Persistent Psychological Symptoms and the Brain in COVID-19

1. COVID-19 and Mental Health

By September 2021, the Centers for Disease Control and Prevention (CDC) reported more than 42 million confirmed cases of COVID-19 and over 672,000 reported deaths attributed to the disease in the United States alone.  These numbers – as staggering as they are – only hint at the true cost the COVID-19 pandemic has exacted over the previous year. SARS-CoV-2, the coronavirus that causes COVID-19, causes a severe acute respiratory syndrome (i.e., SARS) in infected individuals and is associated with a wide variety of other symptoms, including psychiatric symptoms. In a survey of 5412 adults in the US, the CDC found a tripling of anxiety symptoms and a quadrupling of depression in August 2020 compared to a 2019 sample (Czeisler et al., 2020). To further monitor changes in mental health during the COVID-19 pandemic, the CDC, working with the US Census Bureau, began the Household Pulse Survey (HPS). The HPS results from August 19, 2020 through February 1, 2021 show a further, significant increase in the percentage of adults with symptoms of an anxiety or depressive disorder during the past 7 days (from 36.4% to 41.5 %) (Vahratian et al., 2021). These broad surveys capture both direct and indirect effects of the pandemic on mental health. The anxiety of contagion, the effects of isolation, and the toll of economic uncertainty play a role in the increase in anxiety and depressive symptoms reported. But the coronavirus itself has direct effects on the nervous system that lead to increases in psychiatric symptoms of those infected.

An examination of health records from over 60,000 patients diagnosed with COVID-19 in the US revealed that about 1 out of every 5 received a diagnosis of a psychiatric disorder – anxiety, insomnia, and dementia among them – between two weeks and three months after their initial diagnosis (Taquet et al., 2021). Moreover, about 1 in 3 individuals previously hospitalized and diagnosed with COVID-19 show lingering neurological symptoms, including fatigue, memory or attention problems, sleep disturbances, loss of smell, and ‘brain fog’ or cognitive impairments (Pilotto, et al. 2020). Patients requiring hospitalization often have more severe cases of COVID-19, and the stress, isolation, and potential trauma associated with hospitalization may contribute to long-term symptoms. A small, cross-sectional study of patients presented to the emergency department in a hospital in Rome found a prevalence of posttraumatic stress disorder (PTSD) of 30.2% after acute COVID-19 infection, assessed 30 to 120 days following release (Janiri et al., 2021). However, the development of neurological and psychiatric symptoms post-infection is unrelated to the severity of the initial illness. These symptoms emerge post-infection in a variety of situations, including those whose illness did and did not require hospitalization; in asymptomatic individuals; and in children, often seen as less vulnerable to sever COVID (Buonsenso et al., 2021; Graham et al., 2021; Huang et al., 2021).

What are the various psychological effects of COVID-19 infection? How does the coronavirus produce such effects? And what can we learn about coronaviruses and brain function in general? To better understand the true impact of COVID-19, it is vital that we examine the acute and long-term effects that infection has on mental health. In this essay, I describe the various acute and long-term psychological, psychiatric, and neurological symptoms associated with COVID-19, outline neuroanatomical findings in infected patients that may underlie these symptoms, and discuss what we can learn about psychological disorders through the lens of COVID-19.

2. SARS-CoV-2 Associated with Persistent Mental Health Symptoms

Patricia McNamara, a neurologist at the National Hospital for Neurology and Neurosurgery, co-leads a specialty clinic tailored for COVID-19 patients with neurological symptoms. Dr. McNamara describes two categories of neurological symptoms directly associated with COVID-19 (Zimmer, 2021): Acute symptoms, seen in some sever cases of COVID-19 requiring hospitalization. These acute symptoms include confusion, delirium, strokes, peripheral nerve damage, encephalitis, and brain inflammation; and long-term symptoms (usually following milder symptoms), which include headaches, fatigue, numbness or tingling, cognitive difficulties, seizures, and inflammation of the heart. These latter symptoms often develop after the individual has recovered from the initial COVID-19 symptoms (e.g., fever, cough, shortness of breath).

