Damian Sendler, M.D. – Evidence is mounting that mental and physical health are linked by neural systems that control somatic physiology and higher-level cognition. The ventromedial prefrontal cortex and the default-mode network are important systems. Systemic approaches help to build models of the “self in context” by condensing information from various sources and modalities of perception. Autonomic and neuroendocrine functions as well as immune function can be predicted using self-in-context models that give events personal significance. They help students learn from their own experiences and form narratives about themselves and the world around them.. It may be possible to help those with mental and physical health issues, particularly those with high co-occurrence and convergent alterations in functionalities of the ventromedial prefrontal cortex and the default-mode network, by focusing on understanding and shaping mindsets and beliefs about the self, illness, and treatment.
Damian Jacob Sendler: Healthy living was once thought of as a delicate balancing act. When it came time to diagnose and treat an illness, it was necessary to have a complete picture of the patient’s lifestyle and personality. The two are no longer seen as intertwined by the majority of people today. A minority view in Western clinical practice and policy is reflected in integrative medicine and biopsychosocial health models that emphasize interconnections between mind and body, behavior, social context and health. Physical illnesses are commonly viewed as the result of numerous pathological processes, each of which necessitates its own investigation, study, and treatment. There are many parallels between modern approaches to mental disorders and those of the past. When it comes to developing new treatments for conditions like psychiatric disorders, sleep disorders, obesity, or chronic pain, this approach has been particularly effective (for example, by helping to promote the development of vaccines and antibiotics).
Dr. Sendler: changes in brain systems that govern how we perceive ourselves and the world. Individuals construct mental representations of’self-in-context’: models of the situations in which we find ourselves and their implications for our current and future well-being4–11, based on other recent theoretical developments (Fig. 1). As other emerging views emphasize the predictive and regulatory role of conceptual representations, these models go beyond recent concepts such as “task states”7,12 or “cognitive maps”6,13,14 to include personal well-being and brain–body feedback loops. 4,5. Individuals can assign meaning to events and incorporate them into long-term narratives about themselves through the use of self-in-context models. Mental and physical health are intertwined when these models are applied to the self — to one’s present and future well-being. This is when these models become affective.
The default-mode network includes the ventromedial prefrontal cortex (vmPFC), the temporoparietal junction (TPJ), and the posterior cingulate cortex (PCC), which work together to locate the self in a compressed low-dimensional space that encompasses the essential characteristics of a situation in real time. The process of’meaning-making’ involves locating one’s current situation on a mental or conceptual map. According to “Self in context” models, we can predict sensory and interoceptive input based on the use of predictive codes, which can then be used to influence our actions. Beliefs, associative memory, and learning all influence and are influenced by them. It is the social and environmental context of the agent, including but not limited to relationships, cultural beliefs, and neighborhood characteristics that influence the self-in-context models. The hypothalamus and brain stem receive projections from the vmPFC, which in turn can control visceral outflow. vmPFC connections with the basal ganglia and mesolimbic reward circuit or frontostriatal loops20 also influence decision-making and health-relevant behavior (for example, dietary choices and how one works and interacts with others). Both the influences on bodily physiology and decision making can have long term effects on mental and physical health in a variety of ways, such as through their effects on inflammation and allostasis, or their interactions with other health-related systems such as microbiota (for example, via dietary patterns). A dysregulation of the autonomic nervous system, as a result of dysfunctional thought patterns and self-in-context models, can have long-term effects on the body’s organs, such as allostatic load and slowed recovery. It is also possible that changes in health-related behavior, such as poor food choices or drug use, may result from the application of self-in-context models.
