Allostatic interoceptive overload across psychiatric and neurological conditions

Abstract

Emerging theories emphasize the crucial role of allostasis (anticipatory and adaptive regulation of the body’s biological processes) and interoception (integration and regulation of internal bodily states) in adjusting physiological responses to environmental and body demands. This review explores the disruptions in integrated allostatic interoceptive mechanisms present in psychiatric and neurological disorders, including anxiety, depression, Alzheimer’s disease, and frontotemporal dementia. We also assess the biological mechanisms associated with allostatic interoception processes involving whole-body cascades, brain structure and function of the allostatic interoceptive network, heart-brain interactions respiratory-brain interactions, gut-brain-microbiota axis, peripheral biological processes (inflammatory, immune), and epigenetics pathways. These pathophysiological allostatic and interoceptive processes span psychiatric and neurological conditions and call for the development of dimensional and trans-nosological frameworks. We synthesize findings regarding how allostatic interoceptive processes modulate interactions between environmental demands and biological functions in brain disorders. We discuss the current limitations of the framework and future transdisciplinary developments. This review opens a new research agenda for understanding how allostatic interoception involves brain predictive coding and spatiotemporal dynamics. Finally, we discuss how novel composite measures of allostatic interoception across levels of organismic involvement may allow for better clinical application and personalized therapeutic interventions.

Introduction

As a species, we regularly encounter a variety of environmental challenges, including infections, pollution, physical stress, socioeconomic disparities, and trauma. These factors influence our overall well-being(1). Our adaptive capacity is shaped by the intensity of these threats and our inherent biological predispositions(2). Moreover, this adaptation relies on different regulatory physiological mechanisms that anticipate, mediate, and respond to the complexity of environmental and biological interactions(3). These regulatory physiological mechanisms can foster successful resilience or result in physical, neurological, and psychiatric disorders(4). Although previous evidence has focused on how our biological systems respond to external stressors, leading to either adaptability or the emergence of diseases(5), significant gaps persist. As such, the mechanisms through which external challenges (e.g., insufficient income) and internal alterations (e.g., dysregulation of the hypothalamic-pituitary-adrenal axis [HPA]) combine to induce psychiatric or neurological pathological outcomes remain unclear(6). To date limited evidence details how stressors instigate disease by impacting various biological pathways(2, 7). Predominant frameworks, such as the diathesis-stress models, overlook the plethora of biological processes such threats may influence(8). These models also fail to assess how biological processes respond to external challenges based on internal regulatory mechanisms(9, 10). Finally, most research has focused on categorical classification of diseases frameworks(11), bypassing dimensional approaches that may offer insights into psychiatric and neurological disorders arising from environment-biology interactions.

Emerging models could offer new perspectives. Recent studies have underscored the significance of anticipatory biological reactions to upcoming external challenges, or allostasis(12, 13), and the coordination, regulation, and modulation of internal states, or interoception(9, 10, 14, 15) (Figure 1A). Effective coordination of threat anticipation and the regulation of internal bodily demands is crucial for adaptation. Conversely, dysregulation in this coordination is associated with brain disorders. This dysregulation occurs when there’s a mismatch between the anticipated energy expenditure and the actual energy required to cope with stressors, leading to physiological alterations due to overload(16–18). Although research on allostatic interoceptive processes is expanding(14), comprehensive studies that explore the role of these processes throughout the spectrum of psychiatric and neurological disorders are needed(6). Furthermore, a deeper understanding of allostatic interoceptive processes could elucidate the mechanisms governing adaptability or vulnerability to psychiatric and neurological disorders(6, 14, 16, 19), offering an innovative framework for diagnosis, characterization, and intervention.

Figure 1. Allostatic interoception regulates environmental and biological interactions across the lifespan.

The left panel outlines predictive allostatic interoceptive processes. The allostatic–interoceptive system (A) is supported by the allostatic–interoceptive network (AIN), which includes principal hubs such as the anterior mid-cingulate cortex (aMCC), pregenual anterior cingulate cortex (pACC), subgenual anterior cingulate cortex (sgACC), dorsal amygdala (dAmy), agranular insula (vaIns), dorsal mid-insula (dmIns), and dorsal posterior insula (dpIns). The limbic cortices send prediction signals and receive prediction error signals from the internal milieu, initiating psychological responses. Allostatic interoceptive processes, rooted in brain-body interactions including brain-heart, brain-respiratory, and brain-gut-microbiome systems, facilitate anticipation and guide responses to external demands and threats, which may vary across the lifespan (B). Various biological predispositions can either dampen or amplify allostatic interoceptive processes, including the functioning of cardiovascular, metabolic, inflammatory, and stress-hormone systems (C). The degree of responses to external stimuli are influenced by genetic-epigenetic predispositions toward adaptive behaviors related to disease risks (D). Visuals in panels (A, B, and C) are illustrative examples and do not represent actual data.

