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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. [ABSTRACT FROM AUTHOR]

Recent neurocomputational theories have hypothesized that abnormalities in prior beliefs and/or the precision-weighting of afferent interoceptive signals may facilitate the transdiagnostic emergence of psychopathology. Specifically, it has been suggested that, in certain psychiatric disorders, interoceptive processing mechanisms either over-weight prior beliefs or under-weight signals from the viscera (or both), leading to a failure to accurately update beliefs about the body. However, this has not been directly tested empirically. To evaluate the potential roles of prior beliefs and interoceptive precision in this context, we fit a Bayesian computational model to behavior in a transdiagnostic patient sample during an interoceptive awareness (heartbeat tapping) task. Modelling revealed that, during an interoceptive perturbation condition (inspiratory breath-holding during heartbeat tapping), healthy individuals (N = 52) assigned greater precision to ascending cardiac signals than individuals with symptoms of anxiety (N = 15), depression (N = 69), co-morbid depression/anxiety (N = 153), substance use disorders (N = 131), and eating disorders (N = 14)–who failed to increase their precision estimates from resting levels. In contrast, we did not find strong evidence for differences in prior beliefs. These results provide the first empirical computational modeling evidence of a selective dysfunction in adaptive interoceptive processing in psychiatric conditions, and lay the groundwork for future studies examining how reduced interoceptive precision influences body regulation and interoceptively-guided decision-making. Author summary: Interoception is the process by which the nervous system senses the internal state of the body. It provides the brain with important information to adaptively guide the regulation of both internal body states and behavior. Interoceptive dysfunction is thought to play a role in multiple psychiatric disorders. Theoretical models propose that the computational mechanisms of interoceptive dysfunction are caused by overly precise prior beliefs about body states ("hyperprecise priors") or underestimates of the reliability of the information carried by ascending signals from the body ("low sensory precision"). Our empirical approach tested for evidence of these mechanisms across several psychiatric disorders, using a computational model of perception during performance of a heartbeat perception task. We found evidence of low sensory precision within individuals with anxiety, depression, eating disorders, and/or substance use disorders, relative to healthy individuals. This difference occurred only during a breath-holding condition designed to enhance heartbeat signals. We did not find strong evidence for hyperprecise priors in the patient groups. The data from this study support the argument for computational mechanisms of interoceptive dysfunction across several psychiatric disorders, and suggest that these conditions may be characterized by an inability to adjust sensory precision when signals from the body change. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Impaired interoceptive awareness (IA), the subjective perception of internal body sensations, has been proposed as a vulnerability or maintaining factor in anorexia nervosa (AN). We examined whether IA of heartbeat and breathing sensations was impaired in AN across a range of arousal levels, and whether it was influenced by meal anticipation and consumption. Method: IA was assessed using randomized, double-blinded, bolus intravenous infusions of isoproterenol, a peripheral beta-adrenergic sympathetic agonist, and saline. Fifteen women with AN and 15 age-, and sex- matched healthy comparisons (HC) were evaluated before and after consumption of a 1,000 Calorie meal. During each infusion participants rated their moment-to-moment intensity of heartbeat and breathing sensations with a dial. To measure IA we evaluated interoceptive detection thresholds, retrospective ratings of palpitation and dyspnea intensity, and interoceptive accuracy via correlations between subjective dial ratings and observed heart rate responses. Results: Contrary to prediction the AN group was more likely to report detection of interoceptive sensations across all conditions, an effect driven by false discriminations at low arousal levels. Concordant with prediction, meal anticipation was associated with intensified interoceptive sensations, particularly dyspnea. There were no differences in interoceptive accuracy. Discussion: This represents the first demonstration of interoceptive prediction errors in AN. Although IA is unimpaired at high arousal levels in AN, prediction signals are abnormal at low arousal levels, especially during meal anticipation. Altered interoceptive prediction signaling during meal anticipation could contribute to phenotypes of high anxiety in AN or alternatively, might be explained by enhanced meal associated anxiety. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:889-897) [ABSTRACT FROM AUTHOR]

