AN IDEA WORTH RESEARCHING
Advancing Research on Cognitive Flexibility in Eating
Disorders: The Importance of Distinguishing Attentional
Set-Shifting and Reversal Learning
C 2014 Wiley Periodicals, Inc.
Jennifer E. Wildes, PhD* V
Erika E. Forbes, PhD
Marsha D. Marcus, PhD
Introduction
Cognitive inflexibility has received considerable
attention as a putative mechanism that might
increase the risk for eating disorder (ED) onset, and
influence illness course and treatment response.
However, research findings have been mixed and
have not led to advances in treatment outcome.
Using a framework informed by cognitive neuro-
science, we contend that separating two discrete
facets of cognitive flexibility that are conflated in
measures currently employed in the EDs field (i.e.,
attentional set-shifting and reversal learning) will
help elucidate the mechanisms that underlie its
relation with ED symptoms. Moreover, we argue
that research that incorporates measures of atten-
tional set-shifting and reversal learning will promote
understanding of the role of cognitive flexibility in
the expression, course, and treatment of EDs.
Defining Cognitive Flexibility:
Attentional Set-Shifting and Reversal
Learning
A critical step in studying cognitive flexibility is to
clarify the behavioral and neural dimensions that
are most salient to EDs. This is challenging because
research in EDs has relied primarily on multidi-
mensional clinical neuropsychological measures
such as the Wisconsin Card Sorting Test (WCST)
and Brixton Test, and there is considerable diver-
Accepted 31 October 2013
*Correspondence to: Jennifer E. Wildes, PhD, Western Psychiatric
Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213.
E-mail: wildesje@upmc.edu
Department of Psychiatry, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania
Published online 10 January 2014 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/eat.22243
C 2014 Wiley Periodicals, Inc.
V
International Journal of Eating Disorders 47:3 227–230 2014
(Int J Eat Disord 2014; 47:227–230)
sity in the assessments that have been employed.1
For example, many studies have used perseverative
errors on the WCST as an index of cognitive inflexi-
bility in EDs. However, because the WCST is a com-
plex task that requires respondents to match cards
under changing rules and feedback about perform-
ance, perseverative errors indicating cognitive
inflexibility can reflect disruptions in two discrete
neurocognitive processes: (1) attentional set-
shifting, i.e., the ability to shift attention away from
one abstract stimulus dimension (e.g., color)
toward another (e.g., shape); and (2) reversal learn-
ing, i.e., the ability to override a recently acquired
stimulus-reinforcement association (e.g., matching
based on color) to apply a new stimulus-
reinforcement association (e.g., matching based on
shape).2
Importantly, attentional set-shifting and reversal
learning have distinct neural correlates (Table 1).3
For example, in animals, inactivations or lesions of
the orbitofrontal cortex (OFC), but not the lateral
prefrontal cortex, influence reversal learning,
whereas inactivations or lesions of the lateral (pri-
mate) or medial (rodent) prefrontal cortex, but not
the OFC, affect attentional set-shifting. In humans,
reversal learning has been linked to function in the
OFC and ventral striatum (VS), while attentional
set-shifting has been related to the ventrolateral
prefrontal cortex (VLPFC). Finally, there are dis-
tinctions in the neurochemical correlates of these
dimensions, with depletion of prefrontal cortical
dopamine (DA) and norepinephrine disrupting
attentional set-shifting, and striatal DA, in particu-
lar at DA D2 receptors, and serotonin in the OFC
influencing reversal learning. Thus, separating the
behavioral components of attentional set-shifting
and reversal learning, and their neural correlates, is
crucial for advancing research on cognitive flexibil-
ity in EDs.
227
WILDES ET AL.
TABLE 1. Selected neural correlates of attentional set-shifting and reversal learning
Behavior Mediating Neural Structures
Attentional set-shifting Ventrolateral prefrontal cortex (VLPFC)
Anterior cingulate cortex (ACC)
Posterior parietal & temporal areas
Reversal learning Orbitofrontal cortex (OFC)
Ventral striatum (VS)
How Should Attentional Set-Shifting
and Reversal Learning be Discrimi-
nated and Measured?
