Imbalanced brain connectome: A possible link behind functional somatic disorders, multiple chemical sensitivity, and long COVID patients

Background: Functional Somatic Disorders (FSDs) are characterized by persistent physical symptoms that cannot be explained by other somatic or psychiatric conditions. Multiple Chemical Sensitivity (MCS) is a non-allergic FSD characterized by odour intolerance and various somatic symptoms being attributed to the influence of toxic environmental chemicals in low, usually harmless doses. The pathophysiology of FSDs are still not clear. Smell and taste complaints were also among the notable symptoms characterizing the covid epidemic and the latest evidence suggests overlaps between long COVID and FSDs. Method(s): The study includes advanced analysis of MRI-derived functional and structural connectomes acquired on a 3 T MR scanner. Furthermore, it includes questionnaires and paraclinical tests, e.g. the Sniffin' Stick olfactory test, Mini-Mental State Examination, and Sino-Nasal Outcome test 22. The pilot part of the project included 6 MCS patients who were compared with 6 matched healthy participants. Later follow-up included analysis of 8 multiorgan FSD and 4 post-COVID patients. Result(s): The MCS group showed important brain structural connectivity differences in 34 tracts. Notably, for MCS patients, the olfactory cortex (especially in the right hemisphere) showed decreased connectivity with regions in the emotional system. Conclusion(s): We plan to extend these findings with whole-brain modelling of the functional connectivity in the patient groups. Long-term this could be used as a 'fingerprint' which could help with diagnosis and treatment monitoring in FSDs as well as with new diagnoses such as long-COVID.Copyright © 2023

OLFACTORY FUNCTION AND BRAIN STRUCTURAL EFFECTS FOLLOWING SARS-CoV-2 INFECTION

Background: SARS-CoV-2 infection is accompanied by acute olfactory disturbance in as high as 70% of cases. This loss is associated with decreased olfactory bulb volume. As time passes, the anosmia tends to subside, but the OB volume decrease does not. Volume reductions in primary and secondary olfactory cortex are also seen following SARS-CoV-2 infection. Nevertheless, concurrent SARS-CoV-2 infection effects on olfactory discrimination, olfactory bulb volume, primary olfactory cortex and its targets have not been investigated. To explore this possibility, we measured olfactory discrimination, olfactory bulb volume, primary olfactory cortex and basal ganglia volume in patients who had SARS-CoV-2 infection more than 12 weeks previously, who were then divided into COVID and long-COVID groups on the basis of selfreported fatigue and concentration complaints. Method(s): This cross-sectional study included 25 post-infection and 19 demographically-matched, no-COVID control participants, we investigated effects on olfaction using NIH Toolbox Odor Identification Test and the Monell Smell Questionnaire. GM structure was assessed with voxel-based morphometry and manual delineation of high resolution (1mm3), T1- and T2-weighted MRI data. Linear regression was used to model group effects on GM structure, adjusting for age, sex, education and total intracranial volume. CAT12/SPM12 and R were used for image processing and statistical modeling. Result(s): Results. The NIH Toolbox Odor Identification Test failed to show differences among the groups. In contrast, the Monell Smell Questionnaire revealed persistently diminished and distorted smell in 50% of the long-COVID sample. Olfactory bulb volume was lower in the long-COVID group (p=0.02). Primary olfactory cortex volume was reduced in the long-COVID group (p=0.004). Caudate volume was also lower in the long-COVID group (p=0.04). Conclusion(s): Conclusions. In the absence of olfactory discrimination problems, long-COVID, but not COVID, patients experience persistent olfactory loss and distortion. These perceptual problems are associated with lower olfactory bulb, primary olfactory cortex, and caudate volume, suggesting that the effects of SARS-CoV-2 infection can extend beyond the olfactory periphery in some cases to affect central targets. (Figure Presented).

Primary and secondary olfactory centres in human ontogeny.

