Anorexia nervosa is a complex psychiatric illness associated with food restriction and high mortality. Recent brain research in adolescents and adults with anorexia nervosa has used larger sample sizes compared with earlier studies and tasks that test specific brain circuits. Those studies have produced more robust results and advanced our knowledge of underlying biological mechanisms that may contribute to the development and maintenance of anorexia nervosa. It is now recognized that malnutrition and dehydration lead to dynamic changes in brain structure across the brain, which normalize with weight restoration. Some structural alterations could be trait factors but require replication. Functional brain imaging and behavioral studies have implicated learning-related brain circuits that may contribute to food restriction in anorexia nervosa. Most notably, those circuits involve striatal, insular, and frontal cortical regions that drive learning from reward and punishment, as well as habit learning. Disturbances in those circuits may lead to a vicious cycle that hampers recovery. Other studies have started to explore the neurobiology of interoception or social interaction and whether the connectivity between brain regions is altered in anorexia nervosa. All together, these studies build upon earlier research that indicated neurotransmitter abnormalities in anorexia nervosa and help us develop models of a distinct neurobiology that underlies anorexia nervosa.

Eating disorders are severe psychiatric illnesses with a typical age of onset in adolescence. Brain research in youth and young adults may help us identify specific neurobiology that contributes to onset and maintenance of those disorders. This article provides a state-of-the-art review of our current understanding of the neurobiology of anorexia nervosa and bulimia nervosa. This includes brain structure and function studies to understand food restriction, binge-eating or purging behaviors, cognitive and emotional factors, as well as interoception. Binge-eating disorder and avoidant restrictive food intake disorder are also discussed, but the literature is still very small.

Endurance or aerobic exercise has many physical and mental health benefits, but less is known about the specific impact that cardiovascular activity may have on dopamine-associated brain circuits involved in reward processing and mood regulation in humans. Understanding such effects will help to explain individual differences in both exercise uptake and maintenance. This study evaluated neural response to a classical taste-conditioning reward prediction error task with the use of functional magnetic resonance imaging, along with data on self-reported aerobic exercise among healthy young adult females (N = 111). Results indicated positive associations between reported aerobic exercise and regional brain response that remained significant after multiple comparison correction for the right medial orbital frontal cortex response to unexpected sucrose receipt (r = 0.315, p = .0008). The medial orbitofrontal cortex is implicated in reward and outcome value computation and the results suggest that aerobic exercise may strengthen this circuitry, or reciprocally, higher orbitofrontal cortical activity may reinforce exercise behavior. The findings aid in developing a model of how exercise engagement can modify reward-circuit function and could be used therapeutically in conditions associated with altered brain salience response.

Anxious traits are elevated in eating disorders (EDs), are considered risk factors for ED development, and trait anxiety has been linked to ED psychopathology. How trait anxiety relates to ED neurobiology is not well understood. In this study 197 individuals across the ED spectrum (anorexia nervosa n = 91; other specified EDs n = 34; bulimia nervosa n = 56; binge ED n = 16), and 120 healthy controls were assessed for anxious traits and learned to expect and receive caloric or neutral taste stimuli during brain imaging. Amygdala sucrose expectation response differed across groups (Wilk's lambda = 0.945, p = 0.023), and was higher on the left in anorexia nervosa compared to healthy controls (p = 0.002). Expected sucrose receipt response across taste reward regions was not different between groups. In the ED sample, trait anxiety negatively moderated the relationship between amygdala expectation and right dorsal (p = 0.0062) and ventral (p = 0.0046) anterior insula receipt response. A subgroup analysis showed similar results for anorexia nervosa, and partially in bulimia nervosa. Across EDs, appetitive motivation correlated positively with bilateral orbitofrontal cortex, caudate head, and ventral striatal sucrose receipt response (r = 0.215 to 0.179, p = 0.002 to 0.012). Across the study sample, trait anxiety showed an inverted-U-shaped relationship with right (r = 0.147, p = 0.034) and left (r = 0.162, p = 0.016) amygdala expectation response. Amygdala sucrose expectation response is elevated in anorexia nervosa, correlates with sucrose receipt response, and this relationship is negatively moderated by trait anxiety across EDs. Trait anxiety may have an important role in how expectation drives taste stimulus receipt brain response and perhaps food approach in individuals with EDs.

Importance

Eating disorders are severe psychiatric disorders; however, disease models that cross subtypes and integrate behavior and neurobiologic factors are lacking.