This review addresses the allostatic interoceptive framework in psychiatric and neurological disorders. Our search spanned MEDLINE, Embase, and Web of Science databases, focusing on studies published from January 1 1998, up to June 30, 2023. We used keywords pertinent to external demands, biological processes, allostasis, interoception, psychiatric and neurological disorders (Supplement 1). The review is divided into four main sections. In the first section, we introduce the integrative models centered on allostatic interoception. In the second section, we review the whole-body biological mechanisms associated with allostatic interoception processes. In the third section, we delve into the role these biological mechanisms play in prevalent psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s disease (AD), and behavioral-variant frontotemporal dementia (bvFTD). In the fourth section, we synthesize pivotal findings regarding the role of allostatic interoceptive processes in modulating interactions between the environmental demands and biological process across brain disorders. Furthermore, we explore the potential implications of this approach for future research and clinical dimensions, address the caveats associated with this methodology, and underscore the need to harmonize this framework with comprehensive models detailing spatiotemporal dynamics of brain functioning and its consequential effects on diagnosis and therapeutic strategies.

Allostatic interoception and its role in regulating responses to environmental and internal demands

Across the lifespan, humans face different environmental demands such as physical threats, air pollution, infections, as well as social determinants of health, including social disparities, adversities, and psychosocial stress(20) (known together as exposome(21), Figure 1B). In adaptative situations, exposomes activate physiological mechanisms to ensure survival and maintain internal equilibrium(13, 22, 23). Allostasis, which refers to the anticipatory and adaptive regulation of the body’s physiological processes, is central to adaptative processes(12). Allostasis is also modulated by different biological priors, including genetic and epigenetic predisposition to brain disorders, cardiovascular, inflammatory, and metabolic functioning (10, 12, 13)(Figure 1C–D).

Critically, allostasis is also determined by the prediction and integration of internal bodily states known together as interoception(9, 10, 14). Interoception allows us to anticipate, perceive, and regulate sensory signals from innervated visceral organs, including cardiovascular, respiratory, and gastrointestinal systems(24). Interoception also involves chemosensation, changes in the endocrine system(25), immune system(26), temperature, and affective touch(27). Interoception influences decision-making processes, emotion regulation, memory, and social interaction (28). Interoception plays a significant role in allostasis by regulating the behavioral and physiological responses to both environmental demands and bodily needs.

The cost of responding to external and internal demands is known as allostatic load(14, 15, 19, 29). When the exposome or the internal bodily needs exceed the individual’s coping ability, allostatic overload ensues(29). Different triggers, including early adversities, social disparities, lifestyles, and chronic stress, as well as dysregulated internal bodily demands canresult in an allostatic overload state(22, 23, 29–33). Allostatic overload leads to altered biological responses to even minor external threats(22, 31, 34). Particularly, it may trigger pathophysiological changes, including oxidative stress, chronic inflammation(35), and insulin resistance(36). Allostatic overload also impacts neurocognitive processes affecting brain structure and functioning, and has been shown to be associated with reduced volume of the hippocampus, amygdala, and prefrontal cortex(18, 22), and affect the balance in excitatory and inhibitory neurotransmitters(37)allostatic overload is involved in cognitive processes(38), including memory, decision-making, executive functioning, emotion regulation(30, 39), and social behavior(18). As such, this state predisposes the organism to chronic diseases(13, 22, 29, 31, 34, 37, 40), such as cardiovascular and metabolic conditions(36, 41), accelerated aging(34, 42, 43), and psychiatric and neurological disorders(30, 31, 38).

Allostatic interoception

Allostatic interoception refers to the anticipation, integration, and modulation of different biological processes ensuring inner physiological adaptations to environmental demands and stressors(15, 19). Allostatic processes allow us to anticipate, prepare and adjust the body’s systems in anticipation of potential demands, while interoception serves as the internal feedback loop, tracking information from different inner systems ensuring these responses are in accordance with the energy required to meet the demands(14, 15, 19, 29)(see Figure 1A). Allostatic and interoceptive processes collaboratively facilitate the body’s adaptation to internal and external demands by fine-tuning internal model predictions. For instance, in freeze-flight conditions, the body enhances blood flow to vital regions, and diminishes heart rate during sleep.

Allostatic interoceptive processes can be understood through predictive coding, suggesting that the brain anticipates and adjusts its interpretations of external and internal cues(15, 19, 44, 45). A prediction error is generated when a predicted signal differs from the actual input. Prediction errors help refine future anticipations and adapt to new challenges(45, 46). Discrepancies between predicted and actual signals can trigger dysfunctional responses, potentially leading to psychiatric or neurological symptoms(6, 14, 15, 19, 46–48).

Whole-body allostatic interoception

A prototypical case of allostatic interoception

The neurally mediated syncope (NMS), also known as vasovagal syncope, provides a prototypical example of altered regulatory and anticipatory whole-body mechanisms in the presence of external demands(49). NMS is a disorder characterized by a sudden, temporary loss of consciousness, typically caused by a reflex response that leads to a drop in blood pressure, slowed heart rate, and subsequently reduced blood flow to the brain. This phenomenon can be understood as a maladaptive prediction of external and internal demands, paradoxically decreasing cardiovascular mechanisms instead of engaging the expected compensatory mechanisms(50). Individuals with vasovagal syncope have been shown to exhibit other allostatic interoceptive overload responses that affect inflammatory and metabolic processes, which can impact cognition, emotion regulation, and behavior(49, 50). The vasovagal syncope is highly determined by top-down and bottom-up brain control processes that allow the deployment of regulatory mechanisms under stress(51). This condition can be triggered by actual or imagined stress, potentially leading to anxiety-related symptoms, somatic symptom disorders, and health anxiety stemming from the fear of experiencing somatic disorders(52).

