Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa

Abstract

Individuals with anorexia nervosa (AN) engage in relentless restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest that altered eating is a consequence of dysregulated reward and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. An understanding of the neurobiology of this disorder is likely to be important for developing more effective treatments.

Figure 1

Positron emission tomography (PET) studies show altered DA and 5HT function in AN. (a) Comparison of DA D2/D3 receptor binding in one recovered AN (RAN) and one age-matched control woman (CW); Red line indicates level of the right anteroventral striatum;BP, binding potential; *BP = [(region of interest/cerebellum/-1]. (b)Correlation (Spearman [rho] coefficient) of Harm Avoidance Total Score and Dorsal Caudate [¹¹C]raclopride binding potential (BP) in recovered AN subjects; p value Bonferroni corrected.(c) Statistical parametric mapping analysis the of 4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine ([¹⁸F]MPPF) binding for the “clinically recovered AN (REC AN)-Control subjects” contrast. Increased 5-HT1A binding (represented by red) is seen in recovered and lean (not shown) AN in widespread regions including the right temporofrontal cortex, amygdala-parahippocampal complex and temporoparietal junction.

Figure 2

A hypothetical model illustrating the competition/cooperation between DA and 5-HT and the implications for AN. This model is based on previous models^– and shows the hypothetical interaction between 5-HT functional activity (aversive or inhibitory) and DA functional activity (reward or motivation).^, Measures of CSF metabolites suggest that recovered AN subjects have increased brain 5-HT and decreased brain DA. This suggests that individuals with AN may have a temperament that places them in the lower left quadrant of this model, supporting the hypothesis of a skew towards aversive or inhibitory responses, rather than reward and motivation.

Figure 3

Altered neurocircuitry of taste consumption and anticipation in AN revealed with fMRI. (a) Decreased taste-related (sucrose and water) BOLD response was found for recovered AN compared to control women (CW) in the left insula region of interest (ROI; highlighted in gray in axial view) and left ventral putamen (not shown). Corresponding time course of the BOLD signal as a mean of 16 AN and 16 CW in the left insula ROI is depicted. This suggests in AN the insula may not accurately encode gustatory signals, perhaps as part of a more widespread defect in interoceptive awareness, or perhaps encompassing altered ability to gauge satiety or hunger “set-points.” Insula responses may also be modulated by reward determination (e.g., in anterior ventral striatum circuits, specifically the nucleus accumbens) which may fail to properly recognize, scale, or modulate reward response in AN. (b) In support of altered interoceptive/reward processing, BOLD response is correlated with pleasantness rating for sucrose for control women in the left and right (not shown) insula but not for recovered AN (not shown). (c) In response to a taste reward conditioning task that has been associated with activation of dopamine reward circuits, computational model-derived data revealed ill underweight AN had greater brain response during anticipation of taste in the anteroventral striatum, insula, and prefrontal cortex compared to control women and obese (OB) women. These results suggest that brain reward circuits are more responsive to food stimuli in AN, but less responsive in obese women. The mechanism for this association is uncertain, but these brain reward response patterns could be biomarkers for the respective weight state.