in the Capital Region of Denmark. Inclusion
criteria were: an ICD-10 diagnosis of BD confirmed in a semi-structured
clinical interview using the Schedules of Clinical Assessment in Neuro­
psychiatry (SCAN) (Wing et al., 1990) in full or partial remission (full
remission: ≤7, partial remission: 8–14 on the Hamilton Depression
Rating Scale – 17 items (HDRS-17) (Hamilton, 1960) and the Young
Mania Rating Scale (YMRS) (Young et al., 1978), respectively), in line
with the recommendations from the International Society for Bipolar
Disorder (ISBD) Cognition Task Force (Miskowiak et al., 2017), fluent in
Danish, age between 18 and 55 years old, and objective cognitive
impairment (total scores ≤74 or below the cut-offs on ≥2 subtests on the
Screen for Cognitive Impairment in Psychiatry (SCIP) (Jensen et al.,
2015)). Exclusion criteria were: daily use of benzodiazepines (≥22.5
mg), current drug or alcohol abuse, neurological illness or previous se­
vere head trauma, schizophrenia or a schizoaffective disorder, severe
somatic illness, electroconvulsive treatment within the previous three
months, dyslexia, pregnancy, pacemaker or other internal metal objects.
Data from 34 healthy controls (HC) with no personal or first-degree
family history of psychiatric illness from the ongoing Bipolar Illness
Onset (BIO) study (Kessing et al., 2017) were included to assess whether
a treatment-related neuronal change in ABCR vs. control treatment was
towards normalization (i.e. HC activation levels). Data from the same
HC sample were included to standardize the performance of the patient
sample on neuropsychological tests of verbal learning and memory.
Participants were informed about the study procedures and written
consent was obtained. The study was approved by the local ethics
committee (H-16,043,480) and the Danish Data Protection Agency
(2012–58–0004).
2.3. Treatment and control groups
The ABCR program is a manual-based cognitive remediation treat­
ment that provides an action-based top-down approach to restoration of
cognitive impairment (Bowie et al., 2017). Treatment duration was 10
weeks with two-hour sessions twice a week and daily computer training
at home. There were four to six patients in each group session, which
included computerized training on the Danish version of Happy Neuron
Pro (www.happyneuronpro.com/en), cognitive strategy learning, visual
and verbal working memory, attention, memory and executive functions
with application in practical activities (e.g., preparing a meal, updating
one’s calendar etc.). Each session also included goal setting discussions
to encourage participation in cognitively stimulating activities during
daily life. In addition to the group sessions, participants were instructed
to perform the computerized training program for 30 min every day at
home. The control arm involved 10 weeks of weekly one-hour un­
structured group sessions in which themes relevant to patients were
discussed but did not entail any cognitive training (for more details, see
Ott et al. 2018; Ott et al., 2019).
2.4. Neuropsychological assessment
The participants performed a range of neurocognitive tests described
in Ott et al. (2020). Verbal learning and memory was assessed with the
Rey Auditory Verbal Learning Test (RAVLT) consisting of the following
subtests: RAVLT total recall lists I-V, RAVLT distractor list, RAVLT im­
mediate recall, RAVLT delayed recall, and RAVLT recognition (Poreh,
J. Macoveanu et al.
2010). Alternate, matched forms of the RAVLT were used at each
assessment to minimize effects of learning. Executive functions were
assessed using the following tests: RBANS Digit Span (Randolph et al.,
1998), Spatial Working Memory task ‘between errors’ and ‘strategy’
measures from the CANTAB (Goldberg, 2013), Trail Making Test B (TMT
B) (Adjutant General’s Office, 1944), verbal fluency letters “S” and “D”
(Borkowski et al., 1967), and WAIS-III Letter-Number Sequencing
(Wechsler, 1997).
2.5. Picture encoding fMRI task
The fMRI paradigm was programmed in e-prime 2.0 (Psychological
Software Tools, Pittsburgh, PA, USA) and displayed on a screen which
participants viewed using an angled mirror. The paradigm was based on
the picture encoding task from Hariri et al. (2003) and identical to the
one applied in our previous fMRI study (Miskowiak et al., 2016b). Pa­
tients were instructed to classify whether pictures showed ‘indoor’ or
‘outdoor’ scenes and to pay attention as they would be asked to recall the
pictures, process involving memory encoding and executive functions.
