Whether you have contracted COVID-19 or not, your brain is likely to have changed over the past few months. The virus itself can cause a number of neurological problems, along with anxiety and depression.
The isolation and worry caused by the pandemic can similarly alter our brain chemistry and cause mood disorders.
In our new paper, published in Neuropsychopharmacology Reviews, we have investigated how to best overcome the brain changes linked to the pandemic.
Let’s start with COVID-19 infection. In addition to mood disorders, common symptoms include fatigue, headaches, memory loss and problems with attention.
There may be a number of reasons for these brain changes, including inflammation and cerebrovascular events (a syndrome caused by disruption of blood supply to the brain).
Research suggests that the virus may gain access to the brain via the forebrain’s olfactory bulb, which is important for the processing of smell. Loss of smell is a symptom in many patients with COVID-19.
As part of the system responsible for your sense of smell, the olfactory bulb sends information about smell to be further processed in other brain regions – including the amygdala, orbitofrontal cortex and the hippocampus – which play a major role in emotion, learning and memory.
As well as having extensive connections to other brain regions, the olfactory bulb is rich in the chemical dopamine, which is important for pleasure, motivation and action.
It may be that COVID-19 alters the levels of dopamine and other chemicals, such as serotonin and acetylcholine, in the brain, but we can’t say for sure yet.
All these chemicals are known to be involved in attention, learning, memory and mood.
These changes in the brain are likely responsible for the mood, fatigue and cognitive changes that are commonly experienced by COVID-19 patients.
This in turn may underlie the reported symptoms of stress, anxiety and depression in patients who have contracted the virus.
But it’s not just people who have contracted the COVID-19 virus that have suffered from increased anxiety and depression during the pandemic. Excessive worry over contracting or spreading the virus to other family members, as well as isolation and loneliness, can also change our brain chemistry.
Repeated stress is a major trigger for persistent inflammation in the body, which can also affect the brain and shrink the hippocampus and therefore affect our emotions. Stress can also affect levels of brain serotonin and cortisol, which can affect our mood. Eventually, these changes can cause symptoms of depression and anxiety.
The good thing about the brain, however, is that it is incredibly plastic, which means it is changeable and can compensate for damage. Even serious conditions such as memory loss and depression can be improved by doing things that alter the brain function and its chemistry.
Our paper looks at promising solutions to combat symptoms of stress, anxiety and depression – in COVID-19 patients and others.
We already know that exercise and mindfulness training – techniques that help us stay in the present – are helpful when it comes to combating brain stress. Indeed, studies have shown beneficial functional and structural changes in the brain’s prefrontal cortex (involved in planning and decision making), hippocampus and amygdala following mindfulness training.
One study showed an enhanced density of grey matter – the tissue containing most of the brain’s cell bodies and a key component of the central nervous system – in the left hippocampus after eight weeks of training (in comparison to controls).
Importantly, these are all regions that are impacted by the COVID-19 virus. Additionally, gamified cognitive training can also help improve attention, memory function and increase motivation. Those who have persistent or severe mental health symptoms may require clinical evaluation by a psychologist or psychiatrist.
In such cases, there are pharmacological and psychological treatments available, such as antidepressants or cognitive behavioural therapy.
Given that many countries haven’t completely come out of lockdown yet, and there are long delays in accessing healthcare, modern techniques such as wearable devices (activity trackers) and digital platforms (mobile apps), that can be easily integrated into daily life, are promising.
For example, activity trackers can monitor things like heart rate and sleeping patterns, indicating when the wearer may benefit from activities such as meditation, exercise or extra sleep. There are also apps that can help you reduce your stress levels yourself.
These techniques are likely be beneficial to everyone, and may help us to better promote cognitive resilience and mental health – preparing us for future critical events such as global pandemics. As a society, we need to anticipate future challenges to our brain health, cognition and wellbeing. We should be utilising these techniques in schools to promote lifelong resilience starting at an early age.
