Whole-brain functional connectivity identification of functional dyspepsia

Abstract

Recent neuroimaging studies have shown local brain aberrations in functional dyspepsia (FD) patients, yet little attention has been paid to the whole-brain resting-state functional network abnormalities. The purpose of this study was to investigate whether FD disrupts the patterns of whole-brain networks and the abnormal functional connectivity could reflect the severity of the disease. The dysfunctional interactions between brain regions at rest were investigated in FD patients as compared with 40 age- and gender- matched healthy controls. Multivariate pattern analysis was used to evaluate the discriminative power of our results for classifying patients from controls. In our findings, the abnormal brain functional connections were mainly situated within or across the limbic/paralimbic system, the prefrontal cortex, the tempo-parietal areas and the visual cortex. About 96% of the subjects among the original dataset were correctly classified by a leave one-out cross-validation approach, and 88% accuracy was also validated in a replication dataset. The classification features were significantly associated with the patients' dyspepsia symptoms, the self-rating depression scale and self-rating anxiety scale, but it was not correlated with duration of FD patients (p>0.05). Our results may indicate the effectiveness of the altered brain functional connections reflecting the disease pathophysiology underling FD. These dysfunctional connections may be the epiphenomena or causative agents of FD, which may be affected by clinical severity and its related emotional dimension of the disease rather than the clinical course.

Figure 1. Whole-brain functional connectivity discriminates between functional dyspepsia patients and healthy controls within the original samples.

(A) Classification accuracy of patients vs. controls as a function of the significance levels for the permutation test (0.05∼0.00001). Maximum accuracy (83.75%) was achieved at the level of 0.01. (B) Receiver operating characteristic curve based on the level of 0.01. (C) Classification accuracy with the change of the overlap thresholds (100%∼85%) at the significance level of 0.01. AUC, area under receiver operating characteristic curve.

Figure 2. Relative errors of clinical variables showing predictive power of abnormal functional connections at different overlap thresholds (100%, 95%, 90% and 85%).

The duration was poorly predicted at all thresholds and the best prediction of other variables was achieved at the threshold of 90%. NDI, Nepean dyspepsia index; SDS, self-rating depression scale; SAS, self-rating anxiety scale.

Figure 3. Abnormal functional network based on significance level 0.01 and overlap threshold of 90%.

The nodal weights were scaled by the frequency of occurrences in aberrant connections. The biggest region was observed in the right dorsolateral part of the frontal superior gyrus (BA9).

Figure 4. Characteristic patterns of abnormal functional connections within or across each cortical structure including (A) limbic/paralimbic system, (B) prefrontal cortex, (C) tempo-parietal areas and (D) visual cortex.

Dots represent abnormal connections in FD patients. R-value is the coefficient of correlation between functional connectivity and quality of life score, and the length is the Euclidean distance.

Figure 5. Relationship between connectivity severity index (CSI) and clinical measurements including (A) NDI symptom score, (B) SDS, (C) SAS, and (D) duration.

The partial correlation (PC) between CSI and NDI symptom score persisted while controlling for the SDS and SAS, but the correlation between SAS/SDS and CSI disappeared with the NDI symptom score as a covariate. No significant association was found between the CSI and duration. NDI, Nepean dyspepsia index; SDS, self-rating depression scale; SAS, self-rating anxiety scale; r, correlation coefficient.