Guido K. W. Frank

Altered brain reward circuits in eating disorders: chicken or egg?

The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are severe psychiatric disorders with high mortality. Our knowledge about the neurobiology of eating disorders is very limited, and the question remains whether alterations in brain structure or function in eating disorders are state related, remnants of the illness or premorbid traits. The brain reward system is a relatively well-characterized brain circuitry that plays a central role in the drive to eat and individuals with current or past eating disorders showed alterations in those pathways compared to controls. Here we propose that structural and functional alterations in the insula and frontal cortex, including orbitofrontal and cingulate regions, areas that contribute to reward and anxiety processing, could predispose to developing an eating disorder and that adaptive changes in those circuits in response to malnutrition or repeated binge eating and purging could further promote illness behavior, hinder recovery and contribute to relapse.

Advances from neuroimaging studies in eating disorders.

Over the past decade, brain imaging has helped to better define eating disorder-related brain circuitry. Brain research on gray matter (GM) and white matter (WM) volumes had been inconsistent, possibly due to the effects of acute starvation, exercise, medication, and comorbidity, but newer studies have controlled for such effects. Those studies suggest larger left medial orbitofrontal gyrus rectus volume in ill adult and adolescent anorexia nervosa after recovery from anorexia nervosa, and in adult bulimia nervosa. The orbitofrontal cortex is important in terminating food intake, and altered function could contribute to self-starvation. The right insula, which processes taste but also interoception, was enlarged in ill adult and adolescent anorexia nervosa, as well as adults recovered from the illness. The fixed perception of being fat in anorexia nervosa could be related to altered insula function. A few studies investigated WM integrity, with the most consistent finding of reduced fornix integrity in anorexia and bulimia nervosa-a limbic pathway that is important in emotion but also food intake regulation. Functional brain imaging using basic sweet taste stimuli in eating disorders during the ill state or after recovery implicated repeatedly reward pathways, including insula and striatum. Brain imaging that targeted dopamine-related brain activity using taste-reward conditioning tasks suggested that this circuitry is hypersensitive in anorexia nervosa, but hyporesponsive in bulimia nervosa and obesity. Those results are in line with basic research and suggest adaptive reward system changes in the human brain in response to extremes of food intake-changes that could interfere with normalization of eating behavior.

The medical complications associated with purging

OBJECTIVE Purging behaviors, including self-induced vomiting, laxative abuse, and diuretic abuse, are present across many of the eating disorders. Here we review the major medical complications of these behaviors. METHOD Although we identified over 100 scholarly articles describing medical complications associated with purging, most papers involved case studies or small, uncontrolled samples. Given the limited evidence base, we conducted a qualitative (rather than systematic) review to identify medical complications that have been attributed to purging behaviors. RESULTS Medical conditions affecting the teeth, esophagus, gastrointestinal system, kidneys, skin, cardiovascular system, and musculoskeletal system were identified, with self-induced vomiting causing the most medical complications. DISCUSSION Purging behavior can be associated with severe medical complications across all body systems. Mental health professionals should refer patients with purging behaviors to medical providers for screening and treatment as needed. The medical work-up for individuals with eating disorders should include a comprehensive metabolic panel, complete blood count, and a full body exam including the teeth to prevent severe complications. Medical providers should screen patients for purging behaviors and associated medical complications, even in the absence of an eating disorder diagnosis, to increase the detection of eating disorders. Recognizing the link between purging and medical complications can aid in identifying potential eating disorders, particularly those that often elude detection such as purging disorder.

The Perfect Storm - A Bio-Psycho-Social Risk Model for Developing and Maintaining Eating Disorders

The eating disorders (EDs), anorexia nervosa (AN), and bulimia nervosa (BN) are severe psychiatric disorders of unknown etiology. EDs usually begin during adolescence and occur most commonly in females (American Psychiatric Association, 2013). The diagnostic criteria for AN include restriction of energy intake leading to significantly low body weight, intense fear of gaining weight, or persistent behaviors that interfere with weight gain, and disturbance in the way ones body weight, or shape is experienced (American Psychiatric Association, 2013). A restricting type (AN-R), marked by food restriction and commonly over-exercising, has been distinguished from a binge-eating/purging type (AN-B/P), where afflicted individuals eat large amounts of food in a relatively short period of time (“binge eating”), or engage in behaviors to counteract weight gain, such as self-induced vomiting or use of laxatives, or diuretics (“purging”). BN individuals are usually at normal weight, and engage in recurrent binge eating and purging behavior at least once a week for at least 3 months. A new diagnosis, “binge eating disorder” (BED) is part of the ED diagnostic categories in DSM-5. BED is associated with regular binge eating episodes without compensatory mechanisms. Individuals with ED symptoms that do not meet full criteria for AN or BN were classified as ED not otherwise specified (NOS) in the past but now fall into the categories of “other specified feeding or eating disorders (OSFED)” or “unspecified feeding or eating disorder (UFED; American Psychiatric Association, 2013).”

