Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

The workplace culture, mental health and wellbeing of early- and mid-career health academics: a cross-sectional analysis.

There are reports of poor working conditions for early and mid-career academics (EMCAs) in universities, however, empirical data using validated tools are scarce. We conducted an online, cross-sectional survey using validated tools to assess workplace satisfaction, exposure to workplace abuse, and mental health. Participants included employees of medical and health faculties of two of the largest Australian universities, surveyed between October 2020 and January 2021.Overall, 284 participants responded. Many reported job insecurity: half (50.7%) working on contracts with less than one remaining year. Workloads were considerable, with 89.5% of participants working overtime and 54.8% reporting burnout. Workplace abuse in the forms of bullying (46.6%), sexual harassment (25.3%), sexism (49.8%) and racism (22.5%) were commonly reported. Clinically significant symptoms of depression (28.0%), anxiety (21.7%) and suicidal ideation or self-harm (13.6%) were reported; with a higher prevalence among those working more overtime, and those exposed to workplace abuse. Priorities include providing a stable and safe workplace, increasing accountability and transparency in addressing workplace abuse, and supporting professional development.In summary, EMCAs in our study were commonly exposed to precarious employment conditions and workplace abuse. Our findings provide empirical evidence on where universities and funding bodies should direct resources and change organisational risk factors, to improve workplace culture.

Altered task-related decoupling of the rostral anterior cingulate cortex in depression.

Dysfunctional activity of the rostral anterior cingulate cortex (rACC) - an extensively connected hub region of the default mode network - has been broadly linked to cognitive and affective impairments in depression. However, the nature of aberrant task-related rACC suppression in depression is incompletely understood. In this study, we sought to characterize functional connectivity of rACC activity suppression ('deactivation') - an essential feature of rACC function - during external task engagement in depression. Specifically, we aimed to explore neural patterns of functional decoupling and coupling with the rACC during its task-driven suppression. We enrolled 81 15- to 25-year-old young people with moderate-to-severe major depressive disorder (MDD) before they commenced a 12-week clinical trial that assessed the effectiveness of cognitive behavioral therapy plus either fluoxetine or placebo. Ninety-four matched healthy controls were also recruited. Participants completed a functional magnetic resonance imaging face matching task known to elicit rACC suppression. To identify brain regions associated with the rACC during its task-driven suppression, we employed a seed-based functional connectivity analysis. We found MDD participants, compared to controls, showed significantly reduced 'decoupling' of the rACC with extended task-specific regions during task performance. Specifically, less decoupling was observed in the occipital and fusiform gyrus, dorsal ACC, medial prefrontal cortex, cuneus, amygdala, thalamus, and hippocampus. Notably, impaired decoupling was apparent in participants who did not remit to treatment, but not treatment remitters. Further, we found MDD participants showed significant increased coupling with the anterior insula cortex during task engagement. Our findings indicate that aberrant task-related rACC suppression is associated with disruptions in adaptive neural communication and dynamic switching between internal and external cognitive modes that may underpin maladaptive cognitions and biased emotional processing in depression.

Body mass, neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.

Overweight and obesity can worsen disease activity in multiple sclerosis (MS). Although psychobiological stress processing is increasingly recognized as important obesity factor that is tightly connected to proinflammatory metabolic hormones and cytokines, its role for MS obesity remains unexplored. Consequently, we investigated the interplay between body mass index (BMI), neural stress processing (functional connectivity, FC), and immuno-hormonal stress parameters (salivary cortisol and T cell glucocorticoid [GC] sensitivity) in 57 people with MS (six obese, 19 over-, 28 normal-, and four underweight; 37 females, 46.4 ± 10.6 years) using an Arterial-Spin-Labeling MRI task comprising a rest and stress stage, along with quantitative PCR. Our findings revealed significant positive connections between BMI and MS disease activity (i.e., higher BMI was accompanied by higher relapse rate). BMI was positively linked to right supramarginal gyrus and anterior insula FC during rest and negatively to right superior parietal lobule and cerebellum FC during stress. BMI showed associations with GC functioning, with higher BMI associated with lower CD8+ FKBP4 expression and higher CD8+ FKBP5 expression on T cells. Finally, the expression of CD8+ FKBP4 positively correlated with the FC of right supramarginal gyrus and left superior parietal lobule during rest. Overall, our study provides evidence that body mass is tied to neuro-hormonal stress processing in people with MS. The observed pattern of associations between BMI, neural networks, and GC functioning suggests partial overlap between neuro-hormonal and neural-body mass networks. Ultimately, the study underscores the clinical importance of understanding multi-system crosstalk in MS obesity.