The selection of behavioral tasks is critical for
explicating the roles of attentional set-shifting and
reversal learning in EDs. Unlike clinical neuropsy-
chological measures that tap multiple neurocogni-
tive domains, experimental behavioral tasks are
designed to assess specific cognitive processes. For
example, the intradimensional/extradimensional
shift task from the Cambridge Neuropsychological
Test Automated Battery was developed as an exper-
imental analogue of the WCST to separate atten-
tional set-shifting and reversal learning. During
this nine-stage task, respondents are presented
with pairs of stimuli and must learn to select the
correct stimulus based on feedback following each
trial. The rule for correct responding is modified at
the beginning of each stage to dissociate aspects of
cognitive flexibility. For example, the intradimen-
sional shift stage examines rule generalization
when novel stimuli are introduced, whereas the
extradimensional shift stage examines the ability to
inhibit or shift attention away from previous rele-
vant stimulus dimensions (i.e., attentional set-
shifting). A functional imaging paradigm based on
the intradimensional/extradimensional shift task
has been developed, and has been shown to engage
the VLPFC and related set-shifting circuitry.2 Extra-
dimensional shift errors on this task have been
linked to numerous psychiatric disorders.3 How-
ever, research using the intradimensional/extradi-
mensional shift task in ED patients has failed to
document impairments in extradimensional set-
shifting,1 which might suggest that attentional set-
shifting is less salient to the expression of cognitive
inflexibility than reversal learning.
Studies that assess attentional set-shifting and
reversal learning separately within the same sam-
ple will help to clarify the relative roles of these
processes in EDs. In humans, reversal learning
frequently is measured using probabilistic reversal
learning paradigms in which respondents learn to
select the correct stimulus based on feedback, but
some of the feedback is inaccurate. For example,
228
Modulating Neurotransmitters
Norepinephrine (NE) in the prefrontal cortex (PFC)
Dopamine (DA) in the PFC
DA D1 receptors
Serotonin (5-HT) in the OFC
DA in the striatum
DA D2 receptors
during the first stage of a two-stage probabilistic
reversal learning task, respondents are rewarded
for selecting stimulus 1 and punished for selecting
stimulus 2 on 80% of the trials; however, false feed-
back is delivered on 20% of the trials such that
respondents are punished for selecting stimulus
1 and rewarded for selecting stimulus 2. In the sec-
ond stage of the task, the probabilities are
reversed. Probablistic reversal tasks are preferred
over non-probabilistic tasks (e.g., reversal errors
on the intradimensional/extradimensional shift
task) because they are more difficult and more
likely to encourage perseverative behavior after
contingency reversals. Probabilistic reversal learn-
ing paradigms also have been developed for use in
functional imaging studies, and have been shown
to elicit responses in the VS and OFC.3 However,
no study to our knowledge has used a probabilistic
reversal learning task in a sample of individuals
with EDs.
Using Measures of Attentional Set-
Shifting and Reversal Learning to
Advance Research on Cognitive Flexi-
bility in EDs
Future work is needed to clarify whether atten-
tional set-shifting is salient to EDs, or whether
other forms of cognitive inflexibility, such as
impaired reversal learning, are responsible for clin-
ical neuropsychological findings. Hypotheses war-
ranting further exploration include the possibility
that attentional set-shifting is relevant only to par-
ticular forms of ED, or that differences between ED
patients and controls in the neural correlates of
attentional set-shifting exist despite similar task
performance. Below we suggest three lines of
research that could be advanced through the use of
behavioral and neural measures of attentional set-
shifting and reversal learning.
