Testing the monitor and acceptance theory: the role of training-induced changes in monitoring- and acceptance-related capacities after attention-based, socio-emotional, or socio-cognitive mental training in reducing cortisol stress reactivity.

Mindfulness-based interventions have become a popular means to reduce stress. However, the specific mechanisms driving observed stress reduction remain understudied. The Monitor and Acceptance Theory suggests that the cultivation of monitoring and acceptance skills are necessary moderators of practice-induced stress reduction. In the context of the ReSource Project, a large healthy adult sample underwent three 3-month mental training modules targeting either attentional (Presence module), socio-affective (Affect module) or socio-cognitive skills (Perspective module). In the current study, the development of a range of inter-individual differences in mindfulness-, interoception- and compassion-related traits - which mapped to either monitoring or acceptance categories - was tracked. The relationship of these training-induced changes with cortisol stress reactivity after the three distinct 3-month training modules was explored. We found that stress sensitivity was particularly modulated by a differential adaptivity of one cultivated attentional capacity - Attention regulation - which predicted higher cortisol reactivity after mere attention training (Presence) but was associated with lower stress-induced cortisol release after additional socio-affective and socio-cognitive practice (Affect and Perspective). However, this effect did not survive multiple comparisons correction, and analyses were limited by the sample size available. We conclude that our study provides preliminary support of the Monitor and Acceptance Theory, lending weight to the advantage of primary attentional increases in order to fully harness the beneficial effects of socio-affective training, ultimately leading to stress reduction. Although training-induced increases in acceptance were not directly shown to contribute to lowering cortisol stress reactivity, the data suggest an additional benefit of socio-affective and socio-cognitive training that is not directly captured within the current analyses. Our study corroborates the importance of going beyond the training of attention monitoring to foster stress resilience, and highlights that mental training relies on the co-development of several interacting processes to successfully attenuate stress. Further exploring the overarching concept of acceptance in future research may prove beneficial to the theoretical framework of MAT, and in understanding the processes by which stress reduction occurs.

General and anxiety-linked influences of acute serotonin reuptake inhibition on neural responses associated with attended visceral sensation.

Ordinary sensations from inside the body are important causes and consequences of our affective states and behaviour, yet the roles of neurotransmitters in interoceptive processing have been unclear. With a within-subjects design, this experiment tested the impacts of acute increases of endogenous extracellular serotonin on the neural processing of attended internal sensations and the links of these effects to anxiety using a selective serotonin reuptake inhibitor (SSRI) (20 mg CITALOPRAM) and a PLACEBO. Twenty-one healthy volunteers (fourteen female, mean age 23.9) completed the Visceral Interoceptive Attention (VIA) task while undergoing functional magnetic resonance imaging (fMRI) with each treatment. The VIA task required focused attention on the heart, stomach, or visual sensation. The relative neural interoceptive responses to heart sensation [heart minus visual attention] (heart-IR) and stomach sensation [stomach minus visual attention] (stomach-IR) were compared between treatments. Visual attention subtraction controlled for the general effects of CITALOPRAM on sensory processing. CITALOPRAM was associated with lower interoceptive processing in viscerosensory (the stomach-IR of bilateral posterior insular cortex) and integrative/affective (the stomach-IR and heart-IR of bilateral amygdala) components of interoceptive neural pathways. In anterior insular cortex, CITALOPRAM reductions of heart-IR depended on anxiety levels, removing a previously known association between anxiety and the region's response to attended heart sensation observed with PLACEBO. Preliminary post hoc analysis indicated that CITALOPRAM effects on the stomach-IR of the amygdalae corresponded to acute anxiety changes. This direct evidence of general and anxiety-linked serotonergic influence on neural interoceptive processes advances our understanding of interoception, its regulation, and anxiety.

Enhancing interoceptive sensibility through exteroceptive-interoceptive sensory substitution.