The persistent or development of new symptoms following the initial bout of COVID-19 has been termed Long COVID and those with such symptoms described colloquially as ‘long-haulers.’ Chronic or Post-COVID-19 Syndrome includes those symptoms and abnormalities that persist beyond 12 weeks following the onset of COVID-19 (Nalbandian et al., 2021). An analysis of symptoms found in Long COVID patients identified 5 symptom clusters, one of which, Anxiety-tachycardia, emphasizes the neurological and/or psychiatric symptoms of the disorder. Psychiatric or neurological symptoms reported in those with lingering symptoms include depression/anxiety, fatigue, memory and/or attention problems, disturbances in sleep, ‘brain fog’ (i.e., cognitive impairments), loss of smell and taste, numbness/tingling, and headache (Graham et al., 2021; Huang et al., 2021; Pilotto et al., 2020).

In a study of cognitive function in Long-COVID, Graham and colleagues (Graham et al., 2021) examined the first 100 consecutive patients seen at the Neuro-COVID-19 clinic, a clinic specialized in the treatment of Long-COVID patients, between May and November of 2020. Patients were included if they displayed current or previous symptoms of COVID-19 and had one or more neurological symptoms lasting over 6 weeks. Half of the patients tested positive for SARS-CoV-2 while the other half did not (i.e., 50 SARS-CoV-2+ and 50 SARS-CoV-2-). Patients were predominately female (70%) with a mean age of 43.2 (+/- 11.3) years. The main neurological symptoms reported were fatigue (85%), “brain fog” (81%), headache (68%), numbness/tingling (60%), anosmia (55%), and myalgias (55%). To assess the impacts of persistent symptoms on the patient’s quality of life and cognitive functions, thirty-six percent of the patients (37 SARS-CoV-2+ and 39 SARS-CoV-2-) completed the PROMIS quality of life and NIH Toolbox cognition assessments. The results did not indicate group differences between SARS-CoV-2+ and SARS-CoV-2- (recall that both groups reported similar symptoms). However, both groups of patients scored significantly worse than expected on the PROMIS quality of life for cognition and fatigue when compared to a demographic-matched US normative population. This study highlights an important aspect of Long COVID: symptoms significantly impact the quality of life of those affected.

How common is Long COVID? In only study, researchers examined electronic health records of 1407 COVID-19 patients (community dwelling [i.e., not hospitalized]) and report that 27% had persistent symptoms after 60 days (Huang et al., 2021). In a systematic review of clinical studies, the prevalence of Long COVID ranges from 30-75% of patients experiencing at least one symptom at follow-up (Nalbandian et al., 2021).  One study found that about a third of patients with Long COVID did not have any symptoms from their initial coronavirus infection through the 10 days after they tested positive (Huang et al., 2021). These data indicate that long-term effects of Covid-19 affect a significant number of those infected. In the studies reviewed here, patients report symptoms up to and beyond 12 weeks post-infection. Additional studies are needed to evaluate if and when individuals recover from these symptoms. From these data, however, it appears that the true impact of the pandemic will continue to affect people long after the pandemic is over.

3. Long-COVID in Children

During the initial waves of the pandemic, older individuals were at risk for more severe outcomes from COVID-19. Initial reports (February 2020) suggested that only 1% of total COVID-19 infections occurred in children under 10 years of age (Wu & McGoogan, 2020). Data from May of 2021 demonstrate a significant increase in the percentage of children infected with COVID-19. According to the American Academy of Pediatrics, children represented 22.4% of new cases, accounting for 71,649 out of 319,601 cases occurring over the last week of April 2021. COVID-19 in children can produce lingering symptoms following initial infection (Buonsenso et al., 2021; Ludvigsson, 2021; Say et al., 2021), as seen in adults (Nalbandian et al., 2021). For example, data from the UK Office of National Statistics showed that 13% of COVID-19 patients under the age of 11 (and 15% aged 12-16) had at least one symptom more than a month after diagnosis.  An additional study of 129 patients under the age of 18 in Rome found that more than half had not recovered fully within four months (Buonsenso et al., 2021). Children with Long-COVID display similar symptoms to those found in adults: fatigue, muscle and joint pain, headache, insomnia, respiratory problems, and heart palpitations. (Buonsenso et al., 2021). One key finding is that the persistent symptoms were unrelated to the severity of infection. Here, too, long-term follow-up studies are required to assess the true impact the virus has on the child’s health.