Structural Neuroimaging of Anorexia Nervosa: Future Directions in the Quest for Mechanisms Underlying Dynamic Alterations

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and extreme weight loss. Pseudoatrophic brain changes are often readily visible in individual brain scans, and AN may be a valuable model disorder to study structural neuroplasticity. Structural magnetic resonance imaging studies have found reduced gray matter volume and cortical thinning in acutely underweight patients to normalize following successful treatment. However, some well-controlled studies have found regionally greater gray matter and persistence of structural alterations following long-term recovery. Findings from diffusion tensor imaging studies of white matter integrity and connectivity are also inconsistent. Furthermore, despite the severity of AN, the number of existing structural neuroimaging studies is still relatively low, and our knowledge of the underlying cellular and molecular mechanisms for macrostructural brain changes is rudimentary. We critically review the current state of structural neuroimaging in AN and discuss the potential neurobiological basis of structural brain alterations in the disorder, highlighting impediments to progress, recent developments, and promising future directions. In particular, we argue for the utility of more standardized data collection, adopting a connectomics approach to understanding brain network architecture, employing advanced magnetic resonance imaging methods that quantify biomarkers of brain tissue microstructure, integrating data from multiple imaging modalities, strategic longitudinal observation during weight restoration, and large-scale data pooling. Our overarching objective is to motivate carefully controlled research of brain structure in eating disorders, which will ultimately help predict therapeutic response and improve treatment.

Extremes of eating are associated with reduced neural taste discrimination.

OBJECTIVE Eating disorders are severe psychiatric disorders of unknown etiology. Understanding how neuronal function affects food choices could help personalize treatment based on brain function. Here we wanted to determine whether disordered eating behavior is associated with alterations in the primary taste cortexs ability to classify taste stimuli, which could interfere with taste reward processing. METHOD One-hundred and six women, 27 healthy comparison (age 26.15 ± 6.95 years), 21 with restricting-type anorexia nervosa (AN; age 23.10 ± 6.14 years), 19 recovered from restricting-type AN (recovered AN; age 26.95 ± 5.31 years), 20 with bulimia nervosa (BN; age 25.15 ± 5.31 years), and 19 with obesity (age 28.16 ± 8.13 years), received sucrose, control solution or no taste stimulation during functional magnetic resonance brain imaging. Multivariate Bayesian pattern analysis (decoding) and cross-validation tested taste classification accuracy (adjusted for comorbidity, medication use, taste perception, interoception, and brain activation volume). RESULTS For sucrose versus control solution, classification accuracy differed (F = 2.53, P < 0.041). Post hoc tests indicated higher classification accuracy in healthy comparison compared to women with AN (P < 0.016) or obesity (P < 0.027), and in recovered AN as compared to AN (P < 0.016) or obesity (P < 0.047) groups. Taste stimulation resulted in sparse insula voxel activation across all groups. DISCUSSION Reduced classification accuracy across stimuli in women with AN or obesity could indicate low brain encoding discrimination of stimulus quality, which could contribute to altered reward activation and eating drive that is not adjusted to nutritional needs. This deficit appears to normalize with recovery from AN, but adjusting food flavor intensity could aid in the treatment of individuals with AN or obesity.

The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa

OBJECTIVE Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. METHODS Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. RESULTS The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. DISCUSSION The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated.

