Leonie Koban
email: leonie.koban@icm-institute.org

Peter J Gianaros

Hedy Kober

Tor D Wager
email: tor.d.wager@dartmouth.edu

The self in context: brain systems linking mental and physical health

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Introduction

Historically, health was considered a matter of balance among interacting forces.

Diagnosing and treating disease required an understanding of the whole personincluding dietary habits, activities and personality. Today, however, mental health and physical health are viewed by many as separate, unconnected domains. Although integrative medicine and biopsychosocial models of health 1 emphasize interconnections between mind, body, behaviour, social context and health, they still represent a minority view in the face of Western clinical practice and health-care policy.

Physical diseases are typically viewed as resulting from many discrete forms of pathology whose mechanisms must be individually uncovered, studied and remedied 2 . Modern approaches to mental disorders have followed a similar blueprint, fractionating clinical science, practice and policy. Although this approach has been extremely successful in some areas (for example, promoting the development of vaccines and antibiotics), other areas have enjoyed little progress in treatment development -for example, psychiatric disorders, sleep disorders, obesity and chronic pain 3 .

In this Perspective, we suggest that these latter disorders may share something in common: changes in the function of brain systems that govern how we conceptualize ourselves and our relationship to the world. Building on other recent theoretical developments [4][5][6][7][8][9][10][11] , we propose that individuals construct mental representations of the 'self-in-context': models of the situations in which we find ourselves and their implications for our current and future wellbeing (Fig. 1). Such models extend recent concepts of 'task states' 7,12 or 'cognitive maps' 6,13,14 to incorporate personal wellbeing and brain-body feedback loops, consistent with other emerging views that emphasize the predictive and regulatory role of conceptual representations 4,5 . Self-in-context models allow one to assign personal meaning to events and integrate them into long-term narratives about who they are. When these models bear on the self -on one's current and future wellbeing -they become affective, driving motivated behaviour and physiological responses in the body in ways jointly relevant for mental and physical health.

We suggest that the default mode network (DMN; a large-scale network of interacting brain regions that is central to internal and conceptual thought 15,16 ), and particularly the ventromedial prefrontal cortex (vmPFC) and other key multimodal processing hubs within it 17 , play a crucial part in generating conceptual mental models of the self-in-context. At the same time, the vmPFC (alongside other frontal regions 4,5,18,19 and in interaction with other systems such as the mesolimbic dopamine system 20 ) also mediates psychological influences on behaviour and on the body's organs 18,21 , shaping autonomic and neuroendocrine responses 19 , inflammation and other aspects of immunity 19,[22][23][24] . By linking conceptual models of the self-in-context and the regulation of behaviour and peripheral physiology, the vmPFC is positioned as a key mediator of both mental and physical health (Fig. 1).

According to this view, maladaptive models of self-in-context and erroneous attributions of causality are common factors underlying multiple forms of psychopathology. This may help explain the ubiquity of alterations in the vmPFC and DMN in psychopathology 25 , substance use disorders 26 , neurological disorders such as dementia 27 , and chronic pain 28 . Alterations in self-in-context representations and meaning-making are likely to take different forms in different disorders and individuals, posing challenges for measurement and diagnostic models. However, on the bright side, self-in-context representations can be influenced by psychological treatment, social interactions and culture. Indeed, if conceptual processes -the links we make between different events and concepts -can adapt to provide flexible control in changing contexts, they should be able to change rapidly with new information, if one is open to receiving it. This malleability provides new impetus for building on and improving psychosocial treatments for both mental and physical health.

Common influences on health

Converging lines of evidence suggest that shared mechanisms may influence psychiatric and physical diseases. There is a growing awareness of high cooccurrence across mental and physical health disorders 2,29,30 and potential common transdiagnostic genetic risk factors 31,32 and disease mechanisms 33,34 . For example, some estimate that more than 50% of individuals who qualify for one mental health diagnosis qualify for at least one other, and that 50% of those who qualify for two diagnoses, qualify for three 35 . Accordingly, several large-scale analyses have pointed to the possibility that a common factor might underlie multiple types of psychopathology 29,30 . Many psychiatric disorders, especially depression, are also highly comorbid with various somatic health problems, including chronic pain 36 and cardiovascular disease 37 , with evidence for bidirectional causality (Table 1). In addition, shared risk is driven partly by shared genetic risk factors, which have also been associated with measures of negative affective style (such as neuroticism) 31,32 .

A common thread is vulnerability to negative interpretations of life events, negative conceptions of the future and persistent ensuing negative emotion.

Many disorders share common physiological risk factors, too. Increased sympathetic drive and reduced parasympathetic autonomic drive 38,39 are features of acute and chronic psychosocial stress 40,41 . This pattern of altered autonomic function features in multiple psychiatric conditions, including depression, PTSD, anxiety and addiction 42,43 . Autonomic and neuroendocrine outflow influence systemic inflammation, which is a risk factor for multiple diseases and symptoms 34,44 . Systemic increases in several pro-inflammatory cytokines -such as interleukin-1β (IL-1β), IL-6 and TNF-α -have been associated with depression 45 , type 2 diabetes 46 , coronary heart disease 47 and chronic pain 48 . In some cases, blocking the actions of peripheral pro-inflammatory cytokines can reduce depression 49 . Recent work has identified common patterns of inflammatory gene expression across 11 rodent models of diseases (including models of diabetes, asthma, obesity and neuropathic pain) 34 , and identified consistent gene expression alterations that occur in humans in response to adverse environments 50 .