Predictive allostatic interoception and the modulation of whole-body cascades

Allostatic interoception encompasses interrelated biological processes that maintain the body internal balance. A close examination of this system unveils a detailed interplay between brain structure and function, as well as interactions involving the heart, breath, and the gut-brain axis. At the peripheral level, allostatic interoception relates to metabolic, autonomic, inflammatory, immunological, and microbiota processes(53).

Brain structure and function of the allostatic interoceptive network

Recent studies have identified the allostatic interoceptive network (AIN)(46, 54, 55). This brain network is a neuroanatomical and functional system comprising hubs from the salience network and the default mode network and integrating interoceptive information(46, 54–57). Particularly, the AIN comprises a set of regions, including anterior mid-cingulate cortex, pregenual anterior cingulate cortex, subgenual anterior cingulate cortex, dorsal amygdala, agranular insula, dorsal mid-insula, and dorsal posterior insula(46). The limbic cortices send prediction signals and receive prediction error signals from the internal milieu(46).

The AIN mediates cognitive processes such as memory, executive function, emotional processing, and cognitive control while also relating to allostatic load(46, 54–57). The AIN also oversees heart-brain and peripheral activity, subsequently influencing our reactions to environmental stimuli(58). Notably, projections from the limbic cortices to the hypothalamus and brainstem nuclei, considered neuroanatomical routes for predictive signals from limbic cortices, help regulate the neuroendocrine, autonomic, and immune systems(45, 46).

Heart-brain interactions

Heart-brain interactions have been classically studied via the heart-evoked potential (HEP), an indicator of interoceptive processes and neural responses triggered by cardiac activity(21, 57, 59–67). Multimodal evidence has recently associated the HEP with interoception(61, 62, 68, 69), allostasis(66, 69), and allostatic interoceptive dynamics(45). An intensified HEP in resting-state has been described as an indicator of allostatic-interoceptive overload(59, 69). HEP involves source generators in interoceptive and allostatic regions, including the insula, anterior cingulate cortex, and amygdala(57). Modulation of the HEP can arise from both a bottom-up (i.e., instigated by cardiovascular imbalances and associated error processing) and top-down mechanisms (i.e., deviated interoception with misdirected predictive deductions)(63). Beyond traditional active heartbeat detection tasks, HEP changes measured with amplitude difference, latency, and power occur during non-cardiac monitoring tasks and at rest, correlate with hypervigilance to interoceptive signals and allostatic overload(70). HEP has been implicated in mental conditions such as insomnia, anxiety, post-traumatic stress disorder, and depression(67), as well as a broad range of neurological(61, 65, 66, 71) neurodegenerative(59, 61, 62, 64, 67, 68, 71) and neurocardiogenic conditions(72).

The brain controls heart activity via the sympathetic and parasympathetic branches of the autonomic nervous system, affecting cardiac function in response to a range of internal and external stimuli(73). This modulation can also be monitored through the heart rate variability index(74). This index is mediated by the integration between top-down mechanisms of prefrontal and the brainstem nuclei that directly control the heart(75). Heart rate variability has been shown to predict autonomic changes linked to physical stress, cognition, and brain disorders(75).

Respiratory-brain interactions

Respiratory interoception, the ability to sense and regulate breathing, is vital for adapting to external demands(48). Accurate monitoring of respiratory sensations optimizes cardiorespiratory function during activities, acting as a health marker(17, 76). Heightened respiratory awareness is associated with psychiatric conditions like anxiety symptoms and and panic disorder. Persistent breathlessness is linked to increased risks of depression and anxiety(77). Some measures, like breath rate and metacognitive perception, are considered potential allostatic interoception biomarkers(78).

Gut-brain-microbiota axis

The gut-brain microbiota interactions are critical processes determined by predictive allostatic and interoceptive mechanisms(79). The gut-brain axis facilitates bidirectional anticipation and regulation of physiological responses in the presence of external demands(80). Gut-brain-microbiota communication is maintained via a complex network including the brain saliency network, autonomic nervous system, enteric nervous system, hypothalamic–pituitary–adrenal axis, and immune systems(81). Changes in gut microbiota composition influence this axis, impacting interoceptive awareness, allostatic responses, and brain functions related to stress and emotions(76). Diet is one of the critical processes that affect microbiome diversity, impacting the gut-brain-microbiome interactions. Moreover, microbes are themselves able to influence eating behaviors(82). A balanced gut microbiota supports immune function and intestinal barrier integrity(83).

Axis imbalances may lead to “leaky gut” and inflammatory responses, disrupting allostatic processes(84). Allostatic overload can influence gut microbiota balance(84). Gut microbiota-derived metabolites, like short-chain fatty acids, influence brain function, and affect neurotransmission and functional connectivity. Moreover, cognitive processes including memory, emotion regulation, decision-making, motivated behavior, and circadian process regulation, are shown to be impacted by dysregulations in the gut-brain-microbiome axis (85). Individuals with dysregulation in the mentioned axis can exhibit gastrointestinal symptoms, anxiety, depression, avoidance behaviors(86), and poor quality of life(87). Gut-brain-microbiome alterations mediated by inflammatory processes have also been associated with neurodegenerative diseases(88). Critically, microbiome transplants effectively reduced neuroinflammation processes observed in neurodegeneration(88).

