How distributed subcortical integration of reward and threat may inform subsequent approach-avoidance decisions.

Healthy and successful living involves carefully navigating rewarding and threatening situations by balancing approach and avoidance behaviours. Excessive avoidance to evade potential threats often leads to forfeiting potential rewards. However, little is known about how reward and threat information is integrated neurally to inform approach or avoidance decisions. In this preregistered study, participants (Nbehaviour=31, 17F; NMRI=28, 15F) made approach-avoidance decisions under varying reward (monetary gains) and threat (electrical stimulations) prospects during functional MRI scanning. In contrast to theorized parallel subcortical processing of reward and threat information before cortical integration, Bayesian Multivariate Multilevel analyses revealed subcortical reward and threat integration prior to indicating approach-avoidance decisions. This integration occurred in the ventral striatum, thalamus, and bed nucleus of the stria terminalis (BNST). When reward was low, risk-diminishing avoidance decisions dominated, which was linked to more positive tracking of threat magnitude prior to indicating avoidance than approach decisions across these regions. In contrast, the amygdala exhibited dual sensitivity to reward and threat. While anticipating outcomes of risky approach decisions, we observed positive tracking of threat magnitude within the salience network (dorsal anterior cingulate cortex, thalamus, periaqueductal gray, BNST). Conversely, after risk-diminishing avoidance, characterized by reduced reward prospects, we observed more negative tracking of reward magnitude in the ventromedial prefrontal cortex and ventral striatum. These findings shed light on the temporal dynamics of approach-avoidance decision-making. Importantly, they demonstrate the role of subcortical integration of reward and threat information in balancing approach and avoidance, challenging theories positing predominantly separate subcortical processing prior to cortical integration.Significance statement When deciding whether to approach or avoid situations, our decision-making involves balancing potential rewards and threats. Widespread theories of decision-making in humans propose parallel processing of reward and threat information in subcortical regions, followed by cortical integration. Challenging these notions, we found evidence for dual and integrated processing of reward and threat in subcortical regions during decision-making. In contrast, after decision-making, we observed the expected parallel processing while anticipating decision outcomes. These findings advance our understanding of approach-avoidance decision-making processes, opposing traditional views that segregate brain regions as predominantly reward-sensitive or threat-sensitive, thereby paving the way for a more nuanced perspective that takes into account the stage of decision-making.

Pavlovian impatience: The anticipation of immediate rewards increases approach behaviour.

People often exhibit intertemporal impatience by choosing immediate small over delayed larger rewards, which has been implicated across maladaptive behaviours and mental health symptoms. In this preregistered study, we tested the role of an intertemporal Pavlovian bias as possible psychological mechanism driving the temptation posed by immediate rewards. Concretely, we hypothesized that the anticipation of immediate rewards (compared with preference-matched delayed rewards) enhances goal-directed approach behaviour but interferes with goal-directed inhibition. Such a mechanism could contribute to the difficulty to inhibit ourselves in the face of immediate rewards (e.g., a drug), at the cost of long-term (e.g., health) goals. A sample of 184 participants completed a newly developed reinforcement learning go/no-go task with four trial types: Go to win immediate reward; Go to win delayed reward; No-go to win immediate reward; and No-go to win delayed reward trials. Go responding was increased in trials in which an immediate reward was available compared with trials in which a preference-matched delayed reward was available. Computational models showed that on average, this behavioural pattern was best captured by a cue-response bias reflecting a stronger elicitation of go responses upon presentation of an immediate (versus delayed) reward cue. The results of this study support the role of an intertemporal Pavlovian bias as a psychological mechanism contributing to impatient intertemporal choice.

Integrating stereotypes and factual evidence in interpersonal communication.

Stereotypes can exert a powerful influence on our interactions with others, potentially leading to prejudice when factual evidence is ignored. Here, we identify neuroanatomical and developmental factors that influence the real-time integration of stereotypes and factual evidence during live social interactions. The study uses precisely quantified communicative exchanges in a longitudinal cohort of seventeen-year-olds followed since infancy, testing their ability to moderate stereotype tendencies toward children as contrary evidence accumulates. Our results indicate that the impact of stereotypes on communicative behavior is linked to individual variations in gray matter density and cortical thickness in the right anterior cingulate gyrus. In contrast, the ability to moderate stereotype tendencies is influenced by developmental exposure to social interactions during the initial years of life, beyond the effects of familial environment and later experiences. These findings pinpoint a key brain structure underlying stereotype tendencies and suggest that early-life social experiences have lasting consequences on how individuals integrate factual evidence in interpersonal communication.