A key integrative concept is Cole's conserved transcriptional response to adversity (CTRA), a patterned, pro-inflammatory shift in gene expression in blood leukocytes that may confer resistance to infection and promote rapid energy mobilization in adverse environments 51 . However, in the long-term, this shift can confer vulnerability by diminishing the capacity of negative-feedback systems that regulate inflammation (for example, glucocorticoid resistance 52 ). These changes seem to be governed by descending sympathetic nervous system (SNS) efferents 53 , and recent rodent studies support this notion. Stimulation of the ventral tegmental area (VTA), a major source of brain dopamine, reduces inflammation, boosts innate and adaptive immunity in response to a bacterial infection 54 and slows tumour growth in a metastatic melanoma model 24 via SNS innervation of bone marrow, a central site for leukocyte production 24,54 .

Autonomic and inflammatory pathways are sensitive to conceptualization and mental models of events -that is, assigned personal meanings, credited hidden causes and imagined potential futures. Psychosocial stressors, such as a fight with a family member or giving a speech before a panel of critical judges 55 , acutely increase levels of systemic inflammatory markers 56 and cardiovascular risk markers 57 . Indeed, psychosocial stressors increase the risk of developing cardiac pathology 58 . In patients with coronary artery disease, psychosocial stress can cause cardiac ischaemia, which prospectively predicts mortality 5 years later 59 . The CTRA is also enhanced with social isolation in animals and perceived isolation (loneliness) in humans, and responds to psychological interventions (reviewed in 51,52 ).

Persistent psychosocial stress is one example of a transdiagnostic risk factor whose effects depend on how one conceives of oneself and one's relationship with the world. Psychosocial stressors begin as conceptual threats, not physical ones. They depend entirely on our ability to represent, for example, another person's displeasure with us and to imagine that this is a dire signal of future failure in love and work. Such conceptualizations are defining features of other transdiagnostic risk and resilience factors, including depressed mood, anxiety, persistent anger and hostility, loneliness, and positive emotion (Table 1). Conceptualizations can be spread through words and culture and may constitute socially communicable risk factors that enhance resilience or disease susceptibility. For example, loneliness is a feeling supported by a set of beliefs (for example, "I am unlovable" or "I will always be alone"). Similar to other beliefs, loneliness can spread through social networks to negatively influence health outcomes 60 . Finally, a common set of psychosocial treatment principles are effective for multiple mental and physical conditions. Across disorders, symptoms and dysfunction can be ameliorated by activities and events that enhance purpose, self-efficacy (the perceived capacity to deal with novel or challenging situations appropriately), feelings of connection to others, social engagement and positive treatment expectancies 57 . These 'common factors' are thought to mediate most of the benefit of psychotherapy, irrespective of the particular type of treatment and psychopathology 61 . In both mental and physical health conditions, studies of placebo effects show that the act of receiving treatment in itself -along with the cognitive changes that accompany it -can confer benefits in both short-term experimental studies and long-term clinical studies across multiple disorders [62][63][64][65] . Placebo treatments can have clinically meaningful effects on pain, and in Parkinson disease, depression, anxiety, sleep disorders and more 62,63,66 .

The benefits of nonspecific treatment factors are not limited to formal clinical treatments: changing beliefs and mindsets in everyday life can also have beneficial consequences for health outcomes 67 .

Mental models of self-in-context

Most organisms can predict and learn about environmental threats and opportunities. Learning has often been assumed to be based on simple associations between cues or actions and rewards or punishments. However, humans (and probably other mammals 68 ) can form abstract, multimodal representations of the underlying contexts, or 'situations,' that cause events to occur (Fig. 1). Such 'situation representations', are conceptual, and are closely related, although not identical, to the heuristic notions of schemas or mindsets 69 . They are mental models of both sensory information and action-outcome contingencies, organized around recurring causal structures (for example, 'betrayed by a friend' or 'alone in a dangerous place').

Situation representations have several core properties. They integrate across sensory modalities and timescales, enabling context-dependent behaviour and generalization to new, similar scenarios 7,70,71 . The specific sensory cues in a given environment are less important to the construction of situation representations than are the conceptions of the latent causes -intentions, motives and hidden processes -behind actions and events. Thus, situation representations are essentially compressive, reducing complex sets of sensory cues to low-dimensional characterizations. Their formation and use is often automatic and effortless, forming the backdrop of our everyday cognition -but they can also be responsive to deliberation, conferring flexibility based on diverse cognitive and sensory inputs. Such internal models have an adaptive function: they extract causal structure from a complex jungle of sensory and interoceptive signals 7,72 , distilling what is crucial to predict future events and guide anticipatory action.

Here we are concerned with schemas that involve the self. Self-in-context representations connect states -features and action-outcome contingencies relevant for decisions -to signals of current pleasure and pain. However, they are also multitemporal, extending representations of bodily and social wellbeing into the past and future (Fig. 1). For example, the situation 'stock market crash, lost my life savings' can increase one's blood pressure because it is tied to one's conception of long-term future wellbeing. The more relevant for the wellbeing of the self, the more affectively charged the event, and the more strongly the body responds by mobilizing cognitive and metabolic resources for action. Self-in-context models thus represent information along dimensions that are relevant for the self, imbuing sensory features and potential actions with personal meaning.

Self-in-context representations confer a crucial evolutionary advantage over simple associations. They allow prediction of future outcomes from latent causes (for example, another person's hidden intentions) inferred from the integration of sensory and interoceptive signals with prior conceptual knowledge 11,73 . Such predictions can arise from minimal input (such as a single word), can rapidly shift predictions when important relationships change and can generalize to similar situations with very different physical cues. Models can include representations of one's perceived status and coping resources 74 . For example, one's response to being pushed will probably be different if the push was accidental, or if the pusher is a small child. Mental models can also integrate across timescales, combining events that happened seconds ago with those that happened years earlier, permitting re-interpretation of past events in light of new evidence.