Peripheral biological processes

Allostatic interoception regulates the autonomic nervous system to balance stress responses(14, 33). The autonomic system manages functions like heart, respiratory rate and digestion, modulating responses to environmental stressors. Faced with threats, it activates the “fight or flight” response, while in calm situations, it promotes “rest and digest” activities(14, 33). Key stress biomarkers include arterial pressure(35) and resting heart rate(89).

Metabolic processes convert nutrients into energy essential for growth and repair(90). Allostatic interoception modulates these in response to demands. Under stress, it activates the hypothalamic-pituitary-adrenal axis (HPA(33), prompting hormone releases. While short-term allostatic responses are both adaptive and protective, long-term elevations can result in health issues (33) include cortisol (91), body mass (42), waist-hip (23), and cholesterol (92).

Allostatic interoception regulates inflammatory responses based on environmental cues, modulating cytokines like tumor necrosis factor-alpha (TNF-α), interleukins (IL; e.g., IL-1β, IL-6, and IL-10)(27). Elevated cytokine levels during systemic inflammation after stress response mayalter the perception and regulation of inner signals. Although it is an innate defense against threats, persistent inflammation can be harmful (20). Indeed, chronic inflammation is linked to increased risk of suffering depression, anxiety, and neurodegenerative diseases and is measured by interleukins, cytokines, glial responses, and neurodegeneration markers like neurofilament light chain(42).

Epigenetics

The interplay between allostatic processes, epigenetic changes, and environmental stressors has been recently highlighted(93). Epigenetics involves gene activity modifications without altering DNA sequences, influenced by the exposome. These changes may persist across the lifespan or even across generations(94)(Figure 1D). Allostatic load correlates with these epigenetic alterations, especially in stress-response genes(30). Chronic stress affects the hypothalamic-pituitary-adrenal (HPA) axis, resulting in changes that influence brain development and increase susceptibility to mental disorders(95, 96). Stress-induced gut microbiota shifts can also modify neural epigenetics, impacting brain function(97). In addition, recent findings indicate accelerated epigenetic aging due to allostatic overload in older people (43, 93, 98).

Predictive allostatic interoception in psychiatric and neurological conditions

A disparate group of multigenic factors has been recognized in psychiatry. These factors, however, are unon-specific, as revealed by increased pleiotropy (i.e., one gene associated with multiple traits), and they do not exclusively explain the emergence of psychiatric disorders(99). In contrast, various theoretical and empirical models highlight the role of complex environment-biological interactions at the root of psychiatric disorders. Anticipatory and regulatory mechanisms determine adaptation or dysregulation associated with psychiatric disease. Disruptions on predictive allostatic interoceptive processes have proven critical in various psychiatric disorders (Table 1, Supplementary Tables 1–2), with more pronounced evidence in the context of anxiety and depression.

Table 1.

Degree of evidence on allostatic-interoceptive frameworks, allostasis processes, and interoception in psychiatric and neurological conditions

		Integrated allostatic-interoception studies			Allostasis			Interoception
		Brain structure-functioning (allostatic-interoceptive processes) AIN	Brain-systems interactions (HEP)	Peripheral measures of allostatic interoception (inflammatory, metabolic, other systems)	Brain structure-functioning of allostasis	Peripheral measures (allostatic load index)	Brain-systems interactions (HEP)	Brain structure-functioning of interoception	Brain-systems interactions (HEP)	Peripheral measures of interoception (inflammatory, metabolic, other pathways)
Psychiatric	Depression	Emergent	Emergent	Emergent	Emergent	Robust	Emergent	Robust	Robust	Robust
	Anxiety	Incipient	Emergent	Emergent	Emergent	Robust	Emergent	Robust	Robust	Robust
Neurologic	bvFTD	Robust	Robust	Emergent	Emergent	Robust	Emergent	Robust	Emergent	Robust
	AD	Emergent	Emergent	Emergent	Emergent	Robust	Emergent	Robust	Emergent	Robust

Evidence categories: a) incipient: less than 10 articles in the field; b) emergent: around 20 to 30 articles; and c) robust: more than 30 articles. See Supplementary Table 1 and 2 for detailed studies.

Anxiety

Anxiety is a complex emotional response encompassing fear, apprehension, and worry. It often arises in response to stress or perceived threats, whether real or imagined(100). Anxiety is an adaptative natural human experience. When chronic or overwhelming, however, anxiety may interfere with daily functioning leading to anxiety disorder(100). Anticipatory allostatic interoceptive processes are associated with anxiety symptoms and disorders(101, 102).

Previous studies suggest heightened allostatic load in patients with anxiety disorders like panic and generalized anxiety, characterized by increased anticipatory responses to threats(29). This encompasses increases in proinflammatory cytokines, sympathetic dominance, altered HPA axis function, and elevated biological amines during fear reactions(22, 37, 41). Dysfunctions in the anterior insula and anterior cingulate cortex, key for allostatic processing, are tied to anxiety disorders(103). Heightened allostatic load manifests as symptoms like autonomic discharges in panic disorders and somatic symptoms in generalized anxiety disorders(29, 103, 104).