Emotion regulation flexibility: EEG/EMG predictors and consequences of switching between reappraisal and distraction strategies.

Flexible use of emotion regulation (ER) strategies is central to mental health. To advance our understanding of what drives adaptive strategy-switching decisions, in this preregistered study, we used event-related potentials (late positive potential, LPP and stimulus preceding negativity, SPN) and facial electromyography (EMG corrugator activity) to test the antecedents and consequences of switching to an alternative ER strategy. Participants (N = 63, Mage = 24.8 years, all female) passively watched and then implemented an instructed ER strategy (reappraisal or distraction) in response to high-intensity negative pictures that were either easy or difficult to reinterpret (high or low reappraisal affordance, respectively). Next, they decided to "switch from" or "maintain" the instructed strategy and subsequently implemented the chosen strategy. Reappraisal affordance manipulations successfully induced switching. Regarding antecedents, switching was predicted by the reduced ER efficacy of the current strategy (corrugator, but not LPP). Switching to distraction was additionally predicted by increased responses to the stimulus during passive viewing (corrugator and LPP) and increased anticipatory effort in implementing reappraisal (SPN). Concerning consequences, switching to distraction improved, whereas switching to reappraisal impaired post-choice ER effects (LPP). However, starting with reappraisal was overall more effective than starting with distraction, irrespective of the subsequent decision (corrugator). Our results suggest that switching between ER strategies occurs in accordance with situational demands (stimulus affordances) and is predicted by reduced peripheral physiological ER efficacy. However, only switching to distraction leads to improved regulatory effects. These insights provide neurocognitively grounded starting points for developing interventions targeting ER flexibility.

The neurocomputational link between defensive cardiac states and approach-avoidance arbitration under threat.

Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat.

Vulnerabilities in social anxiety: Integrating intra- and interpersonal perspectives.

What are the major vulnerabilities in people with social anxiety? What are the most promising directions for translational research pertaining to this condition? The present paper provides an integrative summary of basic and applied translational research on social anxiety, emphasizing vulnerability factors. It is divided into two subsections: intrapersonal and interpersonal. The intrapersonal section synthesizes research relating to (a) self-representations and self-referential processes; (b) emotions and their regulation; and (c) cognitive biases: attention, interpretation and judgment, and memory. The interpersonal section summarizes findings regarding the systems of (a) approach and avoidance, (b) affiliation and social rank, and their implications for interpersonal impairments. Our review suggests that the science of social anxiety and, more generally, psychopathology may be advanced by examining processes and their underlying content within broad psychological systems. Increased interaction between basic and applied researchers to diversify and elaborate different perspectives on social anxiety is necessary for progress.

Tackling Costly Fearful Avoidance Using Pavlovian Counterconditioning.

Avoidance behavior constitutes a major transdiagnostic symptom that exacerbates anxiety. It hampers fear extinction and predicts poor therapy-outcome. Pavlovian counterconditioning with a reward could alleviate avoidance better than traditional extinction by reducing negative valence of the feared situation. However, previous studies are scarce and did not consider that pathological avoidance is often costly and typically evolves from an approach-avoidance conflict. Therefore, we used an approach-avoidance conflict paradigm to model effects of counterconditioning on costly avoidance (i.e., avoidance that leads to missing out on rewards). Results from our preregistered Bayesian Mixed Model analyses in 51 healthy participants (43 females) indicated that counterconditioning was more effective in reducing negative valuation and decreasing costly avoidance than traditional extinction. This study supports application of a simple counterconditioning technique, shows that its efficacy transfers to more complex avoidance situations, and suggests treatment may benefit from increasing reward drive in combination with extinction to overcome avoidance. Application in a clinical sample is a necessary next step to assess clinical utility of counterconditioning.

A poly(amidoamine)-based polymeric nanoparticle platform for efficient in vivo delivery of mRNA.

