The foundations of mind-body medicine: Love, good relationships, and happiness modulate stress and promote health.

Although stress is an everyday fact of life, it can lead to poor health outcomes, particularly when intense or prolonged. However, humans have unique cognitive abilities and thus may be able to combat stress by engaging critical psychological defence mechanisms. In this review, we discuss the field of mind-body medicine, which focuses on improving our understanding of the mechanisms underlying this response and developing interventions that might be used to limit the effects of chronic stress. We review the findings of past and current research in this field that has focused on the impact of psychological, emotional, and behavioural factors, including love, social connectedness, and happiness on human health and the amelioration of pain as well as other signs and symptoms of disease. While these studies have not yet led to confirmed, quantifiable conclusions, the overall weight of evidence suggests that happiness (defined as a personal sense of well-being) may be directly associated with improved health parameters and reductions in debilitating symptoms. Collectively, these findings suggest that interventions designed to promote stress mitigation, notably those that encourage social activity, may lead to significant improvements in human health.

Quantum Computing and the Future of Neurodegeneration and Mental Health Research.

Quantum computing and supercomputing are two distinct approaches that can be used to solve complex computational problems [...].

Artificial Intelligence: Deciphering the Links between Psychiatric Disorders and Neurodegenerative Disease.

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

Artificial Intelligence as a Tool for the Diagnosis and Treatment of Neurodegenerative Diseases.

While humans have much in common biologically with other mammalian species, they are largely distinguished by their innate intelligence, specifically, their ability to generate complex and sophisticated tools [...].

Independent and sensory human mitochondrial functions reflecting symbiotic evolution.

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.

Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior.

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.

Mobility Coupled with Motivation Promotes Survival: The Evolution of Cognition as an Adaptive Strategy.

Morphine plays a critical regulatory role in both simple and complex plant species. Dopamine is a critical chemical intermediate in the morphine biosynthetic pathway and may have served as a primordial agonist in developing catecholamine signaling pathways. While dopamine remains the preeminent catecholamine in invertebrate neural systems, epinephrine is the major product of catecholamine synthetic pathways in vertebrate species. Given that the enzymatic steps leading to the generation of morphine are similar to those constraining the evolutionary adaptation of the biosynthesis of catecholamines, we hypothesize that the emergence of these more advanced signaling pathways was based on conservation and selective "retrofitting" of pre-existing enzyme activities. This is consistent with observations that support the recruitment of enzymatically synthesized tetrahydrobiopterin (BH4), which is a cofactor for tyrosine hydroxylase, the enzyme responsible for dopamine production. BH4 is also an electron donor involved in the production of nitric oxide (NO). The links that coordinate BH4-mediated NO and catecholaminergic-mediated processes provide these systems with the capacity to regulate numerous downstream signaling pathways. We hypothesize that the evolution of catecholamine signaling pathways in animal species depends on the acquisition of a mobile lifestyle and motivationally driven feeding, sexual, and self-protective responses.

HIV, HSV, SARS-CoV-2 and Ebola Share Long-Term Neuropsychiatric Sequelae.

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 BERN Framework of Mind-Body Medicine: Integrating Self-Care, Health Promotion, Resilience, and Applied Neuroscience.

Background: Mind-body medicine (MBM) focuses on improving our understanding of how the interactions between the brain, mind, body, and behavior can be used to promote health. In this narrative review, we present the basic principles of MBM, including the introduction of a rational framework for the implementation of MBM-based interventions. We also discuss the contributions of MBM to motivation and reward systems in the brain including those that may specifically involve the mitochondria. Results: MBM can be used to promote health in patients with chronic diseases, especially conditions identified as lifestyle-related. MBM builds on salutogenesis, which is a paradigm that focuses on health (as opposed to disease) determinants and the development of individual resilience and coherence factors as a means to reduce stress, decrease the burden of disease, and improve the quality of life. This approach involves several well-known principles of self-healing and self-care. MBM interventions typically include behavioral modification techniques in conjunction with cognitive work focused on stress regulation, exercise, relaxation, meditation, and nutrition. We suggest the use of the acronym "BERN" (Behavior, Exercise, Relaxation, and Nutrition) to summarize the operational framework of this approach. Discussion: Different BERN techniques act via shared autoregulatory central nervous system (CNS) reward and motivation circuitries. These systems rely on numerous neurobiological signaling pathways with overlapping effector molecules that converge, e.g., on nitric oxide (NO) as a common effector molecule. NO is critically coupled to reward physiology, stress reduction, and self-regulation as it modulates the responses of various mitochondrial, nuclear, and chromosomal processes within brain cells. NO has also been implicated in relevant outcomes (e.g., the placebo response). Conclusions: MBM interventions typically follow the BERN model and aim to strengthen health and resilience, and reduce stress. The mechanisms of action of these processes involve the CNS reward systems and correlate with placebo and self-healing pathways.