Objective

To assess brain response during unexpected receipt or omission of a salient sweet stimulus across a large sample of individuals with eating disorders and healthy controls and test for evidence of whether this brain response is associated with the ventral striatal-hypothalamic circuitry, which has been associated with food intake control, and whether salient stimulus response and eating disorder related behaviors are associated.

Design, setting, and participants

In this cross-sectional functional brain imaging study, young adults across the eating disorder spectrum were matched with healthy controls at a university brain imaging facility and eating disorder treatment program. During a sucrose taste classic conditioning paradigm, violations of learned associations between conditioned visual and unconditioned taste stimuli evoked the dopamine-related prediction error. Dynamic effective connectivity during expected sweet taste receipt was studied to investigate hierarchical brain activation between food intake relevant brain regions. The study was conducted from June 2014 to November 2019. Data were analyzed from December 2019 to February 2020.

Main outcomes and measures

Prediction error brain reward response across insula and striatum; dynamic effective connectivity between hypothalamus and ventral striatum; and demographic and behavior variables and their correlations with prediction error brain response and connectivity edge coefficients.

Results

Of 317 female participants (197 with eating disorders and 120 healthy controls), the mean (SD) age was 23.8 (5.6) years and mean (SD) body mass index was 20.8 (5.4). Prediction error response was elevated in participants with anorexia nervosa (Wilks λ, 0.843; P = .001) and in participants with eating disorders inversely correlated with body mass index (left nucleus accumbens: r = -0.291; 95% CI, -0.413 to -0.167; P < .001; right dorsal anterior insula: r = -0.228; 95% CI, -0.366 to -0.089; P = .001), eating disorder inventory-3 binge eating tendency (left nucleus accumbens: r = -0.207; 95% CI, -0.333 to -0.073; P = .004; right dorsal anterior insula: r = -0.220; 95% CI, -0.354 to -0.073; P = .002), and trait anxiety (left nucleus accumbens: r = -0.148; 95% CI, -0.288 to -0.003; P = .04; right dorsal anterior insula: r = -0.221; 95% CI, -0.357 to -0.076; P = .002). Ventral striatal to hypothalamus directed connectivity was positively correlated with ventral striatal prediction error in eating disorders (r = 0.189; 95% CI, 0.045-0.324; P = .01) and negatively correlated with feeling out of control after eating (right side: r = -0.328; 95% CI, -0.480 to -0.164; P < .001; left side: r = -0.297; 95% CI, -0.439 to -0.142; P = .001).

Conclusions and relevance

The results of this cross-sectional imaging study support that body mass index modulates prediction error and food intake control circuitry in the brain. Once altered, this circuitry may reinforce eating disorder behaviors when paired with behavioral traits associated with overeating or undereating.

The prediction error model is a widely used paradigm that is conceptually based on neuronal dopamine function. However, whether dopamine receptor gene alleles contribute to human neuroimaging prediction error results is uncertain. Recent research implicated the dopamine D2 receptor in behavior response during a prediction error paradigm and we expected that polymorphisms of that receptor would contribute to prediction error brain response. In this study, healthy female participants in the early follicular phase of the menstrual cycle underwent a taste prediction error paradigm during functional magnetic resonance imaging. Participants were also genotyped for dopamine receptor polymorphisms. Our data suggest that the dopamine D2 receptor -141C Ins/Del and Taq1A polymorphisms together with body mass index selectively explain putamen prediction error response. This was true using a region of interest analysis as well as for a whole-brain analysis (FWE corrected). Polymorphisms for dopamine D1 or D4 receptors, dopamine transporter, or COMT did not significantly contribute to prediction error activation. The prediction error model is a computational reward-learning paradigm that is important in psychiatric research and has been associated with dopamine. The results from this study indicate that dopamine D2 receptor polymorphisms together with body mass index are important determinants to include in research that tests prediction error response of the brain. Psychiatric disorders are frequently associated with elevated or reduced body weight. Adding BMI to genetic information in brain-imaging studies that use reward and the prediction error paradigm may be important to increase validity and reliability of results.

Objective

The neurobiological underpinnings of anorexia nervosa (AN) are poorly understood. In this study, we tested whether brain gray matter (GM) and white matter (WM) in adolescents with AN would show alterations comparable to those in adults.

Method

We used magnetic resonance imaging to study GM and WM volume, and diffusion tensor imaging to assess fractional anisotropy for WM integrity in 19 adolescents with AN and 22 controls.

