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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.
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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.
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BACKGROUND: Reward processing dysfunction is a core characteristic of major depressive disorder (MDD), yet event-related potential (ERP) research in MDD has predominantly focused on reward receipt as opposed to anticipation. The stimulus-preceding negativity (SPN) ERP reflects anticipatory brain processing. This study examines whether individuals with MDD exhibit deficits during reward anticipation as evidenced by altered SPN amplitude. METHODS: We assessed prefeedback-SPN amplitudes during a monetary incentive delay (MID) task in individuals with MDD (n = 142, 99 with comorbid anxiety disorders [MDD + ANX]) compared to Controls (n = 37). A mixed analysis of variance was performed on prefeedback-SPN amplitude and behavioral measures, with group (MDD, MDD + ANX, Control) as the between-subjects factor, and feedback (gain, loss) and electrode (F3, F4, Fz, C3, C4, Cz, P3, P4, Pz) as within-subjects factors. RESULTS: A group main effect revealed faster reaction times for the Control group than MDD and MDD + ANX groups. A group x feedback interaction indicated that the MDD subgroup had smaller prefeedback-SPN amplitudes than MDD + ANX and Control groups when anticipating gain feedback. Additionally, individuals with current MDD, irrespective of past MDD and comorbid anxiety, exhibited smaller SPN amplitudes than Controls prior to gain feedback. LIMITATIONS: The MID paradigm, designed for functional magnetic resonance imaging (fMRI) data acquisition, lacks optimization for ERP analysis. Moreover, the clinical groups included more females than the Control group. CONCLUSIONS: Reduced resource allocation to reward anticipation may differentiate MDD from MDD + ANX and Control groups. Further investigation of the neural mechanisms of distinct MDD phenotypes is warranted.
Subject(s)
Anticipation, Psychological , Depressive Disorder, Major , Electroencephalography , Evoked Potentials , Reward , Humans , Depressive Disorder, Major/physiopathology , Depressive Disorder, Major/psychology , Depressive Disorder, Major/diagnostic imaging , Female , Male , Adult , Evoked Potentials/physiology , Anticipation, Psychological/physiology , Anxiety Disorders/physiopathology , Anxiety Disorders/psychology , Reaction Time/physiology , Middle Aged , Young Adult , Motivation/physiology , Brain/physiopathology , Brain/diagnostic imagingABSTRACT
Recent Bayesian theories of interoception suggest that perception of bodily states rests upon a precision-weighted integration of afferent signals and prior beliefs. In a previous study, we fit a computational model of perception to behavior on a heartbeat tapping task to test whether aberrant precision-weighting could explain misestimation of cardiac states in psychopathology. We found that, during an interoceptive perturbation designed to amplify afferent signal precision (inspiratory breath-holding), healthy individuals increased the precision-weighting assigned to ascending cardiac signals (relative to resting conditions), while individuals with anxiety, depression, substance use disorders, and/or eating disorders did not. In this pre-registered study, we aimed to replicate and extend our prior findings in a new transdiagnostic patient sample (N = 285) similar to the one in the original study. As expected, patients in this new sample were also unable to adjust beliefs about the precision of cardiac signals - preventing the ability to accurately perceive changes in their cardiac state. Follow-up analyses combining samples from the previous and current study (N = 719) also afforded power to identify group differences between narrower diagnostic categories, and to examine predictive accuracy when logistic regression models were trained on one sample and tested on the other. With this confirmatory evidence in place, future studies should examine the utility of interceptive precision measures in predicting treatment outcomes and test whether these computational mechanisms might represent novel therapeutic targets.
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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.
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BACKGROUND: Inflammatory biomarkers may differentiate clinical disorders, which could lead to more targeted interventions. Analyses within a clinical sample (May et al., 2021) revealed that females with substance use disorders (SUD) exhibited lower C-reactive protein (CRP) and higher interleukin (IL)-8 and -10 concentrations than females without SUD who met criteria for mood/anxiety disorders. We aimed to replicate these findings in a new sample. METHODS: Hypotheses and analyses were preregistered. Treatment-seeking individuals with mood/anxiety disorders and/or SUD (N = 184) completed a blood draw, clinical interview, and questionnaires. Participants were categorized as SUD+ (45F, 43M) and SUD- (78F, 18M). Principal component analysis (PCA) of questionnaire data resulted in two factors reflecting appetitive and aversive emotional states. SUD group and nuisance covariates (PCA factors, age, body mass index [BMI], medication, nicotine [and hormones in females]) predicted biomarker concentrations (CRP, IL-8, and IL-10) in regressions. RESULTS: In females, the omnibus CRP model [F(8, 114) = 8.02, p <.001, R²-adjusted =.32] indicated that SUD+ exhibited lower CRP concentrations than SUD- (ß = -.33, t = -3.09, p =.002, 95% CI [-.54, -.12]) and greater BMI was associated with higher CRP levels (ß =.58, t = 7.17, p <.001, 95% CI [.42,.74]). SUD+ exhibited higher IL-8 levels than SUD- in simple but not omnibus regression models. CONCLUSION: Findings across two samples bolster confidence that females with SUD show attenuated CRP-indexed inflammation. As SUD+ comorbidity was high, replication is warranted with respect to specific SUD classes (i.e., stimulants versus cannabis).
