REVIEW

Using Neuroscience to Augment Behavioral

Interventions for Depression
Meghan Vinograd, MA, and Michelle G. Craske, PhD

Abstract: Depression is both prevalent and costly, and many individuals do not adequately respond to existing psycho-
pharmacological and behavioral interventions. The current article describes the use of neuroscience in augmenting behav-
ioral interventions for depression in two primary areas: anhedonia and cognitive deficits/biases. Neuroscience research has
increased our understanding of the neural bases of reward processing and regulation of positive affect, and anhedonia
among depressed samples can be related to deficits in each of these domains. Treatments that specifically target reward pro-
cessing and regulation of positive affect in order to reduce anhedonia represent a recent advance in the field. Depression is
Downloaded from http://journals.lww.com/hrpjournal by BhDMf5ePHKbH4TTImqenVBLNPkpHwi7kV5Cnod1YhY3bT0DYsF+2WO+0SNOkPYOF on 01/09/2020

also associated with aberrant processes relating to working memory, autobiographical memory, attentional bias, and inter-
pretive bias. Neuroscience findings have increasingly been leveraged to augment the efficacy of cognitive-training and bias-
modification interventions in these domains. The use of neuroscience to inform the development and augmentation of
behavioral interventions for depression is a promising avenue of continued research.
Keywords: anhedonia, cognition, depression, intervention, neuroscience

D
epression is one of the most prevalent psychiatric dis-
orders in the United States and a leading cause of dis-
ability worldwide.1,2 Depression is also associated
with significant impairments in occupational, social, and physical
functioning for the individual and has a large economic impact at
the societal level.3,4 For a substantial proportion of individuals
who seek psychotherapeutic treatment for depression, either they
do not respond, or their improvement is relatively short-lived.
One meta-analysis found that among individuals who met diag-
nostic criteria for major depressive disorder (MDD), only 48%
responded to psychotherapy (defined as a 50% or greater reduc-
tion of symptoms).5 Further, a substantial number of individuals
with MDD who respond to cognitive-behavioral therapy (CBT),
one of the most well-supported treatments, experience relapse or
recurrence: 29% within one year and 54% within two years.6
Clearly, the existing behavioral interventions for this prevalent
and potentially debilitating disorder need to be improved.
The National Institute of Mental Health’s Research Domain
Criteria (RDoC) initiative proposes a shift in focus from categor-
ical diagnostic criteria to transdiagnostic dimensional features of
From the Departments of Psychology (Ms. Vinograd and Dr. Craske) and Psychiatry
and Biobehavioral Sciences (Dr. Craske), University of California, Los Angeles.
Supported by National Institute of Mental Health grant nos. T32MH015750 (Ms.
Vinograd) and R01DA045716-01, R61MH113772-01A1, R61MH115138-01,
R01MH100117, and R01MH102274-01 (Dr. Craske); and Department of Veterans
Affairs Health Services Research and Development grant no. CRE12-314 (Dr. Craske).
Original manuscript received 21 May 2019; revised manuscript received 12
October 2019, accepted for publication 21 October 2019.
Correspondence: Meghan Vinograd, Department of Psychology, University of
California, Los Angeles, 1285 Franz Hall, Box 951563, Los Angeles, CA
90095. Email: mvinograd@ucla.edu
© 2020 President and Fellows of Harvard College
DOI: 10.1097/HRP.0000000000000241
mental disorders.7 The RDoC framework also emphasizes study
of the neural circuitry thought to underlie psychiatric disor-
ders in order to improve upon psychotherapeutic and psycho-
pharmacological interventions.8 One relevant example is the
application of the neuroscience of fear learning to inform
exposure-based therapies for anxiety disorders and posttrau-
matic stress disorder.9,10 In the case of depressive disorders,
clinical neuroscience has increasingly sought to leverage neuro-
scientific findings not only to identify potential biomarkers of
treatment response11,12 but also to develop and improve upon
behavioral treatments. The current article focuses on two fea-
tures of depression that have received the most attention in this
regard: anhedonia and cognitive deficits/biases. First, we dis-
cuss how neuroscience research has expanded our understand-
ing of reward processing and regulation of positive affect, and
describe behavioral interventions that use these findings to tar-
get depressive anhedonia. Second, we describe how the cogni-
tive deficits and information-processing biases associated with
depression have been targeted via interventions such as cognitive
training and bias modification, and how these interventions
may be further improved upon by using neuroscience-based
augmentation strategies. It should be noted that this article is
not a systematic review of the literature on these topics; instead,
it highlights some of the existing research in the area and pro-
vides recommendations for future research.
TARGETING ANHEDONIA: REWARD PROCESSING
AND POSITIVE AFFECT REGULATION
Anhedonia
Anhedonia, one of the cardinal symptoms of MDD, is defined
in the Diagnostic and Statistical Manual of Mental Disorders,

14 www.harvardreviewofpsychiatry.org Volume 28 • Number 1 • January/February 2020

Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.

