Specific Patterns of Endogenous Functional Connectivity Are Associated With Harm Avoidance in Obsessive-Compulsive Disorder.

BACKGROUND: Individuals with obsessive-compulsive disorder (OCD) show persistent avoidance behaviors, often in the absence of actual threat. Quality-of-life costs and heterogeneity support the need for novel brain-behavior intervention targets. Informed by mechanistic and anatomical studies of persistent avoidance in rodents and nonhuman primates, our goal was to test whether connections within a hypothesized persistent avoidance-related network predicted OCD-related harm avoidance (HA), a trait measure of persistent avoidance. We hypothesized that 1) HA, not an OCD diagnosis, would be associated with altered endogenous connectivity in at least one connection in the network; 2) HA-specific findings would be robust to comorbid symptoms; and 3) reliable findings would replicate in a holdout testing subsample. METHODS: Using resting-state functional connectivity magnetic resonance imaging, cross-validated elastic net for feature selection, and Poisson generalized linear models, we tested which connections significantly predicted HA in our training subsample (n = 73; 71.8% female; healthy control group n = 36, OCD group n = 37); robustness to comorbidities; and replicability in a testing subsample (n = 30; 56.7% female; healthy control group n = 15, OCD group n = 15). RESULTS: Stronger inverse connectivity between the right dorsal anterior cingulate cortex and right basolateral amygdala and stronger positive connectivity between the right ventral anterior insula and left ventral striatum were associated with greater HA across groups. Network connections did not discriminate OCD diagnostic status or predict HA-correlated traits, suggesting sensitivity to trait HA. The dorsal anterior cingulate cortex-basolateral amygdala relationship was robust to controlling for comorbidities and medication in individuals with OCD and was also predictive of HA in our testing subsample. CONCLUSIONS: Stronger inverse dorsal anterior cingulate cortex-basolateral amygdala connectivity was robustly and reliably associated with HA across groups and in OCD. Results support the relevance of a cross-species persistent avoidance-related network to OCD, with implications for precision-based approaches and treatment.

Validation of a novel method of ultraviolet-induced cutaneous inflammation and its associations with anhedonia.

Affective immunology of the skin is a growing area; however, established protocols for measuring individual differences in cutaneous inflammation are lacking. To address this, we present a preliminary validation of Precision Implementation of Minimal Erythema Dose (PI-MED) testing as a method for measuring cutaneous inflammation. PI-MED is a recently adapted protocol, optimized for reproducibility and individual differences research, that uses ultraviolet (UV) light to evoke cutaneous erythema, or inflammatory skin reddening. PI-MED's novel UV dosage schedule produces standardized erythema responses across different skin pigmentation types and shows strong internal consistency within person and good test-retest reliability across 8-10 weeks. In line with predictions, increased PI-MED erythema was associated with heightened anhedonia, across several measures, beyond influences of non-affective covariates. While future work should further refine the dosage schedule for the lightest and darkest skin types, overall, evidence supports PI-MED as a protocol for inducing and measuring individual differences in cutaneous inflammation. Further, PI-MED-induced erythema can expand psychoneuroimmunology research by offering a complementary assessment for general inflammatory tone. This work adds to a growing body of evidence demonstrating a distinct relationship between inflammation and anhedonia.

Subjective arousal and perceived control clarify heterogeneity in inflammatory and affective outcomes.

Only a portion of individuals experiencing chronic stress and associated increases in inflammation go on to develop pathological elevations in mood and anxiety symptoms. Some prevailing models suggest that the outcomes of chronic stress may largely depend on individual differences in perceived control. In the current study, we used this theoretical framework to disambiguate the influence of autonomic arousal and perceived control on inflammatory and psychological outcomes in a large sample of adults from the Midlife in the United States dataset (wave 2; MIDUS-2) (Final N â€‹= â€‹1030), and further replicated our approach in a second (MIDUS-Refresher) cohort (Final N â€‹= â€‹728). Using k-means clustering we created subgroups systematically differing in subjective arousal (high/low) and perceived control (low/high) and compared these subgroups on inflammatory markers and psychological outcomes. Overall results showed that individuals in the high subjective arousal subgroups had higher levels of IL-6, CRP, and FIB, independent of level of CNTL. However, distinctive, and pathological psychological symptom patterns became more apparent when individuals were characterized by both subjective arousal and perceived control. These findings suggest that subtyping individuals based on subjective arousal and perceived control can help us disentangle pathological versus adaptive mental health outcomes in those with co-occurring inflammation and may help identify those vulnerable to psychopathology in the context of physical or psychological stressor exposure.

Reward Circuitry and Motivational Deficits in Social Anxiety Disorder: What Can Be Learned From Mouse Models?

Social anxiety disorder (SAD) is a common and serious psychiatric condition that typically emerges during adolescence and persists into adulthood if left untreated. Prevailing interventions focus on modulating threat and arousal systems but produce only modest rates of remission. This gap in efficacy suggests that most mainstream treatment concepts do not sufficiently target core processes involved in the onset and maintenance of SAD. This idea has further driven the development of new theoretical models that target dopamine (DA)-driven reward circuitry and motivational deficits that appear to be systematically altered in SAD. Most of the available data linking systemic alterations in DA neurobiology to SAD in humans, although abundant, remains at the level of correlational evidence. Accordingly, the purpose of this brief review is to critically evaluate the relevance of experimental work in rodent models that link details of DA function to symptoms of social anxiety. We conclude that, despite certain systematic limitations inherent in animal models, these approaches provide useful insights into human biomarkers of social anxiety including that (1) adolescence may serve as a critical period for the convergence of neurobiological and environmental factors that modify future expectations about social reward through experience dependent changes in DA-ergic circuitry, (2) females may show unique susceptibility to social anxiety symptoms when encountering relational instability that influences DA-related neural processes, and (3) separate from fear and arousal systems, the functional neurobiology of central DA systems contribute uniquely to susceptibility and maintenance of anhedonic factors relevant to human models of SAD.

