Neural correlates of olfactory dysfunction: A systematic review

Olfactory dysfunction affects over 20% of the population. Despite progress in understanding its neural pathophysiology, research remains fragmented. This systematic review synthesizes evidence of brain structural and functional measures, and their association with clinical characteristics (e.g., etiology, duration) in patients with olfactory dysfunction. This may help to identify neural correlates and potential neuroimaging biomarkers of olfactory dysfunction's severity and progression. Following PRISMA guidelines, we screened 2374 papers and included 164 studies. Structural MRI studies consistently reported reduced olfactory bulb volume and/or sulcus depth, alongside gray matter reduction in the orbitofrontal cortex, hippocampus, insula, and amygdala in acquired olfactory dysfunction and paradoxical increases in congenital anosmia. Diffusion tensor imaging studies showed widespread white matter abnormalities, with prominent fractional anisotropy reductions. Resting-state and task-based fMRI studies showed heterogeneous, global alterations in connectivity and/or reactivity. PET/SPECT studies generally reported reduced perfusion or hypometabolism in frontal regions, especially in the orbitofrontal regions. Dopamine transporter imaging showed more frequent dopaminergic deficits in Parkinson's and prodromal individuals with hyposmia. Electroencephalography studies, despite methodological heterogeneity, generally found prolonged latencies and reduced amplitudes in olfactory event-related potentials. Across techniques, these brain alterations often showed low-to-moderate correlations with olfactory function. Although etiological and methodological heterogeneity currently obstructs the identification of robust neuroimaging biomarkers of olfactory dysfunction's severity and progression, current evidence indicates that olfactory dysfunction involves widespread structural and functional alterations, mainly in olfaction-related areas, with the orbitofrontal cortex as a key area emerging across techniques. Large-scale, standardized studies are needed to enable stratified diagnosis and personalized prognosis.