This was followed by a free recall test immediately after the scan. Pic­
tures were matched for valence, arousal, and complexity and were
presented in a blocked paradigm to maximize sensitivity for BOLD signal
change (Birn et al., 2002). Six picture blocks (24 s each) were preceded
by an instruction screen (2 s) and interleaved with a fixation cross (24 s),
resulting in a task duration of 4 min and 50 s. Blocks consisted of six
pictures presented serially for 3 s interleaved with a 1 s fixation cross.
Each block contained an equal number of pictures representing indoor
and outdoor scenes. Alternate, matched versions of the task were
administered at baseline and follow-up in a counterbalanced order to
minimize learning effects.
2.6. The fMRI analysis
2.6.1. MRI acquisition protocol
MRI data were obtained at the Copenhagen University Hospital,
Rigshospitalet using a 3 Tesla Siemens Prisma scanner and a 64-channel
head-coil. During the performance of the picture encoding task, blood
oxygen level dependent (BOLD) fMRI was acquired using a T2*-
weighted gradient echo spiral echo-planar (EPI) sequence with an
echo time (TE) of 30 ms, repetition time (TR) of 2 s, and flip angle of 90◦
A total of 146 vol were acquired, each consisting of 32 slices with a slice
thickness of 3 mm with 25% gaps in-between, and a field of view (FOV)
of 230 × 230 mm using a 64 × 64 grid. The BOLD images were regis­
tered to T1-weighted structural images (TR = 1900 ms; TE = 2.58 ms;
flip angle = 9◦ ; distance factor = 50%; FOV=230 × 230 mm; slice
thickness = 0.9 mm). A standard B0 field map sequence was also ac­
quired with the same FOV and resolution as the fMRI sequence (TR =
400 ms; TE = 7.38 ms; flip angle=60◦ ) and used for geometric distor­
tions correction of the BOLD images. The image quality was ascertained
by visual inspection of all individual images.
2.6.1. Regions of interest
Based on our a priori hypothesis, we constructed a dPFC mask using
FSLView 4.0.1 on a standard MNI template based on the Harvard-Oxford
cortical structural Atlas probabilistic maps (Desikan et al., 2006) by
including bilateral superior and medial frontal gyri and the superior
portions of the anterior division of the cingulate gyrus and the frontal
poles thresholded at 5%. The ventral border of the dPFC was defined by
the plane separating the dorsal from the ventral regions of medial PFC
(MNI z > 5), defied according to Veit et al. (2010). Using a similar
procedure, we also constructed a left and right mask for the hippocampi.
To investigate the early neural mechanisms of treatment-related exec­
utive function improvement, we defined two spheric (8 mm radius) re­
gions of interest (ROIs) for the right dlPFC and left middle temporal
gyrus (MTG) centered on the peak coordinates (x = 40, y = 34, z = 29)
and (x = − 64, y = − 54, z = − 6) from Miskowiak et al. (2016b) and
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Psychiatry Research: Neuroimaging 319 (2022) 111418
(Petersen et al., 2021), respectively.
2.6.2. Data pre-processing and subject-level analysis
Functional MRI data processing was performed with the FMRI Expert
Analysis Tool (FEAT; version 6.01) part of FMRIB’s Software Library
(FSL; www.fmrib.ox.ac.uk/fsl). Pre-processing involved image B0 field
distortion correction with acquired field map image, realignment of the
acquired volumes, non-brain removal, spatial normalization to a Mon­
treal Neurologic Institute (MNI) template, and spatially smoothing
(Gaussian kernel, 5 mm full-width-half-maximum). The time series in
each session were high pass-filtered (max 0.02 Hz). At subject level, we
modelled the picture encoding task using a block design, with the pic­
ture presentation (i.e., memory encoding) and fixation cross as events
that were convolved with a double-gamma hemodynamic response
function and added temporal derivatives for improved fit to the data.
2.6.3. Group-level analyses
At the group level, we first estimated task activations at baseline for
the HC group by entering the picture encoding contrast at baseline in a
one-sample t-test. Secondly, we estimated group-by-time interaction
effects for picture encoding responses using a two-way mixed effect
repeated measures ANOVA model (group factor: ABCR vs. control, time
factor: baseline and follow-up). The significance level for clusters was
set at p < 0.05 corrected for multiple comparisons using Gaussian
Random Field (GRF) theory subsequent a cluster-forming threshold of z
= 2.57 (p < 0.005). The models were estimated twice, first restricting
the search volume to the dPFC and secondly at whole brain level.
