Functional and structural olfactory changes in post-COVID-19 patients detected by 7 Tesla MRI, 2026, Leão et al.

[Chandelier]

Functional and structural olfactory changes in post-COVID-19 patients detected by 7 Tesla MRI

Spoiler: Authors

Leão, Felipe Carvalho; Prazeres, C. L. S.; Godoy, M. D. C. L.; Leite, C. C.; Cassol, D. F.; Soares, A L. G.; Gomes Junior, A. M.; Voegels, R. L.; Otaduy, M. C. G.; Pinna, F. R.

Abstract​

Persistent olfactory dysfunction after SARS-CoV-2 infection is common, yet its central neural profile remains poorly defined.

We combined ultra-high-field 7 Tesla resting-state functional MRI with surface-based cortical morphometry to characterise olfactory-network organisation and cortical structure in long-term post-COVID dysosmia.
Thirty adults (14 with persistent dysosmia; 16 normosmic controls) completed psychophysical olfactory testing and 7 Tesla imaging.

Connectivity analyses across 56 olfaction-related regions revealed a coherent pattern centred on insular, orbitofrontal and thalamic nodes: connectivity was reduced between the insula and the orbitofrontal and entorhinal cortices, and between the ventral posterior thalamus and the ventral insula, and increased between interhemispheric orbitofrontal regions and among anterior thalamic nuclei.
Significant connections were predominantly right-lateralised or interhemispheric.
Morphometry showed no volumetric differences but selective left orbitofrontal thinning.
Across the whole sample, greater orbitofrontal and insular thickness was associated with better olfactory performance; however, this reflected the difference between patients and controls rather than a graded relationship within the patient group, and did not persist after accounting for group and age.

Together, these findings provide a preliminary, proof-of-concept characterisation of an orbitofronto-insular signature of long-term post-COVID dysosmia and nominate candidate imaging markers for testing in larger, multi-centre cohorts.

Web | DOI | Scientific Reports

 

[Hutan]

Persistent olfactory dysfunction (OD) is one of the most prevalent and disabling sequelae of SARS-CoV-2 infection, affecting quality of life, nutritional behaviour, and hazard perception; although most individuals recover within months, a clinically significant subset remains impaired for years [1–6]. Initial pathophysiological models focused on primary epithelial injury, with inflammatory and transcriptional disturbances in the olfactory mucosa largely explaining acute-phase anosmia [4,7– 9]. However, the persistence of OD well beyond mucosal recovery has shifted attention toward the central nervous system, where the olfactory network -spanning the olfactory bulb, piriform cortex, orbitofrontal cortex (OFC), insula, entorhinal cortex, and thalamic relays - is increasingly recognised as a substrate for lasting sensory impairment [10–16].

The case of post-covid-19 olfactory changes is interesting to think about. It doesn't sound as though the cause of the changes are understood yet. And that is surprising, because it's a pretty distinct symptom. If the virus causes damage to neurons, perhaps it is a model for what happens in ME/CFS, but with the different neurons affected causing the different symptoms.

Persistent post-COVID-19 OD was associated with convergent cortical and network-level changes centred on the orbitofrontal–insular system. Structural analyses revealed focal cortical thinning within the orbitofrontal cortex and insula, while functional data demonstrated disrupted connectivity linking the dorsal insula, orbitofrontal and entorhinal cortices, and thalamic nuclei. At the same time, enhanced interhemispheric and intra-thalamic connections suggested compensatory reorganisation within olfactory–limbic pathways. This coexistence of degeneration-like and reorganisation-like features points to a dynamic neural adaptation process rather than uniform cortical damage. Together, these findings define an orbitofronto-insular profile of persistent post-viral OD, extending current models of OD beyond primary sensory regions to include higher-order affective and integrative circuits.

Although our cross-sectional design prevents causal inference, the observed structure–function relationship supports the idea that early microstructural changes — such as synaptic loss or dendritic simplification — may precede visible macroscopic atrophy in the OFC [12]

@SNT Gatchaman - I think you have talked about the possibility of brain damage that is not yet visible with the tools we have.

It would be interesting to know more about these post-Covid-19 olfactory issues. Do they fluctuate?

 

[Hutan]

At the network level, we observed increased interhemispheric connectivity between OFC subregions, including stronger coupling between the left anterior piriform–OFC parcel and the right lateral OFC. This pattern may represent an adaptive reorganisation of orbitofrontal circuits in response to degraded peripheral olfactory input, consistent with prior evidence of OFC hyperactivation under conditions of reduced sensory drive [30–33,37]. Longitudinal studies in post-COVID anosmia have documented transient hyperconnectivity that partially normalises as olfactory function recovers [14], whereas cohorts with established chronic OD typically exhibit persistent hypoconnectivity and increased thalamic centrality without
orbitofrontal reinforcement [16,38].

