Despite our ongoing fascination with love's pleasures and pain, psychologists and neurobiologists have only recently begun to explore the neurobiological connections shared by feelings of romantic love and the experience of drug addiction. Functional imaging studies have revealed that feelings resulting from romantic love and those resulting from active drug use both activate the central reward system, which is a series of forebrain and midbrain structures that transmit signals primarily via dopamine release. Similarly, the relaxation response, which is a series of behaviors designed to alleviate stress-related physiologic sequelae, may also be helpful as an adjunct therapy for drug withdrawal. The benefits of the relaxation response and related mind-body practices may stem directly from its impact on mitochondria, organelles that are central to balanced energy production. Nitric oxide (NO) is a central neurotransmitter and also a key regulatory molecule that modulates mitochondrial respiration and oxygen utilization. Thus, we propose that observed behaviorally mediated changes that emerge from engaging the relaxation response may be the result of NO-mediated improvements in mitochondrial bioenergetics. Future research might focus on elucidating the important links between cellular bioenergetics, the relaxation response, and the central reward system and might explore NO modulation as a potentially effective target for drug development.

• Keywords
• Bioenergetics, Brain, Broken heart, Dopamine, Drug addiction, Nitric oxide, Relaxation response, Reward pathway, Romantic love, Stress,
• MeSH
• Central Nervous System * metabolism   MeSH
• Energy Metabolism * physiology   MeSH
• Love * MeSH
• Humans MeSH
• Brain * metabolism   MeSH
• Behavior, Addictive * metabolism   physiopathology   MeSH
• Neurobiology MeSH
• Reward MeSH
• Nitric Oxide metabolism   MeSH
• Substance-Related Disorders * metabolism   physiopathology   MeSH
• Signal Transduction * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Nitric Oxide MeSH

In this manuscript, we highlight the evolutionary origins of mitochondria from bacterial endosymbionts and explore their contributions to health, energy metabolism, and neural-immune communication. Mitochondrial adaptability and the roles played by these organelles in promoting oxygen-dependent ATP production provide critical regulation of cognition, motivation, and inflammation. Hypoxia has been identified as an important initiator of inflammation, neurodegeneration, and mitochondrial dysfunction, emphasizing the overall importance of oxygen homeostasis to health and well-being. The Behavior, Exercise, Relaxation, and Nutrition framework highlights these observations as tools that can be used to optimize mitochondrial efficiency. Interestingly, mitochondrial dysfunction may also be linked to psychiatric disorders (e.g., schizophrenia), a hypothesis that focuses on energy dynamics, a proposal that may extend our understanding of these disorders beyond traditional neurotransmitter-focused concepts. Collectively, these perspectives underscore the critical contributions of mitochondria to health and disease and offer a novel framework that may help to explain the connections featured in mind-body medicine.

• Keywords
• BERN, CNS pathways and networks, evolution, hypoxia, mind–body medicine, mitochondria, motivation,
• MeSH
• Biological Evolution MeSH
• Pain * metabolism   physiopathology   MeSH
• Exercise * physiology   MeSH
• Energy Metabolism * MeSH
• Cognition * physiology   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Motivation * MeSH
• Pleasure * physiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

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.

• Keywords
• behavioral medicine, integrative medicine, meditation, mitochondria, placebo, salutogenesis, self-healing, stress management,
• Publication type
• Journal Article MeSH
• Review MeSH

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.

• Keywords
• HIV-1, SARS-CoV-2, bipolar disorder, depression, mitochondria, reactive nitrogen species, reactive oxygen species, schizophrenia,
• Publication type
• Journal Article MeSH
• Review MeSH

Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.

• MeSH
• Alzheimer Disease * metabolism   pathology   physiopathology   MeSH
• Humans MeSH
• Microglia * metabolism   pathology   MeSH
• Nitric Oxide metabolism   MeSH
• Signal Transduction * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Nitric Oxide MeSH

Nitric oxide (NO) represents a key signaling molecule in multiple regulatory pathways underlying vascular, metabolic, immune, and neurological function across animal phyla. Our brief critical discussion is focused on the multiple roles of the NO signaling pathways in the maintenance of basal physiological states of readiness in diverse cell types mediating innate immunological functions and in the facilitation of proinflammatory-mediated adaptive immunological responses associated with viral infections. Prior studies have reinforced the critical importance of constitutive NO signaling pathways in the homeostatic maintenance of the vascular endothelium, and state-dependent changes in innate immunological responses have been associated with a functional override of NO-mediated inhibitory tone. Accordingly, convergent lines of evidence suggest that dysregulation of NO signaling pathways, as well as canonical oxidative effects of inducible NO, may provide a permissive cellular environment for viral entry and replication. In immunologically compromised individuals, functional override and chronic rundown of inhibitory NO signaling systems promote aberrant expression of unregulated proinflammatory pathways resulting in widespread metabolic insufficiencies and structural damage to autonomous cellular and organ structures. We contend that restoration of normative NO tone via combined pharmaceutical, dietary, or complex behavioral interventions may partially reverse deleterious physiological conditions brought about by viral infection linked to unregulated adaptive immune responses.

• MeSH
• Antiviral Agents pharmacology   MeSH
• Humans MeSH
• Nitric Oxide pharmacology   MeSH
• Oxidation-Reduction MeSH
• Signal Transduction MeSH
• Severe acute respiratory syndrome-related coronavirus drug effects   immunology   MeSH
• Inflammation metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Antiviral Agents MeSH
• Nitric Oxide MeSH

The relaxation response derives its health benefits by reestablishing "normal" equilibria between the sympathetic and parasympathetic branches of the autonomic nervous system. Recent work suggests that this behavioral training provides positive effects on mitochondrial bioenergetics, insulin secretion, and reductions in pro-inflammatory and stress-related pathways. We have previously contended, however, that correlative associations of relaxation training with positive changes in gene expression in selected biological systems are strongly suggestive of adaptive physiological changes, but do not elucidate an underlying, clinically compelling, unified mechanism of action consistent with its purported positive health effects. We surmise that any plausible model of behaviorally-mediated regulatory effects on whole-body metabolic processes must be intrinsically broad-based and multifaceted via integration of differential contributions of functionally interactive peripheral and CNS organ systems. Accordingly, the initiation of multiple cellular protective/anti-bio-senescence processes may have emerged during evolutionary development to ensure the survival of hybrid prokaryotic/eukaryotic progenitor cells, given the evolvement of oxidative metabolism and its associated negative byproducts. As an essential corollary, preservation and adaptation of multifaceted regulatory molecules, notably nitric oxide, paralleled the development of eukaryotic cell types via multifaceted stereo-selective recognition and conformational matching by complex biochemical and molecular enzyme systems. Hence, the relaxation response may be a manifestation of a metabolic corrective process/response, that may now include cognition ("awareness").

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Cell Respiration physiology   MeSH
• Energy Metabolism MeSH
• Humans MeSH
• Mitochondria metabolism   physiology   MeSH
• Nitric Oxide metabolism   MeSH
• Relaxation physiology   MeSH
• Oxygen Consumption physiology   MeSH
• Models, Theoretical MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Nitric Oxide MeSH