Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder.

A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. Sensitivity analyses excluding covariates yielded similar results. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) remained significant and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. NLRC4 and MFN2 were positively correlated with serum C-reactive protein concentrations, while ASC trended significant. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.

The unique face of comorbid anxiety and depression: Increased frontal, insula and cingulate cortex response during Pavlovian fear-conditioning.

BACKGROUND: Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes. METHODS: 195 individuals with MDD (N = 65) or AnxMDD (N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-). RESULTS: MDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp2 = 0.02), dorsolateral prefrontal cortex (ηp2 = 0.01) and dorsal anterior/mid cingulate cortex (ηp2 = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD. LIMITATIONS: Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants. CONCLUSIONS: AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group.

Sensing, feeling and regulating: investigating the association of focal brain damage with voluntary respiratory and motor control.

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire, and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia and left medial temporal lobe showed reduced performance relative to individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60 bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnoea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing. This article is part of the theme issue 'Sensing and feeling: an integrative approach to sensory processing and emotional experience'.

Computational Mechanisms Underlying Multi-Step Planning Deficits in Methamphetamine Use Disorder.

Current theories suggest individuals with methamphetamine use disorder (iMUDs) have difficulty considering long-term outcomes in decision-making, which could contribute to risk of relapse. Aversive interoceptive states (e.g., stress, withdrawal) are also known to increase this risk. The present study analyzed computational mechanisms of planning in iMUDs, and examined the potential impact of an aversive interoceptive state induction. A group of 40 iMUDs and 49 healthy participants completed two runs of a multi-step planning task, with and without an anxiogenic breathing resistance manipulation. Computational modeling revealed that iMUDs had selective difficulty identifying the best overall plan when this required enduring negative short-term outcomes - a mechanism referred to as aversive pruning. Increases in reported craving before and after the induction also predicted greater aversive pruning in iMUDs. These results highlight a novel mechanism that could promote poor choice in recovering iMUDs and create vulnerability to relapse.

Development and validation of the Alimetry Gut-Brain Wellbeing Survey: a novel patient-reported mental health scale for patients with chronic gastroduodenal symptoms.

Objective: There is currently a lack of validated questionnaires designed specifically to assess mental health within patients with chronic gastroduodenal symptoms. This research describes the multi-phase process used to develop and validate a novel mental health scale for patients with chronic gastroduodenal symptoms, the Alimetry® Gut-Brain Wellbeing (AGBW) Survey. Methods: A patient-centered multi-phase process was implemented. In Phase 1, the most relevant concepts for this patient population were selected from existing mental health scales, using data from 79 patients. In Phase 2, an interdisciplinary panel of experts generated scale items. In Phase 3, the scale underwent pre-testing with gastroenterologists (n = 9), health psychologists (n = 3), and patients (n = 12), with feedback incorporated over multiple rounds. Lastly, the psychometric properties of the scale were assessed in a sample of 311 patients via an online survey. Results: The AGBW Survey comprises a patient preface, 10 close-ended questions, and an optional open-ended question. This multidimensional scale assesses general mental health, alongside specific subscales relating to depression, stress, and anxiety. The subscale and total scores demonstrated high internal consistency (α = 0.91 for the total scale; α = 0.72-0.86 for subscales) and good convergent, divergent, concurrent validity, and known groups validity, with large effect sizes. Conclusion: The AGBW Survey is a brief, valid, and reliable scale for assessing mental health in patients with chronic gastroduodenal symptoms. It can be used as a tool to complement physiological tests and has the potential to guide psychological referrals, inform multidisciplinary management, and evaluate treatment outcomes.

Directed exploration is elevated in affective disorders but reduced by an aversive interoceptive state induction.