Subject(s)
Biomarkers , C-Reactive Protein , Substance-Related Disorders , Humans , Female , C-Reactive Protein/metabolism , Adult , Substance-Related Disorders/blood , Male , Biomarkers/blood , Middle Aged , Interleukin-8/blood , Interleukin-10/blood , Mood Disorders/blood , Mood Disorders/epidemiology , Anxiety Disorders/blood , Young AdultABSTRACT
Inhibition, an executive function, is critical for achieving goals that require suppressing unwanted behaviours, thoughts, or distractions. One hypothesis of the emotion and goal compatibility theory is that emotions of sadness and fear enhance inhibitory control. Across Experiments 1-4, we tested this hypothesis by inducing a happy, sad, fearful, and neutral emotional state prior to completing an inhibition task that indexed a specific facet of inhibition (oculomotor, resisting interference, behavioural, and cognitive). In Experiment 4, we included an anger induction to examine whether valence or motivational-orientation best-predicted performance. We found support that fear and sadness enhanced inhibition except when inhibition required resisting interference. We argue that sadness and fear enhance inhibitory control aiding the detection and analysis of problems (i.e. sadness) or threats (i.e. fear) within one's environment. In sum, this work highlights the importance of identifying how negative emotions can be beneficial for and interact with specific executive functions influencing down-stream processing including attention, cognition, and memory.
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Physical activity, beneficial for physical and psychological health, may facilitate affective mechanisms of positive emotion and approach-motivation. Greater resting frontal alpha asymmetry (FAA), an index of greater relative left than right frontal cortical activity, is a neural correlate of affective mechanisms possibly associated with active lifestyles. This study sought to amplify limited literature on the relationship between physical (in)activity, FAA, and gender differences. College students (n = 70) self-reported physical activity (Total PA) and sedentary activity (Total Sitting) via the International Physical Activity Questionnaire-Short Form (IPAQ-SF), followed by a resting electroencephalography session to record FAA. A Total PA × gender interaction (ß = 0.462, t = 3.163, p = 0.002) identified a positive relationship between Total PA and FAA in women (ß = 0.434, t = 2.221, p = 0.030) and a negative relationship for men (ß = -0.338, t = -2.300, p = 0.025). Total Sitting was positively linked to FAA (ß = 0.288, t = 2.228, p = 0.029; no gender effect). Results suggest affective mechanisms reflected by FAA (e.g., positive emotion, approach-motivation) are associated with physical activity for women, indicating a possible mechanism of the psychological benefits linked with physically active lifestyles. A positive relationship between sedentary behavior and greater left FAA may also reflect motivated mechanisms of behavior that aid in minimizing energy expenditure, particularly within the context of our highly active sample.
Subject(s)
Exercise , Sedentary Behavior , Humans , Female , Male , Young Adult , Exercise/physiology , Exercise/psychology , Sex Factors , Alpha Rhythm/physiology , Frontal Lobe/physiology , Electroencephalography , Adult , Adolescent , Self ReportABSTRACT
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.
Subject(s)
Depressive Disorder, Major , Extracellular Vesicles , Interoception , MicroRNAs , Female , Humans , Male , Brain/metabolism , Brain/diagnostic imaging , Brain/physiopathology , Case-Control Studies , Depressive Disorder, Major/metabolism , Depressive Disorder, Major/physiopathology , Depressive Disorder, Major/genetics , Extracellular Vesicles/genetics , Extracellular Vesicles/metabolism , Interoception/physiology , Magnetic Resonance Imaging , MicroRNAs/genetics , MicroRNAs/metabolism , Neurons/metabolismABSTRACT
ABSTRACT: Couple-based HIV interventions that increase uptake of two or more effective biomedical HIV prevention methods may be a promising HIV prevention strategy for young Black and Latino heterosexual couples. We conducted in-depth, semi-structured individual interviews with 23 Black and Latino adolescent and young adult heterosexual couples that explored their attitudes toward using combination HIV prevention methods (CHPMs). A qualitative hybrid thematic analysis approach was used to identify key themes. Themes included: (a) attitudes that encouraged uptake-CHPMs increased assurance of safety against HIV/sexually transmitted infections and (b) attitudes that impeded uptake-CHPMs are too much to do and are not appropriate for serious relationships. Although Black and Latino adolescents and young adults may recognize the combined protective benefits of using multiple HIV prevention methods, personal and relational considerations play an instrumental role in uptake of CHPMs.
