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Objective: Research suggests that disrupted interoception contributes to the development and maintenance of functional neurological disorder (FND); however, no functional neuroimaging studies have examined the processing of interoceptive signals in patients with FND., Methods: The authors examined univariate and multivariate functional MRI neural responses of 38 patients with mixed FND and 38 healthy control individuals (HCs) during a task exploring goal-directed attention to cardiac interoception-versus-control (exteroception or rest) conditions. The relationships between interoception-related neural responses, heartbeat-counting accuracy, and interoceptive trait prediction error (ITPE) were also investigated for FND patients., Results: When attention was directed to heartbeat signals versus exteroception or rest tasks, FND patients showed decreased neural activations (and reduced coactivations) in the right anterior insula and bilateral dorsal anterior cingulate cortices (among other areas), compared with HCs. For FND patients, heartbeat-counting accuracy was positively correlated with right anterior insula and ventromedial prefrontal activations during interoception versus rest. Cardiac interoceptive accuracy was also correlated with bilateral dorsal anterior cingulate activations in the interoception-versus-exteroception contrast, and neural activations were correlated with ITPE scores, showing inverse relationships to those observed for heartbeat-counting accuracy., Conclusions: This study identified state and trait interoceptive disruptions in FND patients. Convergent between- and within-group findings contextualize the pathophysiological role of cingulo-insular (salience network) areas across the spectrum of functional seizures and functional movement disorder. These findings provide a starting point for the future development of comprehensive neurophysiological assessments of interoception for FND patients, features that also warrant research as potential prognostic and monitoring biomarkers.

Meditation is a family of ancient and contemporary contemplative mind-body practices that can modulate psychological processes, awareness, and mental states. Over the last 40 years, clinical science has manualised meditation practices and designed various meditation interventions (MIs), that have shown therapeutic efficacy for disorders including depression, pain, addiction, and anxiety. Over the past decade, neuroimaging has examined the neuroscientific basis of meditation practices, effects, states, and outcomes for clinical and non-clinical populations. However, the generalizability and replicability of current neuroscientific models of meditation are yet to be established, as they are largely based on small datasets entrenched with heterogeneity along several domains of meditation (e.g., practice types, meditation experience, clinical disorder targeted), experimental design, and neuroimaging methods (e.g., preprocessing, analysis, task-based, resting-state, structural MRI). These limitations have precluded a nuanced and rigorous neuroscientific phenotyping of meditation practices and their potential benefits. Here, we present ENIGMA-Meditation, the first worldwide collaborative consortium for neuroscientific investigations of meditation practices. ENIGMA-Meditation will enable systematic meta- and mega-analyses of globally distributed neuroimaging datasets of meditation using shared, standardized neuroimaging methods and tools to improve statistical power and generalizability. Through this powerful collaborative framework, existing neuroscientific accounts of meditation practices can be extended to generate novel and rigorous neuroscientific insights, accounting for multi-domain heterogeneity. ENIGMA-Meditation will inform neuroscientific mechanisms underlying therapeutic action of meditation practices on psychological and cognitive attributes, advancing the field of meditation and contemplative neuroscience., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To evaluate the impact that adjuvant therapies like radiotherapy, chemotherapy, and immunotherapy have on osteobiologic properties and bony regeneration in patients with metastatic spine disease (MSD) undergoing spinal fusion surgery., Methods: PubMed and ClinicalTrials.gov searches were performed. MSD patients undergoing fusion surgery with an osteobiologic and radiotherapy, chemotherapy and/or immunotherapy were included. Demographics, primary tumor, surgery, adjuvant treatments, osteobiologic type, fusion rates with scoring criteria, hardware failure, reoperation rates, follow-up, and survival were extracted. 1487 studies were screened, 20 included., Results: 585 patients (464 with MSD) had fusion rates ranging from 17.9 to 100%. In the setting of radiotherapy, fusion rates of 10 studies using autologous bone graft (autograft), 5 studies using allogenic bone graft (allograft), 5 studies using combination autograft/allograft, 4 studies using biomaterial scaffolds (BMS), 3 studies using demineralized bone matrices (DBM), and 1 study using growth factors (GF), were 50-100%, 17.9-100%, 57.8-100%, 52.9-100%, 20-100%, and 100%, respectively. A higher incidence of fusion in patients with autograft or allograft receiving stereotactic body radiotherapy (SBRT) at lower biologically effective doses (BED) and at least 1-month postoperatively was noted. Chemotherapy had no impact on fusion. No studies evaluated the impact of immunotherapy on fusion., Conclusions: SBRT at lower doses given greater than 1-month postoperatively may enhance bony fusion in patients receiving autograft, allograft, or autograft/allograft. Chemotherapy may delay bony fusion without affecting overall fusion rates. Preclinical studies suggest immunotherapy may prevent osteolysis and promote osteogenesis, but no studies have yet evaluated the clinical impact of these findings on spinal fusion. Further research is needed on osteobiologics in bony regeneration in the MSD population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing that may be generated in the insula and dorsal anterior cingulate cortex (dACC). Low-intensity focused ultrasound (LIFU) can selectively modulate sub-regions of the insula and dACC to better understand their contributions to the HEP., Methods: Healthy participants (n = 16) received stereotaxically targeted LIFU to the anterior insula (AI), posterior insula (PI), dACC, or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was HEP amplitudes. Relationships between LIFU pressure and HEP changes and effects of LIFU on heart rate and heart rate variability (HRV) were also explored., Results: Relative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; PI effects were partially explained by increased LIFU pressure. LIFU did not affect heart rate or HRV., Conclusions: These results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions., Significance: 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., Competing Interests: Declaration of interest The authors declare no conflicts of interest., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