Results

Individuals with AN showed greater left orbitofrontal, right insular, and bilateral temporal cortex GM, as well as temporal lobe WM volumes compared to controls. WM integrity in adolescents with AN was lower (lower fractional anisotropy) in fornix, posterior frontal, and parietal areas, but higher in anterior frontal, orbitofrontal, and temporal lobes. In individuals with AN, orbitofrontal GM volume correlated negatively with sweet taste pleasantness. An additional comparison of this study cohort with adult individuals with AN and healthy controls supported greater orbitofrontal cortex and insula volumes in AN across age groups.

Conclusions

This study indicates larger orbitofrontal and insular GM volumes, as well as lower fornix WM integrity in adolescents with AN, similar to adults. The pattern of larger anteroventral GM and WM volume as well as WM integrity, but lower WM integrity in posterior frontal and parietal regions may indicate that developmental factors such as GM pruning and WM growth could contribute to brain alterations in AN. The negative correlation between taste pleasantness and orbitofrontal cortex volume in individuals with AN could contribute to food avoidance in this disorder.

Despite the prevalence of obesity, our understanding of its neurobiological underpinnings is insufficient. Diffusion weighted imaging and calculation of white matter connection strength are methods to describe the architecture of anatomical white matter tracts. This study is aimed to characterize white matter architecture within taste-reward circuitry in a population of obese individuals. Obese (n = 18, age = 28.7 ± 8.3 years) and healthy control (n = 24, age = 27.4 ± 6.3 years) women underwent diffusion weighted imaging. Using probabilistic fiber tractography (FSL PROBTRACKX2 toolbox) we calculated connection strength within 138 anatomical white matter tracts. Obese women (OB) displayed lower and greater connectivity within taste-reward circuitry compared to controls (Wilks' λ < 0.001; p < 0.001). Connectivity was lower in white matter tracts connecting insula, amygdala, prefrontal cortex (PFC), orbitofrontal cortex (OFC) and striatum. Connectivity was greater between the amygdala and anterior cingulate cortex (ACC). This study indicates that lower white matter connectivity within white matter tracts of insula-fronto-striatal taste-reward circuitry are associated with obesity as well as greater connectivity within white matter tracts connecting the amygdala and ACC. The specificity of regions suggests sensory integration and reward processing are key associations that are altered in and might contribute to obesity.

Objective

To investigate brain white matter (WM) functionality in bulimia nervosa (BN) in relation to anxiety.

Method

Twenty-one control women (CW, mean age 27 ± 7 years) and 20 BN women (mean age 25 ± 5 years) underwent brain diffusion tensor imaging to measure fractional anisotropy (FA; an indication of WM axon integrity) and the apparent diffusion coefficient (ADC; reflecting WM cell damage).

Results

FA was decreased in BN in the bilateral corona radiata extending into the posterior limb of the internal capsule, the corpus callosum, the right sub-insular WM, and right fornix. In CW but not BN, trait anxiety correlated negatively with fornix, corpus callosum, and left corona radiata FA. ADC was increased in BN compared with CW in the bilateral corona radiata, corpus callosum, inferior fronto-occipital, and uncinate fasciculus. Alterations in BN WM functionality were not due to structural brain alterations.

Discussion

WM integrity is disturbed in BN, especially in the corona radiata, which has been associated with taste and brain reward processing. Whether this is a premorbid condition or an effect from the illness is yet uncertain. The relationships between WM FA and trait anxiety in CW but not BN may suggest that altered WM functionality contributes to high anxious traits in BN.

Background

Cognitive disturbances such as impairments in learning are thought to play a role in adult Anorexia Nervosa (AN). It is remains unclear to what extent these disturbances result from starvation of the brain, or relate to an abnormal premorbid cognitive profile. This study investigates learning processes in adolescents with AN, hypothesizing that implicit learning is intact, as found previously in explicit learning tasks. Secondly, we hypothesized that anxiety and depression symptoms, inherent to AN, are associated to learning processes in AN.

Methods

In total 46 adolescents diagnosed with AN and 44 control participants were administered an implicit category learning task in which they were asked to categorize simple perceptual stimuli (Gabor patches) based on a linear integration (i.e., an implicit task) of orientation and spatial frequency of the stimulus. A subgroup of adolescents (n = 38) also completed a task assessing explicit learning.

Results

Model-based analyses indicated that adolescents with AN performed significantly more accurately compared to their healthy peers regardless of whether they used the optimal strategy or not. Depression and anxiety did not relate to learning performance in the AN group.

Conclusions

Overall, our findings of augmented implicit and explicit learning in adolescents with AN corroborate recent studies that suggested higher stimulus-response learning during prediction error paradigms. Learning disturbances in adult AN may then be at least partly due to long-term malnourishment, highlighting the importance of early recognition and refeeding in treatments for AN.