Examining Brain Activity Responses during Rat Ultrasonic Vocalization Playback: Insights from a Novel fMRI Translational Paradigm.

Despite decades of preclinical investigation, there remains limited understanding of the etiology and biological underpinnings of anxiety disorders. Sensitivity to potential threat is characteristic of anxiety-like behavior in humans and rodents, but traditional rodent behavioral tasks aimed to assess threat responsiveness lack translational value, especially with regard to emotionally valenced stimuli. Therefore, development of novel preclinical approaches to serve as analogues to patient assessments is needed. In humans, the fearful face task is widely used to test responsiveness to socially communicated threat signals. In rats, ultrasonic vocalizations (USVs) are analogous social cues associated with positive or negative affective states that can elicit behavioral changes in the receiver. It is therefore likely that when rats hear aversive alarm call USVs (22 kHz), they evoke translatable changes in brain activity comparable with the fearful face task. We used functional magnetic resonance imaging in male and female rats to assess changes in BOLD activity induced by exposure to aversive 22 kHz alarm calls emitted in response to threatening stimuli, prosocial (55 kHz) USVs emitted in response to appetitive stimuli, or a computer-generated 22 kHz tone. Results show patterns of regional activation that are specific to each USV stimulus. Notably, limbic regions clinically relevant to psychiatric disorders (e.g., amygdala, bed nucleus of the stria terminalis) are preferentially activated by either aversive 22 kHz or appetitive 55 kHz USVs. These results support the use of USV playback as a promising translational tool to investigate affective processing under conditions of distal threat in preclinical rat models.

TRPC4/5 inhibitors: Phase I results and proof of concept studies.

Transient receptor potential canonical (TRPC) ion channels are expressed in areas of the brain responsible for processing emotion and mood and have been implicated in the pathophysiology of internalizing disorders such as major depressive disorder and anxiety disorders. This review outlines the rationale for targeting TRPC ion channels for drug development, with specific focus on TRPC4 and TRPC5. We provide preclinical evidence that the lack of TRPC4 and TRPC5 channels or its pharmacological inhibition attenuate fear and anxiety without impairing other behaviors in mice. We also report on clinical studies of BI 1358894, a small molecule inhibitor of TRPC4/5 ion channels, demonstrating reduced psychological and physiological responses to induced anxiety/panic-like symptoms in healthy volunteers. Furthermore, we highlight an imaging study that investigated the acute effects of BI 1358894 and showed reduced activation in several brain regions involved in emotional processing. We conclude that these findings demonstrate a critical role for TRPC4 and TRPC5 in emotional processing, even though it remains an open question if the biological signatures of TRPC4/5 inhibition reported here translate into clinical efficacy and indicate that a TRPC4/5 inhibitor might provide a more effective treatment of internalizing disorders.

Mood and anxiety disorders within the Research Domain Criteria framework of Positive and Negative Valence Systems: a scoping review.

Introduction: While a growing body of research is adopting Research Domain Criteria (RDoC)-related methods and constructs, there is still a lack of comprehensive reviews on the state of published research on Positive Valence Systems (PVS) and Negative Valence Systems (NVS) in mood and anxiety disorders consistent with the RDoC framework. Methods: Five electronic databases were searched to identify peer-reviewed publications covering research on "positive valence" and "negative valence" as well as "valence," "affect," and "emotion" for individuals with symptoms of mood and anxiety disorders. Data was extracted with a focus on disorder, domain, (sub-) constructs, units of analysis, key results, and study design. Findings are presented along four sections, distinguishing between primary articles and reviews each for PVS, NVS, and cross-domain PVS and NVS. Results: A total of 231 abstracts were identified, and 43 met the inclusion criteria for this scoping review. Seventeen publications addressed research on PVS, seventeen on NVS, and nine covered cross-domain research on PVS and NVS. Psychological constructs were typically examined across different units of analysis, with the majority of publications incorporating two or more measures. Molecular, genetic, and physiological aspects were mainly investigated via review articles, primary articles focused on self-report, behavioral, and, to a lesser extent, physiological measures. Conclusions: This present scoping review shows that mood and anxiety disorders were actively studied using a range of genetic, molecular, neuronal, physiological, behavioral, and self-report measures within the RDoC PVS and NVS. Results highlight the essential role of specific cortical frontal brain structures and of subcortical limbic structures in impaired emotional processing in mood and anxiety disorders. Findings also indicate overall limited research on NVS in bipolar disorders and PVS in anxiety disorders, a majority of self-report studies, and predominantly observational studies. Future research is needed to develop more RDoC-consistent advancements and intervention studies targeting neuroscience-driven PVS and NVS constructs.