Spanish Validation of the Long and Short Versions of the Problematic Pornography Consumption Scale (PPCS and PPCS-6) in Adolescents.

Although 1-14% of adolescents may experience problematic pornography use (PPU), psychometrically sound instruments for assessing PPU in Spanish-speaking adolescents are scarce. Given the advantages of the different forms of the Problematic Pornography Consumption Scale (PPCS), the aim of the present study was to assess the psychometric properties of the PPCS and PPCS-6, and to examine associations between PPU and age among boys and girls. Two school-based adolescent samples were recruited in Spain (n = 650; Mage = 16.0 [SD = 1.1]; 50% girls and 50% boys) and Mexico (n1, 160; Mage = 15.8 [SD = 1.1]; 68% girls) to assess the psychometric properties of the PPCS and PPCS-6. Confirmatory factor analysis was applied and convergent and discriminant validity with other measures related to PPU was also tested. The results provided empirical support for the six-factor structure of the PPCS and the one-factor structure of the PPCS-6. Boys with older age showed higher levels of tolerance than girls on the PPCS in both countries. Both the PPCS and the PPCS-6 may be considered valid psychometric instruments for the assessment of PPU in Spanish-speaking adolescents from Spain and Mexico.

Endocrinology-informed neuroimaging in eating disorders: GLP1, orexins, and psilocybin.

The neurobiology of eating disorders [EDs; anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)] remains poorly understood. Here, I describe how neuroimaging, accompanied by peripheral endocrine measures, can provide insights into the neurobiological drivers of eating disorders. Orexins/hypocretins, glucagon-like peptide-1 receptor (GLP1R) agonists, and psilocybin are highlighted as avenues for investigation.

Exploring the influence of circulating endocannabinoids and nucleus accumbens functional connectivity on anorexia nervosa severity.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a harmful persistence of self-imposed starvation resulting in significant weight loss. Research suggests that alterations in the nucleus accumbens (NAcc) and circulating endocannabinoids (eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may contribute to increased severity and maladaptive behaviors in AN, warranting an examination of the interplay between central reward circuitry and eCBs. For this purpose, we assessed NAcc functional connectivity and circulating AEA and 2-AG concentrations in 18 individuals with AN and 18 healthy controls (HC) to test associations between circulating eCBs, NAcc functional connectivity, and AN severity, as defined by body mass index (BMI). Decreased connectivity was observed between the NAcc and the right insula (NAcc-insula; pFWE < 0.001) and the left supplementary motor area (NAcc-SMA; pFWE < 0.001) in the AN group compared to HC. Reduced NAcc-insula functional connectivity mediated the association between AEA concentrations and BMI in the AN group. However, in HC, NAcc-SMA functional connectivity had a mediating role between AEA concentrations and BMI. Although no significant differences in eCBs concentrations were observed between the groups, our findings provide insights into how the interaction between eCBs and NAcc functional connectivity influences AN severity. Altered NAcc-insula and NAcc-SMA connectivity in AN may impair the integration of interoceptive, somatosensory, and motor planning information related to reward stimuli. Furthermore, the distinct associations between eCBs concentrations and NAcc functional connectivity in AN and HC could have clinical implications for weight maintenance, with eCBs being a potential target for AN treatment.

Dynamic fronto-amygdalar interactions underlying emotion-regulation deficits in women at higher weight.

OBJECTIVE: The regulation of negative emotions entails the modulation of subcortical regions, such as the amygdala, by prefrontal regions. There is preliminary evidence suggesting that individuals at higher weight may present with hypoactivity in prefrontal regulatory systems during emotional regulation, although the directionality of these pathways has not been tested. In this study, we compared fronto-amygdalar effective connectivity during cognitive reappraisal as a function of BMI in 48 adult women with obesity and 54 control participants. METHODS: Dynamic causal modeling and parametric empirical Bayes were used to map effective connectivity between the dorsomedial prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and the amygdala. RESULTS: Difficulty in Emotion Regulation Scale scores were higher in the obesity group compared with control participants (p < 0.001). A top-down cortical model best explained our functional magnetic resonance imaging data (posterior probability = 86%). Participants at higher BMI were less effective at inhibiting activity in the amygdala via the orbitofrontal cortex and dorsomedial prefrontal cortex during reappraisal compared with those at lower BMI. In contrast, increased excitatory modulation of dorsolateral prefrontal cortex-to-amygdalar connectivity was found in participants at lower BMI. CONCLUSIONS: These findings support a framework involving alterations in fronto-amygdalar connectivity contributing to difficulties in regulating negative affect in individuals at higher weight.