The idea of self-in-context models builds on recent work on decision-making, in which simple situation representations are modelled using partially observable Markov decision processes 12 . These models encapsulate the idea that an organism infers its underlying state (a set of causal contingencies) from sensory cues but cannot directly observe the underlying causal structure. Cognitive maps -sets of conceptual relationships between objects and events based on their positions in an underlying dimensional space -describe the inferred transitions among underlying states 6,12 .

Markov models capture transitions among discrete 'task states' over time; but at a cognitive level, situation representations are not constrained to the present, and exist as sets of causal contingencies untethered from any particular moment in time.

The predictive control afforded by self-in-context representations may influence perception as well as action, including perception of exteroceptive signals from the environment and interoceptive signals from within the body 11,73,[75][76][77] . According to theories of predictive coding, sensory input is compared with 'top-down' predictions generated by an internal model (exemplified by self-in-context representations).

Sensory systems pass forward only differences from expectation, not all sensory input, which serve to update the model (that is, learning). Perception is thus an inference based on both sensory input and prediction-generating situation conceptions (Fig. 1).

This view emphasizes perception as a constructive process: we perceive what we should perceive in order to optimize perception and behaviour in noisy or uncertain conditions 9 . Predictive coding has been proposed as a general principle of information processing in the brain 9,11,73,75 , whereby higher levels of a processing hierarchy are sources of 'top-down' information, often represented in Bayesian models as formal priors (probability distributions of the likelihood of an event). It has recently been applied to understanding pain 78 , interoception 4,5,8 , physiological regulation and reactivity to stress 79 , depression 77 , social cognition and interpersonal behaviour 80,81 among other phenomena. Although prediction-inference feedback loops may be a general feature of computational systems, including artificial neural networks, self-incontext representations incorporating the future wellbeing of the self require specific types of information integration; we suggest below that they are implemented in particular brain systems.

In sum, 'self-in-context' representations are internal models of situations and underlying causal structures that bear on our future survival and wellbeing. They integrate perceptual information across exteroceptive and interoceptive senses with conceptual information from memory and prospective faculties into a low-dimensional representation that jointly influences sensory perception and behaviour (Fig. 1). Selfin-context representations are generative, in that they allow one to simulate the consequences of potential actions; interpretive, as they allow one to understand incoming sensory signals as clues to one's current state; attributive, as sensory events are assigned to latent causes; instructive, as causal attributions shape what is learned from experience; and predictive, in that they predict what one will experience in a given situation. Finally, because they are tied to wellbeing, such representations can become affectively 'hot' and have a special ability to mobilize physiological (for example, autonomic, endocrine or metabolic) systems.

Self-in-context in the brain

Constructing and acting on mental models necessitates a brain substrate that integrates and flexibly updates many different cognitive, affective and physiological processes. We suggest that the construction of mental models that integrate 'self' and environment is a particular faculty, and that a system centred on the vmPFC (Fig. 2) and other DMN regions 5,11 is particularly important.

The vmPFC is a cortical zone that spans multiple cytoarchitectonic regions (Fig. 2a,b) and that is anatomically and functionally positioned to integrate conceptual thought with peripheral physiology. Presumed vmPFC homologues in rodents include infralimbic and paralimbic cortex (Supplementary information S1), but the mapping with functional zones in primates is complex 82 and some functional roles may differ between species 83 . The vmPFC receives few direct sensory inputs. However, it has strong bidirectional links with sensory-integration regions in the lateral orbitofrontal cortex (OFC) and mediodorsal thalamus; interoceptive regions in the insula; motivational and reward-processing circuits including the amygdala, hypothalamus and ventral striatum (or nucleus accumbens; Fig. 2f) 20 ; and circuits involved in memory and context, including the perirhinal cortex and hippocampus 84 . Strong descending projections from the vmPFC to autonomic and neuroendocrine control regions in the hypothalamus and brainstem, including the periaqueductal gray and dorsal raphe 85 (Fig. 2d), enable the vmPFC to regulate visceromotor output 18,22 .

The vmPFC participates in multiple cortical networks that have been identified in resting-state functional MRI (fMRI) studies (Fig. 2c). The ventral vmPFC (or medial OFC) is part of the so-called limbic network 86 and is functionally coupled with the medial and anterior temporal lobes. In humans and other species, this network mediates stress-related autonomic and immune output 87 . The dorsal vmPFC is a core part of the DMN 86,88,89 , and is coupled with the posterior cingulate cortex, precuneus and temporoparietal junction 90 . Both the dorsal and ventral vmPFC are connected to the lateral OFC, and some neuroanatomists have referred to the combined vmPFC-OFC network as the 'OMPFC' 22 . Although the vmPFC and OFC are functionally dissociable 91 , lesions in rodents and primates often ablate these regions together, and thus many functions attributed to OFC may be shared with vmPFC as well.

The DMN and vmPFC exhibit many of the hallmarks of rapid, flexible and integrative processes described above. Connectomics studies identify ithe DMN as an integrative hub network that sits at the top of a hierarchy combining multiple unimodal sensorimotor processes into integrated, multimodal processes 92,93 . The vmPFC in particular is crucial for regulating physiology and behaviour, putting it in a special position at the interface between conceptual thought, decision-making and bodily regulation (Fig. 3).

Conceptual thought

The DMN was named for its high metabolic activity during rest 94 and is central to self-generated spontaneous thought 95 and (in connection with lateral PFC) goaldirected thought 90,96 . In humans, the vmPFC in particular is activated during the retrieval of episodic (especially autobiographical) memories 97,98 A key basic ability underlying conceptual thought is relational representation.