An Examination of the RDoC Negative Valence Systems Domain Constructs and the Self-Reports Unit of Analysis.

In response to shortcomings with the current diagnostic classification system for mental health disorders, such as poor validity and reliability of categorical diagnoses, the National Institute of Mental Health proposed the Research Domain Criteria (RDoC) initiative to move towards a dimensional approach using translational research. The current study examined associations between measures of behaviors, cognitions, and mental health symptoms and how they overlap in the Negative Valence Systems (NVS) domain. Specifically, we examined how the Self-Reports unit of analysis reflects the RDoC NVS constructs of acute threat, potential threat, sustained threat, frustrative nonreward, and loss. The overall goal was to identify additional self-report measures that reflect these constructs. Participants, two student samples and two community samples (total N = 1,509), completed online self-reported measures. Questionnaire total and subscale scores were submitted to a principal-axis factor analysis with Promax rotation separately for each sample. For both student samples and one community sample six-factor solutions emerged reflecting major aspects of the RDoC NVS and positive valence systems, particularly acute threat (i.e., fear/panic), potential threat (i.e., inhibition/worry), sustained threat (i.e., chronic stress), loss (i.e., low well-being), frustrative nonreward (i.e., reactive aggression), and reduced behavioral activation. The second community sample differed in that fear/panic and frustration/anger was combined in a general distress factor. Recommendations for additional NVS self-report markers are discussed.

Sex-Specific Neural Networks of Cued Threat Conditioning: A Pilot Study.

Cued threat conditioning is the most common preclinical model for emotional memory, which is dysregulated in anxiety disorders and post-traumatic stress disorder. Though women are twice as likely as men to develop these disorders, current knowledge of threat conditioning networks was established by studies that excluded female subjects. For unbiased investigation of sex differences in these networks, we quantified the neural activity marker c-fos across 112 brain regions in adult male and female mice after cued threat conditioning compared to naïve controls. We found that trained females engaged prelimbic cortex, lateral amygdala, cortical amygdala, dorsal peduncular cortex, and subparafasicular nucleus more than, and subparaventricular zone less than, trained males. To explore how these sex differences in regional activity impact the global network, we generated interregional cross-correlations of c-fos expression to identify regions that were co-active during conditioning and performed hub analyses to identify regional control centers within each neural network. These exploratory graph theory-derived analyses revealed sex differences in the functional coordination of the threat conditioning network as well as distinct hub regions between trained males and females. Hub identification across multiple networks constructed by sequentially pruning the least reliable connections revealed globus pallidus and ventral lateral septum as the most robust hubs for trained males and females, respectively. While low sample size and lack of non-associative controls are major limitations, these findings provide preliminary evidence of sex differences in the individual circuit components and broader global networks of threat conditioning that may confer female vulnerability to fear-based psychiatric disease.

Resting state functional connectivity subtypes predict discrete patterns of cognitive-affective functioning across levels of analysis among patients with treatment-resistant depression.

Resting state functional connectivity (RSFC) in ventral affective (VAN), default mode (DMN) and cognitive control (CCN) networks may partially underlie heterogeneity in depression. The current study used data-driven parsing of RSFC to identify subgroups of patients with treatment-resistant depression (TRD; n = 70) and determine if subgroups generalized to transdiagnostic measures of cognitive-affective functioning relevant to depression (indexed across self-report, behavioral, and molecular levels of analysis). RSFC paths within key networks were characterized using Subgroup-Group Iterative Multiple Model Estimation. Three connectivity-based subgroups emerged: Subgroup A, the largest subset and containing the fewest pathways; Subgroup B, containing unique bidirectional VAN/DMN negative feedback; and Subgroup C, containing the most pathways. Compared to other subgroups, subgroup B was characterized by lower self-reported positive affect and subgroup C by higher self-reported positive affect, greater variability in induced positive affect, worse response inhibition, and reduced striatal tissue iron concentration. RSFC-based categorization revealed three TRD subtypes associated with discrete aberrations in transdiagnostic cognitive-affective functioning that were largely unified across levels of analysis and were maintained after accounting for the variability captured by a disorder-specific measure of depressive symptoms. Findings advance understanding of transdiagnostic brain-behavior heterogeneity in TRD and may inform novel treatment targets for this population.

Fear and Coping in Students during the Early Stages of the COVID-19 Pandemic: A Combined Cross-Sectional and Longitudinal Study.