Funding: Barbara Jacquelyn Sahakian has received funding from the Wallitt Foundation and Eton College. She consults for Cambridge Cognition, Greenfield BioVentures and Cassava Sciences .Cambridge Enterprise has technology transferred Wizard and Decoder to PEAK.
Christelle Langley and Deniz Vatansever do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.
Neural spread of COVID-19: the possible routes
The SARS-CoV-2 is reported to be functionally analogous to the SARS-CoV (causative agent of SARS). The usual cellular route is viral binding to Angiotensin Converting Enzyme (ACE)-2 receptor which is widely distributed along the respiratory and gastrointestinal epithelium as well as the endothelial cell surface.
The spread to central nervous system has been correlated with increased age, high viral load, poor immunity, administration of glucocorticosteroids, history of neurotrophic viral infection in the past and increased hospitalization (Singhal, 2020). Both animal and human models studying SARS-CoV have reported various possible neural pathways.
The initial viral spread is hematogenous. In rodents, the virus has been detected in olfactory bulb 4 days after nasal inoculation and after 40 days in the pyriform cortex (Perlman et al., 1989). In another study by the same group, destruction of olfactory bulb prevented the neural dissemination of the coronavirus.
It showed that neural proliferation can happen in the cells of cortex, hypothalamus, thalamus, amygdala, basal ganglia and interestingly also in the brain stem (Perlman et al., 1990). Dinein and kinesin are the two proteins that help in anterograde and retrograde transmission of the virus in neurons.
The nucleus of the solitary fascicle in brainstem (that receives information from the chemoreceptors to alter the respiratory effort) is one of the important sites of viral load during post-mortem in animal models (Wu et al., 2020). This has been postulated as a putative theory how the virus can impair breathing-effort apart from the pulmonary involvement.
Labored breathing or dyspnea is a direct clinical antecedent to Acute Respiratory Distress Syndrome (ARDS) in COVID-19, which in turn is linked to morbidity and mortality (Gattinoni et al., 2020).
Neuropsychiatric manifestations of COVID-19: summary of current evidence
During the first wave of infection in China, Chen et al. (2020b) described the epidemiological and clinical characteristics of 99 patients with SARS-CoV-2 pneumonia. 9 percent and 4 percent of them had confusional state and headache respectively.
Few months later, Mao et al. (2020) retrospectively analyzed 214 patients with molecular diagnosis of COVID-19 from three different hospitals. 36.4 percent had neuropsychiatric symptoms, which were differentiated into central, peripheral/musculoskeletal and psychological.
The central were commonest, with dizziness and headache being most prevalent. Dysgeusia, anosmia and muscle pain were most common among the peripheral symptoms.
Anxiety, depression and delirium were the common psychiatric manifestations.
The neurological symptoms had direct relation with the severity of the illness, serum antibody titer and blood lymphocyte counts. Also, though strokes, encephalopathies and peripheral neuropathies were rare (2 percent of the neuropsychiatric complaints), they were present in the elderly and immunocompromised group.
A specific sub-group had ataxia and gait disturbances who also showed decreased CRP, impaired renal functions, poor oxygen saturation and increased need for ventilation. This was again a pointer towards brain-stem involvement. Similar blood findings have been found in children with CoV-2 infection and encephalitis (McAbee et al., 2020).
It has been postulated that decreased peripheral lymphocytes can either be due to poor immunological response altogether or increased CNS tissue migration. In SARS pneumonia with related clinical findings, Granulocyte Macrophage Colony-stimulating factor (GM-SCF) had been tried as a therapeutic agent, as it helps in the generation and propagation of CNS-targeted monocytes (Verma, 2003).
On similar lines, peripheral lymphocyte counts, CRP and ESR have been used as prognostic markers in COVID-19 pneumonia and GM-CSF is popularized in research as a potential therapeutic target to prevent neuropsychiatric sequalae (Zhou et al., 2020).
The various neuropsychiatric manifestations that have so far been reported in COVID-19 are detailed below. As data is still emerging, various case reports and series mentioned in the literature do not necessarily imply causation but can highlight the associative neuropsychiatric impact.
