New insights into long COVID: brain changes linked to persistent smell loss
Researchers have found measurable differences in brain regions tied to emotion and sensory processing in people who continue to experience olfactory dysfunction (OD) long after a mild COVID-19 infection. The study, published in Scientific Reports, used diffusion tensor imaging (DTI) to explore white matter integrity and connectivity in olfactory-related networks, shedding light on the neural underpinnings of long COVID symptoms beyond the nasal realm.
What the study looked at
The investigation focused on individuals with mild, non-hospitalized COVID-19, aiming to minimize confounding factors associated with severe disease or intensive treatment. A total of 61 participants from the COVIDOM study, all with laboratory-confirmed SARS-CoV-2 infection at least six months prior, were examined. Olfactory function was assessed with the Sniffin’ Sticks test, which yields a threshold–discrimination–identification (TDI) score. Those with a TDI score below 31 were classified as having post-COVID OD (PC-OlfDys); normosmic individuals post-infection served as controls (PC-N).
Beyond objective smell testing, researchers gathered demographic data, infection history, smoking status, and psychological well-being measures, including the PHQ-8 for depression and the GAD-7 for anxiety. Cognitive function was screened with the Montreal Cognitive Assessment (MoCA).
Imaging methods and key findings
The team employed diffusion tensor imaging (DTI) to assess white matter microstructure. They performed tract-based spatial statistics (TBSS) for whole-brain analyses and region-of-interest (ROI) analyses focused on olfactory pathways. Although the whole-brain TBSS did not reveal significant differences after correcting for multiple comparisons, ROI analyses highlighted notable changes in specific brain regions.
Crucially, the left amygdala showed higher fractional anisotropy (FA) in the PC-OlfDys group compared with controls, while the right amygdala exhibited higher radial diffusivity (RD), suggesting alterations in myelin integrity or microstructure within these emotion-related areas. Other olfactory regions, including the piriform cortex and putamen, also displayed diffusion differences that aligned with ongoing olfactory symptoms.
Correlation analyses revealed nuanced relationships: OD severity and duration related to diffusion metrics in olfactory circuits, and higher anxiety and depressive symptoms correlated with certain left amygdala measures in the PC-OlfDys group. Interestingly, overall TDI scores did not uniformly predict diffusion values, indicating a complex, region-specific pattern rather than a global brain change.
What do these findings mean?
These results point to adaptive or compensatory neural changes within olfactory networks following SARS-CoV-2 infection rather than straightforward neurodegeneration. Increases in FA and RD could reflect reorganization, remyelination, or altered connectivity in pathways linking the olfactory system with limbic structures responsible for emotion. The association between diffusion changes and emotional well-being underscores a potential bidirectional link: persistent smell loss may influence mood, while mood disorders could modulate olfactory processing.
Importantly, the study notes that observed brain differences were region-specific and not a global brain alteration. This nuance highlights the need for targeted investigations into olfactory circuits when addressing long COVID symptoms and suggests potential avenues for rehabilitation that bolster plasticity in scent-related networks.
Implications for patients and clinicians
For individuals grappling with persistent OD after COVID-19, the findings offer a biological context for their experiences, validating symptoms that were previously hard to quantify. Clinicians may consider incorporating olfactory-focused therapies alongside mental health support, recognizing the intertwined nature of smell, emotion, and cognition in long COVID. While causality cannot be established from this study, the data emphasize the importance of a holistic approach to post-COVID care, one that treats sensory loss and emotional well-being as connected issues.
Limitations and future directions
The study’s ROI-driven approach revealed meaningful changes, but whole-brain analyses did not show broad differences after correction. Further research with larger cohorts, longitudinal designs, and multimodal imaging could clarify whether diffusion changes reflect progressive adaptation or persistent disruption. Investigations into how odor training, cognitive therapy, or pharmacological interventions might influence these brain pathways are promising next steps.
