Synopsis

The aim was to investigate whether Glutamate and GABA concentrations were altered in the rACC in patients with IBS compared to healthy controls, and to investigate if the GABA and Glutamate concentrations were associated with the level of anxiety in IBS patients. We observed higher rACC GABA+ concentrations in IBS patients, whereas Glx concentrations remained unaltered. Moreover, the changes in GABA concentrations were most pronounced in patients with high severity of anxiety. Thus, our findings provide first evidence of dysregulated rACC GABAergic neurotransmission in IBS, and suggest that altered inhibitory neurotransmission may be linked to comorbid anxiety in IBS patients.

Introduction

Irritable bowel syndrome (IBS) is a common chronic visceral pain disorder that is characterized by abdominal pain and irregular bowel habits in the absence of an identifiable organic cause [1]. IBS is considered an exemplary disease of brain-gut communication and a key role of psychological comorbidities with anxiety and depression, which affect a large portion of patients, is increasingly acknowledged in IBS pathophysiology. In this study, we were inspired by the theory of IBS as a disorder of the brain-gut communication [2,3]. Moreover, functional Magnetic Resonance Imaging (fMRI) studies have shown aberrant function in brain regions associated with emotion processing and regulation in patients with IBS [4]. Given that the changes in brain function are most consistently observed in the rostral anterior cingulate cortex (rACC), which is involved in emotion regulation and top-down corticolimbic inhibitory control [4-5], rACC may be the link between gastrointestinal complaints and psychological symptoms in IBS. Therefore, Magnetic Resonance Spectroscopy (MRS), which is a non-invasive method for metabolite quantification, would be a helpful tool to investigate altered rACC neurotransmission in IBS patients.

The purpose of this work was to investigate whether excitatory (glutamate) and inhibitory (GABA) neurotransmitter concentrations were altered in the rACC in patients with IBS compared to healthy controls. Furthermore, and to investigate if the GABA and Glutamate concentrations were associated with the level of anxiety and depression in the IBS patients compared to the healthy controls.

Materials and Methods

37 female IBS patients and 19 age-matched healthy females underwent an MRS examination using a 3 T Philips Ingenia MR scanner equipped with a 32-channel head coil. Following structural T1 weighted MRI used for voxel placement, data were acquired using a Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) pulse sequence [6-8] (TR/TE = 2000/68 ms, 40 dynamics each consisting of 8 phase cycle steps, edited pulse ON at 1.90 ppm, edited pulse OFF at 7.46 ppm, water suppression MOIST) with the voxel (30x30x30 mm³) placed in the rACC region (Fig. 1A). Directly afterwards, an unsuppressed water reference measurement (2 dynamics, no water suppression) was collected within the same voxel, which was used for water scaling and phase correction. The MRS data were phase corrected [9] using the water reference and frequency aligned based on the water residual in the water suppressed MRS data. The average OFF spectrum was subtracted from the average ON spectrum, which generated a resulting difference spectrum that revealed the GABA signal at 3 ppm (Fig. 1B). This difference spectrum was used as input to LCModel (Version 6.3-1L) to compute the GABA+ concentration (GABA plus coedited macromolecular signal). Solely the OFF spectra were average and used as input to LCModel when computing the Glx (combined Glutamate and Glutamine) concentrations (Fig. 1B).

The Hospital Anxiety and Depression Scale (HADS) [10] was used to assess the level of anxiety and depression in both patients and healthy controls. Furthermore, subgroup analyses (two groups; one with and one without high severity of psychological symptoms) were performed to find any associations between rACC neurotransmitter concentrations and anxiety and depression severity.

Result

Patients with IBS exhibited significantly higher HADS scores (both p < 0.001) and higher rACC GABA+ concentrations (p = 0.04) compared with healthy controls. However, there was no significant difference in Glx concentrations (p > 0.4) between the two groups (Fig.2).

The patient group was split into two subgroups depending on high (IBS+) and low (IBS-) anxiety scores. This analysis revealed a higher GABA+ in patients with higher anxiety scores compared to healthy controls (Fig. 3).

Discussion

Conclusion

Acknowledgements

References

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