Shifting qualities of negative affective experience through adolescence: Age-related change and associations with functional outcomes.

Research shows negative affect increases in healthy adolescents, and this normative change is paralleled by increasing risk for the onset of psychopathology. However, research is limited in characterizing qualitative differences in the type of negative affect experienced beyond the positive-negative valence dimension. In the current study, we establish the relationship between different forms of negative affect and functioning outcomes (i.e., different facets of social functioning and life satisfaction), and examine whether these forms of negative affect are differentially prevalent across late childhood and adolescence. Seven-hundred and 70 participants aged 8-17 years completed self-report measures that assessed a wide range of negative affective experiences. A factor analysis on the negative affect items revealed a four-factor solution that characterized the dimensions of affective experience, with factors reflecting general anxiety, anger, evaluative anxiety, and sadness. Generalized additive model approaches revealed general anxiety increased nonlinearly with age and was associated with decreased reports of emotional support, a facet of social functioning. Anger was associated with increased perceived hostility, perceived rejection, and decreased life satisfaction, and remained stable across the age range. Evaluative anxiety was associated with greater loneliness and increased linearly with increasing age. Sadness was associated with all outcome measures and showed nonlinear changes with age, with notable increases in midadolescence. These results show that subsuming these subtypes of negative affect under a singular concept may obscure meaningful relationships between affect, age, and functioning. Exploring diverse forms of negative affect may help refine theories of emotional development and ultimately inform windows of risk for psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Transdiagnostic Symptom Subtypes to Predict Response to Therapeutic Transcranial Magnetic Stimulation in Major Depressive Disorder and Posttraumatic Stress Disorder.

The diagnostic categories in psychiatry often encompass heterogeneous symptom profiles associated with differences in the underlying etiology, pathogenesis and prognosis. Prior work demonstrated that some of this heterogeneity can be quantified though dimensional analysis of the Depression Anxiety Stress Scale (DASS), yielding unique transdiagnostic symptom subtypes. This study investigated whether classifying patients according to these symptom profiles would have prognostic value for the treatment response to therapeutic transcranial magnetic stimulation (TMS) in comorbid major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). A linear discriminant model was constructed using a simulation dataset to classify 35 participants into one of the following six pre-defined symptom profiles: Normative Mood, Tension, Anxious Arousal, Generalized Anxiety, Anhedonia and Melancholia. Clinical outcomes with TMS across MDD and PTSD were assessed. All six symptom profiles were present. After TMS, participants with anxious arousal were less likely to achieve MDD remission compared to other subtypes (FET, odds ratio 0.16, p = 0.034), exhibited poorer PTSD symptom reduction (21% vs. 46%; t (33) = 2.025, p = 0.051) and were less likely to complete TMS (FET, odds ratio 0.066, p = 0.011). These results offer preliminary evidence that classifying individuals according to these transdiagnostic symptom profiles may offer a simple method to inform TMS treatment decisions.

Mapping Neural Circuit Biotypes to Symptoms and Behavioral Dimensions of Depression and Anxiety.

BACKGROUND: Despite tremendous advances in characterizing human neural circuits that govern emotional and cognitive functions impaired in depression and anxiety, we lack a circuit-based taxonomy for depression and anxiety that captures transdiagnostic heterogeneity and informs clinical decision making. METHODS: We developed and tested a novel system for quantifying 6 brain circuits reproducibly and at the individual patient level. We implemented standardized circuit definitions relative to a healthy reference sample and algorithms to generate circuit clinical scores for the overall circuit and its constituent regions. RESULTS: In new data from primary and generalizability samples of depression and anxiety (N = 250), we demonstrated that overall disconnections within task-free salience and default mode circuits map onto symptoms of anxious avoidance, loss of pleasure, threat dysregulation, and negative emotional biases-core characteristics that transcend diagnoses-and poorer daily function. Regional dysfunctions within task-evoked cognitive control and affective circuits may implicate symptoms of cognitive and valence-congruent emotional functions. Circuit dysfunction scores also distinguished response to antidepressant and behavioral intervention treatments in an independent sample (n = 205). CONCLUSIONS: Our findings articulate circuit dimensions that relate to transdiagnostic symptoms across mood and anxiety disorders. Our novel system offers a foundation for deploying standardized circuit assessments across research groups, trials, and clinics to advance more precise classifications and treatment targets for psychiatry.

Greater baseline connectivity of the salience and negative affect circuits are associated with natural improvements in anxiety over time in untreated participants.