Elevated anxiety and uncertainty avoidance are known to exacerbate maladaptive choice in individuals with affective disorders. However, the differential roles of state vs. trait anxiety remain unclear, and underlying computational mechanisms have not been thoroughly characterized. In the present study, we investigated how a somatic (interoceptive) state anxiety induction influences learning and decision-making under uncertainty in individuals with clinically significant levels of trait anxiety. A sample of 58 healthy comparisons (HCs) and 61 individuals with affective disorders (iADs; i.e., depression and/or anxiety) completed a previously validated explore-exploit decision task, with and without an added breathing resistance manipulation designed to induce state anxiety. Computational modeling revealed a pattern in which iADs showed greater information-seeking (i.e., directed exploration; Cohen's d=.39, p=.039) in resting conditions, but that this was reduced by the anxiety induction. The affective disorders group also showed slower learning rates across conditions (Cohen's d=.52, p=.003), suggesting more persistent uncertainty. These findings highlight a complex interplay between trait anxiety and state anxiety. Specifically, while elevated trait anxiety is associated with persistent uncertainty, acute somatic anxiety can paradoxically curtail exploratory behaviors, potentially reinforcing maladaptive decision-making patterns in affective disorders.

A randomized controlled safety and feasibility trial of floatation-REST in anxious and depressed individuals.

BACKGROUND: Reduced Environmental Stimulation Therapy via floatation (floatation-REST) is a behavioral intervention designed to attenuate exteroceptive sensory input to the nervous system. Prior studies in anxious and depressed individuals demonstrated that single sessions of floatation-REST are safe, well-tolerated, and associated with an acute anxiolytic and antidepressant effect that persists for over 48 hours. However, the feasibility of using floatation-REST as a repeated intervention in anxious and depressed populations has not been well-investigated. METHODS: In this single-blind safety and feasibility trial, 75 individuals with anxiety and depression were randomized to complete six sessions of floatation-REST in different formats: pool-REST (weekly 1-hour float sessions), pool-REST preferred (float sessions with flexibility of duration and frequency), or an active comparator (chair-REST; weekly 1-hour sessions in a Zero Gravity chair). Feasibility (primary outcome) was assessed via an 80% rate of adherence to the assigned intervention; tolerability via study dropout and duration/frequency of REST utilization; and safety via incidence of adverse events and ratings about the effects of REST. RESULTS: Of 1,715 individuals initially screened, 75 participants were ultimately randomized. Six-session adherence was 85% for pool-REST (mean, M = 5.1 sessions; standard deviation, SD = 1.8), 89% for pool-REST preferred (M = 5.3 sessions; SD = 1.6), and 74% for chair-REST (M = 4.4 sessions; SD = 2.5). Dropout rates at the end of the intervention did not differ significantly between the treatment conditions. Mean session durations were 53.0 minutes (SD = 12.3) for pool-REST, 75.4 minutes (SD = 29.4) for pool-REST preferred, and 58.4 minutes (SD = 4.3) for chair-REST. There were no serious adverse events associated with any intervention. Positive experiences were endorsed more commonly than negative ones and were also rated at higher levels of intensity. CONCLUSIONS: Six sessions of floatation-REST appear feasible, well-tolerated, and safe in anxious and depressed individuals. Floatation-REST induces positively-valenced experiences with few negative effects. Larger randomized controlled trials evaluating markers of clinical efficacy are warranted. CLINICAL TRIAL REGISTRATION IDENTIFIER: NCT03899090.

Transdiagnostic failure to adapt interoceptive precision estimates across affective, substance use, and eating disorders: A replication and extension of previous results.

Recent Bayesian theories of interoception suggest that perception of bodily states rests upon a precision-weighted integration of afferent signals and prior beliefs. In a previous study, we fit a computational model of perception to behavior on a heartbeat tapping task to test whether aberrant precision-weighting could explain misestimation of cardiac states in psychopathology. We found that, during an interoceptive perturbation designed to amplify afferent signal precision (inspiratory breath-holding), healthy individuals increased the precision-weighting assigned to ascending cardiac signals (relative to resting conditions), while individuals with anxiety, depression, substance use disorders, and/or eating disorders did not. In this pre-registered study, we aimed to replicate and extend our prior findings in a new transdiagnostic patient sample (N = 285) similar to the one in the original study. As expected, patients in this new sample were also unable to adjust beliefs about the precision of cardiac signals - preventing the ability to accurately perceive changes in their cardiac state. Follow-up analyses combining samples from the previous and current study (N = 719) also afforded power to identify group differences between narrower diagnostic categories, and to examine predictive accuracy when logistic regression models were trained on one sample and tested on the other. With this confirmatory evidence in place, future studies should examine the utility of interceptive precision measures in predicting treatment outcomes and test whether these computational mechanisms might represent novel therapeutic targets.