If the DMN, particularly the vmPFC and other key multimodal processing hubs within it17, plays a critical role in the generation of conceptual models of the self-in-context, then the DMN and the vmPFC in particular should be considered as an important component in this process. Additionally, the vmPFC (along with other frontal regions4,5 and in interaction with other systems, such as the mesolimbic dopamine system20) also mediates psychological influences on behavior and the body’s systems, shaping autonomic and neuroendocrine responses19, inflammation and other aspects of immunity19,22–24. The vmPFC is positioned as a key mediator of mental and physical health by linking conceptual models of the self-in-context and behavior regulation and peripheral physiology (Fig. 1).
A common factor in many types of mental illness, according to this theory, is the use of dysfunctional self-in-context models and incorrect causality assignments. This may explain why alterations in the vmPFC and DMN are so common in psychopathology, substance abuse, and neurological disorders such as dementia.28 Diagnostic and measurement models face difficulties due to the fact that changes in self-context representations and meaning-making are likely to take various forms across a wide range of disorders and individuals alike. Self-context representations can be influenced by psychological treatment, social interactions and cultural contexts. As long as one is willing to accept new information, conceptual processes — the links we create between various events and concepts — should be able to adapt to provide flexible control in changing contexts. Psychosocial treatments for both mental health and physical health can benefit from this newfound flexibility.
Psychiatric and physical diseases may be influenced by the same mechanisms, according to a growing body of evidence. Mental and physical health disorders are increasingly being seen as closely linked2,29,30, and researchers are exploring the possibility of common transdiagnostic genetic risk factors31,32, and disease mechanisms33,34. People who meet the criteria for one mental health diagnosis are likely to also meet the criteria for at least two more; those who meet the criteria for three diagnoses are likely to meet the criteria for all three35. A common factor may be responsible for multiple types of psychopathology, according to several large-scale studies29,30. Co-morbidity between psychiatric disorders, such as depression, and physical health issues, such as chronic pain and cardiovascular disease, has been shown to have bidirectional causality.36 (Table 1). Another factor that contributes to the phenomenon of shared risk is the existence of shared genetic risk factors, which have been linked to negative affective style measures (such as neuroticism)31,32. Vulnerability to negative life events, negative future visions, and persistent negative emotion are all common threads.
Common physiological risk factors can be found in many disorders. Acute and chronic psychological stress are associated with elevated sympathetic and decreased parasympathetic autonomic activity38,39. Multiple psychiatric conditions such as depression, post-traumatic stress disorder, anxiety, and addiction all share this pattern of altered autonomic function. Systemic inflammation, a risk factor for numerous diseases and symptoms34,44, is influenced by autonomic and neuroendocrine outflow. Depression, type 2 diabetes, coronary heart disease, and chronic pain have all been linked to elevated levels of proinflammatory cytokines such as IL-1, IL-6, and TNF. Depression can be lessened in some cases by inhibiting the actions of peripheral proinflammatory cytokines49. Gene expression changes associated with adverse environmental conditions have been found in humans as well as 11 different disease models in rodents (such as diabetes, asthma, obesity, and neuropathic pain)34.
Cole’s conserved transcriptional response to adversity, a patterned, proinflammatory shift in blood leukocyte gene expression that may confer resistance to infection and promote rapid energy mobilization in adverse environments51, is an important integrative concept. Negative feedback systems that control inflammation will be less effective as a result of this shift, making us more vulnerable (for example, glucocorticoid resistance52). Recent rodent studies support the idea that descending sympathetic nervous system efferents are responsible for these changes. The sympathetic nervous system innervation of bone marrow, a key site for leukocyte production, slows tumour growth in a metastatic melanoma model24 by stimulating the ventral tegmental area, a major source of brain dopamine. This also reduces inflammation, boosts innate and adaptive immunity in response to a bacterial infection54.
Mental models of events, such as inferred personal meanings, credited hidden causes, and imagined potential futures, have an effect on autonomic and inflammatory pathways. Inflammatory markers56 and cardiovascular risk markers57 increase acutely in response to psychosocial stressors, such as a fight with a family member or giving a speech in front of a panel of critical judges55. Psychosocial stressors have been linked to an increased risk of heart disease58. Psychosocial stress in patients with coronary artery disease can lead to cardiac ischaemia, which predicts mortality five years later59. Even in animals and humans, the conserved transcriptional response to stress is amplified by social isolation and a sense of loneliness, and it responds to psychotherapy (reviewed in51,52).