Our findings are therefore consistent with a transitional network state in which orbitofrontal reinforcement coexists with broader extrafrontal disconnections, possibly reflecting an evolving balance between adaptive and degenerative processes during the subacute-to-chronic phase of
olfactory network reorganisation.

 

[Hutan]

Within this framework, intra-thalamic hyperconnectivity in the absence of structural change is more parsimoniously interpreted as up-regulation within this higher-order olfactory thalamic loop in response to degraded peripheral input — conceptually analogous, though not anatomically equivalent, to central-gain phenomena described in tinnitus and hyperacusis [57]. Comparable thalamic hyperconnectivity has been reported in post-traumatic anosmia [35] and parosmia [58], suggesting a generalisable subcortical response to chronic olfactory insult rather than a COVID-specific phenomenon.

It's a small study and the controls are poorly matched with the cases (the controls are younger). The findings reported are therefore uncertain.

 

[SNT Gatchaman]

@SNT Gatchaman - I think you have talked about the possibility of brain damage that is not yet visible with the tools we have.

Yes, for example in MS, what was thought to be normal white matter ("normal appearing white matter" aka NAWM) that was first shown to be abnormal at post-mortem and can now be demonstrated on more advanced diffusion studies.

Pathological ultrastructural alterations of myelinated axons in normal appearing white matter in progressive multiple sclerosis (2023, Acta Neuropathologica Communications)

Spoiler: Abstract

Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria.

Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons.

We generated large scale 2D scanning transmission electron microscopy images (‘nanotomy’) of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution.

We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury.

Normal appearing white matter and disability in multiple sclerosis (2025, Preprint: MedRxiv)

Spoiler: Abstract

BACKGROUND AND OBJECTIVES
Multiple sclerosis (MS) is characterized by lesions and atrophy on conventional MRI, yet these often fail to explain disability. Diffusion MRI (dMRI) detects microstructural injury with diffusion tensor (DTI) and kurtosis imaging (DKI) offering sensitivity, and Standard Model Imaging (SMI) providing biologically interpretable parameters. We evaluated whether these clinically feasible dMRI metrics are associated with disability beyond volumetric and lesion measures, and whether effects arise from normal-appearing white matter (NAWM).

METHODS
This cross-sectional study included MS patients who underwent 3T MRI including T1-and T2-weighted and a ~7-minute multi-shell dMRI protocol. Brain volumes (gray matter, white matter, thalamus) and lesion load were derived using FreeSurfer and Icobrain. Diffusion metrics included radial diffusivity (RD) from DTI, radial kurtosis (RK) from DKI, intra-axonal water fraction (f) and fiber dispersion (p2) from SMI. Clinical outcomes were the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), and disease duration. Voxelwise and tract-based regions of interest analyses were adjusted for sex and age at onset and repeated after excluding lesions.

RESULTS
Ninety-two patients (68 women; mean age 48, range 24-73; median disease duration 14 years; EDSS 3.0, range 0-8.5) were included. dMRI revealed widespread associations with all clinical measures that persisted after lesion exclusion, implicating NAWM. Functional outcomes were tract-specific: 9HPT correlated with corticospinal tract and optic radiations (RD r=0.45; RK r=-0.44; f r=-0.42); MSFC with brainstem and optic radiations (RD r=-0.52; RK r=0.40; f r=0.39). SDMT showed widespread correlation with diffusion and atrophy (white matter r=0.49; thalamus r=0.47). EDSS showed weaker diffusion highlighting commissural disorganization (forceps major/minor r=(-0.30 to -0.32) and was most strongly associated to infratentorial lesion load (r=0.42). Disease duration was dominated by gray-matter atrophy (r=-0.54) with commissural p2 reductions (r-0.45).

DISCUSSION
dMRI detects NAWM injury underlying functional impairment beyond atrophy and lesions. SMI adds specificity (f for axonal loss/demyelination; p2 for inflammation). Structural measures capture the effect of cumulative burden in terms of disease duration and EDSS. Together, diffusion, volumetric, and lesion metrics offer complementary insights, supporting multimodal imaging for MS monitoring and stratification. Keywords: Multiple Sclerosis (MS), Diffusion Tensor Imaging (DTI), Diffusion Kurtosis Imaging (DKI), Standard Model of Diffusion (SMI), Brain Volume, Microstructural Pathology, Disease Progression.