Anxiety is also linked to heightened interoception and misinterpretation of bodily signals, causing symptoms like over-monitoring physical responses, apprehensive expectations, somatic tension, tiredness, insomnia, heightened startle reflexes, and anxious affect(101, 102, 105). The discrepancy between expected and actual bodily signals can perpetuate anxiety, maintaining a chronic stress response(48). Such alterations are observed across panic disorders, phobias, and generalized anxiety disorders(101, 102, 105–108).

Although the evidence is not yet conclusive(104), there is some studies indicating brain-heart desynchronization heightened cardiac and respiratory interoceptive sensitivity in anxiety patients(109). Moreover, altered HEP index(78, 104, 106). This increased sensitivity may predispose individuals to anxiety disorders by interpreting typical cardiac and respiratory symptoms as catastrophic. Heightened cardiac and respiratory interoceptive sensitivity relates to various anxiety disorders, insomnia,(67, 104, 107).

Therapeutic approaches to cope with anticipatory allostatic interoceptive overload concur with some non-pharmacological interventions used to reduce anxiety and stress-related symptoms. Those interventions encompass sleep regimens(110), structured physical activity(111), supplementary nutritional initiatives(112), and cognitive behavioral interventions centered on emotional expression and regulation(113). Additionally, emerging interventions using non-invasive brain stimulation have demonstrated efficacy in moderating allostatic load(114) and rectifying interoceptive dysregulation(115), suggesting their prospective utility in promoting brain health.

Depression

Depression is a mental health disorder that affects daily functioning and is characterized by persistent feelings of sadness, hopelessness, lack of interest or pleasure in activities, and changes in appetite and sleep patterns(116). Depression can be considered an allostatic load disorder(14, 16, 47, 90, 117) marked by irregularities in various biological processes(118), including metabolic imbalances(119) with abnormal HPA axis activity, proinflammatory states(9), and skewed autonomic processes(47, 90, 117). Many depressive symptoms, such as fatigue and motor retardation, are linked to allostatic load(47, 90, 117). Chronic stress, a primary driver of allostatic load and depression risk, induces changes in emotion and memory-regulating brain structures like the hippocampus and amygdala(47, 117). Depressed individuals often experience prolonged abnormal brain function, impairing anticipatory allostatic mechanisms, resulting in symptoms like disrupted emotion regulation(47, 117), motor retardation, and slowed cognitive processing(117).

Furthermore, allostatic overload accompanies interoceptive impairments in those with depression(14, 47). Numerous studies indicate anomalies in their processing of interoceptive signals, often manifesting as feelings of bodily disconnection or misjudgment of internal states(9, 47, 120). Evidence suggests altered interoceptive accuracy in those patients (121) and differing interoceptive skill scores(122, 123). These interoceptive disturbances relate to emotion dysregulation and a negative attention bias(124). Additionally, these deficits correlate with structural and functional changes in the insula and other brain regions vital for interoceptive awareness(121, 125).

Interoceptive changes can influence the allostatic system, contributing to depressive symptoms(39, 47, 117). Persistent ruminations and abulia are linked to disruptions in the cardiac and gastric interoceptive feedback, impacting anticipatory allostatic processes(39, 47, 117, 125). Depression’s hallmark symptoms, such as anhedonia and fatigue, are related to heightened body awareness, reduced body trust, and attentional issues(123, 124). Recent reviews indicate that moderate to severe depression is tied to interoceptive alterations affecting decision-making and emotion regulation, regardless of comorbidities or treatments like selective serotonin reuptake inhibitors(120).

Taken together, allostatic load, interoceptive deficits, and alterations in integrated allostatic interoceptive processes are essential predictors of biological and clinical alterations in anxiety and depression. Further research will help to reinforce connections between allostatic interoceptive overload mechanisms, biological processes, and clinical presentation in prevalent psychiatric conditions.

Predictive allostatic interoception in neurological disorders

Studies of allostatic interoception in neurological conditions have been mainly focused on neurodegenerative disorders (Table 1, Supplementary Tables 1–2). Allostatic overload can heighten sensitivity to future stressors, resulting in a state of hypervigilance(22). Such a state can induce chronic stress, leading to inflammation, metabolic imbalances, and increased neurotoxicity, which in turn can cause neural damage. Over time, these detrimental effects may contribute to cognitive and behavioral decline and raise the risk of developing dementia(7, 22, 66).

Alzheimer’s disease (AD)

AD is a neurodegenerative disorder associated with genetic and preventable factors caused by the progressive accumulation of beta-amyloid and tau proteins in the brain, leading to neuronal damage and brain atrophy(126). Clinically, AD is most characterized by deficits in episodic memory, language, visual-constructional abilities, praxis processes, and behavior regulation associated with classical brain atrophy affecting parietal, temporal, and hippocampal regions(127).

The prevalence of AD can be attributed to modifiable factors(128). These include socio-environmental factors such as air pollution, deprived neighborhood conditions, and health-related factors like chronic diseases(22, 36, 40, 41). Such socio-environmental risks correlate with allostatic load and can trigger the dysregulation of physiological processes(22) as supported by studies showing deficits in allostatic and interoceptive processes in AD patients(22, 36, 57, 66, 84).