Frontoamygdalar Effective Connectivity in Youth Depression and Treatment Response.

BACKGROUND: Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo. METHODS: One hundred seven young people with moderate to severe depression and 94 healthy control participants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission. RESULTS: Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p = .003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (-0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r = -0.02, p = .561). CONCLUSIONS: Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depression treatments.

The influence of stress on the neural underpinnings of disinhibited eating: a systematic review and future directions for research.

Disinhibited eating involves overconsumption and loss of control over food intake, and underpins many health conditions, including obesity and binge-eating related disorders. Stress has been implicated in the development and maintenance of disinhibited eating behaviours, but the mechanisms underlying this relationship are unclear. In this systematic review, we examined how the impact of stress on the neurobiological substrates of food-related reward sensitivity, interoception and cognitive control explains its role in disinhibited eating behaviours. We synthesised the findings of functional magnetic resonance imaging studies including acute and/or chronic stress exposures in participants with disinhibited eating. A systematic search of existing literature conducted in alignment with the PRISMA guidelines identified seven studies investigating neural impacts of stress in people with disinhibited eating. Five studies used food-cue reactivity tasks, one study used a social evaluation task, and one used an instrumental learning task to probe reward, interoception and control circuitry. Acute stress was associated with deactivation of regions in the prefrontal cortex implicated in cognitive control and the hippocampus. However, there were mixed findings regarding differences in reward-related circuitry. In the study using a social task, acute stress associated with deactivation of prefrontal cognitive control regions in response to negative social evaluation. In contrast, chronic stress was associated with both deactivation of reward and prefrontal regions when viewing palatable food-cues. Given the small number of identified publications and notable heterogeneity in study designs, we propose several recommendations to strengthen future research in this emerging field.

Differential engagement of the posterior cingulate cortex during cognitive restructuring of negative self- and social beliefs.

Negative self-beliefs are a core feature of psychopathology, encompassing both negative appraisals about oneself directly (i.e. self-judgment) and negative inferences of how the self is appraised by others (i.e. social judgment). Challenging maladaptive self-beliefs via cognitive restructuring is a core treatment mechanism of gold-standard psychotherapies. However, the neural mechanisms underlying the restructuring of these two kinds of negative self-beliefs are poorly understood. Eighty-six healthy participants cognitively restructured self-judgment and social-judgment negative self-belief statements during 7 Tesla functional magnetic resonance imaging scanning. Cognitive restructuring broadly elicited activation in the core default mode network (DMN), salience and frontoparietal control regions. Restructuring self-judgment relative to social-judgment beliefs was associated with comparatively higher activation in the ventral posterior cingulate cortex (PCC)/retrosplenial cortex, while challenging social-judgment statements was associated with higher activation in the dorsal PCC/precuneus. While both regions showed increased functional connectivity with the supplementary and pre-supplementary motor areas during restructuring, the dorsal PCC displayed greater task-dependent connectivity with distributed regions involved in salience, attention and social cognition. Our findings indicate distinct patterns of PCC engagement contingent upon self- and social domains, highlighting a specialized role of the dorsal PCC in supporting neural interactions between the DMN and frontoparietal/salience networks during cognitive restructuring.

Subcortical contributions to salience network functioning during negative emotional processing.

Core regions of the salience network (SN), including the anterior insula (aINS) and dorsal anterior cingulate cortex (dACC), coordinate rapid adaptive changes in attentional and autonomic processes in response to negative emotional events. In doing so, the SN incorporates bottom-up signals from subcortical brain regions, such as the amygdala and periaqueductal gray (PAG). However, the precise influence of these subcortical regions is not well understood. Using ultra-high field 7-Tesla functional magnetic resonance imaging, this study investigated the bottom-up interactions of the amygdala and PAG with the SN during negative emotional salience processing. Thirty-seven healthy participants completed an emotional oddball paradigm designed to elicit a salient negative emotional response via the presentation of random, task-irrelevant negative emotional images. Negative emotional processing was associated with prominent activation in the SN, spanning the amygdala, PAG, aINS, and dACC. Consistent with previous research, analysis using dynamic causal modelling revealed an excitatory influence from the amygdala to the aINS, dACC, and PAG. In contrast, the PAG showed an inhibitory influence on amygdala, aINS and dACC activity. Our findings suggest that the amygdala may amplify the processing of negative emotional stimuli in the SN to enable upstream access to attentional resources. In comparison, the inhibitory influence of the PAG possibly reflects its involvement in modulating sympathetic-parasympathetic autonomic arousal mediated by the SN. This PAG-mediated effect may be driven by amygdala input and facilitate bottom-up processing of negative emotional stimuli. Overall, our results show that the amygdala and PAG modulate divergent functions of the SN during negative emotional processing.

