**6. Neurological E**ff**ects of COVID-19**

Though the consequences of COVID-19 have led to mental health issues, the brain biotypes and brain or the neural taxonomy are likewise affected. Even though COVID-19 mainly affects the respiratory system, recent studies have shown its direct involvement in the central nervous system (C.N.S.). A study done in Wuhan, China showed that almost around 40% of COVID-19 patients experienced neurological symptoms. These were further divided into C.N.S. symptoms, peripheral nervous system (PNS) signs, and musculoskeletal symptoms. COVID-19 patients with mild

neurological symptoms complained of headache and dizziness, and more severe patients suffered from acute cerebrovascular diseases and consciousness impairment [24].

Additionally, reports have indicated olfactory and taste disorders in patients with COVID-19 [25]. COVID-19 is currently found to be affecting the neuroendocrine-immune system and heavily suppressing it [26]. The neuroendocrine-immune system has been said to be involved in stress and coping strategies. This might be one of the reasons for having excessive stress. Another reason for elevated amounts of stress might be because periods of isolation and lack of social contact have been linked to causing high psychological distress and stress-related disorders [27]. Older patients with underlying conditions have been reported with more severe neurological symptoms [24]. Of note, COVID-19 patients in Beijing Ditan Hospital were found to have the presence of SARS-CoV-2 in their cerebrospinal fluid, which was confirmed by genome sequencing, which led to the presentation of viral encephalitis [28].

The mechanism of action of COVID-19 and its neurological effects are currently under study. The C.N.S. is protected from viruses with its multilayer barriers and its immune response system. However, different viruses can affect the brain through a variety of mechanisms. Some proposed mechanisms by which the virus can cause infection include direct brain injury, hypoxic damage, upregulated angiotensin-converting enzyme 2 (ACE-2) receptors, and immune insufficiency, which can lead to toxic, infectious encephalopathy, viral encephalitis, and even acute cerebrovascular disease [28]. The viruses have been found to cause direct brain injury through different mechanisms [29] including via blood circulation where the virus is released into the blood, causing an increase in the penetrability of the blood–brain barrier that leads to the virus entering the brain which causes encephalitis [30]. Some viruses can also direct damage to the brain by involving the sensory or motor nerve endings [31].

It has been proposed that coronavirus causes its neurological symptoms via hypoxia. Since the virus primarily causes respiratory symptoms including shortness of breath and lack of oxygen in the lungs and consequent anaerobic metabolism in the brain, this can lead to brain injury displayed by brain swelling, interstitial edema, or cerebral vasodilation, etc. [32,33]. Thus, hypoxia resulting from COVID-19 infection can result in neurological symptoms. COVID-19 also has the potential to cause hyperinflammation through cytokine storm syndrome [34]. A retrospective study on 150 COVID-19 patients, which was carried out in Wuhan, China, revealed a significant increase in ferritin levels as well as IL-6 levels. Such findings were shown to be positively correlated with the fatality rates in these patients. This would point towards the role of inflammation in multiple COVID-19 symptoms, including its often-devastating neurological issues [35]. Previously, in a mice model, coronavirus was shown to potentially infect nasal cells from where it gets transported to the olfactory bulb before affecting the brain. The removal of the olfactory bulb caused a delay in the transmission of the virus to the mice's brain [32,33]. Recently in Italy, a study reported that in COVID-19 cases, self-reported olfactory and taste disorders were found [25]. Despite such findings in the acute phase, long-term effects have yet to be studied. Another potential mechanism of COVID-19 causing brain injury is thought to be through ACE-2. ACE-2 receptors have been found in glial cells and neurons, which are a potential target of COVID-19. The attachment of the virus to these receptors facilitates the entry of the virus to the brain and resultant brain injury [36].

There is a crashing wave of neuropsychiatric sequelae of COVID-19. The major issues addressed related to COVID-19 are the neuropsychiatric symptoms and understanding the underlying immunological mechanisms. According to Julie Helms et al. (2020), 8 of the 58 COVID-19 patients (14%) admitted in the intensive care unit showed neurological and neuromuscular blockade [37]. Further, RT-PCR assays on the nasopharyngeal samples on all 58 patients revealed from subjects who were positive for acute respiratory syndrome COV2-SARS that seven developed ischemic attack, epilepsy, and mild cognitive impairment [37]. Further, since the impact of COVID-19 and mental health issues has recently been raised worldwide, it is essential to understand whether the rate or the association of suicidality has changed. It would, therefore, be interesting to follow the psychoneuroimmunology of COVID-19 subjects about the extent of mental health issues and the presence of suicidality. As one

could speculate, the virus might lead to the immune response in vulnerable subtypes of the mood disorder population, as it was recently observed in cytomegalovirus [38].