Exploring a novel approach to mental health technology, this study illuminates the intricate interplay between exteroception (the perception of the external world), and interoception (the perception of the internal world). Drawing on principles of sensory substitution, we investigated how interoceptive signals, particularly respiration, could be conveyed through exteroceptive modalities, namely vision and hearing. To this end, we developed a unique, immersive multisensory environment that translates respiratory signals in real-time into dynamic visual and auditory stimuli. The system was evaluated by employing a battery of various psychological assessments, with the findings indicating a significant increase in participants' interoceptive sensibility and an enhancement of the state of flow, signifying immersive and positive engagement with the experience. Furthermore, a correlation between these two variables emerged, revealing a bidirectional enhancement between the state of flow and interoceptive sensibility. Our research is the first to present a sensory substitution approach for substituting between interoceptive and exteroceptive senses, and specifically as a transformative method for mental health interventions, paving the way for future research.

Maternal interoceptive focus is associated with greater reported engagement in mother-infant stroking and rocking.

Parental caregiving during infancy is primarily aimed at the regulation of infants' physiological and emotional states. Recent models of embodied cognition propose that interoception, i.e., the perception of internal bodily states, may influence the quality and quantity of parent-infant caregiving. Yet, empirical investigations into this relationship remain scarce. Across two online studies of mothers with 6- to 18-month-old infants during Covid-19 lockdowns, we examined whether mothers' self-reported engagement in stroking and rocking their infant was related to self-reported interoceptive abilities. Additional measures included retrospective accounts of pregnancy and postnatal body satisfaction, and mothers' reports of their infant's understanding of vocabulary relating to body parts. In Study 1 (N = 151) and Study 2 (N = 111), mothers reported their engagement in caregiving behaviours and their tendency to focus on and regulate bodily states. In a subsample from Study 2 (N = 49), we also obtained an objective measure of cardiac interoceptive accuracy using an online heartbeat counting task. Across both studies, the tendency to focus on and regulate interoceptive states was associated with greater mother-infant stroking and rocking. Conversely, we found no evidence for a relationship between objective interoceptive accuracy and caregiving. The findings suggest that interoception may play a role in parental engagement in stroking and rocking, however, in-person dyadic studies are warranted to further investigate this relationship.

Investigating psychobiological causes and mechanisms in functional seizures and functional motor symptoms: Study protocol.

INTRODUCTION: Advances have been made in understanding the aetiology of functional neurological disorder (FND); however, its pathophysiological mechanisms have not been definitively demonstrated. Evidence suggests interacting roles for altered emotional processing and interoception, elevated autonomic arousal, and dissociation, but there is limited evidence demonstrating their causal influence on specific FND symptoms. Our superordinate aim is to elucidate potentially shared and distinct aetiological factors and mechanisms in two common FND subtypes, functional seizures (FS) and functional motor symptoms (FMS). METHODS: This study has a multimodal, mixed between- and within-groups design. The target sample is 50 individuals with FS, 50 with FMS, 50 clinical controls (anxiety/depression), and 50 healthy controls. Potential aetiological factors (e.g., adverse life events, physical/mental health symptoms, dissociative tendencies, interoceptive insight/sensibility) will be assessed with a detailed medical history interview and self-report questionnaires. A laboratory session will include a neurocognitive battery, psychophysiological testing, cardiac interoception and time estimation tasks and an isometric handgrip task. A subsample will undergo magnetic resonance imaging, including structural, resting-state and task-based scans combined with psychophysiological recording. Remote monitoring with ecological momentary assessment and wearables will measure variability in FND symptoms and their potential predictors/correlates for ≥2 weeks in patients' daily lives. Longitudinal follow-ups at 3, 6, and 12-months will monitor longer-term outcomes in the clinical groups. DISCUSSION: This study employs multimodal research methods to rigorously examine several putative mechanisms in FND, at subjective/experiential, behavioural, and physiological levels. The study will test causal hypotheses about the role of altered emotional processing, autonomic arousal, dissociation and interoception in the initiation or exacerbation of FND symptoms, directly comparing these processes in FS and FMS to healthy and clinical controls. This is the first study of its kind, with potential to reveal important targets for prevention and treatment of FND in future.