fifth edition, as diminished interest or pleasure in one’s activi-
ties.13 It is estimated that approximately one-third of depressed
individuals experience clinically significant anhedonia, as mea-
sured by scales assessing enjoyment of social and physical plea-
sure.14 Lower self-reported positive emotion is a prospective
predictor of poorer course of MDD across a number of stud-
ies.15 Anhedonia is also associated with both current suicidal
ideation after controlling for depression and, among individuals
with affective disorders, later suicide completion.16,17 Finally,
anhedonia is predictive of poorer pharmacological treatment re-
sponse among both adults and adolescents with depression.18,19
Many psychological treatments for depression are de-
signed to reduce negative affect, but as noted above, the effi-
cacy of these psychotherapies can be inadequate. Targeting
positive affect may be one way of improving the efficacy of
psychological treatments for depression, especially with re-
gard to reducing anhedonia.20 The research on positive psy-
chology interventions (PPIs), which broadly aim to cultivate
positive feelings, cognitions, and behaviors, is mixed. Previ-
ous meta-analyses using depressed samples suggested that
PPIs, compared to no-treatment or treatment-as-usual com-
parison groups, are effective for reducing depressive symp-
tomatology.21,22 A more recent meta-analysis of PPIs for
individuals with a range of psychiatric and somatic disorders,
however, found that effect sizes for depression were no longer
significant when low-quality studies were removed.23
An additional limitation in this area of research is that posi-
tive affect and anhedonia are not frequently examined as in-
dependent outcomes. In the studies that do measure these
outcomes, existing treatments that are designed to increase
positive affect do not consistently have this effect. One example
is activity scheduling, a component of behavioral-activation
treatment for depression, which involves increasing a client’s en-
gagement in rewarding activities in order to boost mood.24,25 A
meta-analysis of the effect of activity scheduling on depressive
symptoms among adults revealed a large pooled effect size
(0.87) when compared to control conditions and comparable ef-
fects when compared to other interventions for depression, such
as cognitive therapy.26 Research suggests that behavioral activa-
tion has limited effects on positive affect27 and anhedonia,28
however, suggesting that further development of interventions
targeting positive affect is warranted. Additionally, a compar-
ison of a PPI intervention delivered in a group format versus
traditional CBT found that both interventions reduced de-
pressive symptoms among adult women with dysthymia or
major depression, but that the two treatments were not signif-
icantly different on positive affect, depressive symptoms, clin-
ical diagnosis, and negative affect.29
A pilot study of a “positive activity intervention,” which in-
cluded sessions focusing on gratitude, acts of kindness, and be-
havioral activation, among other topics, was conducted using
a sample of adults with elevated depression and anxiety symp-
toms.30 The intervention group, compared to the waitlist con-
trol group, demonstrated significantly greater improvements in
positive affect and well-being, as well as greater reductions in
Harvard Review of Psychiatry
Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
Augmenting Behavioral Interventions for Depression
negative affect, anxiety symptoms, and depression symp-
toms.30 Although this intervention shows an impact on posi-
tive affect, the study was limited by reliance on a waitlist
control group rather than an active comparison treatment.
The efficacy of interventions for depression that target posi-
tive affect may be bolstered by increased focus on the processes
thought to underlie anhedonia, including dysfunctional reward
processing and dysfunctional positive affect regulation, which
we describe in the following sections. We also highlight behav-
ioral interventions that target reward processing and positive af-
fect regulation, with a focus on positive affect treatment.31,32
Reward Processing
Anhedonia is often broadly conceptualized as dysfunctional re-
ward processing. Historically, anhedonia was primarily
thought to arise from dysfunctional reward consumption or
pleasure.33 More recent reward-processing models, however,
have posited that anhedonia is not a unitary construct but
rather made up of several constituent processes. Treadway
and Zald34 distinguish between motivational anhedonia (re-
ward “wanting”) and consummatory anhedonia (reward
“liking”). Reward learning is also thought to be an important
facet of reward processing.35 Kring and Barch36 propose a
model that includes several reward-related processes: activa-
tion of the reward association, interest, anticipation, motiva-
tion, effort, liking, and feedback integration. As of the 2019
iteration of the RDoC Matrix, the positive valence system is
divided into the constructs and subconstructs of reward re-
sponsiveness (reward anticipation, initial response to reward, re-
ward satiation), reward learning (probabilistic and reinforcement
learning, reward prediction error, habit), and reward valuation (re-
ward [probability], delay, effort).37 Reward approach-motivation,
attainment, and learning are posited as three primary compo-
nents of the reward-processing system across models. As such,
we focus on these reward processes in the current article.
In humans, reward approach-motivation, attainment, and
learning are associated with both overlapping and unique neural
regions, circuits, and neurotransmitters (see Treadway & Zald34
and Der-Avakian & Markou38 for comprehensive reviews).
Briefly, reward approach-motivation has been linked to dopa-
minergic signaling34 and neural regions such as the ventral teg-
mental area, ventral striatum, amygdala, and orbitofrontal
cortex.38,39 Reward attainment is thought to primarily relate
to the opioid system34 and neural regions that include the
ventral striatum (specifically the nucleus accumbens) and
orbitofrontal cortex.38 Reward learning is associated with
dopaminergic signaling40 and neural regions that include
the dorsal basal ganglia and anterior cingulate cortex.38 Al-
though some overlap exists, the association of distinct neuro-
biological substrates with the various components of reward
processing underscores the importance of adopting a process-
based approach to studying anhedonia.
