The effects of acute tryptophan depletion on instrumental reward learning in anorexia nervosa - an fMRI study

Abstract

Background: The serotonin (5-HT) hypothesis of anorexia nervosa (AN) posits that individuals predisposed toward or recovered from AN (recAN) have a central nervous hyperserotonergic state and therefore restrict food intake as a means to reduce 5-HT availability (via diminished tryptophan-derived precursor supply) and alleviate associated negative mood states. Importantly, the 5-HT system has also been generally implicated in reward processing, which has also been shown to be altered in AN.

Methods: In this double-blind crossover study, 22 individuals recAN and 25 healthy control participants (HC) underwent functional magnetic resonance imaging (fMRI) while performing an established instrumental reward learning paradigm during acute tryptophan depletion (ATD; a dietary intervention that lowers central nervous 5-HT availability) as well as a sham depletion.

Results: On a behavioral level, the main effects of reward and ATD were evident, but no group differences were found. fMRI analyses revealed a group × ATD × reward level interaction in the ventral anterior insula during reward anticipation as well as in the medial orbitofrontal cortex during reward consumption.

Discussion: The precise pattern of results is suggestive of a 'normalization' of reward-related neural responses during ATD in recAN compared to HC. Our results lend further evidence to the 5-HT hypothesis of AN. Decreasing central nervous 5-HT synthesis and availability during ATD and possibly also by dieting may be a means to normalize 5-HT availability and associated brain processes.

Keywords: Anorexia nervosa; acute tryptophan depletion; fMRI; reward; serotonin.

Fig. 1.

Instrumental motivation task. Instrumental motivation task during event-related functional MRI (fMRI). During the anticipation phase a visual cue was presented for 3 s to inform the participant about the reward level of this trial [reward levels: 0 (no reward), 1, 10, 100]. The motor (or instrumental) response phase started after a 2 s fixation period. Monetary reward per trial increased with reward level and higher effort and was determined by multiplying number of button presses × reward level × an individual adjustment factor (calculated based on the individual maximum #bp in the test run; for details see Bühler et al., 2010). Acoustic feedback for button presses was provided through headphones. After another fixation period of 4 s, feedback was provided for 3 s by displaying the amount of money gained in this trial and the cumulative amount. Between trials, participants fixated on crosshairs for 3 s (75%) or 7.44 s in 25% of all trials, which improves design efficiency by jittering. The fMRI main run had a total duration of 15.5 min and comprised 48 trials in total (4 reward levels × 12 pseudorandomized repetitions).

Fig. 2.

Behavioral data of both groups during both conditions. Each dot represents the mean value of one participant for each reward level (0, 1, 10, 100). The left panel shows the distribution of reaction times and the right one the number of button presses (plus smooth regression lines). DEPL = acute tryptophan depletion; SHAM = sham depletion; recAN = individuals with a history of AN; HC = healthy control participants.

Fig. 3.

(a) Results of the whole-brain voxelwise mixed model of the reward anticipation phase. Left: significant three-way interaction of group × depletion condition × reward level within the left ventral anterior insula (x = −39). Right: significant three-way interaction of intervention × group × reward level within the right ventral anterior insula (x = 39). FWE corrected with p < 0.05. (b) Mean activation in each group in each reward level (β estimates plus a smooth regression line) in the left and right ventral anterior insula during the reward anticipation phase at both time points (ATD and sham depletion). DEPL = acute tryptophan depletion; SHAM = sham depletion; recAN = individuals with a history of AN; HC = healthy control participants; BOLD = blood oxygen level dependent.

Fig. 4.

Results of the whole-brain voxelwise mixed model of the reward feedback phase. Left: Significant three-way interaction of group × depletion condition × reward level within the mOFC (x = 5). FWE corrected with p < 0.05. Right: Mean activation in each group for each reward level (β estimates plus a smooth regression line) in the mOFC during the reward feedback phase during both time points (ATD and sham depletion). mOFC = medial orbitofrontal cortex; DEPL = acute tryptophan depletion; SHAM = sham depletion; recAN = individuals with a history of AN; HC = healthy control participants; BOLD = blood oxygen level dependent.