Among the many transdiagnostic risk factors, persistent psychosocial stress has effects that are influenced by one’s self-perception and relationship to the rest of the world. Mental and emotional stressors are not necessarily physical in nature. How well we can imagine the consequences of someone’s disapproval of us, for example, and how well we can predict our own failures in love and work. Other transdiagnostic risk and resilience factors, such as depressed mood, anxiety, persistent anger and hostility, loneliness, and positive emotion, are characterized by such conceptualizations (Table 1). Conceptualizations can be transmitted through words and culture, and may be socially communicable risk factors that increase resilience or increase disease susceptibility. If you believe that you are unlovable, or that you will always be alone, your feelings of loneliness are based on those beliefs. Loneliness, like other beliefs, can spread through social networks and have a negative impact on health60.
It is also important to note that a common set of psychosocial treatment principles can be applied to many different mental and physical conditions. By enhancing purpose, self-efficacy (the ability to handle new or challenging situations appropriately), feelings of connection to others, social engagement, and positive treatment expectations, activities and events can alleviate symptoms and dysfunction across disorders. They believe that these “common factors,” regardless of treatment type or psychopathology, are responsible for most psychotherapy’s positive effects. Studies of placebo effects have shown that the act of receiving treatment, along with the cognitive changes that accompany it, can confer benefits in both short-term experimental studies and long-term clinical studies across a wide range of disorders. 62–65. Pain and other disorders, such as Parkinson disease, depression, anxiety, and sleep disorders, can all be helped clinically by using a placebo treatment.62,63,66 Many health outcomes can be improved simply by changing one’s beliefs and mindsets in everyday life rather than by undergoing formal clinical treatment.67
Damian Sendler
Environmental threats and opportunities can be predicted and learned by most organisms. Associating cues or actions with rewards or punishments has long been assumed to be the basis of learning. The underlying contexts or’situations’ that cause events to occur can be represented abstractly and multimodally by humans (and probably other mammals68) (Fig. 1). ‘Status representations’ are conceptual, and closely related, but not identical, to the heuristic notions of schemas or mindsets69. Recurring causal structures (like ‘betrayed by a friend’ or ‘alone in a dangerous place’) form the basis of these mental models of both sensory information and action–outcome contingencies. There are several fundamental characteristics of situation representations. Adaptation to new situations and generalization to similar ones are made possible by the integration of information from different sensory modalities and timescales (7,10–17). It is more important to think about what is going on behind the scenes than what is going on in front of us. Situational representations are therefore compressive, which means that they distill sensory input into low-dimensional descriptions. Although their formation and use is often automatic, they can also be responsive to deliberation, allowing us to adapt to a wide range of cognitive and sensory stimuli. They are able to predict future events and guide action by distilling what is important from the jungle of sensory and interoceptive signals that make up a person’s environment.7,72
Damian Jacob Markiewicz Sendler: Schemas involving the self are the focus of this section. As a result, the self-in-context representation connects states (features and action–outcome contingencies relevant for decision making) with current pleasure and pain. Multitemporal depictions extend bodily and social well-being in both the past and the present (Fig. 1). For example, a situation like “the stock market crashed, and I lost my life savings” can raise one’s blood pressure because it is linked to one’s long-term outlook on life. Whenever an event is directly related to one’s own happiness or health, the body’s response is stronger, resulting in increased mobilization of cognitive and metabolic resources. These models represent information in terms of dimensions that are relevant to the self, giving sensory features and possible actions a personal meaning.