Interoceptive training impacts the neural circuit of the anterior insula cortex.

Interoception is the perception of afferent information that arises from anywhere and everywhere within the body. Recently, interoceptive accuracy could be enhanced by cognitive training. Given that the anterior insula cortex (AIC) is a key node of interoception, we hypothesized that resting functional connectivity (RSFC) from AIC was involved in an effect of interoceptive training. To address this issue, we conducted a longitudinal intervention study using interoceptive training and obtained RSFC using fMRI before and after the intervention. A heartbeat perception task evaluated interoceptive accuracy. Twenty-two healthy volunteers (15 females, age 19.9 ± 2.0 years) participated. After the intervention, interoceptive accuracy was enhanced, and anxiety levels and somatic symptoms were reduced. Also, RSFC from AIC to the dorsolateral prefrontal cortex (DLPFC), superior marginal gyrus (SMG), anterior cingulate cortex (ACC), and brain stem, including nucleus tractus solitarius (NTS) were enhanced, and those from AIC to the visual cortex (VC) were decreased according to enhanced interoceptive accuracy. The neural circuit of AIC, ACC, and NTS is involved in the bottom-up process of interoception. The neural circuit of AIC, DLPFC, and SMG is involved in the top-down process of interoception, which was thought to represent the cognitive control of emotion. The findings provided a better understanding of neural underpinnings of the effect of interoceptive training on somatic symptoms and anxiety levels by enhancing both bottom-up and top-down processes of interoception, which has a potential contribution to the structure of psychotherapies based on the neural mechanism of psychosomatics.

Neural mechanisms of respiratory interoception.

Respiratory interoception is one of the internal bodily systems that is comprised of different types of somatic and visceral sensations elicited by different patterns of afferent input and respiratory motor drive mediating multiple respiratory modalities. Respiratory interoception is a complex system, having multiple afferents grouped into afferent clusters and projecting into both discriminative and affective centers that are directly related to the behavioral assessment of breathing. The multi-afferent system provides a spectrum of input that result in the ability to interpret the different types of respiratory interceptive sensations. This can result in a response, commonly reported as breathlessness or dyspnea. Dyspnea can be differentiated into specific modalities. These respiratory sensory modalities lead to a general sensation of an Urge-to-Breathe, driven by a need to compensate for the modulation of ventilation that has occurred due to factors that have affected breathing. The multiafferent system for respiratory interoception can also lead to interpretation of the sensory signals resulting in respiratory related sensory experiences, including the Urge-to-Cough and Urge-to-Swallow. These behaviors are modalities that can be driven through the differentiation and integration of multiple afferent input into the respiratory neural comparator. Respiratory sensations require neural somatic and visceral interoceptive elements that include gated attention and detection leading to respiratory modality discrimination with subsequent cognitive decision and behavioral compensation. Studies of brain areas mediating cortical and subcortical respiratory sensory pathways are summarized and used to develop a model of an integrated respiratory neural network mediating respiratory interoception.

Changes in interoceptive accuracy related to emotional interference in somatic symptom disorder.