BACKGROUND: There is limited research examining the natural trajectories of depression and anxiety, how these trajectories relate to baseline neural circuit function, and how symptom trajectory-circuit relationships are impacted by engagement in lifestyle activities including exercise, hobbies, and social interactions. To address these gaps, we assessed these relations over three months in untreated participants. METHODS: 262 adults (59.5% female, mean age 35) with symptoms of anxiety and depression, untreated with pharmacotherapy or behavioral therapy, completed the DASS-42, WHOQOL, and custom surveys at baseline and follow-up to assess symptoms, psychosocial function, and lifestyle activity engagement. At baseline, participants underwent fMRI under task-free and task-evoked conditions. We quantified six circuits implicated in these symptoms: default mode, salience, negative and positive affect, attention, and cognitive control. RESULTS: From baseline to 3 months, some participants demonstrated a natural improvement in anxiety (24%) and depression (26%) symptoms. Greater baseline salience circuit connectivity (pFDR=0.045), specifically between the left and right insula (pFDR=0.045), and greater negative affect circuit connectivity elicited by sad faces (pFDR=0.030) were associated with anxiety symptom improvement. While engagement in lifestyle activities were not associated with anxiety improvements, engagement in hobbies moderated the association between negative affect circuit connectivity and anxiety symptom improvement (p = 0.048). LIMITATIONS: The observational design limits causal inference. CONCLUSIONS: Our findings highlight the role of the salience and negative affect circuits as potential circuit markers of natural anxiety symptom improvements over time. Future studies that identify biomarkers associated with symptom improvements are critical for the development of personalized treatment targets.

Voluntary pursuit of negatively valenced stimuli from childhood to early adulthood.

Although common sense suggests that we are motivated to pursue positive and avoid negative experiences, previous research shows that people regularly seek out negative experiences. In the current study, we characterized this tendency from childhood to young adulthood. Due to the known increases in risky behavior and sensation seeking in adolescence, we hypothesized that adolescents would show an increased engagement with negatively valenced stimuli compared to children and adults. Participants aged 4-25 (N = 192) completed a behavioral task assessing motivation to engage with negative, positive, and neutral images. On each trial, participants viewed two small images and selected one to view at a larger size for up to 10s. Trials were organized into three valence conditions: negative versus positive images (matched on arousal), negative versus neutral images, and positive versus neutral images. Although participants chose positive images more than neutral or negative images, participants selected negative images frequently, even when given a positive (28% of trials) or neutral (42% of trials) alternative. Contrary to expectations, the tendency to choose negative images was highest in early childhood and decreased linearly with increasing age, and the tendency to choose positive images increased linearly with age. These results provide insight into how motivation to engage with emotional stimuli varies across age. It is possible that the novelty and rarity of negative experiences drives children to pursue these stimuli. Alternatively, children may find negative images less aversive, which would caution against assuming that these stimuli elicit the same motivational states in individuals of all ages.

Transdiagnostic Symptom Clusters and Associations With Brain, Behavior, and Daily Function in Mood, Anxiety, and Trauma Disorders.

Importance: The symptoms that define mood, anxiety, and trauma disorders are highly overlapping across disorders and heterogeneous within disorders. It is unknown whether coherent subtypes exist that span multiple diagnoses and are expressed functionally (in underlying cognition and brain function) and clinically (in daily function). The identification of cohesive subtypes would help disentangle the symptom overlap in our current diagnoses and serve as a tool for tailoring treatment choices. Objective: To propose and demonstrate 1 approach for identifying subtypes within a transdiagnostic sample. Design, Setting, and Participants: This cross-sectional study analyzed data from the Brain Research and Integrative Neuroscience Network Foundation Database that had been collected at the University of Sydney and University of Adelaide between 2006 and 2010 and replicated at Stanford University between 2013 and 2017. The study included 420 individuals with a primary diagnosis of major depressive disorder (n = 100), panic disorder (n = 53), posttraumatic stress disorder (n = 47), or no disorder (healthy control participants) (n = 220). Data were analyzed between October 2016 and October 2017. Main Outcomes and Measures: We followed a data-driven approach to achieve the primary study outcome of identifying transdiagnostic subtypes. First, machine learning with a hierarchical clustering algorithm was implemented to classify participants based on self-reported negative mood, anxiety, and stress symptoms. Second, the robustness and generalizability of the subtypes were tested in an independent sample. Third, we assessed whether symptom subtypes were expressed at behavioral and physiological levels of functioning. Fourth, we evaluated the clinically meaningful differences in functional capacity of the subtypes. Findings were interpreted relative to a complementary diagnostic frame of reference. Results: Four hundred twenty participants with a mean (SD) age of 39.8 (14.1) years were included in the final analysis; 256 (61.0%) were female. We identified 6 distinct subtypes characterized by tension (n=81; 19%), anxious arousal (n=55; 13%), general anxiety (n=38; 9%), anhedonia (n=29; 7%), melancholia (n=37; 9%), and normative mood (n=180; 43%), and these subtypes were replicated in an independent sample. Subtypes were expressed through differences in cognitive control (F5,383 = 5.13, P < .001, ηp2 = 0.063), working memory (F5,401 = 3.29, P = .006, ηp2 = 0.039), electroencephalography-recorded ß power in a resting paradigm (F5,357 = 3.84, P = .002, ηp2 = 0.051), electroencephalography-recorded ß power in an emotional paradigm (F5,365 = 3.56, P = .004, ηp2 = 0.047), social functional capacity (F5,414 = 21.33, P < .001, ηp2 = 0.205), and emotional resilience (F5,376 = 15.10, P < .001, ηp2 = 0.171). Conclusions and Relevance: These findings offer a data-driven framework for identifying robust subtypes that signify specific, coherent, meaningful associations between symptoms, behavior, brain function, and observable real-world function, and that cut across DSM-IV-defined diagnoses of major depressive disorder, panic disorder, and posttraumatic stress disorder.

