Dynamic recovery of piriform cortex function and its impact on cognitive processing speed following mild COVID-19

Abstract

Background: Although the neurological sequelae of severe COVID-19 are increasingly recognized, the long-term neural impact of uncomplicated mild SARS-CoV-2 infection remains insufficiently characterized. This study investigated post-infection alterations in piriform cortex activity, a region central to olfactory processing and integrative cognitive-emotional networks, and their associations with cognitive outcomes in adults. Methods: Fifty adults with pre- and post-SARS-CoV-2 magnetic resonance imaging (MRI) and clinical/neuropsychological data were analyzed. A demographically matched control group of 50 individuals without prior COVID-19 or vaccination was included. Resting-state functional MRI assessed amplitude of low-frequency fluctuations (ALFF) within the piriform cortex as an index of regional neural activity. Results: Baseline piriform ALFF did not differ between the two groups (p = 0.421). Following infection, piriform ALFF exhibited a significant quadratic trajectory (p = 0.003), characterized by early elevation relative to baseline, a decline to a nadir at approximately three months, and subsequent recovery toward baseline levels by six months. Greater acute COVID-19 symptom burden correlated with higher piriform ALFF (β = 0.34, p = 0.017). Elevated ALFF was associated with reduced processing speed (β = -0.52, p = 0.001). Mediation analysis demonstrated that piriform ALFF significantly mediated the relationship between symptom burden and processing speed (indirect effect b = -0.081, p = 0.037). Conclusions: Piriform cortex function demonstrated a dynamic, nonlinear pattern within six months after mild COVID-19, marked by early hyperactivity, later downregulation, and gradual normalization. Altered piriform activity mediated the association between symptom burden and processing speed deficits, suggesting transient post-infection neurophysiological disruption with potential relevance to cognitive symptoms. Longitudinal follow-up is warranted to clarify underlying mechanisms and long-term implications. © The Author(s) 2026.