Phenotypic Heterogeneity in EDs
Differences in the psychological and biological
correlates of anorexia nervosa-restricting type,
International Journal of Eating Disorders 47:3 227–230 2014
 ATTENTIONAL SET-SHIFTING AND REVERSAL LEARNING

Figure 1. Schematic model linking variations in the salience of neural correlates of attentional set-shifting and reversal learning to phenotypic
heterogeneity across AN-R, AN-BP, and BN. Note. AN-R 5 anorexia nervosa, restricting type; AN-BP 5 anorexia nervosa, binge-eating/purging type;
BN 5 bulimia nervosa; VLPFC 5 ventrolateral prefrontal cortex; ACC 5 anterior cingulated cortex; OFC 5 orbitofrontal cortex; VS 5 ventral striatum;
NE 5 norepinephrine; DA 5 dopamine; 5-HT 5 serotonin.

anorexia nervosa-binge-eating/purging type, and
bulimia nervosa raise the intriguing hypothesis
that these presentations might be differentially
associated with attentional set-shifting and reversal
learning (Fig. 1).4,5 As such, administering behav-
ioral measures of attentional set-shifting and rever-
sal learning to individuals across the ED spectrum,
and conducting imaging studies using conceptu-
ally relevant neurocognitive probes, could help
elucidate phenotypic heterogeneity in ED presen-
tation. Variations in the salience of attentional set-
shifting and reversal learning also might help to
explicate other forms of systematic heterogeneity
in EDs, such as undercontrolled, overcontrolled,
and low psychopathology presentations.
Cognitive Flexibility in Adolescents with Eating
Disorders
Cross-sectional studies using behavioral measures
have failed to document cognitive inflexibility in
adolescents with EDs, leading some scholars to
speculate that cognitive inflexibility is a conse-
quence of disordered eating.6 However, a compelling
alternative explanation for these findings is that indi-
viduals early in the course of an ED may be compen-
sating for disrupted processing during task
performance by: (a) increasing the magnitude of
response in neural circuits underlying attentional
set-shifting and reversal learning in order to success-
fully complete cognitive flexibility tasks; (b) recruit-
ing additional neural structures to offset inadequate
activity in neural circuits underlying attentional set-
shifting and reversal learning; or (c) both. In support
of this idea, research in non-ED-related psychiatric
disorders and older adults has found alterations in
neural processing during cognitive tasks even when
task performance has been equal in the patient and
control groups.7 Thus, studying the neural correlates
of attentional set-shifting and reversal learning in
adolescents with EDs is crucial to explicating
the role of cognitive inflexibility in the early course
of these disorders. Using more precise behavioral
tasks, as opposed to multidimensional clinical neu-
ropsychological measures, also will help to clarify
which aspects of cognitive inflexibility are most
salient to adolescent EDs. Finally, examining

International Journal of Eating Disorders 47:3 227–230 2014 229

WILDES ET AL.
changes in behavioral and neural facets of atten-
tional set-shifting and reversal learning over time
will help elucidate the role of cognitive flexibility in
the early progression of ED symptoms.
Treatment Development
Ultimately, a better understanding of the
behavioral and neural facets of cognitive flexibil-
ity with relevance to EDs will promote develop-
ment of novel interventions and prevention
programs for high-risk groups. For example, sev-
eral medications have been shown to improve
attentional set-shifting in individuals with psy-
chiatric disorders, and animal research has found
that second-generation antipsychotic agents
attenuate reversal learning deficits.3 Finally, one
limitation of cognitive remediation therapy is
that it targets a broad range of neurocognitive
functions that may or may not be salient to the
expression or maintenance of EDs. In contrast,
cognitive retraining strategies that focus on spe-
cific processes that have relevance to particular
psychiatric presentations (e.g., attention bias
modification for anxiety disorders) have
been shown to produce significant decreases in
psychiatric symptoms when compared to control
interventions. Cognitive retraining interventions
230
also can be used to help individuals accommo-
date areas of dysfunction, even if underlying def-
icits do not change.5 Thus, clarifying the
processes that underlie cognitive inflexibility in
EDs will facilitate the development of novel cog-
nitive retraining strategies designed to target spe-
cific mechanisms that have salience to particular
ED symptoms.
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