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 interoceptive precision measures in predicting treatment outcomes and test whether these computational mechanisms might represent novel therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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; ηp 2  = 0.02), dorsolateral prefrontal cortex (ηp 2  = 0.01) and dorsal anterior/mid cingulate cortex (ηp 2  = 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., Competing Interests: Declaration of competing interest This work has been supported in part by The William K. Warren Foundation and the National Institute of General Medical Sciences center grant award number P20GM121312. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Maria Ironside, Rayus Kuplicki, Jennifer Stewart, Robin Aupperle, and Martin Paulus receive funding from the National Institute of General Medical Sciences (NIGMS) center grant P20GM121312; Maria Ironside has additional funding from National Institute of Mental Health (NIMH; R01MH132565). Sahib Khalsa has grant funding from the NIMH (K23MH112949, R01MH127225); Robin Aupperle has additional grant funding from NIMH (K23MH108707; R01MH123691); Jennifer Stewart has additional grant funding from the National Institute of Drug Abuse (NIDA) (R01DA050677), Rayus Kuplicki has additional funding from NIDA (R01DA050677); and Martin Paulus has additional grant funding from the NIDA (U01DA041089, R01DA050677)., (Copyright © 2024. Published by Elsevier B.V.)

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'.

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 C T (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., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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., Competing Interests: GO’G and AG hold grants and intellectual property in the field of gastrointestinal electrophysiology and are Directors in Alimetry Ltd. GO’G is also a Director in The Insides Company. ML, IP, GSe, GSc, PD, CD, CA, and SC are members of Alimetry Ltd. GH holds options in Alimetry. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Law, Pickering, Humphrey, Sebaratnam, Schamberg, Simpson, Varghese, Du, Daker, Huang, Khalsa, Gharibans, O'Grady, Andrews and Calder.)

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, p uncorrected < .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, p uncorrected < .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, p uncorrected < .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., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

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., Competing Interests: Conflict of interest or competing financial interests The authors have no conflicts of interest to report.

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., Competing Interests: Conflict of interest or competing financial interests The authors have no competing interests to disclose.

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., Competing Interests: The authors declare that there are no conflicts of interests., (Copyright: © 2024 Garland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing Interests The authors have no competing interests to declare.

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., (© 2024 World Obesity Federation.)

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., (© 2024. The Author(s).)

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., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The integration of Large Language Models (LLMs) into mental healthcare and research heralds a potentially transformative shift, one offering enhanced access to care, efficient data collection, and innovative therapeutic tools. This paper reviews the development, function, and burgeoning use of LLMs in psychiatry, highlighting their potential to enhance mental healthcare through improved diagnostic accuracy, personalized care, and streamlined administrative processes. It is also acknowledged that LLMs introduce challenges related to computational demands, potential for misinterpretation, and ethical concerns, necessitating the development of pragmatic frameworks to ensure their safe deployment. We explore both the promise of LLMs in enriching psychiatric care and research through examples such as predictive analytics and therapy chatbots and risks including labor substitution, privacy concerns, and the necessity for responsible AI practices. We conclude by advocating for processes to develop responsible guardrails, including red teaming, multi-stakeholder oriented safety, and ethical guidelines/frameworks, to mitigate risks and harness the full potential of LLMs for advancing mental health., Competing Interests: Dr. Obradovich is part of OpenAI’s Researcher Access Program and has received resources from OpenAI to support research activities outside of this work. Dr. Khalsa provides uncompensated service on executive boards of the International Society for Contemplative Research and the Float Research Collective, serves on the editorial boards of Biological Psychology and JMIR Mental Health, and has served on a scientific advisory board for Janssen Pharmaceuticals. Dr. Khan has no conflicts of interest or disclosures to make that are relevant to the content. Dr. Suh is employed by Microsoft Research. Dr. Perlis has served on scientific advisory boards for Circular Genomics, Genomind, Belle Artificial Intelligence, Swan AI Studios, and Psy Therapeutics. Dr. Ajilore is the co-founder of KeyWise AI and has served as a consultant for Otsuka Pharmaceuticals on the advisory boards for Sage Therapeutics, Embodied Labs and Blueprint Health. Dr. Paulus advises Spring Care, Inc., receives royalties from an article on methamphetamine in UpToDate, and has a compensated consulting agreement with Boehringer Ingelheim International GmbH. of this review article.

