Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women

Abstract

Objective: Alterations in serotonin signalling within the brain-gut axis have been implicated in the pathophysiology of irritable bowel syndrome (IBS) and is a treatment target. Acute tryptophan depletion (ATD) decreases brain serotonin (5-hydroxytryptamine; 5-HT) levels, and increases visceral perception and negative emotional bias in patients with IBS. The aim of the present study was to determine the effect of ATD on brain activity and connectivity during visceral stimuli in healthy women, and to compare the ATD-induced brain connectivity of an arousal circuit in female patients with IBS without ATD.

Methods: 12 healthy females (19-25 years) were studied under placebo (PLA) conditions and ATD. Functional MRI measurements were performed during a rectal barostat protocol, consisting of random non-painful and maximal tolerable distensions. Partial least squares analyses and structural equation modelling were used to evaluate the effect of ATD on functional and effective brain connectivity during distension. Results in healthy controls under ATD were compared with the effective connectivity of brain responses to 45 mm Hg rectal distension in 14 female patients with constipation-predominant IBS (IBS-C) (24-50 years).

Results: In healthy controls, ATD resulted in increased response of an extensive brain network to balloon distension, including the amygdala and nodes of emotional arousal and homeostatic afferent networks. The effect was greater during high inflation, suggesting greater engagement of the central serotonion system with more aversive visceral stimuli. Effective connectivity analysis revealed a profound effect of ATD on coupling between emotional arousal network nodes, resulting in loss of negative feedback inhibition of the amygdala. A near-identical pattern was identified in the patients with IBS-C.

Conclusions: The findings are consistent with an ATD-induced disinhibition of and increased connectivity within an emotional arousal network during aversive stimulation. Together with the previous demonstration of ATD-induced visceral hyperalgesia in healthy controls, and the near-identical effective connectivity pattern observed in patients with IBS-C, these findings suggest that dysregulation of this brain network may play a role in central pain amplification and IBS pathophysiology.

Figure 1

Hypothesised emotional arousal network. Anatomical projections among the nodes of the emotional arousal network are represented by unidirectional arrows. The model is based on Pezawas et al, Labus et al and Stein et al. Amyg, amygdala; iACC, infragenual cingulate cortex; omPFC, orbital medial prefrontal cortex; sACC. supragenual anterior cingulate cortex.

Figure 2

Individual rectal pressure values required to produce a sensation of mild urge (low) and maximal tolerable (high) during controlled rectal distension. Despite interindividual variation of individual thresholds, there was no overlap between low and high ratings.

Figure 3

Plot of the linear contrast weights (or design saliences) for the significant latent variable of the brain network. The y-axis represents the numerical weights for the contrast. Inflation conditions for placebo (PL) and during acute tryptophan depletion (ATD) are shown on the x-axis. The design saliences indicate that the network is characterised by an interaction between group (ATD, PL) and condition (low, high inflation). Although differences in brain activity due to the level of balloon inflation were observed in both groups, these differences were greater during ATD compared with PL. For details of the analysis, see the Methods section.

Figure 4

Estimated effective connectivity of the initial response in the hypothesised emotional arousal circuit during high inflation pressure with placebo (PLA) and acute tryptophan depletion (ATD) and in patients with constipation-predominant irritable bowel syndrome (IBS-C). The β coefficients (calculated in effective connectivity analysis) are depicted by the style and colour of the arrows. Solid arrows represent a parameter estimate that was considered statistically significantly different from zero, whereas dashed lines represent non-significant coefficients. Red arrows represent positive coupling whereas blue arrows represent negative coupling. The magnitude of the coefficients associated with each thickness is depicted. Amyg, amygdala; iACC, infragenual cingulate cortex; omPFC, orbital medial prefrontal cortex; sACC, supragenual anterior cingulate cortex. For details of the analysis, see the Methods section. For actual values of β coefficients, see tables 2 and 4.