Delirium and confusional states
Impaired sensorium ranging from mild drowsiness to delirium has been reported in few older adults hospitalized due to SARS-CoV-2 pneumonia, when compared to the younger participants (Liu et al., 2020). They had associated comorbidities and increased Pulmonary Severity Index (PSI).
In another case series of older adults with premorbid cognitive decline (Beach et al., 2020), delirium was observed with COVID-19 infection which necessitated ICU admission. Unique features seen were alogia, abulia, rigidity and increased inflammatory markers.
Obviously, pre-existing cognitive deficits, age, lack of stimulation, metabolic disturbances, urinary retention, constipation and prolonged hospitalization might be the associated contributing factors. Intensive care unit (ICU) delirium management and that during mechanical ventilation have been included in various treatment guidelines for COVID-19 (Xie et al., 2020).
Especially in palliative care settings for COVID-19, among the most severely ill patients and elderly, the prevalence of delirium has been high. Tissue hypoxia, desaturation, neuro-inflammatory cytokines (regulating the ‘cytokine storm’ of SARS-CoV-2) and use of hydroxychloroquine has been associated with prolonged delirium in these patients (Wu and McGoogan, 2020).
Effective management of sleep disturbance and early correction of sensorium are reported to be vital in post intensive care syndrome (PICS) and decreasing morbidity. Melatonin is being studied to have a promising role for the same in COVID-19 patients (Zhang et al., 2020a).
Dysfunction of olfaction and taste sensation
During the SARS outbreak, studies have shown its affinity for the nasal ciliary epithelium. This property has been theorized to be common in the CoV group (Chilvers et al., 2001). In fact, the ACE-2 receptor that is the target for SARS-CoV-2 is expressed in the olfactory lining as well.
This might be a probable mechanism for anosmia or hyposmia early in the COVID-19 infection, though the exact pathways are still being studied. The proportion of cases having olfactory and gustatory disturbances have ranged from 12 to 32 percent in a multi-site European study of COVID-19 cases (Lechien et al., 2020).
Olfactory dysfunction has even been considered as a biomarker for COVID-19 infection (Moein et al., 2020). They proposed that the predilection for the gustatory chemoreceptors and the higher order centers involved in taste and smell perception are more for the SARS-CoV-2 than its earlier congeners.
Hyposmia has also been proposed as an early marker of neurological involvement in COVID-19 based on a European case-series, though structured research is yet to be done (Vaira et al., 2020).
Post-viral olfactory syndrome, a known complication of Influenza and Herpes virus infections, can also be associated with COVID-19, as the cribriform plate penetration and pyriform cortex involvement is common for all.
Acute psychosis and manic disorders
So far, there have been only two case reports mentioning acute psychotic disturbances in cases of COVID-19, one of whom had schizophrenia (Fischer et al., 2020; Zulkifli et al., 2020). However, many known patients of schizophrenia have had exacerbations after getting affected with SARS-CoV-2 even while on medications (Yao et al., 2020).
Whether there is a neuro-biological basis to it is unclear. The study by Mao et al. (2020) mentioned people to have behavioural disturbances. SARS infection has been associated with acute psychiatric manifestations with increased antibody titer, which points out a probable relationship between coronavirus infections and psychosis (Cheng et al., 2004).
The CoV also proliferates in the limbic structures, as shown in animal models that further supports its association with behavior (Subbarao and Roberts, 2006). Also, there has been debate whether vertical transmission is likely in COVID-19 positive mothers that can increase the neuro-developmental risk of psychosis in their off springs, similar to influenza (Qiao, 2020).
As multiple issues like drug compliance, lack of review, poor awareness and stress diathesis are involved during any biological disaster, it is difficult to conceptualize a direct link between increase of pre-existing psychiatric illnesses and the neurotropic effects of the virus.
Encephalitis and encephalopathies
The classic Von Economo’s encephalitis (1917) during the Spanish flu pandemic traditionally marks the association of viral infections and the brain. It was characterized by increased somnolence, behavioral disturbances, catatonic states and movement disorders. Similar encephalitis sequelae with altered consciousness have been reported during the H1N1 influenza and MERS infection (Alakare et al., 2010).