As the sense of the body's internal state, interoception represents the afferent component of the brain-body feedback loop essential for linking internal sensation with body regulation, thereby minimizing erroneous feedback and maintaining homeostasis. The anticipation of potential future interoceptive states enables organisms to take regulatory actions to meet demands before they arise, and alterations of anticipation have been implicated in the pathophysiology of medical and psychiatric conditions. However, laboratory approaches operationalizing the anticipation of interoceptive states are missing. Therefore, we developed two interoceptive awareness paradigms, the Accuracy of Interoceptive Anticipation paradigm, and the Interoceptive Discrepancy paradigm, which we tested in 52 healthy participants on two sensory modalities: nociception and respiroception. Ten participants took part in a retest. The Accuracy of Interoceptive Anticipation paradigm focused on assessing how individuals anticipate and experience interoceptive stimuli of varying strengths. The Interoceptive Discrepancy paradigm extended this measure by manipulating previously learned expectations to induce discrepancies between anticipated and experienced stimuli. We found that anticipation and experience ratings successfully related to stimulus strength in both paradigms and modalities and were stable between test-retest. Furthermore, the Interoceptive Discrepancy paradigm successfully induced the expected discrepancies between anticipation and experience conditions, and discrepancy values were correlated across sensory modalities. Thus, both paradigms are valid and reliable tools for assessing the anticipation of future interoceptive states, and the Interoceptive Discrepancy paradigm is additionally suited to evaluate discrepancy awareness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: This study aimed to test whether there are sex differences in the relationship between impulsivity and amphetamine use disorder (AMP)., Design: A naturalistic cross-sectional design was used., Setting: The Tulsa 1000 study was held in Tulsa, OK, USA., Participants: There were two groups in this study: AMP+ (29F, 20M) and AMP- (57F, 33M)., Measurements: This project focuses on data related to impulsivity: UPPS-P impulsive behavior scale and a stop signal task (SST) during functional magnetic resonance imaging (fMRI) recording. Group, sex and their interaction were compared for UPPS-P ratings and SST fMRI and behavioral responses., Findings: AMP+ reported higher UPPS-P positive and negative urgency scores (Ps < 0.001; r = 0.56 and 0.51) and displayed greater bilateral insula and amygdala responses across correct SST trials (Ps < 0.001, g range = 0.57-0.81) than AMP-. fMRI results indicated that AMP+ exhibited larger right anterior/middle insula, amygdala and nucleus accumbens signals during successful difficult stop trials than AMP- (Ps < 0.01; g = 0.63, 0.54 and 0.44, respectively). Crucially, two group × sex effects emerged: (a) within females, AMP+ reported larger UPPS-P lack of premeditation scores than AMP- (P < 0.001, r = 0.51), and (b) within males, AMP+ showed greater left middle insula signals than AMP- across correct SST trials (P = 0.01, g = 0.78)., Conclusions: Both female and male amphetamine users appear to be characterized by rash action in the presence of positive and negative mood states as well as heightened recruitment of right hemisphere regions during behavioral inhibition. In contrast, planning ahead may be particularly difficult for female amphetamine users, whereas male amphetamine users may need to recruit additional left hemisphere resources during inhibitory processing., (© 2023 Society for the Study of Addiction.)

Background: Body image disturbance and anxiety are core features of anorexia nervosa (AN), a psychiatric disorder with one of the highest mortality rates. This study examined the efficacy of a novel non-pharmacological treatment, floatation-REST (Reduced Environmental Stimulation Therapy) on body image disturbance and anxiety in inpatients with AN., Methods: This parallel group randomised controlled trial compared floatation-REST vs. care as usual in women and girls hospitalised for treatment of AN in Tulsa, Oklahoma, USA. Participants were randomised on a 2:1 ratio to receive eight, twice-weekly, 60-min floatation-REST sessions for 4 weeks, in addition to care as usual, or to receive care as usual. The primary outcome was the average change in body dissatisfaction from pre- to post-float as measured by the Photographic Figure Rating Scale. The secondary outcome was the average change in anxiety from pre- to post-float as measured by the state version of the State Trait Anxiety Inventory. Longitudinal effects of floatation-REST on body dissatisfaction were also examined. All analyses were conducted using the intention-to-treat principle. Planned linear mixed models tested the effect of floatation-REST vs. care as usual. The trial was preregistered (clinicaltrials.govNCT03610451)., Findings: Between March 16, 2018 and February 25, 2021, 133 participants were screened for eligibility, and 86 were consented. Eighteen were excluded after consent, for a final randomisation sample of 68 participants (45 floatation-REST; 23 care as usual). There were two session by condition interactions on body dissatisfaction ( p  = 0.00026) and state anxiety ( p  < 0.0001), such that the floatation-REST group exhibited acute (i.e., pre- to post-session) reductions in body dissatisfaction (floatation-REST group mean change (Δ m ) = -0.43; 95% CI -0.56 to -0.30, p  < 0.0001, Cohen's d  = 0.23), and acute reductions in anxiety (floatation-REST group Δ m  = -15.75; 95% CI -17.95 to -13.56, p  < 0.0001, Cohen's d  = 1.52); however, the care as usual group exhibited no significant changes. With regard to longitudinal results, there was a significant time by treatment interaction between baseline and immediately post intervention ( p  = 0.012) and baseline and six-month follow up ( p  = 0.0019). At immediately post intervention, there was a trending reduction in body dissatisfaction for the floatation-REST group (Δ m  = -0.41, 95% CI -0.86 to 0.03, p  = 0.068) and care as usual group (Δ m  = 0.61; 95% CI -0.04 to 1.27, p  = 0.070). At six-months post-intervention, the floatation-REST group exhibited lower body dissatisfaction (Δ m  = -0.91; 95% CI -1.37 to -0.45, p  = 0.0020, Cohen's d  = 0.53) whereas the care as usual group reported no change in body dissatisfaction (Δ m  = 0.35; 95% CI -0.28 to 0.98, p  = 0.96) relative to baseline. There were no adverse events related to the trial during the study., Interpretation: Our findings suggest that Floatation-REST decreased body dissatisfaction compared to care as usual acutely after each float session and at six-month follow-up. Floatation-REST has potential utility for the treatment of body image disturbance and anxiety in AN. These results may be limited by some generalisability concerns given the recruitment of a modest sample receiving inpatient treatment at a single site., Funding: The William K. Warren Foundation., Competing Interests: Martin Paulus is an advisor to Spring Care, Inc., a behavioral health startup, he has previously received royalties for an article about methamphetamine in UpToDate, and consulting fees from Hoffmann-La Roche Ltd. Justin Feinstein is the president and director of the nonprofit Float Research Collective. Sahib Khalsa is an executive committee member of the International Society of Contemplative Research and a board member of the Float Research Collective, both of which are unpaid roles. All other authors declare no competing interests. Sahib Khalsa was supported by the National Institute of Mental Health (R01MH127225, K23MH112949). Martin Paulus, Justin Feinstein, and Sahib Khalsa were supported by the National Institute of General Medical Sciences (1P20GM121312). Emily Choquette and Michael Flux received support for travel and hotel to speak at the 2022 Float Conference. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication., (© 2023 The Author(s).)