Subject(s)
Black or African American , HIV Infections , Health Knowledge, Attitudes, Practice , Heterosexuality , Hispanic or Latino , Interviews as Topic , Qualitative Research , Humans , Hispanic or Latino/psychology , Hispanic or Latino/statistics & numerical data , Male , HIV Infections/prevention & control , HIV Infections/ethnology , Heterosexuality/psychology , Female , Adolescent , Young Adult , New York City , Black or African American/psychology , Adult , Sexual Partners/psychology , Condoms/statistics & numerical data , Family Characteristics/ethnology , Sexual Behavior/ethnologyABSTRACT
In the past decade, the Canadian system of postgraduate medical education has been transformed with the implementation of a new approach to competency based medical education called Competence by Design. The Royal College of Physicians and Surgeons of Canada (Royal College) developed an approach to time-variable competency based medical education and adapted that design for medical, surgical, and diagnostic disciplines. New educational standards and entrustable professional activities consistent with this approach were co-created with 67 specialties and subspecialties, and implementation was scaled up across 17 universities and over 1000 postgraduate training programs. Partner engagement, systematic design of workshops to create discipline specific competency-based standards of education, and agile adaptation were all key ingredients for success. This paper describes the strategies applied by the Royal College, lessons learned regarding transformative change in the complex system of postgraduate medical education, and the current status of the Competence by Design initiative. The approach taken and lessons learned by the Royal College may be useful for other educators who are planning a transformation to CBME or any other major educational reform.
Subject(s)
Education, Medical , Surgeons , Humans , Canada , Competency-Based Education , CurriculumABSTRACT
BACKGROUND: Dysregulated ventral striatum function has been proposed as one important process occurring in individuals with substance use disorder. This study investigates the role of altered reward and loss anticipation, which is an important component of impaired decision-making, impulsivity, and vulnerability to relapse in individuals with amphetamine use disorder (AMP). AIMS: To determine whether AMP is associated with blunted striatum, prefrontal cortex, and insula signals during win and loss anticipation. METHODS: Participants with and without AMP (AMP+ n = 46, AMP- n = 90) from the Tulsa 1000 study completed a monetary incentive delay (MID) task during functional magnetic resonance imaging. RESULTS: Group main effects indicated that: (1) AMP+ exhibited lower bilateral caudate/putamen and left nucleus accumbens signal than AMP- across anticipation of wins and losses; and (2) AMP+ showed slower reaction times than AMP- during loss anticipation. Group*condition interactions demonstrated that AMP+ exhibited greater right amygdala signal than AMP- while anticipating large wins, a pattern that reversed when anticipating small losses. Left caudate/putamen attenuations in AMP+ during small loss anticipation were also evident. Groups did not differ in prefrontal or insula signals. CONCLUSIONS: AMP+ individuals have altered neural processing and response patterns during reward and loss anticipation, potentially reflecting impairments in dopamine function, which may influence their decision-making and reactions to different win/loss scenarios. These findings help to explain why AMP+ have difficulty with decision-making and exhibit a heightened focus on immediate rewards or punishments.
Subject(s)
Substance-Related Disorders , Ventral Striatum , Humans , Reward , Motivation , Magnetic Resonance Imaging , Ventral Striatum/diagnostic imaging , AmphetaminesABSTRACT
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.
Subject(s)
Anxiety Disorders , Electroencephalography , Heart Rate , Isoproterenol , Magnetic Resonance Imaging , Humans , Male , Female , Adult , Anxiety Disorders/physiopathology , Heart Rate/drug effects , Heart Rate/physiology , Double-Blind Method , Isoproterenol/pharmacology , Isoproterenol/administration & dosage , Young Adult , Brain/physiopathology , Brain/drug effects , Brain/diagnostic imaging , Evoked Potentials/drug effects , Evoked Potentials/physiology , Interoception/physiology , Interoception/drug effects , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/pharmacologyABSTRACT
A 3-year-old Great Dane presented with a history of chronic vomiting and diarrhoea. Abdominal computed tomography followed by exploratory laparotomy revealed a perforated, segmental partial mesenteric volvulus, affecting an abnormal section of distal jejunum, which was resected. Histopathology and immunohistochemistry results were consistent with jejunal lymphangiosarcoma. This case represents the first report of primary small intestinal lymphangiosarcoma in dogs and the importance of immunohistochemistry for definitive diagnosis.