Brain changes, such as atrophy in the AIN hubs and abnormal connectivity in the parietal, default mode network, and saliency network, have been identified in AD patients, impacting memory, emotion regulation, and self-awareness(55, 61, 62, 93). AD neurodegeneration also affects human medial temporal lobes, hippocampus, entorhinal, perirhinal, and parahippocampal cortices, brain regions with high connectivity with AIN hubs of default mode and saliency networks(129) and implicated in declarative memory, semantic cognition, and social interaction processes(54, 61, 66). Moreover, AIN functioning is also affected by the severity of cognitive alteration, as participants with mild states of cognitive decline show decreased connectivity between lateral parietal cortices, temporal cortices, and multiple hubs of the salience network(55).

Peripherally, AD is associated with dysregulation in the hypothalamic-pituitary-adrenal axis, linked with glycemic alterations and insulin resistance(36). Elevated cytokine levels in AD patients indicate chronic inflammation(130). Further, changes in astrocytes and glial cells partially explain AD pathology(131). Altered heart rate variability and blood pressure, both autonomic processes, relate to predictive interoceptive failures(132). Compared to controls, accelerated epigenetic aging due to stress and DNA methylation changes in inflammatory and metabolic pathways have also been reported in AD(133, 134).

Moreover, AD patients exhibit disrupted interoceptive signal processing, manifesting symptoms from mood disturbances to reduced self-awareness(47, 103, 122). Key interoceptive processing regions, the insula and anterior cingulate cortex, show neurodegeneration in AD(135). Compared to healthy controls, AD patients demonstrate reduced interoceptive precision and awareness, arising from altered HEP modulations and abnormalities in the fronto-temporo-insular network(62). Although evidence is still under debate(61, 136), individuals with AD tend to present impaired performance in interoceptive tasks, abnormal modulations of the HEP, and deficits in interoceptive awareness and learning. Such deficits may cause patients to overestimate their task capabilities, leading to problems like irritability and increased stress(136).

Behavioral variant frontotemporal dementia (bvFTD)

bvFTD is a neurodegenerative disease marked by personality and behavioral changes such as apathy, disinhibition, and empathy loss, coupled with language, executive impairments, and variable memory difficulties due to fronto-temporo-insular degeneration(137, 138). Research indicates alterations in predictive allostatic interoceptive processes in bvFTD, involving structural and functional degradation of the AIN and allostatic biomarkers(7, 21, 45, 56, 57, 60–62, 66).

Allostatic load(66) and interoceptive issues have been identified as significant factors affecting the capacity of bvFTD patients to reach appropriate responses to external demands(57, 62, 136). Moreover, combined allostatic-interoception dysregulation in bvFTD underlies the behavioral and cognitive disturbances observed in those patients, including apathy, disinhibition, deficits in social cognitive and emotional deficits, and executive dysfunction(57, 62, 136).

Degeneration in the fronto-temporo-insular networks in bvFTD affects pivotal AIN regions like the anterior insula, amygdala, and anterior cingulate cortices(46, 57, 66). Resting state studies also show disrupted connectivity in critical AIN networks, namely the default mode and salience networks(46). Heart-brain interactions in bvFTD demonstrate modified HEP modulations, with reduced HEP during active tasks and exacerbated HEP during rest(21, 57, 60, 61, 66). These HEP changes relate to bvFTD-associated impairments in the insula and amygdala, impacting emotional and cognitive regulation due to allostatic interoceptive overload(57, 61, 66).

Peripherally, bvFTD patients experience cardiovascular, metabolic, and proinflammatory disturbances linked to allostatic interoception(139). Moreover, they display autonomic disruptions, metabolic imbalances, and inflammatory dysregulation linked to clinical outcomes(139). Allostatic overload also influences TDP-43 aggregation in bvFTD(140). Early axonal damage is indicated by elevated neurofilament light chain levels, linked to other allostatic markers such as body mass index and cardiovascular biomarkers(42).

Hypotheses on interactions between allostatic interoception and neurodegeneration

Allostatic–interoception is related to neurodegeneration on multiple levels. Initially, emerging evidence suggests that neurodegeneration impairs the allostatic–interoceptive system, which is linked to the symptoms(45, 57). Secondly, a circular interaction exists between neurodegeneration and allostatic–interoceptive dysfunction. In this case, initial neurodegenerative alterations can deviate the allostatic interoceptive processes throughout the lifespan. These alterations may exacerbate neurocognitive decline, creating a reciprocal worsening effect(7, 22). Third, a less explored hypothesis suggests a causal relationship between predictive allostatic interoception disruption and neurodegeneration with chronic stress impacting immune regulation and potentially contributing to FTD etiology, TDP-43 aggregation(140), and other neurodegenerative processes(141). In summary, the predictive allostatic interoception processes and their regulatory role in complex environment-biology interactions have been reviewed in AD and bvFTD. Emerging evidence indicates that these mechanisms are connected to variations in the whole-body biological processes and clinical presentation in both diseases.

Discussion

This review explored the role of allostatic interoception in the interaction between environmental factors and biological predispositions, detailing their impact on physiological responses and their contribution to the clinical manifestations of psychiatric and neurological disorders, including anxiety, depression, neurally mediated syncope, AD, and bvFTD.