A substantial body of literature has demonstrated associa-
tions between anhedonia and deficits in reward processing
across levels of analysis. Here, we focus on studies using
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M. Vinograd and M. G. Craske
depressed samples. During reward approach-motivation, de-
pressed participants demonstrate reduced striatal activity com-
pared to control participants,41–43 and hypo-responsiveness in
the ventral striatum was associated with severity of anhedonia
symptoms.42,44 In one study, greater orbitofrontal cortex activ-
ity was associated with greater self-reported hedonic capacity
within a depressed group.45 Depressed individuals have been
shown to expend less effort for rewarding stimuli than control
participants, and less effort expenditure is associated with
greater self-reported anticipatory anhedonia.46–48
Evidence of reduced reward attainment in depressed sam-
ples, as assessed via self-reported liking of sensory stimuli, is
mixed.35 One study found that anhedonia, but not depressive
symptoms broadly, was related to lower self-reported pleas-
antness ratings of odors among currently depressed individ-
uals.49 Depression is associated with hypoactivity in striatal
regions during reward attainment as measured by functional
MRI43,50,51 and reduced feedback-related negativity event-
related potential, an index of neural response to feedback of
loss minus gain, as measured by EEG.43 Self-reported anhe-
donia is also associated with reduced bilateral caudate vol-
ume among depressed participants.50
Depressed individuals also demonstrate aberrant patterns of
responding during reward learning at both the behavioral52
and neural levels.53,54 Further, reward learning deficits have
been specifically associated with greater anhedonia in both
behavioral55–57 and neuroimaging studies in depressed
samples.58
Reward-Processing Interventions
Existing behavioral interventions that target reward processing
are limited in that they typically do not focus on multiple compo-
nent processes simultaneously. For example, traditional behav-
ioral activation primarily targets reward attainment but neglects
reward approach-motivation and learning.59 Augmented depres-
sion therapy (ADepT) is a novel, 15-session individual therapy
protocol that aims to affect both positive and negative valence
systems simultaneously.60,61 When ADepT was tested in a sample
of adults with a current major depressive episode, depression and
anxiety effect sizes were comparable to those observed in other
evidence-based treatments for depression (e.g., CBT and behav-
ioral activation), and effects on anhedonia and positive affect
were larger than those found with the other treatments.60 ADepT
includes techniques that target reward processing, such as mind-
fulness of external senses during activities (reward attainment)
and the keeping of a “positive diary,” which enhances focus on
positive, specific memories and trains attentional style (reward
learning), but it does not target reward approach-motivation.60
Further, the inclusion of techniques that also target negative af-
fect in ADepT makes it difficult to conclude that the reward-
processing techniques drive the treatment effects.
Positive Affect Treatment
Some newly emerging treatments are directly aiming to in-
crease positive affect by targeting all three major components
16 www.harvardreviewofpsychiatry.org
Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
of reward processing via both behavioral and cognitive strat-
egies. Positive affect treatment (PAT) is a recently developed,
transdiagnostic behavioral treatment designed to increase
positive affect by targeting deficits in reward approach-
motivation, attainment, and learning.31,32 PAT consists of
three modules: pleasant-events scheduling, attending to the
positive, and cultivating the positive. Each of the techniques
used in PAT directly targets positive affect or has been shown
to increase positive affect with a focus on reward approach-
motivation, attainment, and learning.31
The first PAT module is modified pleasant-events schedul-
ing. There are three tasks for each pleasant event: designing,
conducting, and recounting. Designing requires the individ-
ual plan for future engagement in the pleasant activity and
targets reward approach-motivation. Conducting targets re-
ward attainment through teaching the client to savor positive
emotions during the activity, and it targets reward learning by
having the client record his or her primary positive emotions
prior to, during, and following the activity in order to consoli-
date activity–mood associations. Recounting involves therapist-
guided visualization and recounting of positive aspects of
pleasant activities (including sensations, thoughts, emotions,
and situational details) in the present tense. Recounting in
PAT is similar to directed-imagery exercises used in cognitive
therapy for rumination62 and autobiographical-memory re-
call exercises used in memory specificity training (MeST),63
but it targets specifically positive features of experiences.
