March 26, 2025
Current technologies do not support imaging of the living human peripheral and central olfactory system with high spatial and temporal resolution. Certain anatomical and functional characteristics of the olfactory system, such as restricted accessibility, multiple cell types, and low signal resolution, create unique technological challenges. Clinicians often resort to invasive surgical biopsies to assess the olfactory epithelium within the nasal cavity. Recent advances in non-invasive and minimally invasive imaging technologies offer innovative opportunities to produce detailed, real-time images of human olfactory epithelium, potentially reducing the need for invasive biopsies and improving diagnostic accuracy.
In this director’s message, I summarize discussions from an NIDCD workshop on leveraging existing technologies and developing new tools to advance non-invasive and minimally invasive imaging of the human olfactory system.
Imaging the Olfactory System, from the Nose to the Brain
The development of in vivo minimally invasive or non-invasive imaging techniques that capture detailed views of human olfactory targets would allow researchers to study the entire olfactory system—from the nose to the brain—with greater temporal and spatial resolution. Research findings could eventually help clinicians determine whether a smell disorder stems from issues in the peripheral or central olfactory system, improving diagnostic accuracy.
In the peripheral olfactory system, advances in technologies such as photoacoustic tomography, dynamic micro-optical coherence tomography, and fluorescent markers offer non-invasive tools to obtain detailed images of the nasal lining and olfactory tissue. In addition, recent advances in brain imaging techniques such as MRI have improved our ability to study the olfactory bulb, an area that remains difficult to image with traditional methods due to its small size, deep location, and interference from adjacent air pockets and bone. Custom development of other brain imaging methodologies—such as metabolic imaging, molecular imaging, and diffusion imaging—could also contribute in the long run to better resolution, coverage, sensitivity, and chemical specificity in the study of the olfactory system.
Targeted Imaging of Nasal Olfactory Tissue
Traditional in vivo imaging technologies cannot easily differentiate between olfactory and respiratory epithelia tissues in the human nasal cavity. This limitation stems from the proximity of these tissues to each other, their composition of multiple cell types, and the difficulty in reaching their location with non-invasive or minimally invasive methods.
Fluorescence-based techniques may help address these challenges. For example, preclinical studies show promise in using unique olfactory epithelial enzymes to turn non-fluorescent compounds into fluorescent markers. Although this technique has not yet been studied in humans, it could allow researchers to distinguish between respiratory and olfactory epithelia as well as between neuronal, stem, and supporting cell types.
Virtual staining is another promising and complementary approach. It uses deep learning algorithms to analyze data generated from autofluorescence microscopy, a technique that detects the natural fluorescence of label-free tissues to identify specific cell types.
If you are an olfaction researcher or in the fields of biomedical imaging, biochemistry, bioengineering, or biophysics, I encourage you to read the summary from our recent workshop, Transformative Non-Invasive/Minimally Invasive Technologies for Imaging the Olfactory System Across Scales, for additional information on in vivo, multimodal imaging approaches to advance the diagnosis and treatment of smell disorders.