Subject(s)
Dog Diseases , Intestinal Volvulus , Lymphangiosarcoma , Dogs , Animals , Intestinal Volvulus/veterinary , Intestinal Volvulus/diagnosis , Lymphangiosarcoma/veterinary , Dog Diseases/pathology , Intestine, Small/pathology , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Major depressive disorder (MDD) and generalized anxiety disorder (GAD) contribute significantly to global health burdens. Identifying disease markers for these comorbid disorders can increase understanding of pathogenesis and improve screening and intervention strategies. This study examined the association of physical health factors with MDD and MDD + GAD, across sexes. METHODS: Two samples of participants from the Tulsa-1000 study (exploratory cohort: N = 136; confirmatory cohort: N = 185) completed body composition measurements, eating behavior (Three Factor Eating Questionnaire [TFEQ], Eating Disorder Diagnostic Scale [EDDS]), exercise questionnaires, and a blood draw. Metabolic hormone concentrations (leptin, insulin, and adiponectin) were analyzed from blood samples. Within each cohort, a two-way analysis of variance compared three groups (MDD, MDD + GAD, and healthy controls [HC]), sex, and their interaction on dependent variables. Hedges g was calculated to reflect effect size magnitude. RESULTS: Medium-to-large group main effects across cohorts indicated that compared to HC: (1) MDD (g = 1.71/0.57) and MDD + GAD (g = 0.93/0.69) reported higher TFEQ Disinhibition scores; (2) MDD endorsed higher TFEQ Hunger scores (g = 0.66/0.48); and (3) MDD (g = 1.60/1.30) and MDD + GAD (g = 0.92/1.72) reported greater EDDS scores. Large sex main effects across cohorts indicated that females exhibited higher levels than males for percent body fat (g = 1.07/1.17), leptin (g = 1.27/1.12), and adiponectin (g=0.82/0.88). LIMITATIONS: The power to detect group*sex interactions was limited due to a greater number of females (than males) in the study, and over half of clinical participants were taking medications. CONCLUSIONS: Individuals with MDD and MDD + GAD demonstrate difficulties in regulating eating behaviors, potentially contributing to functional impairment and increased disease burden.
Subject(s)
Depressive Disorder, Major , Male , Female , Humans , Depressive Disorder, Major/epidemiology , Leptin , Adiponectin , Comorbidity , Anxiety Disorders/epidemiology , Anxiety Disorders/diagnosis , Feeding BehaviorABSTRACT
Recent computational theories of interoception suggest that perception of bodily states rests upon an expected reliability- or precision-weighted integration of afferent signals and prior beliefs. The computational psychiatry framework further suggests that aberrant precision-weighting may lead to misestimation of bodily states, potentially hindering effective visceral regulation and promoting psychopathology. In a previous study, we fit a Bayesian computational model of perception to behavior on a heartbeat tapping task to test whether aberrant precision-weighting was associated with misestimation of bodily states. 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 symptoms of anxiety, depression, substance use disorders, and/or eating disorders did not. A second study also replicated the pattern observed in healthy participants. In this pre-registered study, we aimed to replicate our prior findings in a new transdiagnostic patient sample (N=285) similar to the one in the original study. These new results successfully replicated those found in our previous study, indicating that, transdiagnostically, patients were unable to adjust beliefs about the reliability of interoceptive signals - preventing the ability to accurately perceive changes in their bodily state. Follow-up analyses combining samples from the previous and current study (N=719) also afforded the power to identify group differences within narrower diagnostic groups and to examine predictive accuracy when logistic regression models were trained on one sample and tested on the other. Given the increased confidence in the generalizability of these effects, future studies should examine the utility of interceptive precision measures in predicting treatment outcomes or identify whether these computational mechanisms might represent novel therapeutic targets for improving visceral regulation.
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Background: Sensitivity to threat with dysregulation of fear learning is thought to contribute to the development of psychiatric disorders, including anxiety disorders (AD) and major depressive disorder (MDD). However, fewer studies have examined fear learning in MDD than in AD. Nearly half of individuals with MDD have an AD and the comorbid diagnosis has worse outcomes. The current study used propensity matching to examine the hypothesis that AD+MDD shows greater neural correlates of fear learning than MDD, suggesting that the co-occurrence of AD+MDD is exemplified by exaggerated defense related processes. Methods: 195 individuals with MDD (N = 65) or AD+MDD (N=130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Results: MDD and AD+MDD showed significantly different patterns of activation for [CSplus-CSminus] in the medial amygdala (ηp2=0.009), anterior insula (ηp2=0.01), dorsolateral prefrontal cortex (ηp2=0.002), dorsal anterior cingulate cortex (ηp2=0.01), mid-cingulate cortex (ηp2=0.01) and posterior cingulate cortex (ηp2=0.02). These differences were driven by greater activation to the CS+ in late conditioning phases in ADD+MDD relative to MDD. Conclusions: AD+MDD showed a pattern of increased sustained activation in regions identified with fear learning. Effects were consistently driven by the threat condition, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, and self-relevant processing.These findings help to elucidate the fear signaling mechanisms involved in the pathophysiology of comorbid anxiety and depression, thereby highlighting promising treatment targets for this prevalent treatment group.