A distinct intra-individual suppression subnetwork in the brain's default mode network across cognitive tasks.

Suppression of the brain's default mode network (DMN) during external goal-directed cognitive tasks has been consistently observed in neuroimaging studies. However, emerging insights suggest the DMN is not a monolithic "task-negative" network but is comprised of subsystems that show functional heterogeneity. Despite considerable research interest, no study has investigated the consistency of DMN activity suppression across multiple cognitive tasks within the same individuals. In this study, 85 healthy 15- to 25-year-olds completed three functional magnetic resonance imaging tasks that were designed to reliably map DMN suppression from a resting baseline. Our findings revealed a distinct suppression subnetwork across the three tasks that comprised traditional DMN and adjacent regions. Specifically, common suppression was observed in the medial prefrontal cortex, the dorsal-to-mid posterior cingulate cortex extending to the precuneus, and the posterior insular cortex and parietal operculum. Further, we found the magnitude of suppression of these regions were significantly correlated within participants across tasks. Overall, our findings indicate that externally oriented cognitive tasks elicit common suppression of a distinct subnetwork of the broader DMN. The consistency to which the DMN is suppressed within individuals suggests a domain-general mechanism that may reflect a stable feature of cognitive function that optimizes external goal-directed behavior.

The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor gene polymorphism has been postulated as a potential sex-specific diagnostic biomarker of trauma-related disorders. However, no research to date has evaluated whether the PACAPergic system may act as a vulnerability/resilience neuromechanism to trauma-induced psychopathology in healthy participants without heightened risk to experience traumatic events. Methods: Here, we compared the amygdala and hippocampus response to fearful faces in participants with at-risk genotype versus non-risk participants from the Human Connectome Project (n = 991; 53.4% female). Results: Increased hippocampal response to fearful faces in the female risk group emerged in sex by genetic risk interaction. Conclusions: Our findings revealed the first sex-specific neurogenetic vulnerability factor to trauma-related disorders, and emphasize the importance of prevention-based strategies to ameliorate neuropsychiatric pathophysiology.

Cortico-Striatal Activity Characterizes Human Safety Learning via Pavlovian Conditioned Inhibition.

Safety learning generates associative links between neutral stimuli and the absence of threat, promoting the inhibition of fear and security-seeking behaviors. Precisely how safety learning is mediated at the level of underlying brain systems, particularly in humans, remains unclear. Here, we integrated a novel Pavlovian conditioned inhibition task with ultra-high field (7 Tesla) fMRI to examine the neural basis of safety learning in 49 healthy participants. In our task, participants were conditioned to two safety signals: a conditioned inhibitor that predicted threat omission when paired with a known threat signal (A+/AX-), and a standard safety signal that generally predicted threat omission (BC-). Both safety signals evoked equivalent autonomic and subjective learning responses but diverged strongly in terms of underlying brain activation (PFDR whole-brain corrected). The conditioned inhibitor was characterized by more prominent activation of the dorsal striatum, anterior insular, and dorsolateral PFC compared with the standard safety signal, whereas the latter evoked greater activation of the ventromedial PFC, posterior cingulate, and hippocampus, among other regions. Further analyses of the conditioned inhibitor indicated that its initial learning was characterized by consistent engagement of dorsal striatal, midbrain, thalamic, premotor, and prefrontal subregions. These findings suggest that safety learning via conditioned inhibition involves a distributed cortico-striatal circuitry, separable from broader cortical regions involved with processing standard safety signals (e.g., CS-). This cortico-striatal system could represent a novel neural substrate of safety learning, underlying the initial generation of "stimulus-safety" associations, distinct from wider cortical correlates of safety processing, which facilitate the behavioral outcomes of learning.SIGNIFICANCE STATEMENT Identifying safety is critical for maintaining adaptive levels of anxiety, but the neural mechanisms of human safety learning remain unclear. Using 7 Tesla fMRI, we compared learning-related brain activity for a conditioned inhibitor, which actively predicted threat omission, and a standard safety signal (CS-), which was passively unpaired with threat. The inhibitor engaged an extended circuitry primarily featuring the dorsal striatum, along with thalamic, midbrain, and premotor/PFC regions. The CS- exclusively involved cortical safety-related regions observed in basic safety conditioning, such as the vmPFC. These findings extend current models to include learning-specific mechanisms for encoding stimulus-safety associations, which might be distinguished from expression-related cortical mechanisms. These insights may suggest novel avenues for targeting dysfunctional safety learning in psychopathology.