For example, semantic memory is grounded in an interconnected web of concepts embedded in semantic space 107 . The vmPFC is robustly activated during semantic memory retrieval 99 . Along with the hippocampus, it also encodes position in other relational structures, including physical space, with fMRI signal tracking activity in a hexagonal 'grid cell'-like pattern 108 . Grid cells are thought to help represent relationships among discrete locations (or object features) in a low-dimensional space -effectively, a compressed model that enables the representation of positional similarity and generalization 6 . Recent studies have found grid-cell-like patterns of activity in the vmPFC that code information in conceptual space as well, for example when retrieving relationships among newly learned object categories 14,109 . Thus, vmPFC may facilitate the formation of cognitive maps 6 that represent the position of objects, persons and situations in a relational space 110 (Box 1).

At a computational level, vmPFC and OFC enable the representation of latent states: hidden environmental states that determine outcomes (such as safety or harm) and guide value-based decision making and learning. The simplest stimulus-response associations can be learned and expressed without the PFC, but most natural environments require inferences about what the relevant states of the environment are and which sensory signals indicate them 7,72 . The OFC is crucial for learning in these situations, when states are "perceptually similar but conceptually dissimilar" 7,72 , or when the cues that indicate a state are only partially observable 111 . Indeed, the very ability to form an expectation of a specific future outcome (for example, "if I press, I will get juice") seems to require the vmPFC and/or the OFC 68,112 .

Another example of conceptually driven relations is counterfactual learning or fictive learning tasks, in which the reward value of an action depends on what might have been had one chosen differently. In such tasks, vmPFC activity is a strong correlate of regret 113 , and counterfactual emotions such as regret are reduced in individuals with vmPFC lesions 114 .

Self-referential thought and social cognition. The vmPFC is activated by selfreferential processing across diverse task paradigms 115,116 , including during processing of self-relevant words and personality traits 116 , during interoceptive awareness 8,117 , or when reflecting on one's feelings 118 , self-ownership 119 and social position 120 . Structural connectivity between vmPFC and ventral striatum correlates with individual differences in self-esteem 121 .

Thinking about others and their mental states (known as mentalizing) also activates the dmPFC and vmPFC, along with other DMN regions 122,123 . Whereas the vmPFC is engaged by thinking about others who are close or similar to oneself 124,125 , the dmPFC is more strongly engaged in impression formation and mentalizing about others 116 . When making a choice between immediate and delayed rewards, vmPFC activation tracks personal subjective value 126 , whereas dmPFC activity tracks value on behalf of another person with dissimilar preferences 127 . But when decisions need to be made on another's behalf, vmPFC encodes value for the other 127 . The vmPFC and interconnected regions also encode others' positions in a social network 128,129 , and predict warm and empathetic responses to others in distress 130 . Conversely, vmPFC damage impairs affective perspective taking and empathy 131,132 and the ability to care about potential future harm to others and oneself 133 . Thus, the vmPFC seems to be important for both representing value for the self and representing others' feelings and preferences. A flexible frame of reference enables people to self-project -to "walk a mile in someone else's shoes" -a crucial ability for maintaining social relationships.

Value and affect. In connection with subcortical networks, the vmPFC is central to the representation of affective value [134][135][136][137] and the generation of both positive and negative emotions 138,139 , across induction methods and emotion categories 11,140 .

Across studies, it tracks the value and pleasantness of stimuli across different modalities, including money, food and social rewards 134,141 . On the aversive side, vmPFC is thought to provide context signals that inhibit threat-related responses in the amygdala after threat extinction in humans, primates, and rodents 142 . Its role is broad, but selective: the vmPFC-OFC system does not seem to be necessary for basic behavioural and physiological responses to threats or rewards, for reward preferences, or for behavioural inhibition per se 10 . However, it does seem to be necessary for the flexible use of context information to guide behaviour and physiology 143 . Several recent lines of work highlight the constructive and conceptual nature of valence. For example, when participants imagine meeting a person they like in a neutral place, the place becomes more liked 144 . This associative generalization is encoded by the vmPFC.

Patterns of vmPFC activity also encode attitudes related to racial stereotypes 145 , and vmPFC activity during the experience of pain tracks perceived racial discrimination and mediates enhanced pain sensitivity in African Americans 146 . African Americans show stronger vmPFC responses to painful stimulation, and stronger responses are predictive of greater pain in the African American group.

We suggest that 'value' and 'valence' are psychological descriptors of how selfin-context models operate. Self-in-context models compress data about the internal and external world into reduced-dimensional space. But which dimensions of the myriad possible ways of organizing experience should be represented? A useful simplified model must focus on those that are most central for the survival and wellbeing of the organism (see also 73 ) and are therefore intrinsically linked to value or valence. We suggest that stronger relevance for bodily integrity and wellbeing is what makes a situation more 'affective' and imbues it with positive or negative valence and other motivational properties (such as approach-avoidance motivation). In this view, self-in-context models and the likelihood of wellbeing are updated based on new events or information. The nature and magnitude of the update (that is, its derivative) determines the affective value ascribed to the event, and the possible paths to longterm wellbeing given the current model state determine mood, optimism and selfrelated affect (see refs 147,148 ).

The vmPFC and DMN help construct this representation of the self in this lowdimensional space. This might explain the abundance of vmPFC-OFC neurons that encode both positive and negatively valenced signals 149 and the dysregulation of emotions and situated real-life behaviour after vmPFC damage 132 . Finally, a hallmark of affective valence and processing priority alike is the mobilization of physiological resources. As we outline below, the DMN -and vmPFC in particular -is positioned to guide physiological responses and behavioural decisions based on self-in-context models.

