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Acute tryptophan depletion alters the effective connectivity of emotional arousal circuitry during visceral stimuli in healthy women
  1. J S Labus1,
  2. E A Mayer1,
  3. J Jarcho1,
  4. L A Kilpatrick1,
  5. T O C Kilkens2,
  6. E A T Evers3,
  7. W H Backes4,
  8. R-J M Brummer5,
  9. M A van Nieuwenhoven5
  1. 1Center for Neurobiology of Stress, Department of Medicine, Physiology and Psychiatry, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
  2. 2Department of Psychiatry and Neuropsychology, University Hospital Maastricht, Maastricht, The Netherlands
  3. 3Department of Neuropsychology and Psychopharmacology, Maastricht University, Maastricht, The Netherlands
  4. 4Department of Radiology, University Hospital Maastricht, Maastricht, The Netherlands
  5. 5Department of Gastroenterology, University Hospital Örebro, Örebro, Sweden
  1. Correspondence to Dr M A van Nieuwenhoven, Department of Medicine, Division of Gastroenterology, Örebro University Hospital, 701 85 Örebro, Sweden; m.vannieuwenhoven{at}


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.

  • IBS
  • tryptophan depletion
  • visceral perception
  • fMRI
  • connectivity
  • brain–gut axis
  • brain imaging
  • brain/gut interaction
  • irritable bowel syndrome
  • neurogastroenterology
  • visceral sensitivity

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  • Funding Profileringsfonds University Hospital Maastricht.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Ethics Committee of the University Hospital Maastricht.

  • Provenance and peer review Not commissioned; externally peer reviewed.