The overwhelming impacts of the COVID-19 pandemic have been experienced by individuals across the world. Additional circumstances unique to students affected their studies during the early stages of the pandemic, with changes in living and studying mid-semester. The current study aimed to investigate predictors of fear of COVID-19 in college students during this acute phase using cross-sectional and longitudinal samples. In total, 175 undergraduate students completed an online questionnaire in the spring 2020 semester following lockdown. A subset of 58 students completed a separate survey in fall 2019, which served as a baseline. For the cross-sectional sample, pre-COVID-19 and current living situations did not predict COVID-19 fears. However, a propensity to experience panic was significantly associated with greater COVID-19 fears. How students coped with the pandemic was not associated with COVID-19 fears, although a greater propensity to use denial as a coping style tended to be related to greater COVID-19 fears. In the longitudinal subsample, students showed decreased positive mood and social stress load while depressive mood increased after lockdown. Their preferred coping styles changed, utilizing more self-distraction and acceptance, and less self-blame and substance use. Findings reflect both positive and negative consequences of the pandemic. The unique changes in students' lifestyles will need to be met by tailored interventions.

The NIMH Research Domain Criteria (RDoC) Initiative and Its Implications for Research on Personality Disorder.

PURPOSE OF REVIEW: We discuss the implications of the Research Domain Criteria (RDoC) initiative for neuroscience research on personality disorder (PD). To organize our review, we construct a preliminary conceptual mapping of PD symptom criteria onto RDoC constructs. We then highlight recent neuroscience research, often built around concepts that correspond to RDoC elements, and discuss the findings in reference to the constructs we consider most pertinent to PD. RECENT FINDINGS: PD symptoms were strongly conceptually tied to RDoC constructs within the Social Processes domain, implicating brain systems involved in interpersonal rejection, facial emotion perception, and self-referential processes. Negative and Positive Valence Systems were conceptually associated with many PD symptoms, with particular relevance ascribed to the latter's Reward Valuation construct, which could reflect a more widespread disruption of computational processes involved in estimating the probability and benefits of a future outcome. Within the Cognitive Systems domain, the Cognitive Control construct mainly related to PD symptoms associated with impulse control, suggesting a connection to neural circuits that underlie goal selection and behavioral control. Arousal and Regulatory Systems could only be conceptually mapped onto PD symptoms through the Arousal construct, with different symptoms reflecting either a higher or lower biological sensitivity to internal and external stimuli. The RDoC framework has promise to advance neuroscience research on PD. The Social Processes domain is especially relevant to PD, although constructs falling within the other RDoC domains could also yield important insights into the neurobiology of PD and its connections with other forms of psychopathology. Identifying RDoC constructs (e.g., habit formation) that subserve more fundamental processes relevant to personality functioning warrants further investigation.

Neighborhood affluence is not associated with positive and negative valence processing in adults with mood and anxiety disorders: A Bayesian inference approach.

Survey-based studies show that neighborhood disadvantage is associated with community reported mental health problems. However, fewer studies have examined whether neighborhood characteristics have measurable impact on mental health status of individuals in general and whether neighborhood characteristics impact positive/negative valence processing at both behavioral and brain levels. This study addressed these questions by investigating effects of census-based neighborhood affluence on self-reported symptoms, brain functions, and structures associated with positive/negative valence processing in a sample of individuals with mood and anxiety disorders (n = 262). Employing a Bayesian inference approach, our investigation demonstrates that neighborhood affluence fails to be associated with positive/negative valence processing measured across multiple modalities, with the only effects of neighborhood affluence identified in trait anxiety scores. These findings highlight that while community-based relationships between neighborhood characteristics and mental health problems are strong, it is much less clear that these characteristics have a measurable impact on the individual.

GABA neurons of the ventral periaqueductal gray area modulate behaviors associated with anxiety and conditioned fear.

Emotional behavioral responses related to anxiety and fear comprise the negative valence systems domain as defined by the Research Domain Criteria (RDoC) approach to categorizing related emotional behavioral constructs that are compromised in mental health disorders. Here, we evaluate the role of GABA neurons of the ventral periaqueductal gray (vPAG) in emotional behavioral responses related to anxiety and fear using a chemogenetic approach in Vgat-ires-Cre mice. Functional inhibition of vPAG GABA neurons using selective expression of inhibitory Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADDs) enhanced anxiety-like behavior in the light-dark exploration and open-field tests. Functional inhibition of vPAG GABA neurons during the acquisition of conditioned fear impaired later performance of conditioned fear responses to the fear-associated context. No effects on spontaneous freezing behavior, fear generalization, or conditioned fear responses to the fear-associated cue were observed. Together, these data suggest that activity of vPAG GABA neurons underlies emotional behavioral responses related to anxiety and conditioned fear. As such, vPAG GABA neurons are a common neurophysiological correlate of the negative valence system and dysregulation of this population may contribute to the etiology of mental health disorders in which the negative valence systems domain is compromised.