Regulation of body and behaviour

The vmPFC and DMN, directly and via connections with other networks 11 (Box 1; Fig. 3) are positioned to influence mental and physical health through influences both on health-relevant decision-making and on autonomic and endocrine systems, which together confer vulnerability or resilience over time. However, vmPFC and OFC lesions do affect behaviours that depend on the integration of situational (for example, place), social or interpersonal, temporal or interoceptive (for example, satiety-related) information into reward-guided or threat-guided behavioural decisions. For example, in rats, vmPFC lesions or inactivation do not affect threat learning or extinction, but impair the ability to consolidate and use memories when a context changes from being threatening to being safe 150 . When shocks are escapable, a representation of perceived control (that is, an action-escape contingency) in the vmPFC suppresses threat-related responses in the dorsal raphe nucleus and associated threat behaviours 151 . vmPFC inactivation suppresses the benefits of perceived control, and vmPFC stimulation confers similar benefits for behaviour even when shocks are inescapable 151 . vmPFC lesions also disrupt other context-dependent appetitive behaviours, including selective satiety -a shift in food preferences when one has consumed enough of a particular food -and rapid shifts in choice behaviour when reward contingencies change 152,153 . In humans, lesions of the vmPFC do not generally disrupt basic value preferences, but do disrupt the ability to generate behaviours and emotions appropriate to the situational and social context 154,155 . Accordingly, in human imaging studies, the vmPFC responds to manipulations of the social and informational context that shape reward-and threat-driven behaviour.

Health-related decision

In threat-learning studies, it responds during extinction recall 156 , reversals of cueshock contingencies from threat to safety 157 and manipulations that increase perceived control 142 . Suggestions that a placebo treatment is an effective analgesic activate the vmPFC and OFC, increase vmPFC connectivity with the periaqueductal gray (PAG) 158 and promote opioid release in vmPFC and PAG 65 . In reward studies, the vmPFC responds to selective satiation signals that guide food choices 159 and influences of suggestion on value 135,160 . The vmPFC also responds to vicarious reward, experienced when rewards are given to similar others 161 , and encodes information about social categories related to racial and sociocultural stereotypes 145,162 .

The vmPFC is also prominently involved in cognitive self-regulation, a set of techniques for altering appraisals (conceptualizations of the meanings of situations and events in terms of their hidden causes and likely future trajectories), attributions and construals of affective meaning. Dietary self-control (the ability to regulate behaviour and impulses to achieve long-term goals) is positively correlated with functional activation 136,137 and grey-matter density 163 in the vmPFC and dlPFC.

Focusing on the tastiness of food increases functional connectivity between the ventral striatum and vmPFC, whereas focusing on health aspects of food increases connectivity between the dlPFC and vmPFC 136,137 . Acute stress changes value signals in vmPFC to favour high-calorie foods and increases vmPFC-ventral striatum connectivity 164 . Conversely, reframing appetitive smoking cues by thinking about the long-term consequences of smoking can reduce cigarette craving and vmPFC activity 165 . Another form of self-regulation is engaging in prospective thought and evoking positive memories, both of which can shift value-based choices towards longterm rather than immediate gains (that is, reduced delay discounting). Positive prospection also increases vmPFC activity 166,167 . By contrast, successful cognitive downregulation of negative emotion and pain are also mediated by activation of a pathway from the vmPFC to the nucleus accumbens 168,169 . An emerging view of selfregulation is that it involves selective reinforcement of certain ingredients of self-incontext models -for example, a focus on the future self, or the undesirable properties of cigarettes -that alter the way affective value is constructed.

The consequences of these context-and value-guided decisions can manifest over time in the form of the long-term effects of health-related behaviours: how we sleep, eat, play, work and connect. For example, vmPFC responses to health-related messages (for example, to quit smoking) predict long-term attempts at behaviour change (such as calls to helplines 170 ; reviewed in 171 ).

Peripheral regulation. In addition to shaping behaviour, vmPFC has a key role in controlling the autonomic and neuroendocrine systems, which shape the body's physiological health over time 19,172 . Chronic uncontrollable stressors result in 'wear and tear' on bodily systems that adversely affects health 173 . Whether we conceive of events as threatening and out of our control is particularly important 51,69,[174][175][176] . Low socioeconomic status, low perceived social standing, adverse childhood experiences and perceived racial discrimination constitute risk factors for poor mental health and reductions in longevity 177,178 .

The vmPFC is part of a system that controls the autonomic nervous system via its efferent projections (Fig. 2d; Fig. 3; Supplementary information S1) to structures in the hypothalamus, forebrain (such as the amygdala and nucleus accumbens) and brainstem (such as the PAG) 18,19,41,179 . The sympathetic and parasympathetic branches of the autonomic nervous system influence all of the body's organs, from the heart to the bone marrow (where many immune cells are produced) and more. The vmPFC also governs hormone release via the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal medullary (SAM) axis 18 , which regulate stress responses and homeostatic adaptation; the hypothalamic-pituitary-thyroid axis, which regulates the body's metabolism; and the hypothalamic-pituitary-gonadal axis, which regulates developmental and reproductive functions (Fig. 2e). In turn, autonomic and hormonal responses influence the expression of systemic pro-inflammatory and antiinflammatory cytokines and chemokines 172,180 . vmPFC activity correlates with stress-evoked and task-evoked autonomic responses, including heart rate, heart rate variability, blood pressure and skin conductance 179,181 . In non-human animals, vmPFC-hypothalamus and vmPFC-PAG pathways seem to be topographically organized by behavioural functions that are related to the optimal response to strong threats (for example, 'avoid', 'escape', 'fight', 'flight', 'surrender' or 'defecate') 182,183 .

The vmPFC also has a role in modulating levels of systemic inflammation 44,184 .

