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Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in patients with IBD
Jun Wang1,2, Guangyao Liu2,3, Kai Ai4, Pengfei Zhang1, Wenjing Huang1, and Jing Zhang2,3
1Second Clinical School, Lanzhou University, Lanzhou, China, 2Department of Magnetic Resonance, Lanzhou University Second Hospital, Lanzhou, China, 3Gansu Province Clinical Research Center for Functional and Molecular Imaging, Lanzhou University Second Hospital, Lanzhou, China, 4Department of clinical science, Philips Healthcare, Xi’an, China

Synopsis

Keywords: Neuroinflammation, fMRI

The etiology of IBD complicated with anxiety, depression and other psychological comorbidities is still unclear. The purpose of this study was to quantify neurotransmitter (GABA and Glx) in the medial prefrontal cortex (mPFC) of IBD patients with MEGA-PRESS spectroscopy and explore its relationship with clinical scores. We found that mPFC GABA+ and Glx concentration were significantly decreased in IBD patients and were associated with abdominal pain and depressive symptoms separately, suggesting psychological comorbidities in IBD patients were related to mPFC neurotransmitter dysregulation. It provides a new explanation for the neuropsychological mechanism of IBD in the development of the disease.

Introduction

Inflammatory bowel disease (IBD) is a kind of immune mediated gastrointestinal inflammatory disease [1]. The incidence rate is increasing year by year, affecting the health of about 7 million people around the world, and has become an important global health burden. The two main forms of IBD are ulcerative colitis (UC) and Crohn's disease (CD) [2]. The hypothetical cause of anxiety and depression is systemic low-grade neuroinflammation caused by IBD patients [3-6], but the mechanism is still unclear. Gamma-aminobutyric acid (GABA), as the main inhibitory neurotransmitter in human brain, has an important regulatory effect on brain function [7]. In vivo magnetic resonance spectroscopy (MRS) imaging can non-invasively detect the content of metabolites in human brain tissue [8]. This study aims to explore the mechanism of common psychological symptoms in IBD patients by examining changes in GABA and glutamate + glutamine (Glx) concentrations in mPFC in IBD patients and their relationship with pain and psychological comorbidities.

Materials and Methods

In this prospective study, 26 IBD patients (16 UC, 13 CD) and 26 age/sex-matched health controls were included. The Human Research Ethics Committee of Lanzhou University Second Hospital approved the study, and all participants gave informed written consent in accordance with the Helsinki Declaration. Data were collected using a 3.0 T MR scanner (Ingenia CX, Philips Healthcare, Netherlands) with 32 channel head coils. The edit MRS was obtained from voxels (30 × 30 × 20 mm3) in the medial prefrontal cortex (mPFC). MEGA-PRESS parameters are as follows: [TR]=2000 ms, [TE]=68 ms, Gaussian editing pulses at 1.89 parts per million (ppm) of the proton frequency (edit-ON) and 7.46 ppm (edit-OFF), 288 averages, 1024 acquisition points and VAPOR water suppression. MRS data were analyzed using Gannet 3.0.(http://www.gabamrs.com/) [9]. The measured GABA concentration using MEGA-PRESS protocol commonly referred to as GABA+ with the contribution from macromolecules. The contents of GABA+ and Glx in gray matter were evaluated by segmenting gray matter, white matter, and cerebrospinal fluid with spm12 toolbox.
Statistical analysis was performed using SPSS version 25.0 (IBM). The comparison of group differences was performed using a one-way ANOVA. Significant correlations between parameter data variables were examined by a two-tailed Pearson correlation. Subgroup analysis of UC and CD was performed. In addition, we used logistic regression to assess whether GABA +/Glx concentrations were able to identify IBD patients from normal individuals. A significance level of p < .05 was set.

Results

The results of clinical data are shown in Table 1. Volume-of-interest (VOI) of MRS was placed at mPFC, as shown in Fig. 1a. Mean and standard deviation of GM/WM/CSF were 58.1 ± 5%, 24.3 ± 6%, and 17.6 ± 4%, respectively. A typical GABA +/Glx spectra obtained from mPFC were shown in Fig. 1b, c. Table 2 shows the details of statistical differences between groups. There was no statistical difference between groups for GABA+/tCr. Compared with HC, the GABA+ concentration in mPFC decreased significantly in IBD subjects (shown in Fig. 2a and Fig. 2b). In subjects with IBD, the concentration of GABA+ was positively correlated with IBDQ (r = 0.380, p = 0.042) and SF-MPQ (r = 0.393, p = 0.035). At the same time, we compared Glx/tCr between groups and found that there were significantly different among them. Compared with HC, the Glx concentration decreased significantly (shown in Fig. 2e and Fig. 2f.). The Glx concentration was negatively correlated with HAMD score (r = -0.468, p = 0.011), and significantly positively correlated with disease duration (r = 0.418, p = 0.024). Receiver operating characteristic (ROC) curve analysis was performed to compare the ability of MRS to differentiate IBD from HCs. Overall, the classification performance was better based on GABA+ and Glx (Accuracy = 76.36 %, AUC = 0.763). Compared to GABA+ (Accuracy= 69.09%, AUC=0.699), Glx obtained better classification accuracy (Accuracy = 72.73%, AUC=0.743). Fig 3 shows the ROC curves and the corresponding AUC.

Discussion

In this study, we investigated the neurochemical transmitters’ abnormalities of mPFC in patients with IBD. The main findings were as follows: First, the levels of mPFC Glx and GABA+ in IBD patients decreased significantly, which was related to abdominal pain and depressive symptoms. These findings suggest that the hypothesis that emotional disorders in IBD patients are related to the imbalance of mPFC neurotransmitters. Secondly, we found that the classification model based on MRS can effectively distinguish IBD and HC, indicating that MRS is a potential biomarker. Use quantitative magnetic resonance spectroscopy to solve problems that may be related to symptoms [10, 11]. Above results are consistent with previous studies on chronic pain [12]. It indicates that the change of the level of GABA+ and Glx in mPFC is related to the intensity of pain and the patient's subjective experience of disease.

Conclusion

In conclusion, this study revealed a decrease trend in GABA+ and Glx levels in mPFC associated with clinical symptoms of IBD. These findings provide us a new insight into the neural mechanisms related to IBD. In the future, the results of intestinal microbiome and metabolome research will help us understand the potential rules of brain gut interaction in IBD patients. It also provides a broad prospect for us to find a treatment plan.

Acknowledgements

We are grateful to all the participants for their cooperation and patience.

References

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Figures

Data acquisition and MRS voxel placement for mPFC (a) cortices on a T1-weighted structural image and probabilistic partial volume voxel maps following tissue segmentation for a representative participant in the medial prefrontal cortex. (b) The gannet fit of an off-resonance spectrum from a MEGA-PRESS GABA editing sequence and used to calculate the GABA+ and glutamate signal for both groups.

Group difference and correlation between CSF-corrected GABA+ and Glx with clinical scores. a-b Case-control differences of GABA+ between groups. c-d Correlation between clinical scores and GABA+ concentration. e-f Case-control differences between groups. g-h Correlation between clinical scores and Glx concentration.

Receiver operating characteristic (ROC) curves of the logistic regression model, illustrating the predictive power of the model. The area under the ROC curve for a single variable, i.e. the effect of MRS as a biomarker for the diagnosis of IBD.

Data are presented as mean ± SD; Statistical significance was set to p < 0 .05.

Data are presented as mean ± SEM; Statistical significance was set to p < 0 .05.

Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)
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DOI: https://doi.org/10.58530/2023/0029