Inflammation-induced motivational changes: Perspective gained by evaluating positive and negative valence systems.

Inflammation can profoundly impact motivated behavior, as is the case with inflammation-induced depression. By evaluating objectively measurable basic neurobehavioral processes involved in motivation, recent research indicates that inflammation generally reduces approach motivation and enhances avoidance motivation. Increased effort valuation largely mediates the effects of inflammation on approach motivation. Changes in reward valuation are not uniformly observed in approach motivation. However, inflammation increases the averseness of negative stimuli. Within the context of both approach and avoidance motivation, inflammation appears to enhance the contrast between concurrently presented stimuli. While changes in both approach and avoidance motivation appear to be mediated by midbrain dopaminergic neurotransmission to the ventral striatum, it is unclear if the enhanced contrast is mediated by the same system.

Genetic and Environmental Contributions of Negative Valence Systems to Internalizing Pathways.

The genetic and environmental contributions of negative valence systems (NVS) to internalizing pathways study (also referred to as the Adolescent and Young Adult Twin Study) was designed to examine varying constructs of the NVS as they relate to the development of internalizing disorders from a genetically informed perspective. The goal of this study was to evaluate genetic and environmental contributions to potential psychiatric endophenotypes that contribute to internalizing psychopathology by studying adolescent and young adult twins longitudinally over a 2-year period. This report details the sample characteristics, study design, and methodology of this study. The first wave of data collection (i.e., time 1) is complete; the 2-year follow-up (i.e., time 2) is currently underway. A total of 430 twin pairs (N = 860 individual twins; 166 monozygotic pairs; 57.2% female) and 422 parents or legal guardians participated at time 1. Twin participants completed self-report surveys and participated in experimental paradigms to assess processes within the NVS. Additionally, parents completed surveys to report on themselves and their twin children. Findings from this study will help clarify the genetic and environmental influences of the NVS and their association with internalizing risk. The goal of this line of research is to develop methods for early internalizing disorder risk detection.

Empirically supported psychological treatments and the Research Domain Criteria (RDoC).

BACKGROUND: The Research Domain Criteria (RDoC) has been developed as an alternative approach to studying psychiatric disorders. The RDoC constructs and units of analysis, from genes up through paradigms, are intended to describe a hierarchy of priority measurements. Several of these have been investigated in the context of empirically-supported treatments, as either moderators or mediators of outcome. METHOD: This review considers the available research on the moderating and mediating role of genes, molecules, circuits and physiology in cognitive-behavior therapy (CBT) outcome studies for negative valence system conditions. FINDINGS: Based on the review, research has aspired to identify candidate genes, molecules, circuits and physiological moderators or mediators of treatment, but no definitive tests have been conducted. Instead, several candidate variables have been found that deserve further investigation. LIMITATIONS: The available research is based on diagnoses from the DSM, whereas the RDoC initiative endeavors to determine empirically valid taxonomic signs. CONCLUSIONS: The results of this review are discussed in the joint context of developments in empirically-supported psychological therapy and the specific aims of the RDoC initiative, and conclude with recommendations for future research.

Displacement behaviors in chimpanzees (Pan troglodytes): A neurogenomics investigation of the RDoC Negative Valence Systems domain.

The current study aimed to systematically investigate genetic and neuroanatomical correlates of individual variation in scratching behaviors, a well-validated animal-behavioral indicator of negative emotional states with clear links to the NIMH Research Domain Criteria (RDoC) response to potential harm ("anxiety") construct within the Negative Valence Systems domain. Utilizing data from a sample of 76 captive chimpanzees (Pan troglodytes), we (a) examined the association between scratching and presence or absence of the RS3-containing DupB element in the AVPR1A 5' flanking region, (b) utilized voxel-based morphometry (VBM) to identify gray matter (GM) voxel clusters that differentiated AVPR1A genotype, and (c) conducted a VBM-guided voxel-of-interest analysis to examine the association between GM intensity and scratching. AVPR1A evidenced sexually dimorphic associations with scratching. VBM analyses revealed significant differences in GM by genotype across twelve clusters largely in the frontal cortex. Regions differentiating AVPR1A genotype showed sex-specific associations with scratching. Results suggest that sexually dimorphic associations between AVPR1A and scratching may be explained by genotype-specific neuroanatomical variation. The current study provides an example of the way in which chimpanzee research is uniquely poised for multilevel, systematic investigations of psychopathology-relevant constructs within the context of the RDoC framework.