Objective: Binge eating disorder (BED) is the most common eating disorder, and yet only one pharmacotherapy (lisdexamfetamine), which has known abuse-potential, is FDA-approved. Topiramate is also commonly prescribed off-label for binge eating but has many contraindications. In contrast, the glucagon-like peptide-1 (GLP1) analog semaglutide has profound effects on central satiety signaling leading to reduced food intake, and has been approved for the treatment of obesity based on its efficacy and safety profile. Semaglutide would thus seem to be a potential candidate for the treatment of BED., Methods: This open-label study examined the effects of semaglutide on Binge Eating Scale (BES) scores in individuals with BED. Patients were divided into three groups: those prescribed semaglutide, those prescribed either lisdexamphetamine or topiramate, and those prescribed a combination of semaglutide with lisdexamphetamine or topiramate., Results: Patients receiving semaglutide only exhibited greater reductions in BES scores compared to the other groups. Combined pharmacotherapy with both semaglutide and the other anti-obesity medications did not result in greater reductions in BES scores compared to the semaglutide-only group. Findings were similar in patients with moderate/severe BED, as well as the full sample., Conclusion: The therapeutic effects of semaglutide in binge eating disorder warrant further investigation., Competing Interests: Dr Richards is on Speaker Bureau for Rhythm Pharmaceuticals and Novo Nordisk and is on Advisory Board for Rhythm Pharmaceuticals. The other authors report no disclosures to declare., (© 2023 The Authors.)

Major depressive disorder (MDD) is associated with immunologic and metabolic alterations linked to central processing dysfunctions, including attenuated reward processing. This study investigated the associations between inflammation, metabolic hormones (leptin, insulin, adiponectin), and reward-related brain processing in MDD patients with high (MDD-High) and low (MDD-Low) C-reactive protein (CRP) levels compared to healthy comparison subjects (HC). Participants completed a blood draw and a monetary incentive delay task during functional magnetic resonance imaging. Although groups did not differ in insulin or adiponectin concentrations, both MDD-High (Wilcoxon p = 0.004, d = 0.65) and MDD-Low (Wilcoxon p = 0.046, d = 0.53) showed higher leptin concentrations than HC but did not differ from each other. Across MDD participants, higher leptin levels were associated with lower brain activation during reward anticipation in the left insula (r = - 0.30, p = 0.004) and left dorsolateral putamen (r = -- 0.24, p = 0.025). In contrast, within HC, higher leptin concentrations were associated with higher activation during reward anticipation in the same regions (insula: r = 0.40, p = 0.007; putamen: r = 0.37, p = 0.014). Depression may be characterized by elevated pro-inflammatory signaling via leptin concentrations through alternate inflammatory pathways distinct to CRP., (© 2023. The Author(s).)

Posttraumatic stress disorder (PTSD) is a psychiatric condition characterized by sustained symptoms, including reexperiencing, hyperarousal, avoidance, and mood alterations, following exposure to a traumatic event. Although symptom presentations in PTSD are heterogeneous and incompletely understood, they likely involve interactions between neural circuits involved in memory and fear learning and multiple body systems involved in threat processing. PTSD differs from other psychiatric conditions in that it is a temporally specific disorder, triggered by a traumatic event that elicits heightened physiological arousal, and fear. Fear conditioning and fear extinction learning have been studied extensively in relation to PTSD, because of their central role in the development and maintenance of threat-related associations. Interoception, the process by which organisms sense, interpret, and integrate their internal body signals, may contribute to disrupted fear learning and to the varied symptom presentations of PTSD in humans. In this review, the authors discuss how interoceptive signals may serve as unconditioned responses to trauma that subsequently serve as conditioned stimuli, trigger avoidance and higher-order conditioning of other stimuli associated with these interoceptive signals, and constitute an important aspect of the fear learning context, thus influencing the specificity versus generalization of fear acquisition, consolidation, and extinction. The authors conclude by identifying avenues for future research to enhance understanding of PTSD and the role of interoceptive signals in fear learning and in the development, maintenance, and treatment of PTSD., Competing Interests: The authors report no financial relationships with commercial interests., (Copyright © 2023 by the American Psychiatric Association.)