These findings support the hypothesis that microstructural degeneration in NAWM precedes measurable atrophy, with diffusion abnormalities explaining functional impairment, while volumetric atrophy and lesion burden reflect cumulative damage.

With this paper (I haven't read) I wouldn't want to draw too many inferences with olfactory dysfunction for us. I don't think it's ever been claimed as a particularly notable symptom in ME/CFS. Prominent in acute and recovering Covid, but that may be unrelated to the ME/CFS phenotype of LC, ie a parallel confounding phenomenon.

Olfactory dysfunction is recognised as a precursor to neurodegenerative conditions, esp Parkinson's and Alzheimer's I believe. Also Covid-accelerated cognitive decline, eg Brain microstructure and connectivity in COVID-19 patients with olfactory or cognitive impairment (2024) and Age-dependent phenotypes of cognitive impairment as sequelae of SARS-CoV-2 infection (2025)

I think for us though "brain damage" isn't really on the table. People move down and also up through severity levels and just look at the capabilities of people here after decades of disabling disease! For brain, rather I'd be looking for evidence of things like myelin dysregulation (along with other things like abnormal neurometabolism and neurovascular regulation).

We do need to be mindful of that OLFM4 genetic signal, but I suspect that will relate to things outside the olfactory system itself (see thread).

 

[Hutan]

Yes, I agree that we have not seen a lot of overlap between post-Covid-19 olfactory issues and ME/CFS. Olfactory issues have been reported following a range of infections , but I guess there are a range of mechanisms that might cause that e.g. strokes.

I did see that a lot of people aren't aware of mild olfactory issues, so it's possible that there is under-reporting. (The same is true for post-infection hearing loss.)
Scent of COVID-19: Whole-Genome Sequencing Analysis Reveals the Role of ACE2, IFI44, and NDUFAF4 in Long-Lasting Olfactory Dysfunction

Despite these considerable implications, olfactory dysfunction commonly goes unrecognized. In fact, with an overall population prevalence of OD of up to 24.5% [4], it has been estimated that fewer than 25% of patients are aware of their condition until they are psychophysically tested [5,6]. OD can be secondary to a number of factors, and, among all causes, upper respiratory tract viral infections are recognized as a major determinant of OD. Rhinoviruses, Adenoviruses, Influenza and Parainfluenza viruses, and Herpesviruses have long been known to be implicated in post-viral OD (PVOD) [7]. In recent years, PVOD has been gaining increasing attention from the medical community in consideration of its extraordinary high frequency among patients affected by Coronavirus disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

I agree that if there was a similar mechanism to what happens for ME/CFS and it's just chance what neurons are affected, we probably should expect more reporting of olfactory issues by people with ME/CFS. It seems unlikely that there is both a similar mechanism and it's an either ME/CFS or olfactory changes sort of situation.

But, still, it's worth thinking about, maybe worth checking out any overlaps in genetic risk factors.

 

[Peter T]

I think it is worth mentioning that the neuroanatomy of olfaction is distinct, reflecting the development of this sense early on in evolution of animals. When I was a student at some point a neurology lecturer said something to the effect that you could almost think of the olfactory bulb as part of the brain itself abutting the nasal cavity.

Presumably this means the sense of smell is particularly vulnerable in the context of respiratory infections when compared to the other senses. So it surprises me that we don’t yet fully understand the relationship between Covid and olfactory disturbances, though surely the simplest explanation would be a direct impact of Covid on the olfactory nerve’s structure or functioning. I don’t know how common it is but you do at least occasionally see Long Covid that is solely manifest in olfactory disturbance. Also this surely makes it very surprising if we do see disruptions of the sense of smell in ME/CFS that has an onset independent of any respiratory infections.

 

[EndME]

It is indeed interesting that this seemingly easier problem of OD seemingly hasn't been figured out yet.

Recruitment was in the timeframe 01.2022-01.2024. The median illness duration is 26.4 months. It could be nice to know some further details here (for example whether the variants of virus that people became ill with are roughly known), but at least for this cohort people got ill quite some time ago.

I have been under the strong impression, which might be incorrect, that olfactory dysfunction has been related to the earlier phases of the pandemic (maybe until early 2023) and so it seems instructive to know whether this could be driven by a variant dependent phenomenon, whether it’s more strongly related to some form of immunity (viral or vaccine) or whether there could also be some survivorship bias at play. Current literature seems mixed, which could also be an artefact of terrible studies.

I do think the general thought of invoking brain changes without these having to be permanent can be interesting even if the results of this study are completely uncertain and I think the hypothetical mechanistic parallel to ME/CFS here would very much be that most patients with OD recover quickly and a smaller subset recovers after having been ill for very long, even if there is no direct relationship between ME/CFS and OD.