We report here, for the first time, two cases demonstrating a synergistic application of bilateral cardiac sympathetic decentralization and multimodal psychiatric treatment for the assessment and management of anxiety following recurrent Implantable Cardioverter Defibrillator (ICD) shocks. In a first case the combination of bilateral cardiac sympathetic decentralization (BCSD), cognitive behavioral psychotherapy and anxiolytic medication was sufficient to attenuate the patient's symptoms and maladaptive behaviors, with a maintained benefit at 1 year. Among the more prominent subjective changes in the post-lesion state we observed a decrease in aversive interoceptive sensations, particularly of the heartbeat. The patient continued to experience cognitive threat appraisals on a frequent basis, although these were no longer incapacitating. In a second case, we report the effect of BCSD on autonomic tone and subjective state. In the post-lesion state we observed attenuated sympathetic responses to the valsalva maneuver, isometric handgrip and mental arithmetic stressor, including decreased systolic and diastolic blood pressure and, decreased skin conductance. Collectively, these preliminary findings suggest that an integrative, multidisciplinary approach to treating anxiety disorders in the setting of ventricular arrhythmias and recurrent ICD shocks can result in sustained improvements in physical, psychological, and functional status. These findings raise the possibility of a potential role for the stellate ganglion in the modulation of emotional experience and afferent transmission of interoceptive information to the central nervous system. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Serum C-Reactive Protein (CRP) was negatively correlated with white matter integrity (fractional anisotropy, FA) in participants with major depressive disorder (MDD). • CRP was inversely associated with FA of the cingulum and fornix. • The ratio of kynurenic acid to quinolinic acid (KynA/QA) in serum was positively correlated with FA in participants with MDD. • KynA/QA was positively associated with FA in the fornix, superior thalamic radiations, corpus callosum, and cingulum bundles. • The effect of KynA/QA was equally driven by KynA and QA so that their ratio provided the greatest sensitivity. 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. [ABSTRACT FROM AUTHOR]

Background: Electroencephalography (EEG) studies suggest that major depressive disorder (MDD) is associated with lower left than right frontal brain activity (asymmetry), a pattern appearing stronger in women than men, and when elicited during emotionally-relevant paradigms versus an uncontrolled resting state. However, it is unclear whether this asymmetry pattern generalizes to the common presentation of MDD with co-occurring anxiety. Moreover, asymmetry may differ for anxiety subtypes, wherein anxious apprehension (AnxApp: worry characteristic of generalized anxiety disorder) appears left-lateralized, but anxious arousal (AnxAro: panic characteristic of social anxiety, posttraumatic stress, and panic disorders) may be right-lateralized.Methods: This analysis attempted to replicate frontal EEG asymmetry patterns using functional magnetic resonance imaging (fMRI). Participants completed clinical interviews and a monetary incentive delay (MID) task during fMRI recording. We compared five groups of right-handed women from the Tulsa 1000 study, MDD (n=40), MDD-AnxApp (n=26), MDD-AnxAro (n=34), MDD-Both (with AnxApp and AnxAro; n=26), and healthy controls (CTL; n=24), as a function of MID anticipation condition (no win/loss, win, loss) and hemisphere on frontal blood oxygen-level-dependent (BOLD) signal.Results: CTL exhibited higher bilateral superior, middle, and inferior middle frontal gyrus BOLD signal than the four MDD groups for high arousal (win and loss) conditions. However, frontal attenuations were unrelated to current depression/anxiety symptoms, suggestive of a trait as opposed to a state marker.Limitations: This was a cross-sectional analysis restricted to women.Conclusions: Reduced prefrontal cortex recruitment during processing of both positively and negatively valenced stimuli is consistent with the emotion context insensitivity theory of MDD. [ABSTRACT FROM AUTHOR]

Unmedicated individuals with major depressive disorder (MDD) show abnormal interoception, but it is unclear whether antidepressant treatment via serotonergic medication alters this relationship. The current cross-sectional study examined associations between neural and behavioral indices of interoceptive processing and chronic serotonergic medication administration in MDD. 47 selective serotonin reuptake inhibitor (SSRI)-medicated MDD (MDD-SSRI) individuals were propensity-matched with 48 unmedicated current MDD (MDD-UnMed) and 41 healthy comparison (HC) participants on demographics including age, sex, body mass index, education, as well as on dimensional scales of symptom severity including depression and anxiety. All participants completed an interoceptive attention task during functional magnetic resonance imaging, and a behavioral heartbeat tapping task under three conditions: Guessing, No Guessing, and Breath Hold. Relative to HC, both MDD groups: (1) exhibited lower mid-insula, amygdala, putamen, and caudate activation during interoceptive versus exteroceptive attention; and (2) showed poorer heartbeat tapping performance during the Breath Hold condition. However, the MDD-SSRI group reported higher intensity ratings of heartbeat and stomach sensations than MDD-UnMed and HC during the interoceptive attention task. These findings suggest that the attenuated patterns of neural activation observed in depressed individuals during interoceptive attention are not ameliorated by the chronic administration of serotonergic medications. However, amplified interoceptive sensation ratings suggest a potential impact of chronic serotonergic medication on conscious experiences of internal body states. Future investigations will need to determine the extent to which serotonergic medications acutely influence interoceptive processing, and whether such changes play a role in therapeutic responses during treatment initiation. • MDD patients exhibited lower self-reported interoceptive awareness than HC. • MDD patients showed lower insula, amygdala, and striatum activation than HC. • Insula activation did not differ between unmedicated and SSRI-medicated MDD. • MDD-SSRI displayed greater interoceptive sensation ratings than MDD-UnMed and HC. [ABSTRACT FROM AUTHOR]