A functional connectivity-based neuromarker of sustained attention generalizes to predict recall in a reading task.

Sustaining attention to the task at hand is a crucial part of everyday life, from following a lecture at school to maintaining focus while driving. Lapses in sustained attention are frequent and often problematic, with conditions such as attention deficit hyperactivity disorder affecting millions of people worldwide. Recent work has had some success in finding signatures of sustained attention in whole-brain functional connectivity (FC) measures during basic tasks, but since FC can be dynamic and task-dependent, it remains unclear how fully these signatures would generalize to a more complex and naturalistic scenario. To this end, we used a previously defined whole-brain FC network - a marker of attention that was derived from a sustained attention task - to predict the ability of participants to recall material during a free-viewing reading task. Though the predictive network was trained on a different task and set of participants, the strength of FC in the sustained attention network predicted reading recall significantly better than permutation tests where behavior was scrambled to simulate chance performance. To test the generalization of the method used to derive the sustained attention network, we applied the same method to our reading task data to find a new FC network whose strength specifically predicts reading recall. Even though the sustained attention network provided significant prediction of recall, the reading network was more predictive of recall accuracy. The new reading network's spatial distribution indicates that reading recall is highest when temporal pole regions have higher FC with left occipital regions and lower FC with bilateral supramarginal gyrus. Right cerebellar to right frontal connectivity is also indicative of poor reading recall. We examine these and other differences between the two predictive FC networks, providing new insight into the task-dependent nature of FC-based performance metrics.

Alexithymia as a Transdiagnostic Precursor to Empathy Abnormalities: The Functional Role of the Insula.

Distorted empathic processing has been observed across multiple psychiatric disorders. Simulation theory provides a theoretical framework that proposes a mechanism through which empathy difficulties may arise. Specifically, introspection-centric simulation theory (IST) predicts that an inability to accurately interpret and describe internal affective states may lead to empathy difficulties. The purpose of this review is to synthesize and summarize an empirical literature suggesting that simulation theory provides insights into a cognitive and neurobiological mechanism (i.e., alexithymia and insula pathology) that negatively impacts empathic processing, in addition to how disruptions in these processes manifest across psychiatric disorders. Specifically, we review an emerging non-clinical literature suggesting that consistent with IST, alexithymia and associated insula pathology leads to empathy deficits. Subsequently, we highlight clinical research suggesting that a large number of disorders characterized by empathy pathology also feature alexithymia. Collectively, these findings motivate the importance for future work to establish the role of alexithymia in contributing to empathy deficits across clinical symptoms and disorders. The current review suggests that simulation theory provides a tractable conceptual platform for identifying a potential common cognitive and neural marker that is associated with empathy deficits across a wide array of diagnostic classes.

Spatiotemporal dissociation of brain activity underlying threat and reward in social anxiety disorder.

Social anxiety disorder (SAD) involves abnormalities in social motivation, which may be independent of well-documented differences in fear and arousal systems. Yet, the neurobiology underlying motivational difficulties in SAD is not well understood. The aim of the current study was to spatiotemporally dissociate reward circuitry dysfunction from alterations in fear and arousal-related neural activity during anticipation and notification of social and non-social reward and punishment. During fMRI acquisition, non-depressed adults with social anxiety disorder (SAD; N = 21) and age-, sex- and IQ-matched control subjects (N = 22) completed eight runs of an incentive delay task, alternating between social and monetary outcomes and interleaved in alternating order between gain and loss outcomes. Adults with SAD demonstrated significantly reduced neural activity in ventral striatum during the anticipation of positive but not negative social outcomes. No differences between the SAD and control groups were observed during anticipation of monetary gain or loss outcomes or during anticipation of negative social images. However, consistent with previous work, the SAD group demonstrated amygdala hyper-activity upon notification of negative social outcomes. Degraded anticipatory processing in bilateral ventral striatum in SAD was constrained exclusively to anticipation of positive social information and dissociable from the effects of negative social outcomes previously observed in the amygdala. Alterations in anticipation-related neural signals may represent a promising target for treatment that is not addressed by available evidence-based interventions, which focus primarily on fear extinction and habituation processes.

Attentional control mediates fearful responding to an ecologically valid stressor.

BACKGROUND AND OBJECTIVES: Attentional control (AC) is defined as the ability to voluntarily shift and disengage attention and is thought to moderate the relationship between preexisting risk factors for fear and the actual experience of fear. DESIGN: This longitudinal study elaborates on current models of AC by examining whether AC moderates or mediates effects of an ecologically valid stressor (a college examination) and also whether AC is predictive of state-like fear over longer timescales than previously reported. METHODS: Based on previous findings, we hypothesized that AC would moderate the relationship between trait anxiety and affective distress in response to the examination stressor. We also tested a competing mediational model based on AC theory. These models were tested in two separate samples (sample 1, N = 219; sample 2, N = 129; Total N = 348) at two time points, at the beginning of a college semester in a large undergraduate class and 5 minutes prior to a college examination. RESULTS: Mediation but not moderation of anxiety by AC was supported in both samples using multiple dependent measures. CONCLUSIONS: We conclude that AC may be useful in predicting affective distress in naturalistic settings, particularly in cases where anxiety is anticipatory.