4. COVID-19 and the Brain

The multiple psychiatric and neurological symptoms associated with COVID-19 – both acute and long-term – indicate underlying alterations in brain function and/or structure. SARS-CoV-2 can have either direct or indirect effects on the brain. The brain is surrounded by a protective layer called the blood brain barrier (BBB), which keeps out most pathogens. To have a direct effect on the brain, SARS-CoV-2 must cross the BBB, entering into the brain. Is there evidence of this? Autopsy studies of COVID-19 patients have found damage to multiple areas of the brain, with some evidence of virus mRNA in the brain tissue, although this  is not consistently found (Lee et al., 2020). The virus binds to cells through the S1 spike protein, which does cross the BBB (Rhea et al., 2021). One proposed pathway for virus entry into the brain is through the nose (Meinhardt et al., 2021). SARS-CoV-2 virus enters the body through specific receptors (i.e., ACE2 and TMPRSS2) that are found in multiple areas of the body, including the olfactory mucosa. Viral replication may destroy those cells or induce inflammation, contributing to the loss of taste and smell associated with COVID-19. From the olfactory mucosa, the virus may travel along the olfactory bulb and olfactory nerve into the brain. Although viral protein can be found inside those cells making up the BBB, they do not accumulate inside neurons (like some other viruses, e.g., rabies) (Meinhardt et al., 2021). This suggests that although SARS-CoV-2 can enter the brain, direct virus-mediated effects on nervous tissue is unlikely the major contributor to psychiatric symptoms.

There are multiple indirect effects that SARS-CoV-2 may have on the nervous system that may underlie psychiatric symptoms in COVID-19, including damage due to inflammation, stroke, and immune-mediated effects. Examination of brain tissue following autopsy of deceased COVID-19 patients reveals evidence of inflammation (i.e., acute disseminated encephalomyelitis) (Mukerji & Solomon, 2021), indicating a potential indirect effect by which COVID-19 infection may result in psychiatric symptoms. The virus, via an S1 spike protein, gains entry into the body through ACE2 and TMPRSS2 receptors, which are found in epithelial cells of the heart, bladder, pancreas, kidney, and nose (Muus, et al. 2020). Once in the body, the virus induces an immune response, activating pathogenic Th1 cells that secrete proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (Hu et al., 2021). The sudden rise in circulating cytokines and immune-cell hyperactivation in response to SARS-CoV-2 can produce a life-threatening systemic inflammatory syndrome called a cytokine storm. In addition to systemic effects, cytokines can cross the BBB and cause depression-like symptoms, including a loss of interest in life, an increase desire to rest and sleep, and cognitive impairments (Sutherland, 2021).

COVID-19 is associated with an increased risk of thromboses, which emerge with activation of the innate immune response (Zakeri et al., 2021). Thromboses can induce hypoxic damage to the brain either through stroke (blocking the blood supply) or hemorrhage (leaking of blood into brain tissue). Autopsy studies in COVID-19 reveal hypoxic damage associated with infarcts; hemorrhage is the most common abnormality reported (Mukerji & Solomon, 2021). In their review of autopsy studies, Murkerji & Lolomon (2021) state that a direct causal relationship between brain abnormalities and neurological symptoms in COVID-19 is not straightforward: 65% of the gross brain examinations reported no significant alterations due to illness.

In a retrospective neuroimaging study, Kremer and colleagues (2020) used MRI to examine brain abnormalities in patients with severe COVID -19. Thirty-seven patients (81% male) were evaluated. The common neurological symptoms reported included alterations in consciousness and wakefulness, confusion, and agitation. The most common MRI findings were aberrations in the medial temporal lobe (43%), white matter hemorrhagic lesions (30%), and extensive microhemorrhages (24%; Figure 1) (Kremer et al., 2020). Aberrations identified in the medial temporal love, the authors report, are frequently observed in cases of infectious encephalitis or associated with autoimmune limbic encephalitis. Patients with hemorrhage showed worse respiratory and neurological symptoms. SARS-CoV-2 mRNA was found in the cerebral spinal fluid of only one patient making the direct mechanism of viral infection unclear.