Dissociating Attention and Eye Movements in a Quantitative Analysis of Attention Allocation.

In a recent paper, we introduced a method and equation for inferring the allocation of attention on a continuous scale. The size of the stimuli, the estimated size of the fovea, and the pattern of results implied that the subjects' responses reflected shifts in covert attention rather than shifts in eye movements. This report describes an experiment that tests this implication. We measured eye movements. The monitor briefly displayed (e.g., 130 ms) two small stimuli (≈1.0° × 1.2°), situated one atop another. When the stimuli were close together, as in the previous study, fixations that supported correct responses at one stimulus also supported correct responses at the other stimulus, as measured over the entire session. Yet, on any particular trial, correct responses were limited to just one stimulus. This pattern suggests that the constraints on responding within a trial were due to limits on cognitive processing, whereas the ability to respond correctly to either stimulus on different trials must have entailed shifts in attention (that were not accompanied by eye movements). In contrast, when the stimuli were far apart, fixations that had a high probability of supporting correct responses at one stimulus had a low probability of supporting correct responses at the other stimulus. Thus, conditions could be arranged so that correct responses depended on eye movements, whereas in the "standard" procedure, correct responses were independent of eye movements. The results dissociate covert and overt attention and support the claim that our procedure measures covert attention.

Introducing a Method for Calculating the Allocation of Attention in a Cognitive "Two-Armed Bandit" Procedure: Probability Matching Gives Way to Maximizing.

We tested whether principles that describe the allocation of overt behavior, as in choice experiments, also describe the allocation of cognition, as in attention experiments. Our procedure is a cognitive version of the "two-armed bandit choice procedure." The two-armed bandit procedure has been of interest to psychologistsand economists because it tends to support patterns of responding that are suboptimal. Each of two alternatives provides rewards according to fixed probabilities. The optimal solution is to choose the alternative with the higher probability of reward on each trial. However, subjects often allocate responses so that the probability of a response approximates its probability of reward. Although it is this result which has attracted most interest, probability matching is not always observed. As a function of monetary incentives, practice, and individual differences, subjects tend to deviate from probability matching toward exclusive preference, as predicted by maximizing. In our version of the two-armed bandit procedure, the monitor briefly displayed two, small adjacent stimuli that predicted correct responses according to fixed probabilities, as in a two-armed bandit procedure. We show that in this setting, a simple linear equation describes the relationship between attention and correct responses, and that the equation's solution is the allocation of attention between the two stimuli. The calculations showed that attention allocation varied as a function of the degree to which the stimuli predicted correct responses. Linear regression revealed a strong correlation (r = 0.99) between the predictiveness of a stimulus and the probability of attending to it. Nevertheless there were deviations from probability matching, and although small, they were systematic and statistically significant. As in choice studies, attention allocation deviated toward maximizing as a function of practice, feedback, and incentives. Our approach also predicts the frequency of correct guesses and the relationship between attention allocation and response latencies. The results were consistent with these two predictions, the assumptions of the equations used to calculate attention allocation, and recent studies which show that predictiveness and reward are important determinants of attention.

Developing a clinical translational neuroscience taxonomy for anxiety and mood disorder: protocol for the baseline-follow up Research domain criteria Anxiety and Depression ("RAD") project.

BACKGROUND: Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria (RDoC) initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression ("RAD") project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are a) to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, b) to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and c) to assess the stability of brain-symptom-behavior-function relationships over time. METHODS AND DESIGN: Here we present the protocol for the "RAD" project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who "walk through the door" of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain-based subgroups over time and to assess whether these subgroups predict real-world functional capacity over time. First enrollment was August 2013, and is ongoing. DISCUSSION: This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02220309 . Registered: August 13, 2014.