SARS-CoV-2 infection produces neuroinflammation as well as neurological, cognitive (i.e., brain fog), and neuropsychiatric symptoms (e.g., depression, anxiety), which can persist for an extended period (6 months) after resolution of the infection. The neuroimmune mechanism(s) that produces SARS-CoV-2-induced neuroinflammation has not been characterized. Proposed mechanisms include peripheral cytokine signaling to the brain and/or direct viral infection of the CNS. Here, we explore the novel hypothesis that a structural protein (S1) derived from SARS-CoV-2 functions as a pathogen-associated molecular pattern (PAMP) to induce neuroinflammatory processes independent of viral infection. Prior evidence suggests that the S1 subunit of the SARS-CoV-2 spike protein is inflammatory in vitro and signals through the pattern recognition receptor TLR4. Therefore, we examined whether the S1 subunit is sufficient to drive 1) a behavioral sickness response, 2) a neuroinflammatory response, 3) direct activation of microglia in vitro, and 4) activation of transgenic human TLR2 and TLR4 HEK293 cells. Adult male Sprague-Dawley rats were injected intra-cisterna magna (ICM) with vehicle or S1. In-cage behavioral monitoring (8 h post-ICM) demonstrated that S1 reduced several behaviors, including total activity, self-grooming, and wall-rearing. S1 also increased social avoidance in the juvenile social exploration test (24 h post-ICM). S1 increased and/or modulated neuroimmune gene expression (Iba1, Cd11b, MhcIIα, Cd200r1, Gfap, Tlr2, Tlr4, Nlrp3, Il1b, Hmgb1) and protein levels (IFNγ, IL-1β, TNF, CXCL1, IL-2, IL-10), which varied across brain regions (hypothalamus, hippocampus, and frontal cortex) and time (24 h and 7d) post-S1 treatment. Direct exposure of microglia to S1 resulted in increased gene expression (Il1b, Il6, Tnf, Nlrp3) and protein levels (IL-1β, IL-6, TNF, CXCL1, IL-10). S1 also activated TLR2 and TLR4 receptor signaling in HEK293 transgenic cells. Taken together, these findings suggest that structural proteins derived from SARS-CoV-2 might function independently as PAMPs to induce neuroinflammatory processes via pattern recognition receptor engagement. 

SARS-CoV-2 spike S1 subunit induces neuroinflammatory, microglial and behavioral sickness responses: Evidence of PAMP-like properties

This systematic review evaluated the impact of the COVID-19 pandemic on obsessive–compulsive symptoms. Most studies showed that obsessive–compulsive symptoms worsened during the early stages of the pandemic, particularly for individuals with contamination-related obsessive–compulsive disorder (OCD), though other symptoms dimensions were found to worsen as well. Many patients and individuals in the general population experienced new obsessive–compulsive-like symptoms centered on COVID-19. Self-reported rates of symptom exacerbation and COVID-19-focused symptoms were consistently lower in studies that recruited patients from specialty clinics (compared to online samples). Most studies were conducted in Spring/Summer, 2020. The COVID-19 pandemic has been an enormous stressor for individuals with OCD, especially for those with contamination symptoms. Regardless, there is strong reason to believe gold standard treatment approaches for OCD have maintained strong efficacy. Disseminating and effectively delivering evidence-based treatments for OCD is an urgent public health priority.

/pdf/obsessive-compulsive-disorder-during-the-covid-19-pandemic-a-2rmfe1b8u9.pdf

Obsessive-Compulsive Disorder During the COVID-19 Pandemic: a Systematic Review.

Post-Acute Sequelae of SARS CoV-2 infection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs. Reports of persistent or newly emergent symptoms, including those related to the nervous system, have increased over the course of the pandemic, leading to the introduction of post-COVID-19 syndrome. However, this novel syndrome is still ill-defined and structured objectification of complaints is scarce. Therefore, we performed a prospective observational cohort study to better define and validate subjective neurological disturbances in patients with post-COVID-19 syndrome. A total of 171 patients fulfilling the post-COVID-19 WHO Delphi consensus criteria underwent a comprehensive neurological diagnostic work-up including neurovascular, electrophysiological, and blood analysis. In addition, magnetic resonance imaging (MRI) and lumbar puncture were conducted in subgroups of patients. Furthermore, patients underwent neuropsychological, psychosomatic, and fatigue assessment. Patients were predominantly female, middle-aged, and had incurred mostly mild-to-moderate acute COVID-19. The most frequent post-COVID-19 complaints included fatigue, difficulties in concentration, and memory deficits. In most patients (85.8%), in-depth neurological assessment yielded no pathological findings. In 97.7% of the cases, either no diagnosis other than post COVID-19 syndrome, or no diagnosis likely related to preceding acute COVID-19 could be established. Sensory or motor complaints were more often associated with a neurological diagnosis other than post-COVID-19 syndrome. Previous psychiatric conditions were identified as a risk factor for developing post-COVID-19 syndrome. We found high somatization scores in our patient group that correlated with cognitive deficits and the extent of fatigue. Albeit frequently reported by patients, objectifiable affection of the nervous system is rare in post-COVID-19 syndrome. Instead, elevated levels of somatization point towards a pathogenesis potentially involving psychosomatic factors. However, thorough neurological assessment is important in this patient group in order to not miss neurological diseases other than post-COVID-19. 

https://link.springer.com/content/pdf/10.1007/s40120-022-00395-z.pdf

Post-COVID-19 Syndrome is Rarely Associated with Damage of the Nervous System: Findings from a Prospective Observational Cohort Study in 171 Patients

There is accumulating evidence in the literature indicating that a number of patients with coronavirus disease 2019 (COVID-19) may experience a range of neuropsychiatric symptoms, persisting or even presenting following the resolution of acute COVID-19. Among the neuropsychiatric manifestations more frequently associated with ‘long COVID’ are depression, anxiety, post-traumatic stress disorder, sleep disturbances, fatigue and cognitive deficits, that can potentially be debilitating and negatively affect patients' wellbeing, albeit in the majority of cases symptoms tend to improve over time. Despite variations in results obtained from studies using different methodological approaches to define ‘long COVID’ syndrome, the most widely accepted factors associated with a higher risk of developing neuropsychiatric manifestations include the severity of foregoing COVID-19, the female sex, the presence of comorbidities, a history of mental health disease and an elevation in the levels of inflammatory markers, albeit further research is required to establish causal associations. To date, the pathophysiological mechanisms implicated in neuropsychiatric manifestations of ‘long COVID’ remain only partially elucidated, while the role of the indirect effects of the COVID-19 pandemic, such as social isolation and uncertainty concerning social, financial and health recovery post-COVID, have also been highlighted. Given the alarming effects of ‘long-COVID’, interdisciplinary cooperation for the early identification of patients who are at a high risk of persistent neuropsychiatric presentations, beyond COVID-19 recovery, is crucial to ensure that appropriate integrated physical and mental health support is provided, with the aim of mitigating the risks of long-term disability at a societal and individual level.

/pdf/long-covid-and-neuropsychiatric-manifestations-review-3hgqzmso.pdf

Long COVID and neuropsychiatric manifestations (Review)

It has become evident that coronavirus disease 2019 (COVID-19) has a multi-organ pathology that includes the brain and nervous system. Several studies have also reported acute psychiatric symptoms in COVID-19 patients. An increasing number of studies are suggesting that psychiatric deficits may persist after recovery from the primary infection. In the current systematic review, we provide an overview of the available evidence and supply information on potential risk factors and underlying biological mechanisms behind such psychiatric sequelae. We performed a systematic search for psychiatric sequelae in COVID-19 patients using the databases PubMed and Embase. Included primary studies all contained information on the follow-up period and provided quantitative measures of mental health. The search was performed on June 4th 2021. 1725 unique studies were identified. Of these, 66 met the inclusion criteria and were included. Time to follow-up ranged from immediately after hospital discharge up to 7 months after discharge, and the number of participants spanned 3 to 266,586 participants. Forty studies reported anxiety and/or depression, 20 studies reported symptoms- or diagnoses of post-traumatic stress disorder (PTSD), 27 studies reported cognitive deficits, 32 articles found fatigue at follow-up, and sleep disturbances were found in 23 studies. Highlighted risk factors were disease severity, duration of symptoms, and female sex. One study showed brain abnormalities correlating with cognitive deficits, and several studies reported inflammatory markers to correlate with symptoms. Overall, the results from this review suggest that survivors of COVID-19 are at risk of psychiatric sequelae but that symptoms generally improve over time.

Samia Joca

Papers

Psychiatric and neuropsychiatric sequelae of COVID-19 - A systematic review.