Methodological implications of sample size and extinction gradient on the robustness of fear conditioning across different analytic strategies.

Fear conditioning paradigms are critical to understanding anxiety-related disorders, but studies use an inconsistent array of methods to quantify the same underlying learning process. We previously demonstrated that selection of trials from different stages of experimental phases and inconsistent use of average compared to trial-by-trial analysis can deliver significantly divergent outcomes, regardless of whether the data is analysed with extinction as a single effect, as a learning process over the course of the experiment, or in relation to acquisition learning. Since small sample sizes are attributed as sources of poor replicability in psychological science, in this study we aimed to investigate if changes in sample size influences the divergences that occur when different kinds of fear conditioning analyses are used. We analysed a large data set of fear acquisition and extinction learning (N = 379), measured via skin conductance responses (SCRs), which was resampled with replacement to create a wide range of bootstrapped databases (N = 30, N = 60, N = 120, N = 180, N = 240, N = 360, N = 480, N = 600, N = 720, N = 840, N = 960, N = 1080, N = 1200, N = 1500, N = 1750, N = 2000) and tested whether use of different analyses continued to produce deviating outcomes. We found that sample size did not significantly influence the effects of inconsistent analytic strategy when no group-level effect was included but found strategy-dependent effects when group-level effects were simulated. These findings suggest that confounds incurred by inconsistent analyses remain stable in the face of sample size variation, but only under specific circumstances with overall robustness strongly hinging on the relationship between experimental design and choice of analyses. This supports the view that such variations reflect a more fundamental confound in psychological science-the measurement of a single process by multiple methods.

The influence of the subcortex and brain stem on overeating: How advances in functional neuroimaging can be applied to expand neurobiological models to beyond the cortex.

Functional neuroimaging has become a widely used tool in obesity and eating disorder research to explore the alterations in neurobiology that underlie overeating and binge eating behaviors. Current and traditional neurobiological models underscore the importance of impairments in brain systems supporting reward, cognitive control, attention, and emotion regulation as primary drivers for overeating. Due to the technical limitations of standard field strength functional magnetic resonance imaging (fMRI) scanners, human neuroimaging research to date has focused largely on cortical and basal ganglia effects on appetitive behaviors. The present review draws on animal and human research to highlight how neural signaling encoding energy regulation, reward-learning, and habit formation converge on hypothalamic, brainstem, thalamic, and striatal regions to contribute to overeating in humans. We also consider the role of regions such as the mediodorsal thalamus, ventral striatum, lateral hypothalamus and locus coeruleus in supporting habit formation, inhibitory control of food craving, and attentional biases. Through these discussions, we present proposals on how the neurobiology underlying these processes could be examined using functional neuroimaging and highlight how ultra-high field 7-Tesla (7 T) fMRI may be leveraged to elucidate the potential functional alterations in subcortical networks. Focus is given to how interactions of these regions with peripheral endocannabinoids and neuropeptides, such as orexin, could be explored. Technical and methodological aspects regarding the use of ultra-high field 7 T fMRI to study eating behaviors are also reviewed.

Modulation of the brain's core-self network by self-appraisal processes.

The 'core' regions of the default mode network (DMN) - the medial prefrontal cortex (MPFC), the posterior cingulate cortex (PCC), and inferior parietal lobules (IPL) - show consistent engagement across mental states that involve self-oriented processing. Precisely how these regions interact in support of such processes remains an important unanswered question. In the current functional magnetic resonance imaging (fMRI) study, we examined dynamic interactions of the 'core-self' DMN regions during two forms of self-referential cognition: direct self-appraisal (thinking about oneself) and reflected self-appraisal (thinking about oneself from a third-person perspective). One-hundred and eleven participants completed our dual self-appraisal task during fMRI, and general linear models were used to characterize common and distinct neural responses to these conditions. Informed by these results, we then applied dynamic causal modelling to examine causal interactions among the 'core-self' regions, and how they were specifically modulated under the influence of direct and reflected self-appraisal. As a primary observation, this network modelling revealed a distinct inhibitory influence of the left IPL on the PCC during reflected compared to direct self-appraisal, which was accompanied by evidence of greater activation in both regions during the reflected self-appraisal condition. We suggest that the greater engagement of posterior DMN regions during reflected self-appraisal is a function of the higher-order processing needed for this form of self-appraisal, with the left IPL supporting abstract self-related processes including episodic memory retrieval and shifts of perspective. Overall, we show that core DMN regions interact in functionally unique ways in support of self-referential processes, even when these processes are inter-related. Further characterization of DMN functional interactions across self-related mental states is likely to inform a deeper understanding of how this brain network orchestrates the self.