Background: Anorexia nervosa (AN) is characterized by low body weight, disturbed eating, body image disturbance, anxiety, and interoceptive dysfunction. However, the neural processes underlying these dysfunctions in AN are unclear. This investigation combined an interoceptive pharmacological probe, the peripheral β-adrenergic agonist isoproterenol, with resting-state functional magnetic resonance imaging to examine whether individuals with AN relative to healthy comparison participants show dysregulated neural coupling in central autonomic network brain regions., Methods: Resting-state functional magnetic resonance imaging was performed in 23 weight-restored female participants with AN and 23 age- and body mass index-matched healthy comparison participants before and after receiving isoproterenol infusions. Whole-brain functional connectivity (FC) changes were examined using central autonomic network seeds in the amygdala, anterior insular cortex, posterior cingulate cortex, and ventromedial prefrontal cortex after performing physiological noise correction procedures., Results: Relative to healthy comparison participants, adrenergic stimulation caused widespread FC reductions in the AN group between central autonomic network regions and motor, premotor, frontal, parietal, and visual brain regions. Across both groups, these FC changes were inversely associated with trait anxiety (State-Trait Anxiety Inventory-Trait), trait depression (9-item Patient Health Questionnaire), and negative body image perception (Body Shape Questionnaire) measures, but not with changes in resting heart rate. These results were not accounted for by baseline group FC differences., Conclusions: Weight-restored females with AN show a widespread state-dependent disruption of signaling between central autonomic, frontoparietal, and sensorimotor brain networks that facilitate interoceptive representation and visceromotor regulation. Additionally, trait associations between central autonomic network regions and these other brain networks suggest that dysfunctional processing of interoceptive signaling may contribute to affective and body image disturbance in AN., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Decision-making under approach-avoidance conflict (AAC; e.g., sacrificing quality of life to avoid feared outcomes) may be affected in multiple psychiatric disorders. Recently, we used a computational (active inference) model to characterize information processing differences during AAC in individuals with depression, anxiety and/or substance use disorders. Individuals with psychiatric disorders exhibited increased decision uncertainty (DU) and reduced sensitivity to unpleasant stimuli. This preregistered study aimed to determine the replicability of this processing dysfunction., Methods: A new sample of participants completed the AAC task. Individual-level computational parameter estimates, reflecting decision uncertainty and sensitivity to unpleasant stimuli ("emotion conflict"; EC), were obtained and compared between groups. Subsequent analyses combining the prior and current samples allowed assessment of narrower disorder categories., Results: The sample in the present study included 480 participants: 97 healthy controls, 175 individuals with substance use disorders and 208 individuals with depression and/or anxiety disorders. Individuals with substance use disorders showed higher DU and lower EC values than healthy controls. The EC values were lower in females, but not males, with depression and/or anxiety disorders than in healthy controls. However, the previously observed difference in DU between participants with depression and/or anxiety disorders and healthy controls did not replicate. Analyses of specific disorders in the combined samples indicated that effects were common across different substance use disorders and affective disorders., Limitations: There were differences, although with small effect size, in age and baseline intellectual functioning between the previous and current sample, which may have affected replication of DU differences in participants with depression and/or anxiety disorders., Conclusion: The now robust evidence base for these clinical group differences motivates specific questions that should be addressed in future research: can DU and EC become behavioural treatment targets, and can we identify neural substrates of DU and EC that could be used to measure severity of dysfunction or as neuromodulatory treatment targets?, Competing Interests: Competing interests: M. Paulus is supported by the National Institute on Drug Abuse (U01DA050989). He is an advisor to Spring Care, Inc., a behavioural heatlh startup; has received royalties for an article about methamphetamine in UpToDate; and has a consulting agreement with and receives compensation from F. Hoffmann-La Roche Ltd. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Differences in the correlated activity of networked brain regions have been reported in individuals with generalized anxiety disorder (GAD) but an overreliance on null-hypothesis significance testing (NHST) limits the identification of disorder-relevant relationships. In this preregistered study, we applied both a Bayesian statistical framework and NHST to the analysis of resting-state fMRI scans from females with GAD and matched healthy comparison females. Eleven a-priori hypotheses about functional connectivity (FC) were evaluated using Bayesian (multilevel model) and frequentist (t-test) inference. Reduced FC between the ventromedial prefrontal cortex (vmPFC) and the posterior-mid insula (PMI) was confirmed by both statistical approaches and was associated with anxiety sensitivity. FC between the vmPFC-anterior insula, the amygdala-PMI, and the amygdala-dorsolateral prefrontal cortex (dlPFC) region pairs did not survive multiple comparison correction using the frequentist approach. However, the Bayesian model provided evidence for these region pairs having decreased FC in the GAD group. Leveraging Bayesian modeling, we demonstrate decreased FC of the vmPFC, insula, amygdala, and dlPFC in females with GAD. Exploiting the Bayesian framework revealed FC abnormalities between region pairs excluded by the frequentist analysis and other previously undescribed regions in GAD, demonstrating the value of applying this approach to resting-state FC data in clinical investigations., (© 2023. The Author(s).)