Simple associations have no evolutionary advantage over self-in-context representations. Sensory and interoceptive signals are combined with prior conceptual knowledge to predict future outcomes based on latent causes (for example, another person’s hidden intentions)11,73. A single word, for example, can lead to predictions that change rapidly when important relationships are disrupted, and they can generalize across very different physical contexts. Personal status and resources can be depicted in models.74. If the push is accidental or the pusher is a small child, one’s reaction will likely be different. Mental models can also integrate across timescales, allowing for the reinterpretation of past events in light of new evidence, such as events that occurred just a few seconds ago and those that occurred many years ago.
A recent study on decision-making used partially observable Markov decision processes12 to model simple situation representations. The idea of self-in-context models is based on this work. A set of causal contingencies can be derived from sensory cues, but an organism cannot directly observe the underlying causal structure. It is possible to infer the underlying states by using cognitive maps, which are sets of conceptual relationships between objects and events. A Markov model can capture the transitions between discrete task states over time, but at a cognitive level, situation representations are not constrained to the present and exist as a set of causal contingencies untethered from any particular moment in time
Self-in-context representations may influence perception and action, including the perception of external and internal signals,11,73,75–77. Predictive coding theories state that sensory input is compared to predictions generated by an internal model from the “top-down” (exemplified by self-in-context representations). Only differences from expectations, not all sensory input, are passed on to the model by sensory systems (that is, learning). Based on both sensory input and situational conceptions, perception is an inference that can be made (Fig. 1). When faced with noisy or uncertain environments, we should only focus on what we should be focusing on, according to this theory. Many researchers have proposed “predictive coding,” in which the brain’s higher levels of processing provide top-down information that is often represented in Bayesian models as “formal priors” (probability distributions of the likelihood of an event). Some of its most recent applications include the study of pain78, interoception4,5,8, physiological regulation and reactivity to stress and depression77, social cognition and interpersonal behavior80,81 and many more phenomena. It is possible that self-in-context models, which incorporate future well-being in the context of a particular person’s current situation, require specific types of information integration; we suggest below that these models are implemented in particular brain systems.
In summary, self-in-context representations are internal models of situations and the underlying causal structures that influence our future survival and well-being. Their low-dimensional representation influences sensory perception and behavior by combining information from exteroceptive and interoceptive senses with conceptual information from memory and prospective faculties (Fig. 1). Self-in-context representations can be generative, interpretive, attributive, instructive, and predictive. They allow one to simulate the outcomes of potential actions, understand incoming sensory signals as clues to one’s current state, and assign latent causes to sensory events. They can also be attributive, instructive, and predictive. These representations can also become emotionally “hot” and stimulate physiological systems (such as the autonomic nervous, hormonal, or metabolic systems) because of their connection to well-being.
This region of the brain, the DMN, was named because of its high metabolic activity during rest94 and its role in self-generated, spontaneous thought95 and goal-directed thinking90,96. For episodic (especially autobiographical) and semantic memories, the vmPFC is activated in humans97,98. People who have vmPFC damage have a hard time imagining the future in great detail100,101,102. As the film or story progresses, the vmPFC and other core DMN regions show consistent activation patterns, integrating past information into the representations of narrative meaning. It is possible for activation patterns in the vmPFC to change abruptly when new information provides insight106.
Damian Jacob Sendler
Conceptual thought relies heavily on relational representation. It is based on an interconnected web of concepts embedded in semantic space107, for example, During semantic memory retrieval, the vmPFC is robustly activated. Using functional MRI signal tracking activity in a hexagonal “grid cell” pattern108, it encodes position in relation to other relational structures, including physical space, in addition to the hippocampus’s coding. In a low-dimensional space, grid cells are thought to help represent relationships between discrete locations (or object features) — effectively, a compressed model that enables the representation of positional similarity and generalization6. When retrieving relationships between newly learned object categories14,109, grid cell-like patterns of vmPFC activity have been found to encode information in conceptual space. This suggests that the vmPFC may facilitate the formation of cognitive maps6 that represent the location of objects, people, and situations in a relational space
Damien Sendler: A person’s spatial orientation and long-term memory rely heavily on the hippocampus6,13,108. There are grid-like properties for representing conceptual relationships in the hippocampus and parahippocampal cortex, like the vmPFC 14. However, conceptual maps of the self-in-context may differ between areas despite the fact that they all contribute to the construction of conceptual maps. These self-referential conceptual maps, which prioritize information relevant to bodily integrity and well-being, may be particularly important for the vmPFC, whereas allostatic spatial and conceptual maps, which are less directly involved in physiological regulation, may be encoded in the hippocampus.