Similar to other behavioral approaches for depression,24,64
modified pleasant-events scheduling in PAT focuses on increas-
ing client engagement in pleasurable, meaningful, and mastery
activities; sessions include trouble-shooting potential obstacles
to completion of the selected activities. The PAT module differs
from other behavioral approaches in that reward attainment is
further targeted through in-session recounting exercises. Re-
search in nonclinical samples suggests that positive visual-
attention bias can be trained and subsequently used as an
emotion-regulation strategy.65 It is posited that attentional
training to positive stimuli during therapy sessions may lead
to increased attention to, and encoding of, positive material
in daily life, possibly resulting in greater engagement with re-
warding stimuli and increased positive affect.31,65,66
The second PAT module, attending to the positive, lasts
three sessions. In this module, clients practice three cognitive
techniques: silver lining, taking ownership, and imagining the
positive. Silver lining focuses on reward approach-motivation
and attainment, and, similarly to recounting of activities, pur-
portedly trains attention to positive stimuli through identifying
positive features of daily situations that were otherwise judged
to be negative or neutral. Studies have shown that individuals
with depression, compared to non-depressed individuals,
spend less time attending to positive stimuli67,68 and demon-
strate a lack of attentional bias to positive stimuli.69 Evidence
suggests that attentional regulation can be trained, however,
thereby influencing affective experience.66 Taking ownership
teaches clients to identify their own contributions to positive
Volume 28 • Number 1 • January/February 2020

outcomes and to recognize behavior–mood associations (re-
ward learning). Taking ownership relates to evidence that de-
pressed individuals, compared to non-depressed individuals,
demonstrate an attributional bias in which negative events
are attributed to internal causes and positive events to external
causes.70 Further, research in nonclinical samples suggests that
positive attributional bias can be trained.71 The final strategy,
imagining the positive, targets reward approach-motivation
and trains clients to imagine positive outcomes of future
events, with a focus on positive emotions. This strategy is
based on research that suggests repeated practice of imagining
positive stimuli can be associated with positive effects on mood
and behavior.72–75
The third PAT module, cultivating the positive, lasts four
sessions and consists of four practices: loving-kindness, generos-
ity, appreciative joy, and gratitude. The primary targeted media-
tor for each of these strategies is reward attainment, although
reward learning is also targeted through pre- and post-exercise
mood ratings. In nonclinical samples, loving-kindness medita-
tion has been shown to increase daily experience of positive
emotions, personal resources, (e.g., life purpose, social sup-
port), and life satisfaction.76 Further, a group loving-kindness
meditation intervention (not controlled) had large effects on
self-reported positive affect, negative affect, and depressive
symptoms in individuals with symptoms of depression and di-
agnoses of persistent depressive disorder.77 Studies have also
found effects of gratitude-based interventions on increased
positive affect.78 Daily gratitude-based exercises in PAT include
listing things to be grateful for, writing a gratitude journal, and
carrying a “gratitude rock” as a reminder.
The first randomized, clinical trial compared PAT to nega-
tive affect treatment (NAT), a treatment that includes more-
traditional exposure and cognitive-restructuring techniques,
and also a breathing retraining module.32 Participant inclu-
sion in this trial was based on elevated scores on the depres-
sion, anxiety, or stress subscale of the Depression Anxiety
Stress Scales79 (signifying moderate to severe symptom levels)
and a score of 5 or higher on at least one subscale of the
Sheehan Disability Scale (signifying clinical impairment).80
A total of 96 individuals were randomized to NAT (n = 55)
or PAT (n = 41); 93 participants’ data were analyzed (NAT = 53;
PAT = 40).32 Overall, 54.8% met criteria for a depressive disor-
der, and 86% met criteria for an anxiety disorder. Individuals
randomized to PAT reported greater improvements in positive
affect (d = .52) and higher positive affect at the six-month
follow-up assessment (d = .67) than those randomized
to NAT. PAT participants also reported lower negative affect
(d = .52) and lower symptoms of depression (d = .34), anxiety
(d = .30), and stress (d = .43) at six-month follow-up than
NAT participants. Finally, the probability of endorsing sui-
cidal ideation was lower among PAT participants (1.7%)
than NAT participants (12%) at six-month follow-up.
Further research is needed to replicate these findings and to
examine potential moderators of treatment outcome. Studies
examining potential mediators are also needed, specifically
Harvard Review of Psychiatry
Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
Augmenting Behavioral Interventions for Depression
those that include neuroimaging data in order to evaluate
the extent to which the activation or connectivity of neural re-
gions associated with each component of reward processing is
altered by engagement in the PAT modules. Finally, disman-
tling studies are also needed in order to determine which
PAT modules or skills drove the effects. These initial results
suggest that, in clinical samples with impaired functioning,
PAT—a treatment that exclusively targets positive affect—
not only increases positive affect but also decreases negative
affect, depressive symptoms, and anxious symptoms.
Positive Affect Regulation
Difficulties regulating negative affect are central to the onset
and maintenance of depression, but aberrant regulation of
positive affect also plays an important role in the disorder.81
Studies of depressed samples have found evidence for increased
dampening, in which positive affect is down-regulated,82 and re-
ward devaluation, in which positive information is inhibited or
avoided.83 In community samples, higher levels of dampen-
ing have been associated with higher levels of depressive
symptoms concurrently84 and prospectively.85 In a sample
of individuals with remitted MDD, self-reported amplifica-
tion (up-regulation) was associated with increased positive
affect during a goal-related rumination induction.86 Fur-
ther, reduced amplification of positive affect and lower
levels of rumination on positive affect have been associated
with increased anhedonia.82,84 Finally, instructed use of
dampening appraisals reduced positive affect and increased
negative affect during pleasant events in a non-depressed
sample.87 Dampening and amplification of positive affect,
which can be achieved through cognitive reappraisal, rep-
resents an important intersection of the positive-affect and
cognitive systems.