Though initially reported as a rare association in the current pandemic, multiple case reports of encephalitis have been reported since the first wave of infection. Moriguchi et al. (2020) reported the first case of meningoencephalitis in a COVID-19 patient with recent onset convulsions, who showed hyperintensity of bilateral mesial temporal lobes on brain imaging.
Of special interest was a case of acute necrotizing haemorrhagic encephalopathy in a woman affected with COVID-19 where magnetic resonance tomography (MRI) of the brain showed rim-enhancing lesions in bilateral thalami, medial temporal lobes and sub-insular regions (Poyiadji et al., 2020).
The ‘cytokine storm’ responsible for ARDS and multi-organ dysfunction syndrome (MODS) in COVID-19 is marked by the surge of inflammatory cytokines in the circulation namely Interleukins (IL)-6, 8, 10, 18, Tumour Necrosis Factor (TNF)-alpha, Interferon-gamma and GM-CSF (Mehta et al., 2020).
Most of these factors were increased in 20 percent of COVID-19 positive cases in the study reported by Chen et al. (2020a,b,c), who were diagnosed to have persistent encephalopathy. The association of exaggerated cell-mediated immunity with encephalitis has been studied in SARS as well (Huang et al., 2005).
Especially in the COVID-19 patients receiving intensive care and ventilation, increased somnolence, agitation and confusion have been seen in those who had increased blood cytokines (Yang et al., 2020). Further, factors like pre-existing cognitive deficits, age and chronic psychiatric illness can increase the post-ICU recovery time and lead to long-lasting neuropsychological sequelae in such patients.
Overall, encephalopathy has been considered to be the most serious acute neurological effect of COVID-19, as steroids (an important component of treatment) are restricted due to the pulmonary decompensation.
Acute cerebrovascular events
In the retrospective study by Mao et al. (2020) among SARS-CoV-2 pneumonia cases, six patients reported acute cerebrovascular accident (CVA), in which most were ischemic strokes that developed within a week of pulmonary presentation.
Another study of neurological symptoms in COVID-19 mentioned acute CVA to be more associated with the elderly, lower platelet count and increased D-dimer levels (Liu et al., 2020,b). A case-series from United States (US) reported four elderly patients of COVID-19 who presented to the emergency with stroke, three of them had no prior CVA or associated risk factors (Avula et al., 2020).
A probable mechanism might be viral effects on the ACE-2 receptors on the endothelial cells and platelets that can lead to hypertension and hyper-coagulable states respectively. But the cause or effect dilemma is debatable. On the other side, recurrent CVA has also been mentioned as a risk for severe COVID-19 infections. A pooled analysis of the published literature showed a 2.5-fold increase in the risk of severe CoV-2 infection in stroke patients (Aggarwal et al., 2020).
However, there was no significant association between stroke and mortality due to COVID-19. A case series by Oxley et al. (2020) reported five young patients presenting with stroke and comorbid COVID-19. A comparative theoretical analysis of non-human primate pathogenesis model in SARS, MERS and COVID-19 has implicated the SARS-CoV-2 spike protein to have a neuro-inflammatory role contributing to endothelial dysfunction and blood stasis (Rockx et al., 2020).
Though evidence is equivocal, this study warned about the potential role of ACE-inhibitors and ibuprofen in facilitating coronavirus infections. A recent study from Netherlands demonstrated that 31 percent of ICU patients developed thrombotic complications (Klok et al., 2020).
Another study concluded that thromboplastin time-based clot waveform analysis (CWA) can determine hypercoagulability and risk of strokes associated with high viral loads in COVID-19 (Tan et al., 2020). Multiple reports of pulmonary embolism are also available (Chen et al., 2020a; Danzi et al., 2020). Keeping in mind this probable bi-directional relationship, separate guidelines have emerged for stroke management during the times of COVID-19.
Khosravani et al. (2020) has also proposed a Protected Code Stroke (PCS) framework during the ongoing pandemic which modifies the screening guidelines and includes rational use of personal protective equipment (PPE) and crisis management.