Individuals with Methamphetamine Use Disorder Show Reduced Directed Exploration and Learning Rates Independent of an Aversive Interoceptive State Induction.

Methamphetamine Use Disorder (MUD) is associated with substantially reduced quality of life. Yet, decisions to use persist, due in part to avoidance of anticipated withdrawal states. However, the specific cognitive mechanisms underlying this decision process, and possible modulatory effects of aversive states, remain unclear. Here, 56 individuals with MUD and 58 healthy comparisons (HCs) performed a decision task, both with and without an aversive interoceptive state induction. Computational modeling measured the tendency to test beliefs about uncertain outcomes (directed exploration) and the ability to update beliefs in response to outcomes (learning rates). Compared to HCs, those with MUD exhibited less directed exploration and slower learning rates, but these differences were not affected by aversive state induction. These results suggest novel, state-independent computational mechanisms whereby individuals with MUD may have difficulties in testing beliefs about the tolerability of abstinence and in adjusting behavior in response to consequences of continued use.

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.

Could neurofeedback improve therapist-patient communication? Considering the potential for neuroscience informed examinations of the psychotherapeutic relationship.

Empathic communication between a patient and therapist is an essential component of psychotherapy. However, finding objective neural markers of the quality of the psychotherapeutic relationship have been elusive. Here we conceptualize how a neuroscience-informed approach involving real-time neurofeedback, facilitated via existing functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) technologies, could provide objective information for facilitating therapeutic rapport. We propose several neurofeedback-assisted psychotherapy (NF-AP) approaches that could be studied as a way to optimize the experience of the individual patient and therapist across the spectrum of psychotherapeutic treatment. Finally, we consider how the possible strengths of these approaches are balanced by their current limitations and discuss the future prospects of NF-AP.

Leptin's Inverse Association With Brain Morphology and Depressive Symptoms: A Discovery and Confirmatory Study Across 2 Independent Samples.

BACKGROUND: Major depressive disorder has a complex, bidirectional relationship with metabolic dysfunction, but the neural correlates of this association are not well understood. METHODS: In this cross-sectional investigation, we used a 2-step discovery and confirmatory strategy utilizing 2 independent samples (sample 1: 288 participants, sample 2: 196 participants) to examine the association between circulating indicators of metabolic health (leptin and adiponectin) and brain structures in individuals with major depressive disorder. RESULTS: We found a replicable inverse correlation between leptin levels and cortical surface area within essential brain areas responsible for emotion regulation, such as the left posterior cingulate cortex, right pars orbitalis, right superior temporal gyrus, and right insula (standardized beta coefficient range: -0.27 to -0.49, puncorrected < .05). Notably, this relationship was independent of C-reactive protein levels. We also identified a significant interaction effect of leptin levels and diagnosis on the cortical surface area of the right superior temporal gyrus (standardized beta coefficient = 0.26 in sample 1, standardized beta coefficient = 0.30 in sample 2, puncorrected < .05). We also observed a positive correlation between leptin levels and atypical depressive symptoms in both major depressive disorder groups (r = 0.14 in sample 1, r = 0.29 in sample 2, puncorrected < .05). CONCLUSIONS: The inverse association between leptin and cortical surface area in brain regions that are important for emotion processing and leptin's association with atypical depressive symptoms support the hypothesis that metabolic processes may be related to emotion regulation. However, the molecular mechanisms through which leptin may exert these effects should be explored further.

Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study.