A growing body of research examines the neural correlates
of positive affect regulation in depressed samples. During
instructed amplification, individuals with MDD showed de-
creased nucleus accumbens activity over time, representative
of a difficulty sustaining positive affect.88 Further, connectiv-
ity analyses suggested that aberrant connectivity with the left
middle frontal gyrus may, in part, account for this reduction
in nucleus accumbens activation over time.89 Depressed indi-
viduals who demonstrated reduced right ventrolateral pre-
frontal cortex activation during dampening showed greater
reductions in anhedonia after eight weeks of treatment with
antidepressant medication.90
Positive Affect Regulation Interventions
Existing interventions that target the regulation of positive affect
are limited in number. Positive affect stimulation and sustainment
(PASS) targets the difficulty in sustaining positive affect and the
tendency of individuals with elevated depressive symptoms
and depression diagnoses to attribute positive events to exter-
nal causes.91 The PASS intervention used a 20-minute written
disclosure paradigm92 that participants completed three times
over the course of two weeks. The paradigm instructed
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M. Vinograd and M. G. Craske
participants to recall a positive event in the past week, consider
how the event might lead to other future positive events, and
identify their contributions to positive events.91 In a study of
college-aged women with elevated depressive symptoms, the
PASS group demonstrated moderate reduction in depressive
symptoms, as well as a pre- to post-session increase in positive
affect, compared to the active control group.91 Contrary to the
hypothesis, however, the PASS group did not show a pre- to
postintervention (versus post-session) increase in positive af-
fect. Possible explanations are that the participants had diffi-
culty generalizing from the experience of positive affect
during the writing sessions to the experience of positive affect
outside the sessions and that the relatively brief (two weeks)
duration of the intervention was not sufficiently long to change
participants’ experience of positive affect.91 Given the robust
evidence for increased reward dampening and devaluation
among depressed samples, as well as decreased reward ampli-
fication, the development of additional interventions that tar-
get these processes is warranted.
COGNITIVE DEFICITS, BIASES, AND INTERVENTIONS
Depression is associated with a range of cognitive deficits and
information-processing biases, the latter of which are thought
to be particularly relevant to the onset and maintenance of the
disorder (see LeMoult & Gotlib93 and Gotlib & Joormann94
for extensive reviews). Two diagnostic criteria of MDD that
may be particularly relevant to cognitive deficits are indeci-
siveness and the diminished ability to think or concentrate.13
Among individuals with MDD, cognitive impairments are asso-
ciated with psychosocial dysfunction, including social and oc-
cupational functioning.95,96 Cognitive deficits also predict
poorer response to psychopharmacotherapy96,97 and are a risk
factor for relapse98 in depressed samples. Finally, evidence sug-
gests that cognitive impairments can persist even when other de-
pressive symptoms improve.99 Given these and other findings,
it has been argued that cognitive dysfunction should be consid-
ered a key treatment target in depression.100 Cognitive remedi-
ation and bias modification have been investigated as possible
intervention strategies to target cognitive impairment and biases
in depressed individuals, specifically as a way of augmenting the
benefits of psychotherapy.98,101
One of the challenges in the literature on cognitive pro-
cesses and depression is the lack of precision regarding termi-
nology, especially when drawing upon research from various
fields. For example, the term executive function is often used
to collectively refer to processes such as response inhibition,
interference control, working memory, and cognitive flexibil-
ity.102 Yet the Cognitive Systems domain of the RDoC Matrix
eschews the term executive function and delineates the con-
structs of attention, perception, declarative memory, lan-
guage, cognitive control, and working memory, with each
having subconstructs.37 Other cognitive processes, such as
information-processing biases, are not explicitly represented
in the RDoC Matrix but are relevant to depression.93,94 Here,
we highlight four domains for which neuroscience research is
18 www.harvardreviewofpsychiatry.org
Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
being used to augment existing cognitive interventions for de-
pression: working memory, autobiographical memory, atten-
tional bias, and interpretive bias.