Interoception and physiological regulation rely on networks other than the DmN. Interoception and visceromotor control can be explained using the ePIC (embodied predictive interoception coding) model, which combines interoception and visceromotor control4. Viscomotor function is controlled by agranular cortical regions (such as the cingulate cortex and anterior insula) via connections to subcortical areas, and sensory prediction signals are sent to granular cortical regions, such as primary interoceptive cortex4. It has been hypothesized that the DmN15 and the salience250 (or’ventral attention’86) networks may form a unified system for allostasis5 in the brain, based on the findings of a recent study.
For example, the DmN and the salience network could both contribute to allostasis in different ways, in accordance with their distinct dynamics. Predictive control of bodily functions and behavior may be provided by DmN regions like the prefrontal cortex (vmPFC), while the salience network may do so reactively, based on the detection of salient events or new information that necessitates changes in states. It’s possible to test these and other hypotheses in the future.
Choosing what to eat, what to avoid, and when to exert effort based on values is critical in the biopsychosocial model of health. In the context of self-in-context representations, the vmPFC and the OFC are particularly important. VmPFC homologues do not affect basic reward preferences, reward learning, unconditioned threat responses, or basic conditioned threat acquisition or extinguishing (for a review, see10). But the integration of situational (for example, place), social, temporal, or interoceptive (for example, satiety-related) information into reward-guided or threat-guided behavioural decisions can be affected by vmPFC and OFC lesions.. If, for example, vmPFC lesions or inactivation impairs the ability to consolidate and use memories when a context shifts from threatening to safe150, this is a significant limitation. An action–escape contingency (the vmPFC representation of control) suppresses threat-related responses in the dorsal raphe nucleus and associated threat behaviors151 when shocks are avoidable. VmPFC inhibition reduces the benefits of perceived control, and stimulation of the vmPFC has the same effect on behavior even when shocks are unavoidable.151 Selective satiety — a shift in food preferences when one has consumed enough of a particular food — and rapid shifts in choice behavior when reward contingencies change are also disrupted by vmPFC lesions, which are also context-dependent appetitive behaviors. 152,153. Lesions of the vmPFC in humans do not generally alter basic value preferences, but they do interfere with the ability to generate appropriate behaviors and emotions in response to the context in which they occur. 154,155.
For this reason, the vmPFC responds to changes in the social and informational context that influence reward-driven behavior, as demonstrated in human imaging studies. In threat-learning studies, it responds during extinction recall156, reversals of cue–shock contingencies from danger to safety157 and manipulations that increase perceived control142. The vmPFC and OFC are activated, the vmPFC is more connected to the PAG158, and the vmPFC and the PAG65 release opioids in response to the suggestion that a placebo treatment is an effective analgesic. Reward experiments have shown that the vmPFC responds selectively to cues of satiation that influence food selections159 and suggestions that alter perceived value135,160. Additionally, the vmPFC reacts to the experience of vicarious reward, which occurs when rewards are given to others who are like oneself161, and encodes information about social categories linked to racial and sociocultural stereotypes.
