Until now, it remains unclear whether Long-COVID is a novel, distinct syndrome or whether it is the sum of multiple, overlapping syndromes, with the pathophysiological correlates still being poorly understood . In general, depressive symptoms and emotional disturbances are of high relevance in the post-COVID population. In a report of COVID-19 patients sixty days following discharge, 362 of 1250 patients reported being mildly or moderately emotionally affected by health conditions, and 28 patients reported needing health care related to mental care . In this first study investigating BR alterations in TCS in patients with Long-COVID syndrome, we discovered an independent relationship between hypoechogenic BR and depressive symptoms in this patient population.
This finding raises two hypotheses that could explain the association. Unlikely, TCS alteration of the BR might appear reactive to COVID-19, reflecting changes in the serotonergic systems that remain and cause depressive symptoms as part of Long-COVID syndrome. Interestingly, it has been postulated that modifications of the dopamine and serotonin synthetic pathways might be involved in COVID-19 pathophysiology [10, 11]. In this context, the serotonin reuptake inhibitor fluvoxamine has been proven to reduce clinical deterioration after SARS-CoV-2 infection, indicating a link between serotonin and COVID-19 course . Furthermore, there are similarities in the gene co-expression, co-regulation, and function between Angiotensin I Converting Enzyme 2 (ACE2) and Dopa Decarboxylase (DDC). It has been shown that the mRNA levels of the interferon-inducible truncated isoform of ACE (dACE2) and DDC negatively correlate with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus load in COVID-19 patients . DDC encodes the enzyme that catalyzes the biosynthesis of dopamine, serotonin, and histamine, supporting a possible link between SARS-CoV-2 invasion via ACE2 and the consecutive downregulated expression that might parallel a DDC dysfunction resulting in alterations of the serotonin metabolism . The possibility of a straight DDC dysfunction culminating in a structural correlate is speculative. Nevertheless, it has been suggested that short- and long-term neuropsychiatric disorders, including depression in COVID-19 patients, might partly be explained by a neurotransmitter dysfunction . Therefore, an ongoing dysfunction of the serotonergic neurotransmission after COVID-19 could be responsible for depressive symptoms in Long-COVID patients. There is also evidence for a negative correlation of depression and post-traumatic distress following COVID-19 with grey matter volumes in the anterior cingulate (ACC) and insular cortex as well as axial diffusivity and functional connectivity, supporting the idea that COVID patients might develop alterations in brain structure .
On the other hand, a hypoechogenic raphe in TCS might reflect a higher susceptibility to depressive symptoms in the general population. In this context, Walter et al. reported similar prevalence rates of BR alterations in patients with adjustment disorder with depressed mood and patients with major depressive disorder . Individuals with a hypoechogenic raphe might be more vulnerable to developing depressive symptoms due to different events, including critical life events but also acute or chronic diseases such as COVID-19. The inflammatory state that is associated with COVID-19 might be a crucial trigger for continuous depressive symptoms in patients with hypoechogenic raphe. Although the assumption that BR alterations are a risk factor for depressive symptoms cannot be answered conclusively by our cross-sectional study design, it is supported by the similar frequency of a hypoechogenic raphe in our cohort (28.6%) compared to the frequency in healthy controls from various different cross-sectional studies, in which BR hypoechogenicity ranges between 6 and 43% [6, 22]. If the hypothesis that alterations of the brainstem raphe appear reactive to COVID-19 were true, we would expect a higher frequency of this finding in our Long-COVID cohort. Furthermore, we would expect differences in the clinical course of COVID-19 between hypoechogenic and normoechogenic patients, postulating a COVID-19 severity-depending effect of serotonergic dysfunction, which was not seen. Therefore, our data support that a BR hypoechogenicity might be a risk factor for depressive symptoms in Long-COVID. Furthermore, our data do not support a strong association between depressive symptoms in Long-COVID and comorbid psychiatric disease.
There are some limitations to our study. The relatively small sample size might influence the reliability of our findings. However, there were no significant differences in demographics and clinical characteristics between hypoechogenic and normoechogenic patients, suggesting a low risk of confounding. Furthermore, anxiety and depressive symptoms were explored by a self-report measure (HADS). Common limitations of self-report measures, such as introspective limits or the tendency to answer socially desirable need to be taken into account when interpreting these data. General limitations of TCS are the need for a sufficient transtemporal bone window and the reliability of a high-quality ultrasound system, as well as the qualification of the investigator. For our investigation, TCS was conducted by two experienced and DEGUM-certified (German Society for Ultrasound-certified) investigators being blinded to any clinical information of the patients. Therefore, we do not expect a systematic error in this study. Another limitation is associated with the potential of selection bias since we only included Long-COVID patients who presented to our outpatient clinic. Overall, these patients experienced a mild COVID-19 disease course. More severely affected patients might have been missed because of the inability to present to our outpatient clinic due to care-dependency or motivational problems. This should also be considered when interpreting the data.