Neural characterisation of persistent quantitative and qualitative COVID-19-related olfactory dysfunction: The COVORTS study

The mechanism underlying persistent COVID-19-related olfactory dysfunction (OD) remains unknown. There are indications for both peripheral (within the nose) and central (in the brain) mechanisms. Patients can experience a decrease in olfactory ability (quantitative OD) or a distorted odour perception (qualitative OD). The mechanisms might differ between these two symptom presentations. In this (f)MRI study, we investigated structural and functional brain alterations in patients with persistent (> 1 month) quantitative OD (Sniffin’ Sticks score < 30.75, n=21) or parosmia (self-reported, n=27) following SARS-CoV-2 infection, aged 19-60 years and, on average, included 472 days after diagnosis (the COVORTS study). Additionally, a control group of 49 normosmic subjects aged 22-60 years was included. Olfactory bulb volume (OBV) was determined by manual segmentation; whole-brain and regional grey matter density (GMD) of olfactory-related areas was assessed using voxel-based morphometry; and odour-induced brain activation was examined with an olfactory fMRI task. When grouped together, patients with OD had a smaller OBV than controls (84.4 vs 95.3 mm3, p =0.026). The two patient groups did not differ in OBV. ROI analysis of olfactory-related brain regions at an exploratory threshold showed lower GMD in primary and secondary olfactory regions in patients compared to controls, which appears to be mainly driven by quantitative OD. No difference in odour-induced brain activation was found. The observed smaller olfactory bulbs, along with modest findings beyond this primary olfactory structure, provide important insights into potential mechanisms of persistent COVID-19-related OD and highlight the need for longer follow-up to evaluate further neural degradation or recovery.