Possible neuropsychiatric sequelae of COVID-19: insights from earlier CoV studies
The COVID-19 pandemic is still in its early stages. The human-human transmission is higher than its earlier congeners (Singhal, 2020) and the projected spread is ominous. As efforts for containment are on the rise, the upcoming months and years will add more to the understanding of long-term neuropsychiatric sequelae in COVID-19.
Even if that affects a less proportion of cases, it is going to be associated with an immense public health burden. The SARS and MERS outbreaks also had far-reaching consequences that included chronic encephalopathies, neuromuscular disorders, neuropathies, demyelinating and degenerative conditions occurring long time after the initial presentation (Hui et al., 2009).
As health-care priorities change with the timing of the pandemic, the initial flattening of curve might be assuring for the spread but at the same time brings about more serious and chronic manifestations of the infection, that remain mostly unknown till date.
Though the data of long-term manifestations is yet not available for COVID-19, a few possible long-term neuropsychiatric conditions are proposed based on similar occurrences in the past CoV outbreaks.
Viral infections involving the brain are known to cause myopathy, neuropathy, GBS and brainstem encephalitis (Arciniegas and Anderson, 2004). These often take a month to manifest after the respiratory complaints. Multiple sclerosis patients had shown worsening during the SARS-Co-V infection and post-mortem studies have shown increased viral ribonucleic acid (RNA) load.
A study by Wu et al. (2020) attributed the demyelinating effect of coronaviruses to tissue hypoxia, direct neuronal injury, neuro-inflammation and major histocompatibility complex (MHC) mediated cell-mediated-immune (CMI) response to the virus. Murine models have shown the neuro-muscular concentration of the viruses to be strain dependent (Bender et al., 2010).
Peripheral neuropathies in COVID-19 have been reported in few cases across the globe (Abdelnour et al., 2020). A comprehensive review of neurological symptoms in coronavirus diseases mentions COVID-19 as a potential risk factor for long-term demyelinating and neuromuscular conditions (Troyer et al., 2020).
Chronic psychiatric conditions
There have been worsening of pre-existing psychiatric conditions namely mood and bipolar disorders, especially in the vulnerable populations. Increased incidence of depression, anxiety, adjustment disorders, acute stress reaction, somatization and obsessive-compulsive disorders have also been reported (Rajkumar, 2020).
Whether they are due to the adverse psychosocial situations and uncertainty of the pandemic crisis or whether the virus has a direct effect on the brain contributing to this, has not been well studied. Animal models have shown increased behavioral problems and poor performance in maze-finding, social play, mating and learned helplessness tasks after nasal inoculation of coronavirus (Fung and Liu, 2014).
The translation to humans is still far-fetched. The mood disorders consequent to the SARS epidemic were related to host immune reaction (Hui et al., 2009). Recent studies among COVID-19 patients have found greater occurrence of depressive and anxiety disorders in people who are in quarantine, front-line workers or among family members of affected patients (Qiu et al., 2020).
However, the biological markers for same have not yet been studied. Okusaga et al. (2011) while studying people with SARS-CoV infection, found exacerbations of mood disorders and psychosis in the long run but no association with the typology, mood polarity or suicidality. However, pandemic responses have classically been associated with marked increase in psychiatric morbidity.
There has been specific rise in pain, depressive, obsessive compulsive disorders (OCD) and post-traumatic stress disorders (PTSD). The PTSD following such biological disasters might often be complex and chronic, unlike the commonly described ones. As time progresses, with the global burden of SARS-CoV-2 infection, more data on the psychiatric consequences of this pandemic are expected to come.
There is a theoretical risk for any coronavirus infected patient to develop Parkinson’s like features, as the virus has been shown to proliferate in the basal ganglia in murine models (Fishman et al., 1985). Borrowing from the motor involvement in ‘encephalitis lethargica’, movement disorders can be potential risk for any neurotrophic viral infection. Anti-CoV antibodies found in the cerebrospinal fluids of patients with motor disorders might have been incidental (Fazzini et al., 1992), as no clear literature is present about association of clinical Parkinson’s disease with CoV infections. Also, considering coronavirus can stay latent in neural tissue for a long time (Johnson, 1984), there might be a plausible risk for chronic degenerative conditions like dementia in the long run.
