title: 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.
authors.affiliation: Center for Neurobiology of Stress, Department of Medicine, Physiology and Psychiatry, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Labus
authors.forename: E A
authors.initials: EA
authors.lastname: Mayer
authors.forename: J
authors.initials: J
authors.lastname: Jarcho
authors.forename: L A
authors.initials: LA
authors.lastname: Kilpatrick
authors.forename: T O C
authors.initials: TO
authors.lastname: Kilkens
authors.forename: E A T
authors.initials: EA
authors.lastname: Evers
authors.forename: W H
authors.initials: WH
authors.lastname: Backes
authors.forename: R-J M
authors.initials: RJ
authors.lastname: Brummer
authors.forename: M A
authors.initials: MA
authors.lastname: van Nieuwenhoven
mesh_terms: D000328:Adult; D000679:Amygdala / Q000503:physiopathology; D001143:Arousal / Q000502:physiology*; D001921:Brain / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D004106:Dilatation; D004644:Emotions / Q000502:physiology*; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D009415:Nerve Net / Q000503:physiopathology; D010812:Physical Stimulation / Q000379:methods; D011312:Pressure; D012007:Rectum / Q000503:physiopathology; D012684:Sensory Thresholds / Q000502:physiology; D014364:Tryptophan / Q000172:deficiency*; D055815:Young Adult
chemical_list: D014364:Tryptophan