Microscopic examination of brain tissue in COVID-19 provides additional information. Here the data suggest effects resulting from the immune response, including T-lymphocyte infiltrates found in large numbers, increases in microglial activation in the brainstem, and axonal damage in a few cases (Mukerji & Solomon, 2021). Yang and colleagues (2020) examine how COVID-19 infection affects gene expression in neurological tissue. Layer 2/3 excitatory neurons show a downregulation of genes that encode proteins involved in storing and transmitting neurotransmitters (e.g., SNARE); similar changes in gene regulation are associated with cognitive dysfunction, schizophrenia, and depression (Yang et al., 2020). These alterations in neuronal gene expression may originate from inflammatory signaling that arises from viral infection of other nervous tissues, including cortical brain vasculature, meninges, and choroid plexus.  Further, inflammatory cytokines and immune cells produced in the periphery can, as stated earlier, cross the BBB into the brain. Once in brain tissue, microglia can mediate phagocytosis of neurons and astrocytes can dysregulate gene expression involved in regulating neurotransmitter homeostasis (Yang et al., 2020).

5. Concluding Remarks

As the world continues to grapple with the COVID-19 pandemic, one troubling sign is clear: COVID-19 causes persistent mental health challenges in many of those infected. Infection is associated with both acute and long-term psychological effects. During the acute phases of the illness, individuals may suffer from confusion and delirium. About one out of every four individuals present one or more linger symptoms  after 60 days from the onset of infection (Huang et al., 2021). The long-term symptoms most reported include headache, fatigue, and cognitive impairment or ‘brain fog.’ These long-term effects disproportionately affect women but have been reported in both adults and children. About a third of those with Long-COVID were initially asymptomatic with COVID-19.

Both direct and indirect effects of the virus on brain function may underlie psychological symptoms associated the acute or long-term SARS-CoV-2 infection. Inflammation resulting from infection can produce a cytokine storm, initiating a cascade of effects that can increase the likelihood of developing stroke or hemorrhage (Zakeri et al., 2021), activate programs mediating the phagocytosis of neurons, and prompting astrocytes to dysregulate genes involved in neurotransmitter homeostasis (Yang et al., 2020).

A small, but significant number of children develop multisystem inflammatory syndrome (MIS-C) following COVID-19 infection. The symptoms of MIS-C include fever, signs of general inflammation, hypotension and shock, and multiple organ dysfunction; neurological symptoms including headache, these symptoms developed days to weeks after initial infection (Dufort et al., 2020). Most MIS-C illnesses are believed to result from asymptomatic or mild COVID-19 and result from delayed immunological response to SARS-CoV-2 infection (Belay et al., 2021). According to a small longitudinal study (Penner et al., 2021), most children with SARS-CoV-2-related MIS-C (PIMS-TS in the British study) referred to as fully recover from systemic inflammation and associated symptoms; yet, after 6-months, about 20% of patients still exhibited sever emotional distress as measured by the PedsQL 4.0 Generic Core Scales and self-report.

An autoimmune disorder may underlie persistent symptoms in a small percentage of adults with Long-COVID. Postural orthostatic tachycardia syndrome (POTS) is a blood circulation disorder in which the antibodies produced after COVID infection may attack the autonomic nervous system. POTS may account for many of the symptoms of Long-COVID, including fatigue, racing heart-beat, and cognitive impairments resulting from poor blood circulation.

The pandemic continues to exact its toll on the physical and mental health of the world. What can we learn about the coronavirus and brain function? There lies within the devastation brought by the pandemic an opportunity to learn more about the brain and mental health. In February 2021, the National Institutes of Health (NIH) announced a new initiative to identify the causes of and treatments for Long-COVID. The initiative will assess the prevalence and underlying biological bases of prolonged symptoms following COVID-19 infection, among other aims. The pandemic has highlighted the role of inflammation and the immune response in affecting normal brain function leading to psychiatric symptoms. Continued exploration of the relationship between inflammation, the immune response, and psychiatric illness are warranted; such an understanding could lead to potential treatments for Long-COVID as well as other psychiatric disorders.

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