Using a heuristic lens, self-in-context models can be viewed as a way of thinking that influences our openness to information, the hidden causes we assign to past and present events, and the lessons we take away from our experiences. A positive outlook on life and a willingness to see the good in others are hallmarks of a healthy mindset, as are the absence of unwarranted blame and hostility (both toward oneself and others). Negative self-evaluation and a lack of faith in one’s own ability to grow and change are two of the most common unhealthy mindsets. Running endurance and lung gas exchange measures were reduced when subjects were randomly assigned to the idea that they were genetically intolerant to exercise189. There is a link between negative beliefs about ageing and a decrease in healthy behaviors175 and a decrease in life span176. To amplify the effects of stress, a negative stress mindset (the belief that stressors are debilitating (rather than helpful opportunities for growth)190) is needed. There was a 43 percent higher death rate among 28,000 people who reported high levels of perceived stress and a belief that stress negatively affects health191 compared to those who did not report these factors.
Research suggests the vmPFC and OFC mediate the effects of various brief mindset interventions192,193, supporting the importance and malleability of representations of oneself in context. Pain and autonomic responses can be increased by implying that other people have experienced a painful stimulus as particularly intense194,195. Social manipulations, on the other hand, such as receiving supportive touch from a romantic partner196 or voluntarily accepting pain on behalf of another person197, reduce pain experience and measures of pain-associated brain activity. Changes in vmPFC and OFC activity are responsible for all of these outcomes. Pain and negative emotions, as well as the brain responses associated with them, can be reduced with just a few sessions of mindfulness training198 or meditation199. It is possible for these interventions to have meaningful effects on physiology, as they influence the most sensitive and specific brain measure related to pain currently available, with larger effect sizes than those found in placebo interventions200.
Mindsets also influence how we learn from our experiences, resulting in long-term gains or losses. When it comes to social anxiety disorder, for example, sufferers have a negative outlook on themselves and their social standing. It has been shown that people with social anxiety disorder are more susceptible to the negative reinforcement of others than they are to the positive reinforcement of others148. This could lead to a vicious cycle of anxiety and self-doubt. Experiencing the pain that one expects can become a self-reinforcing cycle201. There are two critical components to self-reinforcing feedback cycles: first, that experience is assimilated to initial beliefs (that is, negative expectations enhance pain), and second, that experiences incongruent with initial beliefs are discounted or ignored201.
Changing one’s self-in-context representations over time may be a method of psychotherapy’s success. There are many types of psychotherapy that focus on helping people cultivate health-promoting beliefs, causal attributions, and meaningfulness. Patients’ mindsets are shifted as a result of factors like positive expectation, self-efficacy, and engagement61, not because of specific treatment protocols. After therapy for a variety of mental health conditions, the vmPFC–OFC, hippocampus, and amygdala all undergo significant changes202,203. Common factors can have significant effects on a wide range of medical conditions, including migraine, depression, anxiety, Parkinson’s disease, asthma, irritable bowel syndrome, and arthritis204. They are not limited to any one treatment.
It is possible to influence the development of healthy self-in-context representations in a variety of ways: through interactions with family and friends; by practicing mindfulness and self-regulation; and by influencing public health policy. Among more than 300 trials of psychological interventions for cancer patients, those with strong social support networks survived longer206. Those who are more socially isolated may benefit from psychosocial interventions, which can increase their survival time and improve cancer-related immune measures205,208. Improved mood, longer cancer survival, and measures of cellular immunity such as natural killer cell proliferation and lymphocyte cytotoxicity were found in two randomized clinical trials of psychosocial interventions209.
We still have a lot to learn about the effects of psychosocial interventions and mindset shifts. Individuals’ self-in-context representations differ inherently, and they can be harmful in a variety of ways across a wide range of disorders. In addition, they unquestionably rely on intricate neural interactions involving numerous brain regions and systems to perform their duties.. It’s important to keep in mind, however, that there is a central point from which all of our experiences are integrated into a coherent picture of the world and our path through it. This may help us rethink the role of the brain in both mental and physical disorders if we see it as a common driving force. This means that there is hope that people can learn to change their own and their loved ones’ self-in-context models for the better.