Working Memory
The RDoC Matrix defines working memory as “the active main-
tenance and flexible updating of goal/task relevant information
(items, goals, strategies, etc.) in a form that has limited capacity
and resists interference.”37 Meta-analyses have found mixed sup-
port for impaired visuospatial and auditory working memory in
depressed samples.103,104 One explanation for this discrepancy
in the literature is that working-memory deficits surface only
when attention is not constrained by the task, possibly leading
to depressive rumination and impaired task performance.93,105
Multiple studies provide support for this idea, demonstrating
that rumination is associated with aberrant working-memory
processes among depressed individuals.106,107 It has also been
proposed that deficits in controlling the contents of working
memory may contribute to maladaptive emotion-regulation
strategies characteristic of depression.108–111 During working-
memory tasks, depressed individuals demonstrate aberrant
patterns of neural activation in a number of cortical and
subcortical regions, including the prefrontal cortex, insula,
precuneus, and superior temporal areas.112
Working memory has been investigated in the context of
both working-memory training paradigms and mindfulness,
albeit primarily in non-depressed samples. A meta-analysis
of working-memory training yielded large effect sizes in unse-
lected samples but revealed that effects were typically limited
in duration and did not generalize to other tasks.113 Twenty
days of emotional working-memory training was shown to
improve emotional working-memory in healthy adults—and
improvement was associated with increased efficiency of
frontoparietal regions thought to subserve cognitive con-
trol.114 In a sample of individuals with elevated depressive
symptoms at baseline, working-memory training was shown
to improve working-memory capacity and filtering efficiency
compared to an active control group, but the improvement
had no effect on depressive symptoms post-training.115 Simi-
larly, in a sample of participants with high self-reported rumina-
tion, six days of working-memory training did not significantly
affect rumination or depression.116 An emotional working-
memory training intervention for adolescents did not outperform
a placebo intervention, although both groups demonstrated im-
proved working memory and reductions in depressive and anx-
ious symptoms from pre- to post-training, possibly due to
training or time effects.117 Research also suggests that mind-
fulness meditation practices can enhance working-memory
capacity in nonclinical samples.118,119 In summary, studies
of interventions for working memory have primarily relied
upon nonclinical samples, and the effects on depressive symp-
toms and rumination appear limited.
Transcranial direct current stimulation (tDCS), a neuro-
modulatory technique, has recently been investigated as a tool
for enhancing the effects of cognitive control training (CCT)
Volume 28 • Number 1 • January/February 2020

on working memory and depressive symptoms. Briefly, tDCS
can enhance functional activity of the target brain region by in-
creasing cortical excitability.120 The dorsolateral prefrontal cor-
tex (DLPFC) has been a primary target of tDCS, given the
region’s role in executive control, in general, and working mem-
ory, in particular.120,121 In a meta-analysis examining studies
using both nonclinical and clinical samples, DLPFC tDCS has
been shown to significantly improve reaction time (but not accu-
racy) on working-memory tasks.120
CCT is an adjunctive intervention that includes the Wells
attentional training paradigm, designed to build focused at-
tention, attentional switching, and divided attention, and a
modified paced serial addition task (PSAT), designed to enhance
cognitive control.122 CCT has been shown to reduce depres-
sive symptomatology in intensive outpatient and community
samples with MDD or elevated depressive symptoms,
respectively.122–124 CCT also targets the decreased DLPFC
activation during cognitive tasks characteristic of depression
and thus has been used in conjunction with tDCS. In a sample
of adults with MDD, combined CCT and tDCS to the DLPFC
resulted in antidepressant effects at three-week follow-up,
whereas sham conditions did not demonstrate this sustained
effect.125 Within a combined CCT and DLPFC tDCS group,
depressed participants who demonstrated better task perfor-
mance had greater depression improvement, which the au-
thors propose was possibly indicative of greater DLPFC
activation.126 Another study found that tDCS to the DLPFC
did not moderate the association between changes in working
memory and rumination following PSAT training in individ-
uals with major depression, possibly due to electrode place-
ment or the nature of the task used in the training.127 Taken
together, the use of tDCS to augment the effects of cognitive
training for working memory in depressed samples is a prom-
ising area of research that deserves further attention.
Autobiographical Memory
Depression is characterized by aberrant processing of autobio-
graphical memories, including negative recollection bias, reduced
access to positive memories, overgeneralization, and rumination
and avoidance.128 Overgeneral autobiographical memory has
been prospectively associated with future depressive symptoms
and onset of major depressive episodes among participants with
higher levels of life stress.129–131 Depressed individuals, com-
pared to control groups, demonstrate increased neural activa-
tion in regions of the brain associated with reexperiencing,
processing of emotional salience, and self-referential process-
ing during retrieval of specific memories.132 Individuals with
depression also demonstrate reduced activation in the insula
(thought to underlie emotional salience) and precuneus
(self-referential processing), as well as increased activation
in the lateral prefrontal cortex (executive function) during
cued retrieval of positive specific memories.132
Autobiographical episodic memory–based training programs
have been investigated as possible interventions for increasing
specificity and positivity of autobiographical memories in
Harvard Review of Psychiatry
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Augmenting Behavioral Interventions for Depression
affective disorders, and these programs generally demonstrate
promising effects on depressive symptoms.133 One interven-
tion, memory specificity training, is designed to increase speci-
ficity of memory retrieval in depressed individuals.63 Non–
randomized control studies provide evidence that MeST both
increases memory specificity and decreases depressive symp-
toms,63,134,135 although a meta-analysis revealed that the effects
of MeST generally do not last beyond the initial postintervention
assessment.135 In the first randomized, controlled trial of MeST,
adults with MDD who completed MeST demonstrated greater
memory specificity at postintervention and three-month follow-
up than those in a psychoeducation and supportive counseling
condition.136 In that trial, participants in both groups demon-
strated a reduction in self-reported depressive symptoms, but
the difference between groups was nonsignificant.