The olfactory centres are the evolutionary oldest and most conservative area of the telencephalon. Olfactory deficiencies are involved in a large spectrum of neurologic disorders and neurodegenerative diseases. The growing interest in human olfaction has been also been driven by COVID-19-induced transitional anosmia. Nevertheless, recent data on the human olfactory centres concerning normal histology and morphogenesis are rare. Published data in the field are mainly restricted to classic studies with non-uniform nomenclature and varied definitions of certain olfactory areas. While the olfactory system in model animals (rats, mice, and more rarely non-human primates) has been extensively investigated, the developmental timetable of olfactory centres in both human prenatal and postnatal ontogeny are poorly understood and unsystemised, which complicates the process of analysing human material, including medical researches. The main purpose of this review is to provide and discuss relevant morphological data on the normal ontogeny of the human olfactory centres, with a focus on the timetable of maturation and developmental cytoarchitecture, and with special reference to the definitions and terminology of certain olfactory areas.

Investigational drugs for the treatment of olfactory dysfunction.

INTRODUCTION: Olfactory dysfunction could be the sign of acquired or degenerative diseases. The loss of the sense can be caused by a damage in the nasal structure (olfactory epithelium) or a neuro inflammation/degeneration in the superior olfactory pathway. The understanding of the origin of the smell alteration would be desirable for appropriate management of the problem. Unfortunately, clinical investigations do not always allow to define the exact cause. AREAS COVERED: This review discusses the treatments available and their mechanism of action based on the administration methods; in fact, just looking at the results obtained by the researcher using topic versus systemic treatment, might be possible to speculate about the peripheral or central origin of the olfactory disorder. EXPERT OPINION: Because COVID-19 causes olfactory loss and several treatments (topical and systemic) have been tested in this disease, we have decided to use this model of acquired olfactory loss to discuss the different therapeutical option. The authors believe these treatments might be an option also for treating olfactory disease related to neurodegeneration.

Anosmia and dysgeusia among corona virus disease (Covid-19) patients-A review

COVID-19 is a viral infection of the respiratory tract presenting with fever, cough and fatigue. Absence of specific symptoms makes diagnosis and control of transmission of this disease a challenging task.Some recent studies have reported smell and taste dysfunction in COVID 19 patients. However, little is known about the prevalence and pathogenesis of these two symptoms with conflicting reports on the duration of these symptoms, recovery rate as well as the prognosis of patients who have anosmia and /or dysgeusia. To seek answers, a literature review on this topic from databases like PubMed, Clinical Key, Science Direct, Scopus and Google Scholar was conducted. The objective of this review was to further examine the prevalence of the smell and taste dysfunction in COVID-19 patients, explorethe pathophysiology for the occurrence of these two symptoms and evaluate its prognostic value.It was observed that olfactory and gustatory dysfunction was more prevalent among COVID-19 patients who belonged to younger age group and among females. Patients who presented with anosmia and dysgeusia as their main symptoms had lesser severity of the COVID-19 infection when compared to patients without these symptoms indicating that patients with chemosensory dysfunction have good prognosis.

A comparative neuroimaging perspective of olfaction and higher-order olfactory processing: on health and disease.

Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that pathological changes in the peripheral olfactory system where the body is exposed to many adverse environmental stressors may have a causal role for the brain alteration. Whether and how the peripheral pathology spreads to more central brain regions may be effectively studied in rodent models, and there is successful precedence in experimental models for Parkinson's disease. It is of interest to study whether a similar mechanism may underlie the pathology of psychiatric illnesses, such as schizophrenia. However, direct comparison between rodent models and humans includes challenges under light of comparative neuroanatomy and experimental methodologies used in these two distinct species. We believe that neuroimaging modality that has been the main methodology of human brain studies may be a useful viewpoint to address and fill the knowledge gap between rodents and humans in this scientific question. Accordingly, in the present review article, we focus on brain imaging studies associated with olfaction in healthy humans and patients with neurological and psychiatric disorders, and if available those in rodents. We organize this review article at three levels: 1) olfactory bulb (OB) and peripheral structures of the olfactory system, 2) primary olfactory cortical and subcortical regions, and 3) associated higher-order cortical regions. This research area is still underdeveloped, and we acknowledge that further validation with independent cohorts may be needed for many studies presented here, in particular those with human subjects. Nevertheless, whether and how peripheral olfactory disturbance impacts brain function is becoming even a hotter topic in the ongoing COVID-19 pandemic, given the risk of long-term changes of mental status associated with olfactory infection of SARS-CoV-2. Together, in this review article, we introduce this underdeveloped but important research area focusing on its implications in neurological and psychiatric disorders, with several pioneered publications.