How Can Animal Models Inform the Understanding of Cognitive Inflexibility in Patients with Anorexia Nervosa?

Abstract

Deficits in cognitive flexibility are consistently seen in patients with anorexia nervosa (AN). This type of cognitive impairment is thought to be associated with the persistence of AN because it leads to deeply ingrained patterns of thought and behaviour that are highly resistant to change. Neurobiological drivers of cognitive inflexibility have some commonalities with the abnormal brain functional outcomes described in patients with AN, including disrupted prefrontal cortical function, and dysregulated dopamine and serotonin neurotransmitter systems. The activity-based anorexia (ABA) model recapitulates the key features of AN in human patients, including rapid weight loss caused by self-starvation and hyperactivity, supporting its application in investigating the cognitive and neurobiological causes of pathological weight loss. The aim of this review is to describe the relationship between AN, neural function and cognitive flexibility in human patients, and to highlight how new techniques in behavioural neuroscience can improve the utility of animal models of AN to inform the development of novel therapeutics.

Keywords: activity-based anorexia; animal models; anorexia nervosa; cognitive flexibility; dopamine; prefrontal cortex; serotonin.

Figure 1

Common cognitive tests that are used to assess cognitive flexibility in humans. (a) The Wisconsin Card Sorting Task (WCST) is the most commonly used test in the examination of cognitive flexibility. Participants need to match the response card to the stimulus cards based on either colour, shape or number. The sorting rule changes after several consecutive correct matches without warning. (b) The Trail Making Test (TMT) is used to assess set-shifting. Participants need to link the circled numbers in sequence in part A, while linking alternating numbers and letters in order in part B. (c) The probabilistic reversal learning task is used to assess reversal learning. Participants need to learn that the two stimuli are associated with different levels of reward and generate preference for the stimulus with high reward. The reward–stimulus association will be reversed without warning once they learn the relationship. (d) The Brixton Spatial Anticipation Test focuses on reversal learning. Participants need to predict the position of the filled circle on the following page according to the rule learnt from the previous page. (e) The Iowa Gambling Task (IGT) is used to assess decision-making and flexibility. Participants are required to maximise profit by preferentially choosing cards from the advantageous over the disadvantageous card decks.

Figure 2

Cognitive tests for assessing cognitive flexibility in rodents. (a) The attentional set-shifting test (ASST) assesses both set-shifting and reversal learning. In the compound discrimination (CD), intradimensional shift (ID) and extradimensional shift (ED) stages, the rodent needs to switch attention either between two odours or between odour and digging medium to identify the reward-related stimulus. The ID and ED phases are thus used to assess set-shifting. The reward-stimulus association is changed in the reversal stages (Rev1,2,3) between the set-shifting stages (ID and ED) to assess reversal learning. (b) Reversal learning tasks can also be performed on a touchscreen. In the task, the rodents first learn to discriminate between the two visual stimuli and identify the one associated with reward. Once the reward-stimulus association is acquired by the rodent, it will be reversed, and the rodent needs to learn that the previously rewarded stimulus has become unrewarded and vice versa. (c) The Iowa gambling task (IGT) can be also used in rodents. In this task, rodents are required to choose between four nose-poke holes, varying in associated rewards and punishments. The advantageous choices are associated with less immediate rewards but short punishment time, whereas disadvantageous choices are associated with more immediate rewards but longer punishment time. CD: compound discrimination; Rev 1: first reversal; ID: intradimensional shift; Rev 2: second reversal; ED: extradimensional shift; Rev 3: third reversal.

Figure 3

Neural circuits and brain areas involved in AN. (a) The 5-HT and (b) DA circuits are shown to be disrupted in patients with AN, contributing to an (c) imbalance between the reward and control neurocircuits in AN. The activity of prefrontal regions that are responsible for cognitive control is enhanced, while the subcortical regions that regulate reward processing are hypoactive in individuals with AN. dlPFC: dorsolateral prefrontal cortex; mPFC: medial prefrontal cortex; NAc: nucleus accumbens, OFC: orbitofrontal cortex; VTA: ventral tegmental area.