OBJECTIVE: The somatic symptom disorder (SSD) is characterized by one or more distressing or disabling somatic symptoms accompanied by an excessive amount of time, energy and emotion related to the symptoms. These manifestations of SSD have been linked to alterations in perception and appraisal of bodily signals. We hypothesized that SSD patients would exhibit changes in interoceptive accuracy (IA), particularly when emotional processing is involved. METHODS: Twenty-three patients with SSD and 20 healthy controls were recruited. IA was assessed using the heartbeat perception task. The task was performed in the absence of stimuli as well as in the presence of emotional interference, i.e., photographs of faces with an emotional expression. IA were examined for correlation with measures related to their somatic symptoms, including resting-state heart rate variability (HRV). RESULTS: There was no significant difference in the absolute values of IA between patients with SSD and healthy controls, regardless of the condition. However, the degree of difference in IA without emotional interference and with neutral facial interference was greater in patients with SSD than in healthy controls (p = 0.039). The IA of patients with SSD also showed a significant correlation with low-frequency HRV (p = 0.004) and high-frequency HRV (p = 0.007). CONCLUSION: SSD patients showed more significant changes in IA when neutral facial interference was given. These results suggest that bodily awareness is more affected by emotionally ambiguous stimuli in SSD patients than in healthy controls.

The anterior cingulate cortex is involved in intero-exteroceptive integration for spatial image transformation of the self-body.

Spatial image transformation of the self-body is a fundamental function of visual perspective-taking. Recent research underscores the significance of intero-exteroceptive information integration to construct representations of our embodied self. This raises the intriguing hypothesis that interoceptive processing might be involved in the spatial image transformation of the self-body. To test this hypothesis, the present study used functional magnetic resonance imaging to measure brain activity during an arm laterality judgment (ALJ) task. In this task, participants were tasked with discerning whether the outstretched arm of a human figure, viewed from the front or back, was the right or left hand. The reaction times for the ALJ task proved longer when the stimulus presented orientations of 0°, 90°, and 270° relative to the upright orientation, and when the front view was presented rather than the back view. Reflecting the increased reaction time, increased brain activity was manifested in a cluster centered on the dorsal anterior cingulate cortex (ACC), suggesting that the activation reflects the involvement of an embodied simulation in ALJ. Furthermore, this cluster of brain activity exhibited overlap with regions where the difference in activation between the front and back views positively correlated with the participants' interoceptive sensitivity, as assessed through the heartbeat discrimination task, within the pregenual ACC. These results suggest that the ACC plays an important role in integrating intero-exteroceptive cues to spatially transform the image of our self-body.

Alcohol effects on interoception shape expectancies and subjective effects: a registered report using the heart rate discrimination task.

AIMS: Alcohol acutely impacts interoceptive processes, which in turn affect the perception of alcohol effects and the development of alcohol expectancies. However, previous research is limited by the tools used to measure cardiac interoception and subjective alcohol effects. This registered report proposes a re-examination of previous findings using a state-of-the-art measure of interoceptive capacity, the heart rate discrimination task, and measurements of subjective alcohol effects across both ascending and descending limbs. METHODS: In a double-blind, placebo-controlled experiment, n = 36 participants were given 0.4 g/kg of ethanol, and a baseline measure of alcohol expectancies was obtained. Changes in interoceptive capacity after beverage administration, along with measures of light-headedness, mood, and biphasic alcohol effects, were assessed over two sessions. HYPOTHESES: As registered in this secondary data analysis, alcohol was expected to acutely impact different indices of interoceptive capacity, and those changes were hypothesized to correlate with subjective alcohol effects and expectancies. Analyses were conducted only following in-principle acceptance. RESULTS: Alcohol-induced changes in interoceptive capacity predicted the development of light-headedness, stimulation, and negative mood. Changes in interoceptive capacity were also correlated with negative alcohol expectancies, as measured 2 weeks prior to the experiment. These effects were unique to the interoceptive condition, as null effects were observed in an exteroceptive control task. DISCUSSION: This report offers a replication of key previous findings that alcohol impacts interoceptive processes to shape the detection of subjective alcohol effects. We propose that, through repeated drinking occasions, bodily responses feed into the experience of intoxication, shaping future expectancies about alcohol effects.

The role of interoceptive awareness in shaping the relationship between desire thinking and cigarette consumption.