For the ROI analysis, we extracted the mean percent BOLD signal
change from a right dlPFC, left MTG, and the hippocampi ROIs in all
participants. Using two-sample t-tests we first compared HC and BD
participants at baseline in all ROIs. We secondly estimated the longitu­
dinal effect of ABCR treatment vs. control in BD patients using a
repeated measures general linear model implemented in SPSS v25 (IBM,
Armonk, New York, United States).
2.7. Statistical analyses of behavioral data
A cognitive domain composite score of ‘verbal learning and memory’
were created by standardizing and averaging the following RAVLT
subtests: RAVLT total recall lists I-V, RAVLT immediate recall, RAVLT
delayed recall, and RAVLT recognition based on the mean and standard
deviations (SD) of the HC group. Verbal learning and memory composite
scores were created for the baseline scores, two weeks of treatment
scores, and the treatment completion scores. A similar procedure was
used for calculation of the ‘executive function’ composite score, which
was used for a post-hoc analysis of the association between changes in
the ‘verbal learning and memory’ and ‘executive function’ domains; for
details see Miskowiak et al. (2021).
To assess the effect of ABCR vs. control treatment on verbal learning
and memory, we conducted linear mixed-effect models. Factors were
time, stratum (classifying age and gender), and treatment (control
treatment as reference category). Fixed effects were time, stratum,
time*stratum, and time*treatment. Baseline correction was applied.
To assess the association between changes in ‘verbal learning and
memory’ and ‘executive function’ (a key target for ABCR), we conducted
a multiple regression analysis with adjustments for demographic and
clinical variables (age, gender, years of education, verbal IQ, and change
in HDRS-17 and YMRS scores, respectively).
Finally, performance on the picture encoding task outside the scan­
ner (total recall and false recall) was assessed with repeated measures
analyses of variance (ANOVA) with time as the within-subjects variables
and group at the between-subjects factor. Behavioural data was analysed
in SPSS at the α-level = 0.05.
J. Macoveanu et al.
3. Results
3.1. Participants
Among the patients included in the ABCR trial (ABCR: n = 32, con­
trol: n = 29), fMRI data were complete and analyzed for n = 45 patients;
n = 26 (81%) in the ABCR group and n = 19 (66%) in the control group
(see Fig. 1 for CONSORT flow diagram). There were no significant
clinical or demographic differences between patients with complete
fMRI data (n = 45) and patients without fMRI data (n = 16) in age,
gender, years of education, verbal IQ, mood symptoms, mood episodes,
illness duration, hospitalizations, and BD type (ps ≥ 0.23). There was no
significant between-group difference in the time from the fMRI scanning
at baseline to after two weeks of treatment (ABCR: Mdn = 21.5 days,
Fig. 1. CONSORT flow diagram.
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Psychiatry Research: Neuroimaging 319 (2022) 111418
interquartile range = 2; control: Mdn = 21.0, interquartile range = 2, U
= 207, p ≥ 0.34). The demographic and clinical data in the ABCR and
control groups were well-balanced, although more patients in the con­
trol group took antidepressants (p = 0.02) (Table 1).
Patients in the trial had more subsyndromal mood symptoms and
fewer years of education compared to the HC sample included for
baseline verbal memory and fMRI comparisons (ps ≤ 0.01) (Table 2).
3.2. Behavioral results
Remitted BD patients showed deficits in the domain of verbal
learning and memory at baseline with a large effect size (t(77) = − 5.6,
95% CI [ − 2.68, − 1.28], p < 0.001, Cohen’s d = 1.32). There was a
significant effect of ACBR vs. control treatment on the verbal learning
J. Macoveanu et al. Psychiatry Research: Neuroimaging 319 (2022) 111418

Table 1 3.3. fMRI results

ABCR vs. Control group demographic and clinical characteristics at baseline.
ABCR (N = Control (N = p- In HC at baseline, episodic memory encoding activated a fronto-
26) 19) value occipital network (Fig. 3, peak effect paracingulate gyrus at x = 10, y
Gender (F/M%) 77/23 79/21 0.87a = 18, z = 40, p < 0.048, z-max = 3.85, cluster size=256 voxels; and
Age in years, median (IQR) 36 (23) 38 (22) 0.77 temporal occipital fusiform cortex, peak effect at x = 28, y = − 48, z = −
Educational years, mean (SD) 13 (3) 14 (3) 0.35 8, p < 0.0001, z-max = 7.54, cluster size = 17,152 voxels).