Understanding the neural processes governing the human gut-brain connection has been challenging due to the inaccessibility of the body's interior. Here, we investigated neural responses to gastrointestinal sensation using a minimally invasive mechanosensory probe by quantifying brain, stomach, and perceptual responses following the ingestion of a vibrating capsule. Participants successfully perceived capsule stimulation under two vibration conditions (normal and enhanced), as evidenced by above chance accuracy scores. Perceptual accuracy improved significantly during the enhanced relative to normal stimulation, which was associated with faster stimulation detection and reduced reaction time variability. Capsule stimulation induced late neural responses in parieto-occipital electrodes near the midline. Moreover, these 'gastric evoked potentials' showed intensity-dependent increases in amplitude and were significantly correlated with perceptual accuracy. Our results replicated in a separate experiment, and abdominal X-ray imaging localized most capsule stimulations to the gastroduodenal segments. Combined with our prior observation that a Bayesian model is capable of estimating computational parameters of gut-brain mechanosensation, these findings highlight a unique form of enterically-focused sensory monitoring within the human brain, with implications for understanding gut feelings and gut-brain interactions in healthy and clinical populations., (© 2023. The Author(s).)

Background: Reduced Environmental Stimulation Therapy (REST) is a behavioral intervention that systematically attenuates external sensory input to the nervous system. Previous studies have demonstrated acute anxiolytic and antidepressant effects of single sessions of REST in anxious individuals, however the duration and time course of these effects is unknown. In the current study, we used experience sampling and multiple sessions of REST to explore the time course of the anxiolytic and antidepressant effects over a 48-hour time period., Methods: 75 adults with anxiety and/or depression were randomized to complete 6 sessions of REST (either pool-REST, pool-REST preferred, or chair-REST). Post-REST effects were tracked using experience sampling on a smartphone with a ten-item survey administered at 6 time points for each session (i.e., immediately before and after REST and then 4, 8, 24, and 48 hours later). Using principal component analysis, responses to survey items at baseline were reduced to broad symptom clusters of anxiety, depression, and serenity and were utilized in linear mixed effects models to determine the magnitude and time course of post-REST effects., Results: REST was associated with significant decreases in anxiety and depression, and significant increases in serenity, with effects lasting for 48 hours. Repeated exposure to REST was associated with lower baseline levels of anxiety at later sessions., Conclusion: These initial findings suggest that the anxiolytic and antidepressant effects of REST persist for at least two days, and that repeated REST sessions may have additive effects on lowering anxiety-related symptoms. These findings could help to determine the optimal intervention frequency of REST and facilitate future investigations focused on the combination of REST with standard treatments for anxiety and depression., Competing Interests: Declaration of Conflicting Interests ACA. is founder of Insight Health Systems, Arevian Technologies, and Open Science Initiative. ACA. developed the Chorus platform, which is licensed from the University of California Los Angeles to Insight Health Systems. There are no other competing interests to report for any authors.

Background: Repetitive negative thinking (RNT) is a symptom that can negatively impact the treatment and course of common psychiatric disorders such as depression and anxiety. We aimed to characterize behavioral and genetic correlates of RNT to infer potential contributors to its genesis and maintenance., Methods: We applied a machine learning (ML) ensemble method to define the contribution of fear, interoceptive, reward, and cognitive variables to RNT, along with polygenic risk scores (PRS) for neuroticism, obsessive compulsive disorder (OCD), worry, insomnia, and headaches. We used the PRS and 20 principal components of the behavioral and cognitive variables to predict intensity of RNT. We employed the Tulsa-1000 study, a large database of deeply phenotyped individuals recruited between 2015 and 2018., Results: PRS for neuroticism was the main predictor of RNT intensity (R 2 =0.027,p<0.001). Behavioral variables indicative of faulty fear learning and processing, as well as aberrant interoceptive aversiveness, were significant contributors to RNT severity. Unexpectedly, we observed no contribution of reward behavior and diverse cognitive function variables., Limitations: This study is an exploratory approach that must be validated with a second, independent cohort. Furthermore, this is an association study, limiting causal inference., Conclusions: RNT is highly determined by genetic risk for neuroticism, a behavioral construct that confers risk to a variety of internalizing disorders, and by emotional processing and learning features, including interoceptive aversiveness. These results suggest that targeting emotional and interoceptive processing areas, which involve central autonomic network structures, could be useful in the modulation of RNT intensity., Competing Interests: Declaration of competing interest The authors have no competing interests to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Anxiety and depression commonly co-occur, yet the underlying brain and behavioral processes are poorly understood. Here we examined the hypothesis that individuals with comorbid anxiety and depression would show increased fearful reactivity to an aversive interoceptive perturbation relative to depressed-only individuals. One-hundred and eighty anxious and/or depressed participants from the Tulsa 1000 study completed multi-level behavioral or functional magnetic resonance imaging assessments of interoception and nociception including breath-hold and cold-pressor challenges, and heartbeat perception and interoceptive attention tasks. One-hundred and four individuals with comorbid depression and anxiety disorders (Dep+Anx) were propensity matched with 52 individuals with depression-only (Dep). Data were analyzed using mixed-effects linear regression. The Dep+Anx group showed significantly greater self-reported fear of suffocation during breath holding (Wilcoxon r = 0.23) and reduced cold pain tolerance ( R 2 = 0.027) signified by hand removal during immersion. However, these groups did not differ with respect to neutrally-valenced behavioral indices of heartbeat perception or neural indices of interoceptive attention. Individuals with comorbid depression and anxiety, vs. those with only depression, show increased respiratory fearfulness and nociceptive reactivity during perturbations of these signals, whilst showing similar interoceptive awareness in the absence of perturbation. Our findings suggest that individuals with comorbid anxiety and depression process aversive interoceptive and nociceptive signals differently than those with depression alone, providing support for a process model of increased threat sensitivity and hyperarousal in anxious depression., Competing Interests: MP is an advisor to Spring Care, Inc., a behavioral health startup, he has received royalties for an article about methamphetamine in UpToDate. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ironside, DeVille, Kuplicki, Burrows, Smith, Teed, Paulus and Khalsa.)