Interoception, the ability to sense and interpret bodily sensations, has recently emerged as a crucial factor in substance use disorders, including smoking. However, the role of interoceptive awareness in tobacco use remains poorly understood. The relationship between interoceptive ability and addictive behavior is complex, and attempting to conceptualize it as a linear association is unlikely to fully capture the complexity of the mechanisms underlying cravings and urges. We hypothesized that the role played by interoceptive awareness in tobacco use is deeply linked to desire thinking, that is, the conscious and voluntary cognitive process orienting to prefigure images, information, and memories about positive target-related experiences. Desire thinking is typically observed in addiction, where it may contribute to interpreting specific bodily sensations, such as the perceived need for a cigarette. From this perspective, the physiological impact and inclination toward desire thinking contribute to a higher daily cigarette consumption, particularly in situations of low interoceptive awareness. To test this hypothesis, we assessed the physiological activation, the tendency toward desire thinking about smoking, cigarette consumption, and the interoceptive abilities of smoking volunteers. Through a moderation analysis, we showed that desire thinking about smoking predicts a higher number of cigarettes per day in individuals with lower interoceptive awareness (p < .05). These findings suggest that the relationship between desire thinking and interoceptive awareness is a fundamental component of tobacco use, highlighting the importance of taking into account the bodily feedback deriving from the cognitive representation of smoking in addiction research and therapy.

The multidimensional assessment of body representation and interoception in multiple sclerosis.

BACKGROUND: The mental representation of the body (or body representation, BR) derives from the processing of multiple sensory and motor inputs and plays a crucial role in guiding our actions and in how we perceive our body. Fundamental inputs for BR construction come also from the interoceptive systems which refer to the whole bidirectional processes between the brain and the body. People with Multiple sclerosis (MS) show an abnormal multisensory integration which may compromise BR and interoception integrity. However, no study has evaluated possible deficits on distinct and dissociable dimensions of body representation (i.e., action-oriented, aBR; and a nonaction-oriented body representation, NaBR) and interoception (i.e., interoceptive accuracy, interoceptive sensibility, and interoceptive awareness) in MS. OBJECTIVE: In the present study, we aimed to determine whether participants with MS present changes in BR and interoceptive dimensions. METHODS: We performed comparison analyses on tasks and questionnaires tapping all BR and interoceptive dimensions between 36 people with relapsing-remitting MS (RRMS) and 42 healthy controls, and between 23 people with progressive MS (PMS) and 33 healthy controls. RESULTS: Overall, patients with MS exhibited lower interoceptive accuracy than matched controls. The RRMS group also showed higher visceral interoceptive sensibility levels. No differences were found in BR accuracy measures, but the PMS reported longer response times when performing the aBR task. CONCLUSION: These findings open a new issue on the role of inner-signal monitoring in the body symptomatology of MS and highlight the need for an accurate BR and interoceptive assessment in a clinical setting.

Effects of a Chatbot-Based Intervention on Stress and Health-Related Parameters in a Stressed Sample: Randomized Controlled Trial.