Across disorders, most studies focused independently on either allostatic load or interoceptive alterations. Studies on allostatic load suggest anticipatory responses to external stimuli, leading to various biological alterations such as inflammatory, metabolic, microbiome, and epigenetic changes, which are in turn correlated with different symptomatology. On the other hand, associations between altered interoception and the dysregulation of biological processes affect the syndromic presentation of different conditions. A few studies have assessed in an integrated way the role of alterations in predictive allostatic interoception processes in neurodegeneration(7, 45, 61, 66, 69). These studies reveal that altered predictive allostatic interoception overload predict whole-body biological changes and clinical profiles observed in AD and bvFTD.

Our review reveals that the allostatic interoceptive framework provides a comprehensive biological account integrating multiple aspects of brain functioning, biological mechanisms and disease development, encompassing the interplay of exposome, exteroceptive, interoceptive, cognitive processes, and clinical phenotypes across psychiatry and neurology(142–144).

Dimensional and transdiagnostic implications

Traditional categorical models of psychiatric and neurological disorders tend to be overly simplistic. Mental and brain health exists along a continuum, with varying symptoms and impairments(145). Viewing psychiatric and neurological disorders in a dimensional way acknowledges this complexity and allows for a more accurate representation of the diversity of clinical presentations (Figure 2A–D). Studies on allostatic interoception align with dimensional approaches as they assess underlying mechanisms and shared neurobiological pathways that contribute to overlap in clinical presentations across different conditions(146) (Box 1, Figure 2B–C).

Figure 2. Predictive allostatic interoception influence whole-body biological processes.

The left panel illustrates the primary biological and regulatory processes of allostatic interoception. The right panel showcases the whole-body biological cascades influenced by allostatic interoception processes, including inflammatory-immune, metabolic and microbiome. Additionally, the bottom-right panel highlights the impact of these cascades in dimensional changes seen in both psychiatric and neurological disorders.

Box 1. Biological and clinical dimensionality.

Research domain criteria (RDoC) brings a biological perspective of psychiatric disorders(155) and promotes primary constructs from genes to brain connectivity to self-report of behaviors(156). Allostatic interoception processes are linked to the framework proposed by RDoC. First, allostasis and interoception align with constructs assessed by the RDoC, including those evaluating how humans react in the presence of harmful stimuli, including threats, stress, or fear (negative valence systems). Dysregulation in allostatic interoception can contribute to heightened emotional responses and maladaptive stress reactions, impacting negative valence systems. Although the RDoC does not originally includeinteroception, recent studies have made such a claim for inclusion(53). Furthermore, the allostatic interoception processes affect different biological and physiological pathways from genes to complex behaviors, which concur with the multilevel units of analysis structure of RDoC. Future studies could incorporate the study of allostatic interoception processes by following the RDoC structure, including multiple units of analyses (genes-to-complex behaviors) of processes critical for adaptation and disease.

A deeper understanding of allostatic interoception could improve dimensional clinical models for psychiatric and neurological disorders. This approach aligns with the Hierarchical Taxonomy of Psychopathology framework (HiTOP)(157), which represents a significant paradigm shift towards dimensional and quantitative nosology of altered behaviors, echoing contemporary calls for broader transdiagnostic clinical characterizations. Both frameworks emphasize dimensional clinical characterization(7, 61). A more profound understanding of the clinical patterns linked to various physiological pathways of allostatic interoception can enhance transdiagnostic and dimensional characterizations of psychiatric and neurological disorders. This approach aligns with current advocacy for integrated frameworks, such as combining HiTOP and the Research Domain Criteria (RDoC), to foster a dimensional and transdiagnostic understanding of the clinical and pathophysiological pathways underlying brain disorders(11).

Particularly, allostatic interoception framework dialogues with dimensional approaches by integrating multiple environment-biological interactions(145), multiple biological pathways (including gene expression and epigenetics (147), immune, inflammatory, and neurochemical balance (148), circadian regulation (149), brain dynamics and cognition (142, 143, 150, 151)), and multiple co-expression of clinical profiles(152).

Limitations of the current framework

This review highlights the importance of allostatic interoceptive processes in psychiatric and neurological disorders, but the exploration of these interactions is still in its initial stages. A limited number of studies have assessed the combined role of allostasis and interoception on psychiatric and neurological diseases. Most of current research has assessed these processes separately. Our current understanding of the role of allostatic interoception in encompassing biological and clinical patterns of psychiatric and neurological disorders is primarily based on correlations, needing a better integration of environment-biology levels and clinical patterns in neuropsychiatric diseases. Furthermore, current studies within this framework lack the generation of multi-level analyses, the formulation of causal models, and the inclusion of complexity approaches(2, 6). There is also a need for integrating physiological indicators into holistic biological approaches that consider multiple layers of influence.

Future directions

The study of predictive allostatic interoception processes opens new avenues for research. Allostatic interoception studies across the lifespan has not been integrated. Allostatic interoceptive overload has been observed in psychiatric and neurological disorders prevalent in childhood and adolescence (e.g., autism spectrum disorders(153) and attention deficit hyperactivity disorders(25)), as well as in adulthood (e.g., anxiety(13) and depression(47)) and older age (e.g., neurodegenerative AD, bvFTD(57, 60, 61, 66), and Parkinson’s disease(61, 66)). Future studies should analyze the role of allostatic interoceptive processes during each and in subsequent life stages, pinpointing both common and unique environment, biological, and clinical pathways for specific disorders (Box 2). Moreover, various external demands vary by life stage and can impact whole-body physiology in distinct ways (Figure 1B). Allostatic interoceptive responses could be shaped by cumulative lifetime exposure to external factors in internal dysregulation.