Real-time functional MRI neurofeedback (rtfMRI-nf) has
been investigated as a tool for increasing amygdala activity
during positive autobiographical-memory recall in depressed
samples.137 In rtfMRI-nf, participants are shown a graphical
depiction of their blood oxygen level–dependent signal in a
given brain region and instructed to change the signal while
completing an fMRI task. The amygdala was selected as the
target region, given its well-established role in affective expe-
rience, emotional-memory recall, and depression onset.137
Further, these studies have focused on increasing amygdalar
response to positive autobiographical memories, rather than
decreasing amygdalar response to negative memories. This
focus stems from the associations between depressive symp-
toms and activity in the amygdala during recall of positive
memories in both currently depressed and remitted depressed
samples.138,139 As such, this approach targets both positive
affect and cognitive processes.
To date, one randomized clinical trial has investigated
rtfMRI-nf autobiographical-memory training among adults
with MDD.140 Participants in that trial received neurofeedback
regarding activity in either the left amygdala (experimental con-
dition) or the left horizontal segment of the intraparietal sulcus
(control condition) while recalling positive memories over the
course of two training sessions. Participants in the experimental
condition demonstrated significant clinical improvement and an
increase in the percentage of specific memories recalled during
the final autobiographical-memory test. Further, amygdala ac-
tivity during the final task mediated the effect of positive specific
autobiographical-memory recall and depressive symptom scores
at one-week follow-up. Secondary analyses of this clinical trial
revealed that amygdalar response to positive autobiographical
memories was associated with improved processing of positive
stimuli (e.g., words, faces) in the experimental condition, which
the authors argue is similar to findings following pharmacother-
apy.140 Further research is needed, however, to assess both the
duration of these effects versus those with pharmacological
agents and the utility of rtfMRI-nf as an adjunct to antidepres-
sant medication. A randomized, clinical trial is currently under
way comparing CBT augmented with amygdala rtfMRI-nf (ex-
perimental group) versus CBT augmented with right parietal
www.harvardreviewofpsychiatry.org 19
M. Vinograd and M. G. Craske
rtfMRI-nf (control group).141 Initial results from this trial show
that participants in the experimental group demonstrate greater
symptom improvement and that a larger proportion of this
group experience sudden gains during the first three weeks of
augmented CBT than the control group. Future research could
also examine the effects of rtfMRI-nf on other brain regions
thought to subserve autobiographical memory, such as the
insula and precuneus.132
Attentional Bias
Individuals with depression demonstrate both attentional def-
icits and biases, but we focus here on attentional biases.142,143
Depression is characterized by selective attention toward neg-
ative stimuli69 and difficulty disengaging attention from neg-
ative stimuli.94 In eye-tracking studies, depression has been
associated with reduced orienting to, and reduced gaze dura-
tion on, positive stimuli, as well as increased gaze mainte-
nance on negative stimuli.67 Biased attention for negative
stimuli has been linked to the DLPFC, anterior cingulate cor-
tex, ventrolateral prefrontal cortex, and superior parietal cor-
tex; studies have shown reduced functional activation in each
of these regions among depressed samples.108
Attention-bias modification (ABM) has been investigated
as an intervention for individuals with depression. In ABM
paradigms, participants are trained to avoid negative stimuli by
shifting attention to neutral or positive stimuli. Although evidence
suggests that positive attentional biases can be trained,65,66
meta-analyses have found that the effect of ABM on depres-
sive symptoms is limited overall.144–146 Given the limited di-
rect effects on depressive symptoms, it is possible that ABM
may be more effective as an augmentation tool for traditional
psychotherapeutic intentions or as a relapse-prevention strat-
egy, but additional research is needed. Interestingly, existing
meta-analyses do not examine the possible differential effects
of training attention to neutral stimuli versus positive stimuli.
Given that depressed individuals demonstrate decreased allo-
cation of attention to positive stimuli,67,68 ABM paradigms
may be optimized by training attention to positive (rather than
neutral) stimuli. Similarly, positive search training (a form of
attentional training) shows promise as an intervention strategy
for reducing anxious symptoms in children.147,148 Future re-
search could measure the effects of ABM to positive stimuli
on other facets of reward processing in order to explore the
utility of this intervention in addressing anhedonia and atten-
tional bias simultaneously.
One study examined the effects of ABM on resting-state
connectivity in an attentional-control network in a sample
of adults with MDD.149 ABM reduced negative attention bias
and increased connectivity within the medial frontal gyrus
and dorsal anterior cingulate cortex among the active group
but not the placebo group.149 Importantly, depressive symp-
toms improved in both conditions, and exploratory analyses
suggested that increased resting-state connectivity in a circuit
associated with sustained attention was associated with
symptom improvement among individuals in the placebo
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Copyright © 2020 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
condition. The authors suggest that attentional training, using
both emotional and non-emotional content, may be beneficial
in alleviating depressive symptoms, although these findings
were exploratory in nature. This investigation highlights the
importance of examining the neural substrates of cognitive
processes in order to refine interventions, as this type of re-
search can reveal unanticipated treatment targets.
