Mitochondria, the cellular powerhouses with bacterial evolutionary origins, play a pivotal role in maintaining neuronal function and cognitive health. Several viruses have developed sophisticated mechanisms to target and disrupt mitochondrial function which contribute to cognitive decline and neurodegeneration. The interplay between viruses and mitochondria might be traced to their co-evolutionary history with bacteria and may reflect ancient interactions that have shaped modern mitochondrial biology.

Neurotropic pathogens, notably, herpesviruses, have been associated with significant neuropsychiatric effects. As a group, these pathogens can exploit molecular mimicry mechanisms to manipulate the host central nervous system to their advantage. Here, we present a systematic computational approach that may ultimately be used to unravel protein-protein interactions and molecular mimicry processes that have not yet been solved experimentally. Toward this end, we validate this approach by replicating a set of pre-existing experimental findings that document the structural and functional similarities shared by the human cytomegalovirus-encoded UL144 glycoprotein and human tumor necrosis factor receptor superfamily member 14 (TNFRSF14). We began with a thorough exploration of the Homo sapiens protein database using the Basic Local Alignment Search Tool (BLASTx) to identify proteins sharing sequence homology with UL144. Subsequently, we used AlphaFold2 to predict the independent three-dimensional structures of UL144 and TNFRSF14. This was followed by a comprehensive structural comparison facilitated by Distance-Matrix Alignment and Foldseek. Finally, we used AlphaFold-multimer and PPIscreenML to elucidate potential protein complexes and confirm the predicted binding activities of both UL144 and TNFRSF14. We then used our in silico approach to replicate the experimental finding that revealed TNFRSF14 binding to both B- and T-lymphocyte attenuator (BTLA) and glycoprotein domain and UL144 binding to BTLA alone. This computational framework offers promise in identifying structural similarities and interactions between pathogen-encoded proteins and their host counterparts. This information will provide valuable insights into the cognitive mechanisms underlying the neuropsychiatric effects of viral infections.

Prion’ is a term used to describe a protein infectious particle responsible for several neurodegenerative diseases in mammals, e.g., Creutzfeldt-Jakob disease. The novelty is that it is protein based infectious agent not involving a nucleic acid genome as found in viruses and bacteria. Prion disorders exhibit, in part, incubation periods, neuronal loss, and induce abnormal folding of specific normal cellular proteins due to enhancing reactive oxygen species associated with mitochondria energy metabolism. These agents may also induce memory, personality and movement abnormalities as well as depression, confusion and disorientation. Interestingly, some of these behavioral changes also occur in COVID-19 and mechanistically include mitochondrial damage caused by SARS-CoV-2 and subsequenct production of reactive oxygen species. Taken together, we surmise, in part, long COVID may involve the induction of spontaneous prion emergence, especially in individuals susceptible to its origin may thus explain some of its manesfestions post-acute viral infection.

Artificial Intelligence (AI), which is the general term used to describe technology that simulates human cognition [...].

Mitochondria are complex endosymbionts that evolved from primordial purple nonsulfur bacteria. The incorporation of bacteria-derived mitochondria facilitates a more efficient and effective production of energy than what could be achieved based on previous processes alone. In this case, endosymbiosis has resulted in the seamless coupling of cytochrome c oxidase and F-ATPase to maximize energy production. However, this mechanism also results in the generation of reactive oxygen species (ROS), a phenomenon that can have both positive and negative ramifications on the host. Recent studies have revealed that neuropsychiatric disorders have a pro-inflammatory component in which ROS is capable of initiating damage and cognitive malfunction. Our current understanding of cognition suggests that it is the product of a neuronal network that consumes a substantial amount of energy. Thus, alterations or perturbations of mitochondrial function may alter not only brain energy supply and metabolite generation, but also thought processes and behavior. Mitochondrial abnormalities and oxidative stress have been implicated in several well-known psychiatric disorders, including schizophrenia (SCZ) and bipolar disorder (BPD). As cognition is highly energy-dependent, we propose that the neuronal pathways underlying maladaptive cognitive processing and psychiatric symptoms are most likely dependent on mitochondrial function, and thus involve brain energy translocation and the accumulation of the byproducts of oxidative stress. We also hypothesize that neuropsychiatric symptoms (e.g., disrupted emotional processing) may represent the vestiges of an ancient masked evolutionary response that can be used by both hosts and pathogens to promote self-repair and proliferation via parasitic and/or symbiotic pathways.