Encephalopathy or cerebral edema consequent to CoV pathogenesis can lead to new-onset seizures or reactivation of latent epilepsy (Wu et al., 2020). The associated psychological stress can also be a triggering factor.
A couple of case reports mention patients with COVID-19 presenting with generalized tonic-clonic seizures (Karimi et al., 2020; Sohal and Mossammat, 2020). One however had the primary diagnosis of encephalitis.
Drug compliance risks during pandemics can increase the risk of status epilepticus, as reported earlier during the SARS outbreak (Lai et al., 2005). Certain anti-virals like remdesavir and lopinavir that have been used in COVID-19 patients can have cytochrome-based interactions with common anti-epileptics. The direct epileptogenic potential of CoV is however not established.
Neuropsychiatric effects of COVID-19: possible pathogenic mechanisms
Even though research in this field has just begun, based on the pathogenic models of the earlier CoV infections, here are some possible mechanisms in which SARS-CoV-2 might cause the above-mentioned manifestations. These are summarized with the evidence as under (Table 1 ).
Possible mechanisms of pathogenesis for the neuropsychiatric manifestations of COVID-19.
|Mechanism of pathogenesis||Details||Neuropsychiatric effects|
|Direct injury (Blood circulation)|
(Koyuncu et al., 2013; Desforges et al., 2020)
|• Exaggerated immune response• Cytokines increasing blood-brain-barrier (BBB) permeability||• Encephalopathy• Delirium and acute confusional state|
|Direct injury (Neuronal route)|
(Mori, 2015; Bohmwald et al., 2018)
|• Predilection for olfactory epithelium, bulb and vagal centers• Anterograde and retrograde neural proliferation via dynein and kinesin• Structural preference for the forebrain, basal ganglia and hypothalamus||• Anosmia• Dysguesia• Psychiatric disorders|
(Abdennour et al., 2012; Guo et al., 2020)
|• Impaired pulmonary exchange and pulmonary oedema can cause cerebral hypoxia• Cerebral oedema, vasodilation, ischaemia and vascular congestion• Increased intracranial pressure||• Encephalopathy• Somnolence• Coma• Headache• Confusion|
(Fu et al., 2020; Mehta et al., 2020; Wan et al., 2020)
|• Cytokine storm (surge of peripheral IL-6,8,10,18, TNF-alpha, etc.)• Systemic Inflammatory Response Syndrome (SIRS)• Upregulation of oligodendrocytes and astrocytes (increased release of IL-15, TNF-alpha)• Leaky BBB• Disturbed neurotransmission||• Encephalitis• MODS• Acute psychosis• Seizures|
|Immune cell transmigration to CNS|
(Wohleb et al., 2015; Desforges et al., 2020)
|• Increased neuro-inflammation• Microglial activation• Neural and glial cells as latent ‘viral-carriers’||• Both acute and chronic neuropsychiatric effects|
|ACE-2 and CoV spike protein interaction|
(Miller and Arnold, 2019; Wrapp et al., 2020)
|• Vascular and endothelial damage• Hyper-coagulability• Increased blood-pressure• Microangiopathy||• Cerebro-vascular accidents• Pulmonary and cerebral venous thromboembolism• Risk of chronic neurodegeneration|
(Kim et al., 2017; Rose, 2017)
|• Molecular mimicry (cross-reaction of myelin, glia and beta-2 glycoprotein with viral epitopes||• Demyelination• GBS• Neuropathy|
(Reinhold and Rittner, 2017)
|• High ‘viral-latency’ in CNS• Lack of MHC in brain• Homeostasis of neural issue||• Persistent or relapsing-remitting neurological sequelae• Reactivation of seizures• Chronic psychiatric conditions|
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422836/
Source: The Conversation