Viruses Broaden the Definition of Life by Genomic Incorporation of Artificial Intelligence and Machine Learning Processes.

Viruses have been classified as non-living because they require a cellular host to support their replicative processes. Empirical investigations have significantly advanced our understanding of the many strategies employed by viruses to usurp and divert host regulatory and metabolic processes to drive the synthesis and release of infectious particles. The recent emergence of SARS-CoV-2 has permitted us to evaluate and discuss a potentially novel classification of viruses as living entities. The ability of SARS CoV-2 to engender comprehensive regulatory control of integrative cellular processes is strongly suggestive of an inherently dynamic informational registry that is programmatically encoded by linear ssRNA sequences responding to distinct evolutionary constraints. Responses to positive evolutionary constraints have resulted in a single-stranded RNA viral genome that occupies a threedimensional space defined by conserved base-paring resulting from a complex pattern of both secondary and tertiary structures. Additionally, regulatory control of virus-mediated infectious processes relies on extensive protein-protein interactions that drive conformational matching and shape recognition events to provide a functional link between complementary viral and host nucleic acid and protein domains. We also recognize that the seamless integration of complex replicative processes is highly dependent on the precise temporal matching of complementary nucleotide sequences and their corresponding structural and non-structural viral proteins. Interestingly, the deployment of concerted transcriptional and translational activities within targeted cellular domains may be modeled by artificial intelligence (AI) strategies that are inherently fluid, self-correcting, and adaptive at accommodating temporal changes in host defense mechanisms. An in-depth understanding of multiple self-correcting AIassociated viral processes will most certainly lead to novel therapeutic development platforms, notably the design of efficacious neuropharmacological agents to treat chronic CNS syndromes associated with long-COVID. In summary, it appears that viruses, notably SARS-CoV-2, are very much alive due to acquired genetic advantages that are intimately entrained to existential host processes via evolutionarily constrained AI-associated learning paradigms.

Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders.

Mitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

Biomedical Perspectives of Acute and Chronic Neurological and Neuropsychiatric Sequelae of COVID-19.

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.

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms.

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.

SARS-CoV-2, Trait Anxiety, and the Microbiome.

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.

Time Perception is a Focal Symptom of Attention-Deficit/Hyperactivity Disorder in Adults.

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.

Editorial: The Pathogenesis of Long-Term Neuropsychiatric COVID-19 and the Role of Microglia, Mitochondria, and Persistent Neuroinflammation: A Hypothesis.

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.

Interoception, Trait Anxiety, and the Gut Microbiome: A Cognitive and Physiological Model.

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.

Historical Insight into Infections and Disorders Associated with Neurological and Psychiatric Sequelae Similar to Long COVID.

Long-term sequelae of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized. However, there is still a lack of consensus regarding the terminology for this emerging chronic clinical syndrome, which includes long COVID, chronic COVID syndrome, post-COVID-19 syndrome, post-acute COVID-19, and long-hauler COVID-19. In this review, I will use the term "long COVID". A review of the medical history and epidemiology of past pandemics and epidemics in modern literature review identifies common long-term post-infectious disorders, with the common finding of altered cognition. In the brain, the cerebral hypoxia induced by SARS-CoV-2 infection may be caused by mitochondrial dysfunction, resulting in "brain fog". Historically, the common symptom of altered cognition has been reported during earlier pandemics, which include the influenza pandemics of 1889 and 1892 (Russian flu), the Spanish flu pandemic (1918-1919), encephalitis lethargica, diphtheria, and myalgic encephalomyelitis (chronic fatigue syndrome or post-viral fatigue syndrome). There are similarities between chronic fatigue syndrome and the "brain fog" described in long COVID. During past viral epidemics and pandemics, a commonality of neural targets may have increased viral survival by conformational matching. The neurological and psychiatric sequelae of SARS-CoV-2 infection, or long COVID, may have emerged from neural effects that have emerged from an invertebrate and vertebrate virosphere. This review aims to present a historical overview of infections and disorders associated with neurological and psychiatric sequelae that have shown similarities with long COVID.

Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce 'Brain Fog' and Results in Behavioral Changes that Favor Viral Survival.

Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or 'long COVID', also include serious long-term mental and cognitive changes, including the condition recently termed 'brain fog'. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.