A meta-analysis of human brain-immune correlations identified a network involving the mPFC, amygdala, ventral striatum, hippocampus, hypothalamus and pons 23 , including areas of both the DMN and limbic network. Brain correlates of immune markers were identified in both the dorsal mPFC and posterior (subgenual) vmPFC.

The vmPFC was the region most strongly co-activated with the brainstem, and its activity correlated with inflammatory measures during emotion-induction tasks (rather than cognitive tasks) in particular. Thus, vmPFC-subcortical pathways may mediate inflammation driven by conceptualization of the self-in-context.

Future outlook

A common factor

Alterations in the vmPFC and interconnected areas of the DMN have been implicated in multiple psychiatric conditions, including major depressive disorder (MDD), anxiety, schizophrenia, attention deficit-hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD) and drug addiction 25 . Pathology in this system may represent a common underlying factor across disorders 30,29 , and may explain the high rate of cooccurrence of different disorders. Grey-matter reductions in the DMN and vmPFC in particular were among the features most consistently associated with psychopathology in a recent meta-analysis of transdiagnostic features in ADHD, MDD, PTSD, anxiety disorders, autism, bipolar disorder, obsessive-compulsive disorder and schizophrenia 185 (although the dlPFC is also important 186 ). Resting-state hypoconnectivity in the ventral DMN and hyperconnectivity in the dorsal DMN was also a transdiagnostic feature, along with reductions in negative coupling between DMN and frontoparietal networks 185 . These brain features may extend to somatic disorders as well: Reductions in vmPFC grey matter are also consistently associated with chronic pain across studies 187 , paralleling functional and structural changes in mPFC-NAc circuits in rodent models of chronic pain 188 . Such alterations need not reflect only 'organic' changes in brain organization independent of cognition. Rather, they might reflect the cumulative effects of altered self-in-context models. For instance, depression and anxiety are associated with negatively biased beliefs regarding the self and/or its ability to cope with events. Chronic pain may be increased and maintained by perceiving pain as threatening and body movement as potentially dangerous. Over time, these models may manifest as maladaptive alterations in behavioural and physiological responses to life eventsfor example, avoidance of novel situations or exercise, or dysregulation of the autonomic or neuroendocrine system.

Leverage points

Self-in-context models can be thought of heuristically as mindsets that shape what information we are open to accepting, to which hidden causes we attribute past and current events, and what we learn from experience. Healthy mindsets reduce negative beliefs about the future (such as hopelessness) and unwarranted blame and hostility (particularly that directed towards the self), and induce openness to potential benefits and opportunities 69 . Unhealthy mindsets, particularly negative self-evaluation and negative beliefs about the potential for positive change, are associated with poor health. For example, random assignment to the suggestion that one is genetically intolerant of exercise reduced running endurance and measures of lung gas exchange 189 . Negative beliefs about ageing are associated with less engagement in healthy behaviours 175 and reduced longevity 176 . Having a negative stress mindsetthe belief in stressors as debilitating (versus as helpful opportunities for growth) 190can amplify negative effects of stress. In a study of >28,000 individuals, high perceived stress coupled with the belief that stress negatively affects health was associated with a 43% increase in death rate compared with the absence of either risk factor 191 .

Recent studies suggest that the vmPFC and OFC mediate effects of several types of brief mindset interventions 192,193 , supporting the centrality and malleability of self-in-context representations. Suggestions that other people experienced a painful stimulus as particularly intense increased both pain experience and autonomic responses 194,195 . Conversely, social manipulations, such as receiving supportive touch from a romantic partner 196 or voluntarily accepting pain on behalf of another person 197 , reduce pain experience and measures of pain-related brain activity -effects mediated by changes vmPFC and OFC activity. Brief training in mindful acceptance 198 or meditation 199 also reduce pain and negative emotion, along with brain responses associated with these 198 , including reduced activity in vmPFC and other DMN regions during pain 199 . These interventions can meaningfully affect physiology; they influence the most sensitive and specific brain measure related to pain currently available, with effect sizes larger than those found in placebo interventions 200 .

Mindsets also shape what we learn from experience, creating benefits or harms that compound over time. For example, individuals with social anxiety disorder have a negative mindset about themselves and their social standing. In laboratory experiments, individuals with social anxiety disorder learn more quickly from negative than positive social feedback than do non-anxious controls 148 , potentially creating a self-reinforcing cycle of anxiety and self-doubt. Expectations about pain can also become self-reinforcing, such that one 'gets the pain one expects' 201 . Computational models of self-reinforcing feedback cycles indicate that two key factors are required: 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 ignored 201 . Psychotherapy may work by reshaping one's self-in-context representations over time. Many forms of psychotherapy focus on helping individuals foster healthpromoting appraisals, causal attributions and meaning-making. In addition, much of the benefit of therapy is not due to specific protocols, but to 'common factors' such as positive expectation, self-efficacy and engagement 61 , which shift patients' mindsets.

