**2. Cognitive and neuropsychiatric manifestations of COVID-19**

Pandemics are considered to be one of the most devastating disaster types, since they have global consequences that particularly affect mental health. Although not of pandemic proportions, previous outbreaks of viral infections involving coronaviruses, SARS (SARS-CoV) and MERS (MERS-CoV), and other viruses such as Ebola and Zika, provided valuable insights into the potential devastating effects on mental health status [10, 11].

Multiple reports and meta-analyses described that most common neuropsychiatric manifestations of COVID-19 are insomnia, depression and anxiety, PTSD, and various psychoses. In terms of prevalence, almost one quarter (22.5%) of those infected were found to have experienced some neurological and/or psychiatric episodes among 40,469 patients of whom majority was in the United States [3]. Subsequent studies from Europe reported similar outcomes [12–14]. Critically ill

*Chronic Mild Stress and COVID-19 Sequelae DOI: http://dx.doi.org/10.5772/intechopen.106578*

#### **Figure 1.**

*Direct and indirect effects of COVID-19 on the central nervous and cardiovascular systems. Individuals who became infected with SARS-CoV2 virus could experience neurologic and cardiovascular dysfunction due to the direct neurotrophic effects of the virus as well as indirectly, via experiencing chronic stress associated with the pandemic (i.e. loss of loved ones, loss of income, lack of exercise, poor nutrition etc.). Individual who evaded infection, although spared from the direct effects of the virus, are also at an increased risk of developing neuropsychiatric and cardiovascular diseases via experiencing chronic stress associated with the pandemic. Therefore, those who survived COVID-19 and those who never got the disease but lived through the pandemic should be monitored both for mental health and cardiovascular health changes in the years to come.*

individuals who required intensive care unit (ICU) admissions are particularly at risk of developing cognitive and neuropsychiatric manifestations, due to sedation, intubation, presence of comorbidities and older age [15–19]. One study from France reported that in a small cohort of 45 patients, 15 of them reported cognitive disturbances in form of dysexecutive syndrome (dysregulated movement patterns and lack of attention) at discharge from ICU [14]. Furthermore, almost half of them presented with confusion upon admission that was accompanied by brain hypoperfusion in several individuals revealed after brain imaging [14]. Depressive symptoms were also prevalent among individuals who recovered from COVID-19 in China [20–22]. Moreover, immune system suppression was evidenced in those with depressive symptoms indicated by increased white blood cell count and pro-inflammatory markers [21].

The impact of COVID-19 on one's neuropsychological well-being can be a direct result of SARS-CoV2 viral infection of the central nervous system (CNS) and/or an indirect result of endured psychological stress due to the devastating elements of the pandemic, such as fear of infection, social isolation, loss of income etc. The characteristic, mechanisms and implications of the first are detailed below throughout Section 2 of this Chapter, and those of the latter are elaborated on in Section 3 of this Chapter.

#### **2.1 Mechanisms of cognitive and neuropsychiatric sequelae of COVID-19**

Initially in early 2020, it was speculated but not confirmed that SARS-CoV2 is indeed a neurotrophic virus [23]. Shortly thereafter, the first case of viral encephalitis was reported in May of 2020 [24], making it obvious that the virus is capable of invading the CNS. Similar to other coronaviruses, SARS-CoV1 and MERS-CoV, SARS-CoV2 infection can cause CNS issues that range from mild such as loss of taste and smell (ageusia and anosmia, respectively), headache and dizziness, to very serious such as stroke, seizures, loss of balance and mental status alterations [25]. These consequences could result from: (i) the direct infection of neuronal cells by the virus, (ii) immune system dysregulation, (iii) autoimmunity resulting from the infection itself and/or (iv) any combination of the above three [26]. In addition to the direct invasion of neuronal cells, a secondary systemic mechanism could also be at play. This mechanism involves acute respiratory distress syndrome (ARDS). ARDS is accompanied by hypoxemia, oxidative stress and uremia resulting from multi-organ failure, including the cardiovascular system derangements and such complications could lead to encephalopathy. Immune system dysregulation may involve the cytokine storm and subsequent breakdown of the blood brain barrier (BBB) allowing entry of SARS-CoV2 into the CNS. This model is further supported by the fact that the virus binds ACE2 receptor that is present on capillary endothelium, thus leading to BBB damage and entry of the virus into the CNS [27]. Furthermore, immune system involvement could occur at the level of toll like receptors (TLRs), of which there are 10 identified members in humans, numbered 1–10 [28]. In particular, TLR 7/8 is recruited in response to single stranded RNA viruses, such as SARS-CoV2, leading to the production of pro-inflammatory mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor alpha and interferon gamma [29]. Uncontrolled production of the pro-inflammatory mediators may lead to cytokine storm which causes ARDS, leading to encephalopathy secondary to an inflammatory response [30]. In another model, it was suggested that SRAS-CoV2 may operate similar to HIV in that HIV causes encephalopathy via a mixed approach: both directly via neuronal cell invasion and indirectly via the above discussed inflammatory mechanisms [26].