Background: The heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing. The insula and dorsal anterior cingulate cortex (dACC) are brain regions that may be involved in generating the HEP. Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that can selectively target sub-regions of the insula and dACC to better understand their contributions to the HEP. Objective: Proof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP. Methods: In a within-subject, repeated-measures design, healthy human participants (n=16) received 10 minutes of stereotaxically targeted LIFU to the AI, PI, dACC or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was change in HEP amplitudes. Relationships between LIFU pressure and HEP changes were examined using linear mixed modelling. Peripheral indices of visceromotor output including heart rate and heart rate variability (HRV) were explored between conditions. Results: Relative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; this was partially explained by increased LIFU pressure. LIFU did not affect time or frequency dependent measures of HRV. Conclusions: These results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.

Highway to the danger zone? A cautionary account that GLP-1 receptor agonists may be too effective for unmonitored weight loss.

Glucagon-like peptide 1 (GLP-1) receptor agonists are revolutionizing obesity and type 2 diabetes treatment, delivering remarkable weight loss outcomes. These medications, leveraging the effects of the insulin-regulating hormone GLP-1 via actions on peripheral and central nervous system targets, have raised hopes with their bariatric surgery-rivaling results. However, questions remain about their long-term safety and efficacy. Drawing from our expertise in obesity medicine and psychiatry, we reflect upon our experiences with the clinical use of these medications and delve into the nuanced challenges and risks they pose, particularly for those prone to disordered eating or those diagnosed with rare genetic diseases of obesity. We contend that effectively managing weight loss within this "danger zone" necessitates (1) proactive screening and continuous monitoring for disordered eating, (2) vigilant monitoring for appetite-related maladaptive responses, including food aversion and dehydration, and (3) ongoing assessment for broader health impacts. A multifaceted, interdisciplinary approach that melds medical, psychological, dietary, and behavioral strategies is crucial to delivering tailored and thorough care to each patient.

Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation.

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat-evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, µg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 µg isoproterenol infusion, the GAD group (n = 24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the healthy comparison (HC) group (n = 24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than the HC group during saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 µg isoproterenol infusion. Using analyzable blood oxygenation level-dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing in prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

Increased expression of ER stress, inflammasome activation, and mitochondrial biogenesis-related genes in peripheral blood mononuclear cells in major depressive disorder.

A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in the endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammation in MDD. RT-qPCR was used to measure mRNA expression of key organellar genes from peripheral blood mononuclear cells (PBMCs) isolated from 186 MDD and 67 healthy control (HC) subjects. The comparative CT (2-ΔΔCT) method was applied to quantify mRNA expression using GAPDH as the reference gene. After controlling for age, sex, BMI, and medication status using linear regression models, expression of the inflammasome (NLRC4 and NLRP3) and the ER stress (XBP1u, XBP1s, and ATF4) genes was found to be significantly increased in the MDD versus the HC group. After excluding outliers, expression of the inflammasome genes was no longer statistically significant but expression of the ER stress genes (XBP1u, XBP1s, and ATF4) and the mitochondrial biogenesis gene, MFN2, was significantly increased in the MDD group. ASC and MFN2 were positively correlated with serum C-reactive protein concentrations. The altered expression of inflammasome activation, ER stress, and mitochondrial biogenesis pathway components suggest that dysfunction of these organelles may play a role in the pathogenesis of MDD.

Sensing, Feeling, and Regulating: Investigating the Association of Focal Brain Damage with Voluntary Respiratory and Motor Control.

Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal, or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia, and left medial temporal lobe showed reduced performance than individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60-bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal, or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing. Highlights: Impaired human respiratory regulation is associated with cortical/subcortical brain lesionsFrontolimbic/temporal regions contribute to rhythmic breathing and hand motor controlFrontolimbic/temporal damage is associated with anxiety during tachypnea/irregular breathingThe human forebrain is vital for affective and interoceptive experiences during breathing.

The vagus nerve in cardiovascular physiology and pathophysiology: From evolutionary insights to clinical medicine.

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease.

Hemispheric divergence of interoceptive processing across psychiatric disorders.

Interactions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals, whereas during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e., when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Further, the dysgranular mid-insula may indeed be a "locus of disruption" for psychiatric disorders.