Verbal IQ, mean (SD) 111 (6) 111 (8) 0.92 The voxel-wise analyses showed no significant differences between
BD type (I/II) 35/65 32/68 0.83
HDRS-17, mean (SD) 7 (5) 6 (4) 0.46
the HC and BD groups at baseline within the dPFC mask and at whole
YMRS, median (IQR) 1 (3) 2 (5) 0.50 brain. However, the ROI analysis showed dPFC hypoactivity in BD
Illness duration in years, median 15 (16) 14 (10) 0.75 compared to HC in the dlPFC ROI (F(1,77)= 5.695, p = 0.019, ηp2 =
(IQR) 0.069) and the paracingulate cluster activated in the HC group (F(1,77)=
Depressive episodes, median (IQR) 5 (7) 6 (11) 0.50
8.030, p = 0.006, ηp2 = 0.094). No significant group difference was
Manic episodes, median (IQR) 0 (1) 0 (2) 0.95
Hypomanic episodes, median (IQR) 3 (8) 2 (8) 0.66 observed in the hippocampi or the MTG ROIs (p > 0.195).
Mixed state episodes, median (IQR) 0 (1) 0 (1) 0.91 There were no significant differential longitudinal changes in
Total number of episodes, median 9 (14) 15 (12) 0.20 neuronal response to episodic memory encoding (group-by-time inter­
(IQR) action effects) between the ABCR and control BD patients within the
Hospitalizations, median (IQR) 1 (2) 1 (3) 0.85
Medication:
dPFC mask or at whole brain. Similarly, the ROI analyses of the
Antidepressants, no. (%) 2 (8) 7 (37) 0.02a,* extracted BOLD signal change showed no group-by-time interaction
Antipsychotics, no. (%) 12 (4) 9 (47) 0.95 effects in any of the tested ROIs (p > 0.54, Fig. 3).
Anticonvulsants, no. (%) 15 (58) 13 (68) 0.46
Lithium, no. (%) 16 (62) 10 (53) 0.56
4. Discussion
No medication, no. (%) 1 (4) 1 (5) 0.82a
Number of medications, median 2 (1) 2 (1) 0.11
(IQR) This is the first randomized controlled fMRI study to investigate the
neuronal correlates of improved verbal learning and memory in
Chi-square for binary variables, Mann-Whitney for non-parametric data (median
(IQR)), independent t-tests for normally distributed data (mean, (SD)). remitted BD patients following ABCR treatment. In this subgroup of 45
Abbreviations: ABCR: Action-based cognitive remediation, BD: Bipolar disorder, patients with complete longitudinal fMRI data, we confirmed our pre­
HDRS-17: Hamilton Depression Rating Scale 17-items, IQR: Interquartile range, vious preliminary report on treatment-related improvements in verbal
YMRS: Young Mania Rating Scale. learning and memory for ABCR vs. control treatment, which emerged
*
Significant at the 0.05-level. already after two weeks of treatment. Specifically, ABCR-treated pa­
a
Likelihood ratio 2-sided due to violation of Chi-squared assumption of ex­ tients showed improvement in a domain composite score of verbal
pected count. learning and memory, which correlated directly with increase in exec­
utive functions. At a neural level, patients showed encoding-related
dlPFC hypoactivity relative to HC. However, in contrast with the hy­
Table 2
potheses, we observed no early encoding-related neuronal activity
Demographic characteristics at baseline for the bipolar patients and healthy
change in the dPFC, hippocampus or MTL after ABCR vs. control
controls.
treatment.
BD (N = 61) HC (N = 34) p-value
The absence of differential neuronal activity changes between ABCR
Gender (F/M%) 74/26 65/35 0.35 and control treatment contrasts with our previous findings of increased
Age in years, mean (SD) 38 (11) 34 (10) 0.13 ABCR-related dlPFC activity during working memory in the same sam­
Educational years, mean (SD) 14 (3) 16 (2)
ple of patients (Ott et al., 2021). This change in prefrontal activity was
<0.01
Verbal IQ, mean (SD) 112 (6) 113 (5) 0.15
interpreted as a treatment-related modulation of dorsal neuronal re­
Abbreviations: BD: Bipolar disorder, HC: Healthy controls. sources during executive performance. Given our preliminary findings
of potential effects of ABCR on executive functions and the importance
and memory composite score, which was present after two weeks of of executive functions in strategic aspects of verbal memory, we had
treatment (treatment effect = 0.73, 95% CI [0.09, 1.37], p = 0.03, hypothesized that we would observe similar activity in the dorsal pre­
Cohen’s d = 0.40) and prevailed at end of treatment (treatment effect = frontal area in addition to change in MTL activity using the picture
1.01, 95% CI [0.32, 1.71], p = 0.005, Cohen’s d = 0.54). Change in encoding task. The absence of such neuronal changes was therefore
verbal learning and memory correlated with change in executive func­ surprising and could suggest that patients did not employ strategic
tion from baseline to end of treatment after controlling for demographic learning in the applied picture encoding paradigm as expected. Indeed,
and clinical variables (F(6,37) = 2.705, p = 0.028), with executive examining the task-related activations at baseline did not show expected
function increase as the strongest predictor of verbal learning and prefrontal engagement in our patient cohort. While the HC displayed
memory improvements (B = 0.85, p = 0.02). encoding-related dorsomedial PFC activation (Fig. 3), patients showed
The post-scan picture recall test showed a lower performance at hypoactivity in this prefrontal region. This absence of encoding-related
baseline for the BD patients compared to the HC participants with a prefrontal activity in patients suggests that they failed to implement
lower total recall (F(1,71)= 4.973, p = 0.029, ηp2 = 0.70), but also lower strategic encoding strategies, which may also explain their poorer recall
false recall rate (F(1,71 )= 5.378, p = 0.023, ηp2 = 0.70). There was no performance compared to HC after the scan. Our findings also contrast
difference between the ABCR and the control BD patients on the picture with the previous study of erythropoietin (EPO) in which we found
encoding performance at baseline nor after two weeks of treatment treatment-related increase in dPFC and temporo-parietal regions during
(total recall: p=.93, false recall: p=.75). However, in both treatment picture encoding, which correlated with improvement in post-scan
groups there was a general improvement in the number of recalled picture recall (Miskowiak et al., 2016b). These differences in the
pictures after two weeks of treatment compared to baseline (F(1,43)= neuronal activity after EPO and ABCR interventions could reflect the
25.55, p < 0.001, ηp2 = 0.37, Fig. 2). distinct mechanisms of these treatments. Specifically, neuroplasticity
increase with EPO treatment may account for the more global changes in
cognition-relevant cortical networks, including the dPFC, parietal and
temporal regions as well as hippocampal volume and function

5
J. Macoveanu et al. Psychiatry Research: Neuroimaging 319 (2022) 111418

Fig. 2. Behavioral performance for the picture encoding post-scan recall in the Action-Based Cognitive Remediation (ABCR) and Control bipolar patient groups, and
healthy controls (HC). Error bars represent standard error of the mean. Data from 5 HC is missing.

Fig. 3. Neuronal response to picture encoding in the Action-Based Cognitive Remediation (ABCR) and Control bipolar patient groups, and healthy controls (HC). Top
panel – statistical map showing task activations at baseline in HC together with investigated regions-of-interest (green). Bottom panels - bar charts displaying
neuronal response extracted from the regions-of-interest (ROIs) in ABCR (red), control treatment (blue), and HC (green) participants. Error bars represent standard
error of the mean.

6
J. Macoveanu et al.
(Miskowiak et al., 2016b; Miskowiak et al., 2015). In contrast, ABCR
seems to primarily increase executive functions and associated dPFC
activity (Ott et al., 2021), which was a key focus in the interventions and
is likely to mediate the observed improvement in verbal memory.
Indeed, we observed a direct correlation between changes in verbal
memory and executive functions in our participants after controlling for
demographic and clinical variables. This association is in line with ev­
idence for an impact of executive functions on strategic aspects of verbal
learning and memory, especially in encoding and recall tasks (Chang
et al., 2010; Hill et al., 2012).
This present report has implications for future cognition trials in BD.
Based on the current findings, an episodic memory encoding fMRI
paradigm may not be sensitive to capture treatment related neuronal
activity following ABCR in BD patients. This is in line with our previous
report in which we observed no underlying activity difference in
cognitively impaired vs. intact BD patients using the same picture
encoding task (Petersen et al., 2021). In addition, the encoding para­
digm did not show sensitivity towards change in activity due to the
occurrence of mood episodes. The present findings add to this emerging
evidence indicating that this fMRI paradigm does not capture the
neuronal correlates of episodic memory improvements. In contrast, WM
tasks seem more sensitive to detect underlying neuronal changes of
treatment related improvement in cognition following ABCR (Ott et al.,
2021). We therefore recommend that future cognition trials in mood
disorders implement fMRI paradigms that are more focused on the
cognitive domain that shows treatment-related improvement to examine
neurocircuitry target engagement.
Strengths of the present study were that it followed the recommen­
dations from the ISBD Cognition Task Force regarding inclusion of
remitted patients with objective cognitive impairments and investiga­
tion of underlying neuronal activity in relation to the patient’s outside
scanner cognitive performances (Miskowiak et al., 2017). Since signifi­
cant levels of subsyndromal symptoms were allowed in patients within
our trial, the findings may not be representative of patients in full
remission. However, ABCR and control groups showed no differential
change in subsyndromal symptoms over time (Ott et al., 2020), sug­
gesting that the present findings were not confounded by unspecific
effects of mood. A limitation of the current study was that we used an
fMRI paradigm that probes visual memory for investigating the neuronal
correlates of verbal memory improvement. Nevertheless, both the verbal
learning and memory (RAVLT) and picture encoding tests probe
episodic memory processes that involve strategic processes and the
integrity of overlapping fronto-temporal regions (Kim, 2011). In addi­
tion, almost all participants in the patient group received psychopha­
rmacological treatment which may have influenced their neuronal
response (e.g., in the hippocampus). However, this does not explain the
absence of changes in encoding related neuronal activity given the
previous observation of dorsal prefrontal activity change following
ABCR treatment in the same cohort (Ott et al., 2021). Another limitation
was the significant increase in post-scan picture recall from baseline to
follow-up in both patient groups which suggests a learning effect which
may have precluded ABCR-related treatment effects. Lastly, verbal
learning and memory was only a tertiary outcome in the original ACBR
trial (Ott et al., 2020) and the findings should therefore be considered
exploratory. Nevertheless, our calculation of an overall domain composite
score for verbal learning and memory in the present report revealed
robust treatment-related change in this measure, which emerged already
after two weeks of treatment and had a large effect size after treatment
completion.
In the present fMRI study, we investigated the neuronal correlates of
verbal learning and memory improvement following 10 weeks of ABCR
in remitted patients with BD. We showed ABCR-related improvement in
an overall measure of verbal learning and memory after two and 10
weeks of treatment. This effect correlated directly with improved ex­
ecutive functions and was likely mediated by strengthened strategic
processing – a key focus in ABCR. Nevertheless, neuronal activity during
7
Psychiatry Research: Neuroimaging 319 (2022) 111418
picture encoding was not affected by ABCR. We suggest that picture
encoding paradigms that do not explicitly tap into strategic cognitive
processes may be suboptimal for capturing the neuronal underpinnings
of memory improvement following cognitive remediation interventions
in BD.
Contributors
KWM, VD and CVO planned and conducted the behavioral analyses.
JM conducted the fMRI analyses. VD and KWM created the first draft of
the manuscript, which was then revised by JM. GMK and LVK were
involved in the original trial design together with KWM. All authors
reviewed and approved the final version of the manuscript.
Funding
The study was funded by the Lundbeck Foundation Fellowship grant
awarded to KWM (grant no. R215–2015–4121). The funding source had
no involvement in study design; in the collection, analysis and inter­
pretation of data; in the writing of the report; and in the decision to
submit the article for publication.
Declaration of Competing Interest
The authors declare no potential conflicts of interest with respect to
this work. KWM declare to have received consultancy fees from Lund­
beck and Janssen-Cilag in the past three years.
Acknowledgements
We would like to acknowledge the Copenhagen Affective Disorder
Clinic, Rigshospitalet, Copenhagen, Denmark for assistance with
recruitment, and specialist in psychotherapy Nanna Tuxen for her
involvement in the ABCR treatment. The computer software used in the
ABCR group is provided free of charge by HappyNeuron Pro (www.
happyneuronpro.com).
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