#### **2.2 Potential long-term neuro-psychiatric effects: long haul COVID-19**

The syndrome of persistent symptoms associated with COVID-19 that extend beyond the period of initial infection was originally termed long haul (LH) COVID-19 by a patient [31], the features of which have been identified in individuals irrespective of the initial illness severity [32]. One characteristic of LH COVID-19 is that the symptoms may either persist past the 3–4 week mark and/or new symptoms may develop after the 3–4 week mark. In fact, the National Institute for Health and Care Excellence has defined the LH or post-COVID-19 syndrome as "signs and symptoms that develop during or after an infection consistent with COVID-19, continue for more than 12 weeks ( 3 months) and are not explained by an alternative diagnosis" [33]. LH COVID-19 appears in the literature under several synonyms: post-COVID-19 condition (WHO defined), post-acute COVID-19 syndrome (PACS) [34] and postacute sequelae of COVID-19 [32].

Neurological symptoms discussed above may contribute individually or synergistically to the persistence of neurological pathophysiology past the acute phase. The loss of BBB integrity and neuroinflammation [35–37], coupled with coagulopathy and the development of micro-emboli in the CNS [38, 39] may lead to the progression

#### *Chronic Mild Stress and COVID-19 Sequelae DOI: http://dx.doi.org/10.5772/intechopen.106578*

of LH COVID-19. Additionally, factors associated with hospital stay (i.e. intubation, mechanical ventilation and the use of sedatives) may further exacerbate the clinical course in those with severe acute symptoms. Neuro-psychiatric features of LH COVID-19 are likely related to prolonged stress associated with the pandemic and loss of family members/friends [40].

A recently published meta-analysis aimed to evaluate the neurological and neuropsychiatric features of LH COVID-19 in three cohorts: outpatient (community), non-ICU hospitalized an ICU hospitalized and at two different time points: 3–6 months and past the 6 month mark after the initial infection [41]. Primary outcomes included neurologic and psychiatric symptoms. Neurologic symptoms included: anosmia, dysgeusia, headache, cognitive dysfunction, fatigue, chronic fatigue syndrome, post exertional malaise, pain, peripheral nervous system symptoms. Neuropsychological symptoms included: anxiety, depression, sleep disturbances and/or insomnia and PTSD. A total number of full text articles screened were 80, and 18 studies, including 10,530 patients met the inclusion criteria. The most frequent neurological symptom of LH COVID-19 was fatigue (37%), followed by brain fog (32%), sleep disturbances (31%) and memory issues (28%). The prevalence of these symptoms tended to be higher in non-hospitalized individuals. Similarly, the neuropsychiatric symptoms of anxiety (31%) and depression (27%) were higher in the community cohort compared to the hospitalized patients (6% and 12%, respectively). Additionally, the neuropsychiatric symptoms substantially increased from mid-term follow-up to long term follow-up (i.e. past 6 months), suggesting that LH COVID-19 patients may experience increasing neuropsychiatric burden well past the initial infection. It is however not known when and whether it tapers off. On the other hand, the neurological symptoms in this cohort appear to progress from mid- to long-term highlighting that this may be the critical period of LH COVID-19 during which patients should be screen for neurological pathophysiological events and represents the critical therapeutic window. Other large retrospective cohort studies reported similar timelines [40, 42]. This may be explained by the chronic aspect of neuro-inflammation that ensues secondary to initial infection, leading to neuronal loss in that critical time period.

Taken together, the existing large cohort studies [40, 42] and meta-analyses [41] indicate that neurological and neuropsychiatric symptoms are a common feature of LH COVID-19, with specific symptoms occurring in as much as a third of the individuals who were infected with SARS-CoV2. Future research should be directed towards identifying the therapeutic strategies during the critical window, which appears to be 3–6 months post-acute illness, in an effort to decrease neuroinflammation, restore the blood brain barrier and prevent neuronal loss.