Background: Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive, and trauma- and stressor-related disorders; however, many patients do not improve, resulting in prolonged suffering and poorly used resources. Basic research on fear extinction may inform the development of a biomarker for the selection of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction and we have demonstrated that reactivity to an inhaled carbon dioxide (CO 2 ) challenge-a safe, affordable, and easy-to-implement procedure-can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents. Building upon this basic research, the goal for the proposed study is to validate CO 2 reactivity as a biomarker of exposure-based therapy non-response., Methods: We will assess CO 2 reactivity in 600 adults meeting criteria for one or more fear- or anxiety-related disorders prior to providing open exposure-based therapy. By incorporating CO 2 reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related predictor variables, we will establish the mechanistic specificity and the additive predictive utility of the potential CO 2 reactivity biomarker. By developing models independently within two study sites (University of Texas at Austin and Boston University) and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples., Discussion: Representing a necessary stage in translating basic research, this investigation addresses an important public health issue by testing an accessible clinical assessment strategy that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders, and enhanced understanding of the mechanisms governing exposure-based therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT05467683 (20/07/2022)., (© 2022. The Author(s).)

The central nervous system (CNS) exerts a strong regulatory influence over the cardiovascular system in response to environmental demands. Floatation-REST (Reduced Environmental Stimulation Therapy) is an intervention that minimizes stimulation from the environment, yet little is known about the autonomic consequences of reducing external sensory input to the CNS. We recently found that Floatation-REST induces a strong anxiolytic effect in anxious patients while paradoxically enhancing their interoceptive awareness for cardiorespiratory sensations. To further investigate the physiologic nature of this anxiolytic effect, the present study measured acute cardiovascular changes during Floatation-REST using wireless and waterproof equipment that allowed for concurrent measurement of heart rate, heart rate variability (HRV), breathing rate, and blood pressure. Using a within-subjects crossover design, 37 clinically anxious participants with high levels of anxiety sensitivity and 20 non-anxious comparison participants were randomly assigned to undergo a 90-min session of either Floatation-REST or an exteroceptive comparison condition that entailed watching a relaxing nature film. Measures of state anxiety and serenity were collected before and after each session, while indices of autonomic activity were measured throughout each session. HRV was calculated using both time-series and frequency domain analyses. Linear mixed-effects modeling revealed a significant main effect of condition such that relative to the film condition, Floatation-REST elicited significant decreases ( p < 0.001) in diastolic blood pressure, systolic blood pressure, breathing rate, and certain metrics of HRV including the standard deviation of the interbeat interval (SDNN), low-frequency HRV, and very low-frequency HRV. Heart rate showed a non-significant trend ( p = 0.073) toward being lower in the float condition, especially toward the beginning of the session. The only metric that showed a significant increase during Floatation-REST was normalized high-frequency HRV ( p < 0.001). The observed physiological changes were consistent across both anxious and non-anxious participants, and there were no significant group by condition interactions. Blood pressure was the only cardiac metric significantly associated with float-related reductions in state anxiety and increases in serenity. These findings suggest that Floatation-REST lowers sympathetic arousal and alters the balance of the autonomic nervous system toward a more parasympathetic state., Clinical Trial Registration: [https://clinicaltrials.gov/show/NCT03051074], identifier [NCT03051074]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Flux, Fine, Poplin, Al Zoubi, Schoenhals, Schettler, Refai, Naegele, Wohlrab, Yeh, Lowry, Levine, Smith, Khalsa and Feinstein.)