The vmPFC-OFC, hippocampus, and amygdala are among the regions most consistently altered after psychotherapy in various mental health disorders 202,203 The effects of psychosocial interventions and changes in mindsets are undoubtedly complex, and we have much to learn. Self-in-context representations inherently vary across individuals and may be maladaptive in myriad ways across different disorders. In addition, they surely depend on complex neural interactions involving multiple brain regions and systems. However, the central idea here is that there is a focal point, a neural hub for integrating the various elements of experience into a coherent view of the world and our trajectory through it. Understanding this as a common, driving force underlying wellbeing may help us reconceptualize the role of the brain in mental and physical disorders alike. And, because self-in-context models are fundamentally ideas, there is hope that people can learn to change them for the better in themselves and in those they care for. In turn they can regulate visceral outflow via vmPFC projections to the hypothalamus and the brainstem. Self-in-context models also shape decision-making and healthrelevant behaviour (for example, dietary choices and how one works and connects with others) via vmPFC connections with the basal ganglia and the mesolimbic reward circuit or frontostriatal loops 20 . Together, these dual pathways can shape mental and bodily health in multiple ways, such as via their effects on inflammation and allostasis, or their interactions with other health-relevant systems such as microbiota (for example, via dietary patterns). For instance, maladaptive thought patterns and self-incontext models may lead to a dysregulation of the autonomic nervous system, which leads to allostatic load and diminished recovery, with long-term effects on bodily organs. At the same time, self-in-context models may lead to changes in health-related behaviour such as unhealthy food choices, insufficient exercise or drug use, which also impact health in the short and long term. The hippocampus is crucial for the formation of long-term memories and 'cognitive maps', and for spatial orientation 6,13,108 . Similar to the vmPFC, the hippocampus and parahippocampal cortex have grid-cell-like properties for representing conceptual relationships 14 . Though they may jointly contribute to constructing conceptual maps of the self in context, conceptual maps may also differ between areas. For example, vmPFC may be especially important for self-referential conceptual maps that prioritize information relevant for bodily integrity and wellbeinga particular type of egocentric map-whereas hippocampus might preferentially encode information relevant for allostatic spatial and conceptual maps less directly involved in physiological regulation. (or ventral attention 86 ) networks, which together may form a unified brain system for allostasis 5 .

One intriguing hypothesis is that DMN and salience networks may underlie allostasis in two distinct but complementary ways, in line with the distinct dynamics of these two networks: DMN regions such as the vmPFC may predictively regulate body function and behaviour based on conceptual information and self-in-context models, whereas the salience network may do so reactively, based on the detection of 'salient' events or new information that require adjustments or 'switching' of states. These and other hypotheses could be tested in future work.

Box S2 | Prospective studies of the effects of psychological and social factors on health

Psychological and social factors have been associated with diverse health outcomes. The strongest evidence for these associations derives from prospective clinical and epidemiological studies that attempt to overcome the interpretive problem of reverse causation. This problem is inherent to cross-sectional studies, in which psychological and social factors are measured at the same time as a health outcome and then correlated with one another. Here, it is always possible that poor health led to an unfavourable psychological or social state. By contrast, prospective studies assess a given psychological or social factor among individuals who are symptomatic or asymptomatic for a clinical illness, and then follow these individuals for many years to track the new development (that is, incidence) of a particular health outcome (such as fatal or nonfatal myocardial infarction), the progression of disease (for example, how rapidly a disease advances in its severity), the recurrence of a disease state or survival. If a given psychological or social factor predicts the future development of a health outcome, and this predicted effect is not explained by other influences (such as age, sex, ethnicity or family history of disease), the factor is implicated as a potential determinant of health.

Psychological and social factors are most often measured by self-report instruments (for example, questionnaires or surveys) that have demonstrable psychometric properties (such as good test-retest reliability and internal consistency), but some studies also rely on clinical diagnoses (such as in studies of depression and anxiety) and diary-like self-report measures taken from individuals in daily life (for example, through use of cellular phones or other electronic devices).

Complementing these epidemiological studies are laboratory and field studies that measure psychological and social factors in relation to biological indicators of autonomic nervous system activity, hypothalamic-pituitary-adrenal axis activity and immune activity. The importance of these studies is that they often provide evidence for the plausible physiological pathways (that is, a specific pathophysiology or particular brain circuitry) that link psychological and social factors to a particular health outcome.

  and semantic memory 99 . It is crucial for prospection (imagining future events) 100,101 ; vmPFC damage impairs people's ability to imagine the future in rich detail 102 . Activation patterns in vmPFC and other core DMN regions are stable across movie or story segments with coherent narrative themes 103 , integrating past information 104 into representations of narrative meaning 105 . Activation patterns in the vmPFC, like conceptual understanding, can also shift suddenly when new information allows insight 106 .

  -making. In the biopsychosocial model of health, valuebased decision-making -what to eat, what to avoid, and when to exert effort -is paramount. The vmPFC and OFC are particularly important when decisions are guided by context-dependent affective value, consistent with the idea of self-in-context representations. Lesions of vmPFC homologues in rodents and non-human primates do not affect basic reward preferences, reward learning, unconditioned threat responses or basic conditioned threat acquisition or extinction (for review, see 10 ).

  . The benefits of common factors are not exclusive to any particular treatment, and can have substantial effects on diverse medical conditions, including migraine, depression, anxiety, Parkinson disease, asthma, irritable bowel syndrome and arthritis 204 . Beyond formal psychotherapy and medical treatment, shifts in conceptual thinking towards healthier self-in-context representations can be influenced in various ways: through interactions with friends, family and communities; through mindfulness and self-regulation training; and through public health policy. For example, across more than 300 trials of psychological interventions in individuals with cancer 205 , people with strong social support networks survive longer 206 . Psychosocial interventions can increase survival time, particularly for those who are more socially isolated 207 , and improve cancer-relevant immune measures 205,208 . Two randomized trials of psychosocial interventions showed improvements in mood, in cancer survival 7-11 years later and in measures of cellular immunity, including natural-killer-cell cytotoxicity and lymphocyte proliferation 209,210 .