BACKGROUND: Stress levels and the prevalence of mental disorders in the general population have been rising in recent years. Chatbot-based interventions represent novel and promising digital approaches to improve health-related parameters. However, there is a lack of research on chatbot-based interventions in the area of mental health. OBJECTIVE: The aim of this study was to investigate the effects of a 3-week chatbot-based intervention guided by the chatbot ELME, specifically with respect to the ability to reduce stress and improve various health-related parameters in a stressed sample. METHODS: In this multicenter two-armed randomized controlled trial, 118 individuals with medium to high stress levels were randomized to the intervention group (n=59) or the treatment-as-usual control group (n=59). The ELME chatbot guided participants of the intervention group through 3 weeks of training based on the topics stress, mindfulness, and interoception, with practical and psychoeducative elements delivered in two daily interactive intervention sessions via a smartphone (approximately 10-20 minutes each). The primary outcome (perceived stress) and secondary outcomes (mindfulness; interoception or interoceptive sensibility; subjective well-being; and emotion regulation, including the subfacets reappraisal and suppression) were assessed preintervention (T1), post intervention (T2; after 3 weeks), and at follow-up (T3; after 6 weeks). During both conditions, participants also underwent ecological momentary assessments of stress and interoceptive sensibility. RESULTS: There were no significant changes in perceived stress (ß03=-.018, SE=.329; P=.96) and momentary stress. Mindfulness and the subfacet reappraisal significantly increased in the intervention group over time, whereas there was no change in the subfacet suppression. Well-being and momentary interoceptive sensibility increased in both groups over time. CONCLUSIONS: To gain insight into how the intervention can be improved to achieve its full potential for stress reduction, besides a longer intervention duration, specific sample subgroups should be considered. The chatbot-based intervention seems to have the potential to improve mindfulness and emotion regulation in a stressed sample. Future chatbot-based studies and interventions in health care should be designed based on the latest findings on the efficacy of rule-based and artificial intelligence-based chatbots. TRIAL REGISTRATION: German Clinical Trials Register DRKS00027560; https://drks.de/search/en/trial/DRKS00027560. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-doi.org/10.3389/fdgth.2023.1046202.

Mindfulness and Interoceptive Awareness: A Network Analysis.

ABSTRACT: Higher trait mindfulness is correlated with higher interoceptive awareness. However, there is a gap in understanding which mindfulness dimensions connect to which interoceptive awareness dimensions. This study ( N = 1005) used network analysis to identify central and bridge nodes driving the linkage between mindfulness and interoceptive awareness. Central nodes included trusting body sensations, feeling a sense of calm when bringing awareness to the body, the ability to refocus one's attention from thinking to sensing the body, and the ability to accept all emotions. Bridge nodes included noticing how food and drink affect thoughts, bodily sensations, and emotions; staying alert to the sensations of the body when taking a shower; and noticing and letting go of distressing thoughts and feelings. Future research studies should explore whether mindfulness-based interventions may be more effective by targeting observations of sensations related to eating and the body as well as noticing and letting go of distressing thoughts and feelings.

When the interoceptive and conceptual clash: The case of oppositional phenomenal self-modelling in Tourette syndrome.

Tourette syndrome (TS) has been associated with a rich set of symptoms that are said to be uncomfortable, unwilled, and effortful to manage. Furthermore, tics, the canonical characteristic of TS, are multifaceted, and their onset and maintenance is complex. A formal account that integrates these features of TS symptomatology within a plausible theoretical framework is currently absent from the field. In this paper, we assess the explanatory power of hierarchical generative modelling in accounting for TS symptomatology from the perspective of active inference. We propose a fourfold analysis of sensory, motor, and cognitive phenomena associated with TS. In Section 1, we characterise tics as a form of action aimed at sensory attenuation. In Section 2, we introduce the notion of epistemic ticcing and describe such behaviour as the search for evidence that there is an agent (i.e., self) at the heart of the generative hierarchy. In Section 3, we characterise both epistemic (sensation-free) and nonepistemic (sensational) tics as habitual behaviour. Finally, in Section 4, we propose that ticcing behaviour involves an inevitable conflict between distinguishable aspects of selfhood; namely, between the minimal phenomenal sense of self-which is putatively underwritten by interoceptive inference-and the explicit preferences that constitute the individual's conceptual sense of self. In sum, we aim to provide an empirically informed analysis of TS symptomatology under active inference, revealing a continuity between covert and overt features of the condition.

Probing corporeal awareness in women through virtual reality induction of embreathment illusion.