The bacterial origin of mitochondria has been a widely accepted as an event that occurred about 1.45 billion years ago and endowed cells with internal energy producing organelle. Thus, mitochondria have traditionally been viewed as subcellular organelle as any other – fully functionally dependent on the cell it is a part of. However, recent studies have given us evidence that mitochondria are more functionally independent than other organelles, as they can function outside the cells, engage in complex “social” interactions, and communicate with each other as well as other cellular components, bacteria and viruses. Furthermore, mitochondria move, assemble and organize upon sensing different environmental cues, using a process akin to bacterial quorum sensing. Therefore, taking all these lines of evidence into account we hypothesize that mitochondria need to be viewed and studied from a perspective of a more functionally independent entity. This view of mitochondria may lead to new insights into their biological function, and inform new strategies for treatment of disease associated with mitochondrial dysfunction.

[...]a "leaky" BBB may facilitate direct viral access to cortical neurons involved in the processing and integration of cognitive behaviors. Viruses may elicit CNS dysfunction via direct penetration of the BBB or they may enter the brain by hijacking the immune cell trafficking network (e.g., via circulating macrophages).11 Alternatively, active molecular agents generated by virus infection at a distant site (e.g., the lung) may have the capacity to modify the cognitive function of the host.12 CNS tissues may also serve as virus reservoirs, thereby promoting viral persistence and leading to chronic and/or recurrent cognitive dysfunction.12 Interestingly, the capacity to target the brain may be the result of virus-directed natural selection, as this process may ultimately promote the longevity and persistence of these pathogens. Bidirectional immune cell trafficking together with the development of virus-induced inflammation at the vascular endothelium may enhance normal immune cell trafficking to the brain, similar to a phenomenon that has been already reported in cases of Alzheimer's disease.13 Likewise, the virus-induced cytokine storm and enhanced immune cell trafficking may result in inflammation-associated psychiatric manifestations similar to those reported in cases of dementia, HIV infection, and post-cardiotomy delirium.11 Insights into the molecular basis of bidirectional trafficking and the limited protection provided by the selectively-penetrable BBB offer the opportunity for the development of efficacious novel therapeutics. [...]a full characterization of cognitive changes associated with SARS-CoV-2 and other severe virus infections will be critical for the diagnosis, prognosis, and plans for long-term care of these patients.

Long COVID, in which disease-related symptoms persist for months after recovery, has led to a revival of the discussion of whether neuropsychiatric long-term symptoms after viral infections indeed result from virulent activity or are purely psychological phenomena. In this review, we demonstrate that, despite showing differences in structure and targeting, many viruses have highly similar neuropsychiatric effects on the host. Herein, we compare severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus 1 (HIV-1), Ebola virus disease (EVD), and herpes simplex virus 1 (HSV-1). We provide evidence that the mutual symptoms of acute and long-term anxiety, depression and post-traumatic stress among these viral infections are likely to result from primary viral activity, thus suggesting that these viruses share neuroinvasive strategies in common. Moreover, it appears that secondary induced environmental stress can lead to the emergence of psychopathologies and increased susceptibility to viral (re)infection in infected individuals. We hypothesize that a positive feedback loop of virus-environment-reinforced systemic responses exists. It is surmised that this cycle of primary virulent activity and secondary stress-induced reactivation, may be detrimental to infected individuals by maintaining and reinforcing the host's immunocompromised state of chronic inflammation, immunological strain, and maladaptive central-nervous-system activity. We propose that this state can lead to perturbed cognitive processing and promote aversive learning, which may manifest as acute, long-term neuropsychiatric illness.

The incidence of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent for coronavirus disease 2019 (COVID-19), has dramatically escalated following the initial outbreak in China, in late 2019, resulting in a global pandemic with millions of deaths. Although the majority of infected patients survive, and the rapid advent and deployment of vaccines have afforded increased immunity against SARS-CoV-2, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized. These include, but are not limited to, chronic pulmonary disease, cardiovascular disorders, and proinflammatory-associated neurological dysfunction that may lead to psychological and neurocognitive impairment. A major component of cognitive dysfunction is operationally categorized as "brain fog" which comprises difficulty concentrating, forgetfulness, confusion, depression, and fatigue. Multiple parameters associated with long-term neuropsychiatric sequelae of SARS-CoV-2 infection have been detailed in clinical studies. Empirically elucidated mechanisms associated with the neuropsychiatric manifestations of COVID-19 are by nature complex, but broad-based working models have focused on mitochondrial dysregulation, leading to systemic reductions of metabolic activity and cellular bioenergetics within the CNS structures. Multiple factors underlying the expression of brain fog may facilitate future pathogenic insults, leading to repetitive cycles of viral and bacterial propagation. Interestingly, diverse neurocognitive sequelae associated with COVID-19 are not dissimilar from those observed in other historical pandemics, thereby providing a broad and integrative perspective on potential common mechanisms of CNS dysfunction subsequent to viral infection. Poor mental health status may be reciprocally linked to compromised immune processes and enhanced susceptibility to infection by diverse pathogens. By extrapolation, we contend that COVID-19 may potentiate the severity of neurological/neurocognitive deficits in patients afflicted by well-studied neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Accordingly, the prevention, diagnosis, and management of sustained neuropsychiatric manifestations of COVID-19 are pivotal health care directives and provide a compelling rationale for careful monitoring of infected patients, as early mitigation efforts may reduce short- and long-term complications.

Trait anxiety is characterized as a constant and often subliminal state that persists during daily life. Interoception is the perception of internal states and sensations, including from the autonomic nervous system. This review aims to develop a predictive model to explain the emergence, manifestations, and maintenance of trait anxiety. The model begins with the assumption that anxiety states arise from active interoceptive inference. The subsequent activation of autonomic responses results from aversive sensory encounters. A cognitive model is proposed for trait anxiety that includes the aversive sensory components from interoception, exteroception, and proprioception. A further component of the hypothesis is that repeated exposure to subliminal anxiety-evoking sensory elements can lead to an overgeneralization of this response to other inputs that are generally non-aversive. Increased uncertainty may result when predicting the sensory environment, resulting in arbitrary interoceptive anxiety responses that may be due to unjustifiable causes. Arbitrary successful or unsuccessful matching of predictions and responses reduces the individual's confidence to maintain the anxiety trait. In this review, the application of the proposed model is illustrated using gut microbial dysbiosis or imbalance of the gut microbiome.

Attention-Deficit/Hyperactivity Disorder (ADHD) is classically associated with symptoms that include inattentiveness, hyperactivity, and impulsivity together with a variety of other observable externalized symptoms. ADHD has also been associated with specific internalized cognitive symptoms, including restlessness and emotional impulsivity. This disorder has been recognized as a lifelong condition and can be recognized by a variety of unique cognitive phenomena. In addition to the frequently ignored affective symptoms exhibited by individuals diagnosed with ADHD, problems with time perception have been noted, although these are considered to be secondary issues. Temporal shifts in cognitive processing, however, may be at the very root of ADHD-related symptoms, given the importance of coordinated signal translation in the construction of behavior. In this review, we consider the evidence that suggests that differences in time perception are a central symptom in adults with ADHD. Some of these differences include the feeling of time moving faster, which causes difficulties in prospective time tasks and inaccuracies in time estimation tasks. We analyze the literature from both neurological and psychological perspectives and include an assessment of tools that can be administered via computer to measure time perception. We also suggest several computer-based methods that might be used to address problems with time perception in both children and adults. We strongly recommend the inclusion of ADHD symptoms associated with time perception in the next revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) published by the American Psychiatric Association.

During the COVID-19 pandemic, research on the relationships between the virus and its human host has become fundamental to understand this pathology and its effects. Attaining this profound understanding is critical for the effective containment and treatment of infections caused by the virus. In this review, we present some possible mechanisms by which psychopathological symptoms emerge following viral infections of the central nervous system (CNS). These proposed mechanisms are based on microbial communication and the induced priming of microglial antibody activation within the CNS through Toll-like receptor signaling. In this process, chronic microglial activation causes increased glutamate release in virally-altered, high-density neuronal structures, thereby modulating cognitive networks and information integration processes. This modulation, in turn, we suggest, affects the accuracy of sensory integration and connectivity of major control networks, such as the default mode network. The chronic activation of immunological responses and neurochemical shifts toward an elevated glutamate/gamma-aminobutyric acid ratio lead to negative reinforcement learning and suboptimal organismic functioning, for example, maintaining the body in an anxious state, which can later become internalized as trait anxiety. Therefore, we hypothesize that the homeostatic relationship between host, microbiome, and virome, would be decisive in determining the efficiency of subsequent immunological responses, disease susceptibility, and long-term psychopathological effects of diseases that impact the CNS, such as the COVID-19.

Persistent comorbidities occur in patients who initially recover from acute coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 'Long COVID' involves the central nervous system (CNS), resulting in neuropsychiatric symptoms and signs, including cognitive impairment or 'brain fog' and chronic fatigue syndrome. There are similarities in these persistent complications between SARS-CoV-2 and the Ebola, Zika, and influenza A viruses. Normal CNS neuronal mitochondrial function requires high oxygen levels for oxidative phosphorylation and ATP production. Recent studies have shown that the SARS-CoV-2 virus can hijack mitochondrial function. Persistent changes in cognitive functioning have also been reported with other viral infections. SARS-CoV-2 infection may result in long-term effects on immune processes within the CNS by causing microglial dysfunction. This short opinion aims to discuss the hypothesis that the pathogenesis of long-term neuropsychiatric COVID-19 involves microglia, mitochondria, and persistent neuroinflammation.