Cortical thickness patterns as state biomarker of anorexia nervosa

OBJECTIVE Only few studies have investigated cortical thickness in anorexia nervosa (AN), and it is unclear whether patterns of altered cortical thickness can be identified as biomarkers for AN. METHOD Cortical thickness was measured in 19 adult women with restricting-type AN, 24 individuals recovered from restricting-type AN (REC-AN) and 24 healthy controls. Those individuals with current or recovered from AN had previously shown altered regional cortical volumes across orbitofrontal cortex and insula. A linear relevance vector machine-learning algorithm estimated patterns of regional thickness across 24 subdivisions of those regions. RESULTS Region-based analysis showed higher cortical thickness in AN and REC-AN, compared to controls, in the right medial orbital (olfactory) sulcus, and greater cortical thickness for short insular gyri in REC-AN versus controls bilaterally. The machine-learning algorithm identified a pattern of relatively higher right orbital, right insular and left middle frontal cortical thickness, but lower left orbital, right middle and inferior frontal, and bilateral superior frontal cortical thickness specific to AN versus controls (74% specificity and 74% sensitivity, χ2 p < .004); predicted probabilities differed significantly between AN and controls (p < .023). No pattern significantly distinguished the REC-AN group from controls. CONCLUSIONS Higher cortical thickness in medial orbitofrontal cortex and insula probably contributes to higher gray matter volume in AN in those regions. The machine-learning algorithm identified a mixed pattern of mostly higher orbital and insular, but relatively lower superior frontal cortical thickness in individuals with current AN. These novel results suggest that regional cortical thickness patterns could be state markers for AN.

Toward valid and reliable brain imaging results in eating disorders

Human brain imaging can help improve our understanding of mechanisms underlying brain function and how they drive behavior in health and disease. Such knowledge may eventually help us to devise better treatments for psychiatric disorders. However, the brain imaging literature in psychiatry and especially eating disorders has been inconsistent, and studies are often difficult to replicate. The extent or severity of extremes of eating and state of illness, which are often associated with differences in, for instance hormonal status, comorbidity, and medication use, commonly differ between studies and likely add to variation across study results. Those effects are in addition to the well-described problems arising from differences in task designs, data quality control procedures, image data preprocessing and analysis or statistical thresholds applied across studies. Which of those factors are most relevant to improve reproducibility is still a question for debate and further research. Here we propose guidelines for brain imaging research in eating disorders to acquire valid results that are more reliable and clinically useful.

Association of Brain Reward Learning Response With Harm Avoidance, Weight Gain, and Hypothalamic Effective Connectivity in Adolescent Anorexia Nervosa

Importance Anorexia nervosa (AN) is associated with adolescent onset, severe low body weight, and high mortality as well as high harm avoidance. The brain reward system could have an important role in the perplexing drive for thinness and food avoidance in AN. Objective To test whether brain reward learning response to taste in adolescent AN is altered and associated with treatment response, striatal-hypothalamic connectivity, and elevated harm avoidance. Design, Setting, and Participants In this cross-sectional multimodal brain imaging study, adolescents and young adults with AN were matched with healthy controls at a university brain imaging facility and eating disorder treatment program. During a sucrose taste classical conditioning paradigm, violations of learned associations between conditioned visual and unconditioned taste stimuli evoked the dopamine-related prediction error (PE). Dynamic effective connectivity during sweet taste receipt was studied to investigate hierarchical brain activation across the brain network that regulates eating. The study was conducted from July 2012 to May 2017, and data were analyzed from June 2017 to December 2017. Main Outcomes and Measures Prediction error brain reward response across the insula, caudate, and orbitofrontal cortex; dynamic effective connectivity between hypothalamus and ventral striatum; and treatment weight gain, harm avoidance scores, and salivary cortisol levels and their correlations with PE brain response. Results Of 56 female participants with AN included in the study, the mean (SD) age was 16.6 (2.5) years, and the mean (SD) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 15.9 (0.9); of 52 matched female controls, the mean (SD) age was 16.0 (2.8) years, and the mean (SD) BMI was 20.9 (2.1). Prediction error response was elevated in participants with AN in the caudate head, nucleus accumbens, and insula (multivariate analysis of covariance: Wilks &lgr;, 0.707; P = .02; partial &eegr;2 = 0.296), which correlated negatively with sucrose taste pleasantness. Bilateral AN orbitofrontal gyrus rectus PE response was positively correlated with harm avoidance (right &rgr;, 0.317; 95% CI, 0.091 to 0.539; P < .02; left &rgr;, 0.336; 95% CI, 0.112 to 0.550; P < .01) but negatively correlated with treatment BMI change (right &rgr;, −0.282; 95% CI, −0.534 to −0.014; P < .04; left &rgr;, −0.268; 95% CI, −0.509 to −0.018; P < .045). Participants with AN showed effective connectivity from ventral striatum to hypothalamus, and connectivity strength was positively correlated with insula and orbitofrontal PE response. Right frontal cortex PE response was associated with cortisol, which correlated with body dissatisfaction. Conclusions and Relevance These results further support elevated PE signal in AN and suggest a link between PE and elevated harm avoidance, brain connectivity, and weight gain in AN. Prediction error may have a central role in adolescent AN in driving anxiety and ventral striatal-hypothalamus circuit-controlled food avoidance.