We capitalized on the respiratory bodily illusion that we discovered in a previous study and called 'Embreathment' where we showed that breathing modulates corporeal awareness in men. Despite the relevance of the issue, no such studies are available in women. To bridge this gap, we tested whether the synchronization of avatar-participant respiration patterns influenced females' bodily awareness. We collected cardiac and respiratory interoceptive measures, administered body (dis)satisfaction questionnaires, and tracked participants' menstrual cycles via a mobile app. Our approach allowed us to characterize the 'Embreathment' illusion in women, and explore the relationships between menstrual cycle, interoception and body image. We found that breathing was as crucial as visual appearance in eliciting feelings of ownership and held greater significance than any other cue with respect to body agency in both women and men. Moreover, a positive correlation between menstrual cycle days and body image concerns, and a negative correlation between interoceptive sensibility and body dissatisfaction were found, confirming that women's body dissatisfaction arises during the last days of menstrual cycle and is associated with interoception. These findings have potential implications for corporeal awareness alterations in clinical conditions like eating disorders and schizophrenia.

Interoceptive signals from the heart and coronary circulation in health and disease.

This review considers interoceptive signalling from the heart and coronary circulation. Vagal and cardiac sympathetic afferent sensory nerve endings are distributed throughout the atria, ventricles (mainly left), and coronary artery. A small proportion of cardiac receptors attached to thick myelinated vagal afferents are tonically active during the cardiac cycle. Dependent upon location, these mechanoreceptors detect fluctuations in atrial volume and coronary arterial perfusion. Atrial volume and coronary arterial signals contribute to beat-to-beat feedback control and physiological homeostasis. Most cardiac receptors are attached to thinly myelinated or nonmyelinated C fibres, many of which are unresponsive to the cardiac cycle. Of these, there are many chemically sensitive cardiac receptors which are activated during myocardial stress by locally released endogenous substances. In contrast, some tonically inactive receptors become activated by irregular ventricular wall mechanics or by distortion of the ischaemic myocardium. Furthermore, some are excited both by chemical mediators of ischaemia and wall abnormalities. Reflex responses arising from cardiac receptors attached to thinly myelinated or nonmyelinated are complex. Impulses that project centrally through vagal afferents elicit sympathoinhibition and hypotension, whereas impulses travelling in cardiac sympathetic afferents and spinal pathways elicit sympathoexcitation and hypertension. Two opposing cardiac reflexes may provide a mechanism for fine-tuning a composite haemodynamic response during myocardial stress. Sympathetic afferents provide the primary pathway for transmission of cardiac nociception to the central nervous system. However, activation of sympathetic afferents may increase susceptibility to life-threatening arrhythmias. Notably, the cardiac sympathetic afferent reflex predominates in pathophysiological states including hypertension and heart failure.

Hepatic interoception in health and disease.

The liver is a large organ with crucial functions in metabolism and immune defense, as well as blood homeostasis and detoxification, and it is clearly in bidirectional communication with the brain and rest of the body via both neural and humoral pathways. A host of neural sensory mechanisms have been proposed, but in contrast to the gut-brain axis, details for both the exact site and molecular signaling steps of their peripheral transduction mechanisms are generally lacking. Similarly, knowledge about function-specific sensory and motor components of both vagal and spinal access pathways to the hepatic parenchyma is missing. Lack of progress largely owes to controversies regarding selectivity of vagal access pathways and extent of hepatocyte innervation. In contrast, there is considerable evidence for glucose sensors in the wall of the hepatic portal vein and their importance for glucose handling by the liver and the brain and the systemic response to hypoglycemia. As liver diseases are on the rise globally, and there are intriguing associations between liver diseases and mental illnesses, it will be important to further dissect and identify both neural and humoral pathways that mediate hepatocyte-specific signals to relevant brain areas. The question of whether and how sensations from the liver contribute to interoceptive self-awareness has not yet been explored.

Exploring the role of neuronal-enriched extracellular vesicle miR-93 and interoception in major depressive disorder.

Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 41) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (L1CAM/CD171) biotinylated antibody. The origin of NEEVs was validated with two other neuronal markers - neuronal cell adhesion molecule (NCAM) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3). NEEV specificities were confirmed by flow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation during interoceptive versus exteroceptive attention. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin re-organization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals.