Changes in the Intranetwork and Internetwork Connectivity of the Default Mode Network and Olfactory Network in Patients with COVID-19 and Olfactory Dysfunction

Abstract

Olfactory dysfunction (OD) is a common symptom in coronavirus disease 2019 (COVID-19) patients. Moreover, many neurological manifestations have been reported in these patients, suggesting central nervous system involvement. The default mode network (DMN) is closely associated with olfactory processing. In this study, we investigated the internetwork and intranetwork connectivity of the DMN and the olfactory network (ON) in 13 healthy controls and 22 patients presenting with COVID-19-related OD using independent component analysis and region of interest functional magnetic resonance imaging (fMRI) analysis. There was a significant correlation between the butanol threshold test (BTT) and the intranetwork connectivity in ON. Meanwhile, the COVID-19 patients with OD showed significantly higher intranetwork connectivity in the DMN, as well as higher internetwork connectivity between ON and DMN. However, no significant difference was found between groups in the intranetwork connectivity within ON. We postulate that higher intranetwork functional connectivities compensate for the deficits in olfactory processing and general well-being in COVID-19 patients. Nevertheless, the compensation process in the ON may not be obvious at this stage. Our results suggest that resting-state fMRI is a potentially valuable tool to evaluate neurosensory dysfunction in COVID-19 patients.

Keywords: COVID; default mode network; functional connectivity; olfactory dysfunction; olfactory network; resting-state fMRI.

Figure 1

Flow diagram showing the subject recruitment process in this study.

Figure 2

Olfactory network (ON) and default mode network (DMN) of this cohort. (A) ON (left caudate nuclei (−9, 15, 0) as seed), (B) DMN (left precuneus (−6, −57, 18) as seed). FDR correction, p < 0.05, voxel size > 2700 mm³.

Figure 3

(A) A total of 31 ROIs from ON and (B) 37 ROIs from DMN are used for ROI-wise analysis between/within ON and DMN.

Figure 4

Schematic representation of the comparison of average intra- and inter-network connectivity in ON and DMN between COVID patients and healthy adults. Each subject has a 68 × 68 functional connectivity matrix. The values in the blue triangle indicate the correlation coefficients between pairs of the 31 regions within the ON, and in the green triangle represent the functional connectivity between the corresponding regions in DMN (37 regions). Voxels in the purple rectangle illustrate the functional connections between regions in ON and regions in DMN. In healthy control and patients, the comparison of (A) average intranetwork connectivity in ON; (B) average internetwork connectivity between ON and DMN and (C) average intranetwork connectivity in DMN. (Error bar shows the standard deviation of measurements, * indicates that p < 0.05).

Figure 5

Scatter plot showing correlation between the average intranetwork connectivity in olfactory network and butanol threshold test (BTT) (r = 0.499 *, p = 0.025); smell identification test (SIT) (r = 0.367, p = 0.112) in COVID-19 patients.