Box 2. Allostatic interoception across the lifespan.

Environmental risks and experiences vary across lifespan stages(20). For instance, environmental threats or social determinants of health, such as infections, attachment issues, neighborhood deprivation, difficulties for education attainment, social adversities and exclusion are more impactful in childhood and adolescence(158). In contrast, stress and social isolation are more critical in adulthood or older ages. Differential environmental risks at various stages of the lifespan interact with the integrity and development of biological systems, leading to the adaptation of disease processes over time(31).

Early childhood experiences are foundational in shaping stress management mechanisms. Brain areas essential for interoception, such as the insula and anterior cingulate cortex, undergo maturation during this period, and affects stress processing(135). Experiences of trauma or persistent stress during childhood can alter these neural pathways, resulting in emotional and cognitive challenges in later life(31) than can create long-lasting interoceptive dysregulation.

Physiological and emotional changes characterize adolescence. Pubertal hormonal fluctuations can influence interoceptive sensitivity and the body’s response to stress(32). This stage is often marked by the emergence of mental health issues, with interoceptive processing disruptions increasing vulnerability to mood-related disorders(159). Notably, disorders commonly diagnosed in childhood and adolescence, such as autism spectrum disorders (ASD)(160) and attention-deficit/hyperactivity disorder (ADHD)(161), exhibit allostatic load and interoceptive anomalies(162).

In adulthood, multiple stressors ranging from professional challenges to parenthood can affect interoceptive perceptions. Prolonged stress may intensify one’s perception of bodily sensations, contributing to somatic symptoms and pain-associated disorders(163). The wear and tear on the body due to constant stress adaptation becomes increasingly evident with age(22, 31, 159, 164) and contribute to neurological disorders. Moreover, early adversities are associated with increased allostatic overload in adulthood and older ages, as revealed by metabolic and autonomic alterations(98, 164).

In the later years, the cumulative burden becomes pronounced. Elevated allostatic load is linked to memory challenges and executive functioning impairments(101). Prolonged stress and increased allostatic load can deepen health issues such as cardiovascular disease and osteoporosis(164). Additionally, the compound effects of chronic stress and innate predispositions to neurodegeneration influence allostatic interoceptive processes, which are central to clinical symptoms in common dementias(102, 164).

Brain allostatic interoceptive processes are typically addressed in linear, hierarchical predictive coding models, partially neglecting complex brain spatiotemporal dynamics(154). The interplay between external demands, interoceptive processes, and cognitive inputs favored by the allostatic interoceptive processes require synergetic spatiotemporal dynamics. It is unclear how such dynamics interacts also with whole-body biological and physiological changes triggered by anticipatory allostatic interoceptive processes in brain health and disease. Future research should integrate spatiotemporal analyses to study the predictive allostatic interoceptive processes and their relationships with different pathways (56, 154)(Box 3).

Box 3. Allostatic interoception and spatiotemporal dynamics.

Recent models of allostatic interoception have been linked with models of biological complexity and brain spatiotemporal dynamics(154). The interplay between external demands, interoceptive processes, and cognitive inputs favored by the allostatic interoceptive processes requires complex spatiotemporal processing. Specifically, each type of input, interoceptive or exteroceptive, has its temporal rhythm and specific neural microstructures. For instance, interoceptive inputs from the heart have a constant rhythm compared to exteroceptive environmental signals(165). Moreover, brain areas of allostatic interoceptive network have intrinsic neural timescales at different sites, as the prefrontal cortex manages longer timescales of processing compared to regions like the anterior insula(165). The complexity of prediction processes also involves different timescales; while prediction signals lean towards slower beta range oscillations, prediction errors lean towards faster gamma range oscillations(166). Today, how brain spatiotemporal dynamics dialogue with whole-body biological and physiological changes promoted by anticipatory allostatic interoceptive processes is unknown. Future research should integrate spatiotemporal analyses to study the complexity of the predictive allostatic interoceptive processes (56, 154) and their relationships with different pathways.

Our approach underscores the need to refine and validate allostatic interoceptive metrics to enhance their utility in clinical settings and enable personalized interventions. Furthermore, future research should investigate the development and validation of cumulative exposome and allostatic interoceptive indices. Concurrently, studies should examine the links between individual environmental-biological risks, individual indices of allostasis interoception, biological measures, and clinical metrics of psychiatric and neurological disorders.

Conclusions

This review outlines the importance of allostatic-interoceptive processes in anticipating and responding to environmental and biological interactions leading to adaptive or dysregulated response in psychiatric and neurological disorders. Our review presents evidence of allostatic and interoceptive changes in common psychiatric and neurological disorders, including anxiety, depression, AD, and bvFTD. This work illustrates how allostatic interoception alterations can predict a range of physiological, neurocognitive, and clinical features in different disorders. Our approach aligns with dimensional and transnosological frameworks aiming to foster a comprehensive understanding of biological and clinical patterns across other psychiatric and neurological conditions. The field of allostatic interoception requires future breakthroughs to develop and validate more comprehensive research on its role in brain health and disease. This work opens the door to creating new metrics, enhancing their practicality in clinical environments, and supporting personalized interventions.