In a second study, ABM training toward positive faces re-
duced amplitude of low-frequency fluctuations of the right
insula and right middle frontal gyrus in a sample of women
with elevated depressive symptoms, thereby normalizing
spontaneous brain activity.150 Finally, low-level light therapy
(LLLT) has recently been investigated as a neuroenhancement
strategy for ABM in adults with elevated depression symp-
toms.151 LLLT increases mitochondrial cytochrome oxidase,
which improves neural oxygenation and metabolic effi-
ciency.151 In this proof-of-concept study, LLLT administered
to the right forehead led to greater reduction in depression
symptoms among participants who were more responsive to
ABM than in those who received sham LLLT and those who
did not respond to ABM.151 Research on the neural effects
of ABM, although in its infancy, suggests that the intervention
can induce changes in neural regions important to depression
and may be amenable to neuroenhancement strategies. Addi-
tional research that makes use of larger group sizes and inclu-
sion of active control groups is an important next step in
the field.152
Interpretative Bias
Interpretive bias is the tendency to interpret ambiguous stimuli
(e.g., words, scenarios) as having either positive or negative emo-
tional qualities. Negative interpretive bias is central to Beck’s cog-
nitive model of depression,153 and a meta-analysis found a
medium overall effect size of interpretive bias across samples of
individuals with diagnoses of depression, remitted depression,
and elevated depressive symptomatology.154 Cognitive-bias
modification for interpretation (CBM-I) has been studied as a
possible intervention for individuals with depression. A meta-
analysis found that benign (neutral or positive) CBM-I results
in increased positive interpretation bias and decreased negative
mood state, although these effects were not always different
when compared to control conditions.155 Similar to ABM, this
meta-analysis grouped CBM-I to neutral and positive stimuli to-
gether, although there are possibly differential effects of the two
training types.
Imagery CBM has been proposed as a means of augmenting
the effects of CBM-I, in part because of the impact that imagery
can have on emotional neural systems that are responsive to sen-
sory stimuli.73,156 Imagery CBM teaches participants to use
mental imagery to generate positive resolutions to ambiguous
stimuli; as such, it targets both reward and cognitive deficits.156
In nonclinical samples, imagery CBM leads to greater increases
in positive affect than verbal CBM.72,157 Further, imagery CBM
buffered against the effects of a later negative mood induc-
tion.158 In depressed samples, the effects of imagery CBM have
Volume 28 • Number 1 • January/February 2020

been mixed. From pre- to postintervention, individuals in the
positive-imagery CBM group, compared to those in the control
condition, demonstrated a significant improvement in depres-
sive symptoms.158 In a large randomized, controlled trial, imag-
ery CBM did not outperform a control condition in improving
overall depressive symptoms in individuals with major de-
pression, although imagery CBM did lead to reductions in
anhedonia from pre- to postintervention.159 Another study
examining the use of imagery CBM as an adjunct to
internet-based CBT for depression found no significant dif-
ferences between the positive and control CBM groups, al-
though those in the positive CBM group who completed all
CBM sessions demonstrated greater reductions in depressive
symptoms, including anhedonia (analyzed post hoc), than
the control group.160 Further research is needed to optimize
imagery CBM for depressed samples, potentially by targeting
specific components of reward processing, including approach-
motivation, attainment, or amplification.
CONCLUSION
The continued development of effective behavioral interven-
tions for depression is a primary research priority. There is a
growing interest in using neuroscience research and tech-
niques to inform the development of new interventions and
augment existing ones. Anhedonia and cognitive deficits/
biases are two features of depression that have received the
most attention in this regard. Neuroscience research has ex-
panded our understanding of reward processing and regula-
tion of positive affect as related to anhedonia. These findings
have contributed to renewed focus on positive psychology in-
terventions and also on developing new treatments that spe-
cifically target underlying deficits in reward processing.
Cognitive-training and cognitive-bias modification interven-
tions have been used to target the cognitive deficits and biases
associated with depression. Techniques grounded in neuro-
science are now being used to augment these cognitive inter-
ventions, an area of promising research for the treatment of
individuals with depression.
Importantly, both anhedonia and cognitive deficits/biases
are implicated in a range of other psychiatric disorders and,
as such, are transdiagnostic. Anhedonia is a diagnostic crite-
rion of posttraumatic stress disorder and schizophrenia,13
and has been associated with social anxiety disorder161 and
generalized anxiety disorder.162 Cognitive deficits and biases
are features of various disorders, including schizophrenia and
bipolar disorder,163 anxiety disorders,164 and posttraumatic
stress disorder.165 Patients in clinical settings often present with
multiple psychiatric diagnoses. Hopefully, an increased focus
on the processes underlying transdiagnostic features of psycho-
pathology will improve treatment outcomes across diagnoses.
Further research on the role of co-occurring disorders
as moderators of outcomes in the interventions described
above is warranted. Continued research on these trans-
diagnostic processes will likely prove beneficial toward
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Augmenting Behavioral Interventions for Depression
our understanding and treatment of both depression and
other forms of psychopathology.
Declaration of interest: The authors report no conflicts of in-
terest. The authors alone are responsible for the content and
writing of the article.
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