Fig. 1 |

 1 Fig. 1 | A schematic of self-in-context models and their role in health and disease. The ventromedial prefrontal cortex (vmPFC), together with other key regions of the default-mode network (DMN) such as the temporoparietal junction (TPJ) and posterior cingulate cortex (PCC), locates the current position of the self-in-context in a compressed low-dimensional space that captures the essential features of a situation-what we could also call 'meaning-making' or locating the current state of the self on a mental or conceptual map. Self-in-context models are inference-based models of the current state that predict sensory and interoceptive input and guide behaviour and

Fig. 2 |Fig. 3 |

 23 Fig. 2 | Anatomy and functional connectivity of the ventromedial prefrontal cortex. a | The anatomy of the ventromedial prefrontal cortex (vmPFC) includes the ventral anterior and the subgenual cingulate cortex, the gyrus rectus, the medial parts of the rostral gyrus and frontal pole, and inferior parts of the superior or medial frontal gyrus. b | Multimodal parcellation of vmPFC and adjacent areas, based on an established whole-brain parcellation 244 , illustrating the heterogeneity of vmPFC in terms of anatomical features and functional co-activation patterns. c | Cortical restingstate networks. Most of vmPFC is part of the default mode Network (DMN), especially the Default A network or core-DMN (here based on the parcellation by Yeo et al. 86 ) that serves as a hub between the medial temporal and the dorsal subnetworks of the DMN 89 . The most ventral part of vmPFC (that is, the rostral gyrus and parts of subgenual anterior cingulate cortex) is part of the limbic network. d | Brain areas

  Networks beyond the default mode network (DMN) are also important for interoception and physiological regulation. The EPIC (Embodied Predictive Interoception Coding) model has been proposed to explain how intrinsic brain networks underlie allostasis, unifying interoception and visceromotor control 4 . This model proposes that agranular cortical regions (including the cingulate cortex and anterior insula) control visceromotor function via their connections to subcortical areas and, in parallel, send sensory prediction signals to granular cortical regions, especially primary interoceptive cortex 4 .Testing this model, a recent study found evidence for two large-scale networks around several key visceromotor regions, closely aligning with the DMN 15 and the salience 250

Table 1 | Associations among psychosocial factors, physiology and health outcomes

 1 note on the advantages of prospective studies (such as those referenced here) is available in the Supplementary information S2.

	Psychological	Physiological correlates	Health outcomes	Refs*
	and	social
	factors
	Anger, hostility		Adrenaline and noradrenaline	Risk of CHD events in non-patients	211-215
				Cardiovascular stress reactivity	¯ Prognosis in CHD patients
				Systemic inflammation	Risk of future stroke in non-patients
				ACTH and CORT
			¯	Parasympathetic	cardiac
			control
	Depression		Adrenaline, noradrenaline	CHD mortality in patients with	208,216-
				Systemic inflammation	unipolar and bipolar depression
				ACTH and CORT	¯ Prognosis among CHD patients
			¯	Parasympathetic	cardiac	Risk of CHD events in non-patients
			control	Cancer progression
					¯ Survival in cancer patients
					Risk of mortality in diabetes
					Risk of diabetes in non-patients

Acknowledgements

The authors are grateful for support from the US National Institutes of Health, including grants R01MH076136 and R01DA035484 (T.D.W.), R01DA043690 and R01DA042911 (H.K.) and NHLBI P01 040962 (P.J.G.), and for a Marie-Skłodowska-Curie/PRESTIGE fellowship (PRESTIGE-2018-2-0023) from Campus France (L.K.). The authors thank Dr. Meghan Meyer for helpful feedback, and L. Feldman Barrett and two anonymous reviewers for constructive peer-review comments on prior drafts of this manuscript. ACTH, adrenocorticotropic hormone; CHD, coronary heart disease; CORT, cortisol; HIV, human immunodeficiency virus; HPA, hypothalamic-pituitary-adrenal. *A general

Code availability

Instructions and code to generate the visualizations of the term-based meta-analytic association maps in Fig. 3 are included in Supplementary information S3.

Author contributions

LK and TW conceptualized the article, wrote the first draft, and created the figures. PG and HK contributed to the conceptual model, literature review, interpretation, and writing.

Competing interests

The authors declare no competing interests. measures. These associations were centred in a network connecting dACC and medial prefrontal cortex with thalamic, diencephalic, brainstem and cerebellar regions, including coverage of many nuclei identified in part a. Pro-parasympathetic effects included positive correlations with HF-power, HRV and RSA, and negative correlations with HR, SBP and MAP. These associations were mainly found in parts of ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC), insula, amygdala, ventral striatum-ventral pallidum (vSt/vPal) and subthalamic nucleus (STN). BarN, Barrington nucleus; C1+, C1 cells; ON, Onuf's nucleus.

Supplementary information

S1 (figure); S2 (box); S3 (box).

Box S3 | Recreating meta-association maps in Fig. 3

Software needed to run the script to reproduce our visualizations is below. Once the software is installed, save the script below as an .m file in the same folder as the Neurosynth maps, and run the script from this folder. The Neurosynth maps visualized in Figure 3 were downloaded on Jan 6, 2021. Files and code can be found on Github at https://github.com/canlab/2021_Koban_NRN_SelfInContext

The Neurosynth maps can alternatively be visualized using other neuroimaging software (for example, SPM orthviews, FSLeyes, Caret/Connectome Workbench, pycortex, etc).

Software dependencies

Visualizing the latest Neurosynth maps in the Neurosynth web browser

The latest maps can be viewed and downloaded at Neurosynth.org (although these are not guaranteed to remain the same as the database may be updated).

1. On neurosynth.org, click 'Meta-analyses' and select the 'Terms' option.

2. Enter the term (that is, 'thoughts', 'decision making', 'self referential' or 'autonomic') into the search bar, and click on the closest term identified in the search results. 3. Ensure that the association test layer and anatomical layer are both visible (but that the uniformity test layer is not visible). 4. Enter the X coordinate -6 in the space provided and uncheck the 'crosshairs' and 'labels' boxes.

Script