paring the healthy control group20. In our opinion, normal oxyhemoglobin AUS based on the functional near-infrared spectroscopy (fNIRS) study could not rule out biochemical changes in neuronal damage 20.
Overall, the findings of this study suggest that olfactory dysfunction in patients with COVID-19 related anosmia is significantly associated with central nervous system impairment. Since the NAA originates from mitochondria, it can reflect neuronal integrity and viability; the significant decrease of NAA andNAA/Cho in the OFC in COVID-19 related anosmia strongly suggests regional neuronal OFC impairment in the context of persistent COVID-19 anosmia. The second significant alteration in our patients was a reduction of Cr levels within OFC. Cr works as an indirect intermediator of cellular energy and previous studies have shown its reduction following nerve injuries1. Although this cellular dysfunction emphasized the hypothesis that impairment of OFC function is significantly associated with permanent anosmia, these results could not answer a controversy about the cause-and-effect relationship between brain neurometabolite dysfunction and COVID-19 related anosmia.
Finally, it should be noted that the results of recent clinical trials that did not achieve significant improvement from intranasal corticosteroids raise the property of central nervous system mechanisms for COVID-19 related anosmia 21-23.

4.2 Limitations and comments of the study

The small number of patients is certainly a major limitation of our study, but this is a well-designed preliminary study. Another limitation of our study was the nature of our scanner. More powerful scanners and multivoxel spectroscopy can detect extra metabolites such as Myo-inositol, glutamate, glutamine, glutathione, gamma-aminobutyric acid, and lactate.
Despite the limitations of this study, we believe that the MRS is a valuable advanced neuroimaging technique and could provide very important landmarks in the diagnosis, treatment and follow-up of patients with anosmia.
Interestingly, as MRS provides valuable, quantifiable data, it would be possible to build a predictive score based on future longitudinal studies and neural network to predict the outcomes of patients with acquired anosmia.
According to a suggestive origin of injury in patients with COVID-19 related anosmia, pharmacologic or nonpharmacologic therapies in order to increase NAA levels using electroconvulsive therapy, cognitive behavioral therapy, and physical exercise or short-course pharmacological therapies with lithium, valproate, or antipsychotics could be tried in these patients as they can lead to a widespread increase in brain NAA levels 24,25.
Conclusions
MRS is an exciting and novel approach to evaluating prolonged olfactory dysfunction after COVID-19 related anosmia. However, it is still not entirely clear that abnormalities in the CNS are the cause or the result of olfactory loss due to COVID-19. We believe further neuroimaging studies and clinical trials could answer some controversies about the cause-and-effect relationship between the neurometabolic alterations within OFC in COVID-19 anosmia.
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