A transdiagnostic and translational framework for delineating the neuronal mechanisms of compulsive exercise in anorexia nervosa

Abstract

Objective: The development of novel treatments for anorexia nervosa (AN) requires a detailed understanding of the biological underpinnings of specific, commonly occurring symptoms, including compulsive exercise. There is considerable bio-behavioral overlap between AN and obsessive-compulsive disorder (OCD), therefore it is plausible that similar mechanisms underlie compulsive behavior in both populations. While the association between these conditions is widely acknowledged, defining the shared mechanisms for compulsive behavior in AN and OCD requires a novel approach.

Methods: We present an argument that a better understanding of the neurobiological mechanisms that underpin compulsive exercise in AN can be achieved in two critical ways. First, by applying a framework of the neuronal control of OCD to exercise behavior in AN, and second, by taking better advantage of the activity-based anorexia (ABA) rodent model to directly test this framework in the context of feeding pathology.

Results: A cross-disciplinary approach that spans preclinical, neuroimaging, and clinical research as well as compulsive neurocircuitry and behavior can advance our understanding of when, why, and how compulsive exercise develops in the context of AN and provide targets for novel treatment strategies.

Discussion: In this article, we (i) link the expression of compulsive behavior in AN and OCD via a transition between goal-directed and habitual behavior, (ii) present disrupted cortico-striatal circuitry as a key substrate for the development of compulsive behavior in both conditions, and (iii) highlight the utility of the ABA rodent model to better understand the mechanisms of compulsive behavior relevant to AN.

Public significance: Individuals with AN who exercise compulsively are at risk of worse health outcomes and have poorer responses to standard treatments. However, when, why, and how compulsive exercise develops in AN remains inadequately understood. Identifying whether the neural circuitry underlying compulsive behavior in OCD also controls hyperactivity in the activity-based anorexia model will aid in the development of novel eating disorder treatment strategies for this high-risk population.

Keywords: activity‐based anorexia; anorexia nervosa; compulsive exercise; cortico‐striatal circuits; obsessive‐compulsive disorder.

Figure 1.. Genetic and phenotypic overlap between anorexia nervosa (AN) and obsessive-compulsive disorder (OCD).

Both AN and OCD are hallmarked by repetitive and inflexible patterns of thoughts and behaviors with shared pathological features including increased compulsivity and habit reliance, indicating a clear similarity in presentation across disorders. There are also substantial rates of co-morbidity, with genetic studies revealing high genetic correlations and sizeable single nucleotide polymorphism (SNP) heritability. Articles referenced are specifically in relation to the AN population (Frank, 2021; Kaye et al., 2013; Salbach-Andrae et al., 2008; Steding et al., 2019; Yilmaz et al., 2020; Yilmaz et al., 2022).

Figure 2.. Temporal and regional changes in striatal activation throughout the development of compulsive exercise.

The progression of hyperactivity in anorexia nervosa (AN) and activity-based anorexia (ABA) (A) is hallmarked by a decrease in body weight and fat mass (B) as food restriction and exercise becomes increasingly excessive or “compulsive.” These behaviors that seemingly start as goal-oriented, eventually transition to habitual, and then subsequently become impaired (compulsive). This change in the rewarding properties of these behaviors such as food intake may be due to a slow decline in ventral striatal dysfunction (C – as food reward is altered during illness progression) while behaviors that are required to be more goal-driven like exercise may be impeded by alterations in dorsal striatal function. For example, the typical transition from dorsomedial to dorsolateral striatal activation that underlies the consolidation of a skill (D) may develop abnormally, with the dorsomedial striatum becoming over-engaged (E – additional peak when goal directed control is impaired) to exert excessive cognitive control and/or elicit compulsive behavior.

Figure 3.. Bridging the translational gap between preclinical and clinical research in anorexia nervosa (AN).

Using the framework of neural circuitry involved in the generation of compulsive behavior in obsessive-compulsive disorder (i.e. the neural circuits that make up the basal ganglia, including subregions of the cortex, striatum and ventral midbrain) and applying this to wheel running in activity-based anorexia (ABA) rats (A) will inform the targeted treatment of compulsive exercise in anorexia nervosa, that has shown differential activation in the human equivalents of these brain regions (D). Advanced genetic tools in awake, freely-moving animals allow the measurement (i.e. using in vivo fiber photometry; see (B) and manipulation (i.e. chemogenetics and optogenetics) of specific circuitries in order to assess their casual role in executive functions relevant to compulsivity (i.e., behavioral inhibition, impulsivity, reward processing and cognitive flexibility), preferably using touchscreen-based cognitive tasks in rodents (C) that are equivalent to human cognitive tasks (E). The translation of these findings could aid in the development of precision medicines including multisite pharmacotherapy, or the refinement of neuromodulatory treatments such as transcranial magnetic stimulation, both of which can be tailored to individual patients based on clinical subtypes (F). Brain regions of interest (see A for the analogous regions in the rat brain relevant to those regions that have been shown to have altered function in human anorexia nervosa in D): mPFC; medial prefrontal cortex, OFC; orbitofrontal cortex, dlPFC; dorsolateral prefrontal cortex, DMS; dorsomedial striatum, DLS; dorsolateral striatum, NAc; nucleus accumbens, VS; ventral striatum, SN; substantia nigra, VTA; ventral tegmental area.