A recent study published in Scientific Reports investigates the structural integrity and connectivity of white matter pathways in brain regions involved in olfactory processing among people with post-COVID olfactory dysfunction (OD). The research adds to growing evidence that the olfactory symptoms of COVID-19 can persist long after the acute infection, highlighting the need for effective management strategies for affected individuals.
Study design and participant details
The study enrolled 61 adults from the COVIDOM cohort, all of whom had a confirmed SARS-CoV-2 infection at least six months prior. To minimize confounding factors such as severe disease or intensive treatment, the researchers focused on individuals with mild, non-hospitalized infections. Exclusion criteria included pregnancy, MRI-incompatible implants, and claustrophobia.
Olfactory assessment and clinical data
Olfactory function was measured with the Sniffin’ Sticks test, and a threshold-discrimination-identification (TDI) score was calculated from its three components. Participants with a TDI score below 31 were categorized as having post-COVID OD (PC-OlfDys); those with normosmia after infection served as post-COVID normosmic (PC-N) controls.
Additional data collection included demographic information, medical history, the course of acute infection, and smoking status. Participants also rated their sense of smell on a 10-point scale before, during, and after infection. Psychological health and cognitive function were evaluated with the generalized anxiety disorder questionnaire (GAD-7), the patient health questionnaire (PHQ-8), and the Montreal Cognitive Assessment (MoCA).
Imaging methods
Diffusion tensor imaging, an advanced MRI technique, was employed to examine white matter microstructure. Tract-based spatial statistics (TBSS) provided voxelwise analyses of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). In addition, region-of-interest (ROI) analyses focused on olfactory-related brain regions. Statistical comparisons used the Mann-Whitney U-test for group differences and independent-samples t-tests for diffusion metrics between groups. Correlations between questionnaire data and diffusion metrics were assessed with Pearson’s method.
Key findings
Group differences were most evident in ROI analyses, while whole-brain TBSS did not reveal significant differences after multiple comparison corrections.
The PC-OlfDys group had a markedly reduced sense of smell during and after infection compared with the PC-N group. Parosmia, a distorted sense of smell, was reported by 38% of PC-OlfDys participants, with no reports of such changes in controls.
In the Sniffin’ Sticks test, the PC-N group outperformed the PC-OlfDys group on the TDI score.
Psychological health differed between groups: average PHQ-8 scores were 9 in PC-OlfDys versus 2 in PC-N, and average GAD-7 scores were 6 versus 1, respectively. MoCA scores showed no significant difference.
ROI analyses revealed neuroanatomical changes in olfactory circuits. Specifically, FA values in the left amygdala were higher in PC-OlfDys participants than in controls, while RD values in the right amygdala were elevated in PC-OlfDys. Other ROIs showed no significant diffusion changes.
No overall correlation emerged between the TDI score and diffusion metrics in the PC-OlfDys group. However, subtest scores for identification, discrimination, and threshold showed region-specific relationships with AD, MD, and RD in the anterior piriform cortex, left amygdala, and right putamen, respectively.
In controls, higher TDI scores correlated with certain diffusion metrics in the putamen and amygdala, while in PC-OlfDys participants, OD duration was positively correlated with AD in the left amygdala and MD in several left-sided olfactory regions.
Psychological symptoms also related to diffusion measures in PC-OlfDys: PHQ-8 and GAD-7 scores correlated with left putamen and left amygdala diffusion metrics in this group but not in controls.
Interpretation and implications
The study suggests that persistent OD after SARS-CoV-2 infection is associated with measurable changes in brain regions tied to olfactory processing, particularly the amygdala, piriform cortex, and putamen. The observed increases in FA may reflect adaptive myelination or reorganization of white matter pathways, while higher RD could indicate microstructural alterations or compromised myelin integrity. The authors caution that diffusion tensor imaging findings do not equate to neurodegeneration, but may indicate compensatory neural plasticity within olfactory circuits.
Moreover, longer OD duration correlated with greater diffusion abnormalities in key olfactory regions, and higher anxiety and depressive symptom scores were associated with these neural changes. While this suggests a bidirectional relationship between persistent olfactory loss and emotional well-being, causality remains to be established.
Limitations and future directions
The study’s ROI-based findings underscore the importance of targeted analyses to detect subtle brain changes when whole-brain analyses are inconclusive.
The cross-sectional design limits causal inferences about whether brain changes drive OD or result from it.
Future longitudinal studies are needed to track diffusion metrics over time and to determine whether interventions targeting olfactory function can modulate neural connectivity and improve quality of life.
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