Repetitive negative thinking (RNT) is a transdiagnostic symptom associated with poor outcomes in major depressive disorder (MDD). MDD is characterized by altered interoception, which has also been associated with poor outcomes. The present study investigated whether RNT is directly associated with altered interoceptive processing. Interoceptive awareness toward the heart and stomach was probed on the Visceral Interoceptive Attention (VIA) task with fMRI in MDD individuals who were propensity-matched on the severity of depression and anxiety symptoms and relevant demographics but different in RNT intensity (High RNT [H-RNT, n = 48] & Low RNT [L-RNT, n = 49]), and in matched healthy volunteers (HC, n = 27). Both H-RNT and L-RNT MDD individuals revealed reduced stomach interoceptive processing compared to HC in the left medial frontal region and insular cortex (H-RNT: β = -1.04, L-RNT: β = -0.97), perirhinal cortex (H-RNT: β = -0.99, L-RNT: β = -1.03), and caudate nucleus (H-RNT: β = -1.06, L-RNT: β = -0.89). However, H-RNT was associated with decreased right medial temporal lobe activity including the hippocampus and amygdala during stomach interoceptive trials (β = -0.61) compared to L-RNT. Insular interoceptive processing was similar in H-RNT and L-RNT participants (β = -0.07, p = 0.92). MDD individuals with high RNT exhibited altered gastric interoceptive responses in brain areas that are important for associating the information with specific contexts and emotions. Attenuated interoceptive processing may contribute to RNT generation, non-adaptive information processing, action selection, and thus poor treatment outcome., Competing Interests: Declaration of competing interest Dr. Paulus is an advisor to Spring Care, Inc., a behavioral health startup, and he has received royalties for an article about methamphetamine in UpToDate. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data., Methods: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251)., Results: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients., Conclusions: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated with gray matter volume in depression. This study examined whether the inflammatory mediator, C-reactive protein (CRP) and the putative neuroprotective index, KynA/QA, were associated with white matter integrity in MDD, and secondly, whether any such associations were independent of each other or whether the effect of CRP was mediated by KynA/QA. One hundred and sixty-six participants in the Tulsa 1000 study with a DSM-V diagnosis of MDD completed diffusion tensor imaging and provided a serum sample for the quantification of CRP, KynA, and QA. Correlational tractography was performed using DSI Studio to map the specific white matter pathways that correlated with CRP and KynA/QA. CRP was negatively related to KynA/QA (standardized beta coefficient, SBC = -0.35 with standard error, Std.E = 0.13, p < 0.01) after controlling for nine possible confounders, i.e., age, sex, body mass index (BMI), medication status, lifetime alcohol use, severity of depression, severity of anxiety, length of illness, and smoking status. Higher concentrations of CRP were associated with decreased white matter integrity (fractional anisotropy, FA) of the bilateral cingulum and fornix after controlling for the nine potential confounders (SBC = -0.43, Std.E = 0.13, p = 0.002). Greater serum KynA/QA was associated with increased white matter integrity of the bilateral fornix, bilateral superior thalamic radiations, corpus callosum, and bilateral cingulum bundles after controlling for the same possible confounders (SBC = 0.26, Std.E = 0.09, p = 0.005). The relationship between CRP and FA was not mediated by KynA/QA. Exploratory analyses also showed that KynA/QA but not CRP was associated with self-reported positive affect, attentiveness, and fatigue measured with the PANASX (SBCs = 0.17-0.23). Taken together, these results are consistent with the hypothesis that within a subgroup of MDD patients, a higher level of systemic inflammation alters the balance of KP metabolism but also raise the possibility that CRP and neuroactive KP metabolites represent independent molecular mechanisms underlying white matter alterations in MDD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Lenrispodun is a potent and highly selective inhibitor of phosphodiesterase (PDE) type 1, which is thought to prolong intracellular second messenger signaling within cortical and subcortical dopaminergic brain regions. This is the first study of a PDE1 inhibitor in healthy volunteers using behavioral and neuroimaging approaches to examine its effects on neural targets and to provide a safety and tolerability assessment. The primary objectives were to determine whether lenrispodun induces changes in BOLD fMRI signals in the inferior frontal gyrus (IFG) during the stop signal task, and the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning/extinction task. Using a double-blind, placebo-controlled, within-subjects design, 26 healthy individuals (22 completed all fMRI sessions) received in random order a single oral dose of placebo, lenrispodun 1.0 milligram (mg) or lenrispodun 10.0 mg and completed several tasks in the scanner including the stop signal (n = 24) and fear conditioning/extinction tasks (n = 22). Prespecified region-of-interest analyses for the IFG and dAI were computed using linear mixed models. Lenrispodun induced increases in IFG activity during the stop signal task at 1.0 mg (Cohen's d = 0.63) but not 10.0 mg (Cohen's d = 0.07) vs. placebo. Lenrispodun did not induce changes in dAI activity during fear extinction at either dose. Exploratory outcomes revealed changes in cardiac interoception. Lenrispodun administration was well-tolerated. These results provide evidence that 1.0 mg lenrispodun selectively improved neural inhibitory control without altering fear extinction processing. Future investigations should determine whether lenrispodun improves inhibitory control in target populations such as individuals with attention deficit hyperactivity disorder. Trial registration: ClinicalTrials.gov identifier: NCT03489772., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)