The successful use of mRNA vaccines enabled and accelerated the development of several new vaccine candidates and therapeutics based on the delivery of mRNA. In this study, we developed bioreducible poly(amidoamine)-based polymeric nanoparticles (PAA PNPs) for the delivery of mRNA with improved transfection efficiency. The polymers were functionalized with chloroquinoline (Q) moieties for improved endosomal escape and further stabilization of the mRNA-polymer construct. Moreover, these PAAQ polymers were covalently assembled around a core of multi-armed ethylenediamine (Mw 800, 2 % w/w) to form a pre-organized polymeric scaffolded PAAQ (ps-PAAQ) as a precursor for the formation of the mRNA-loaded nanoparticles. Transfection of mammalian cell lines with EGFP mRNA loaded into these PNPs showed a favorable effect of the Q incorporation on GFP protein expression. Additionally, these ps-PAAQ NPs were co-formulated with PEG-polymer coatings to shield the positive surface charge for increased stability and better in vivo applicability. The ps-PAAQ NPs coated with PEG-polymer displayed smaller particle size, electroneutral surface charge, and higher thermal stability. Importantly, these nanoparticles with both Q and PEG-polymer coating induced significantly higher luciferase activity in mice muscle than uncoated ps-PAAQ NPs, following intramuscular injection of PNPs loaded with luciferase mRNA. The developed technology is broadly applicable and holds promise for the development of new nucleotide-based vaccines and therapeutics in a range of infectious and chronic diseases.

Developmental shift in testosterone influence on prefrontal emotion control.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

Cell uptake and intracellular trafficking of bioreducible poly(amidoamine) nanoparticles for efficient mRNA translation in chondrocytes.

Disulfide-containing poly(amidoamine) (PAA) is a cationic and bioreducible polymer, with potential use as a nanocarrier for mRNA delivery in the treatment of several diseases including osteoarthritis (OA). Successful transfection of joint cells with PAA-based nanoparticles (NPs) was shown previously, but cell uptake, endosomal escape and nanoparticle biodegradation were not studied in detail. In this study, C28/I2 human chondrocytes were transfected with NPs co-formulated with a PEG-polymer coating and loaded with EGFP mRNA for confocal imaging of intracellular trafficking and evaluation of transfection efficiency. Compared with uncoated NPs, PEG-coated NPs showed smaller particle size, neutral surface charge, higher colloidal stability and superior transfection efficiency. Furthermore, endosomal entrapment of these PEG-coated NPs decreased over time and mRNA release could be visualized both in vitro and in live cells. Importantly, cell treatment with modulators of the intracellular reducing environment showed that glutathione (GSH) concentrations affect translation of the mRNA payload. Finally, we applied a D-optimal experimental design to test different polymer-to-RNA loading ratios and dosages, thus obtaining an optimal formulation with up to ≈80% of GFP-positive cells and without toxic effects. Together, the biocompatibility and high transfection efficiency of this system may be a promising tool for intra-articular delivery of therapeutical mRNA in OA treatment.

Perceptual control or action-selection? Comment on: a perceptual control theory of emotional action.

The Perceptual Control Theory of Emotional Action provides a compelling view of the synergy between action and perception in the context of emotion. In this invited response, we outline three suggestions to further clarify and concretesise the theory in the hope that it can provide a solid basis for the theoretical, empirical, and clinical fields of emotion and emotion regulation. First, we emphasise the importance of concretesising these ideas in a way that is biologically plausible and testable in terms of its neuronal implementation, which has not been addressed in the main manuscript. Secondly, we highlight the challenges for this account to effectively describe core symptoms in emotional disorders, an essential step if the theory aims to foster the development of better-tuned neurocognitively grounded interventions. Finally, we take a leap on what action-oriented accounts of emotion can mean for the field of emotion regulation.

Emotion regulation from an action-control perspective.

Despite increasing interest in emotional processes in cognitive science, theories on emotion regulation have remained rather isolated, predominantly focused on cognitive regulation strategies such as reappraisal. However, recent neurocognitive evidence suggests that early emotion regulation may involve sensorimotor control in addition to other emotion-regulation processes. We propose an action-oriented view of emotion regulation, in which feedforward predictions develop from action-selection mechanisms. Those can account for acute emotional-action control as well as more abstract instances of emotion regulation such as cognitive reappraisal. We argue the latter occurs in absence of overt motor output, yet in the presence of full-blown autonomic, visceral, and subjective changes. This provides an integrated framework with testable neuro-computational predictions and concrete starting points for intervention to improve emotion control in affective disorders.

Social avoidance and testosterone enhanced exposure efficacy in women with social anxiety disorder: A pilot investigation.

Social avoidance has been associated with more persistent social anxiety disorder (SAD) symptoms and low testosterone levels in individuals with SAD. We tested whether pre-treatment avoidance tendencies moderate the efficacy of testosterone-augmented exposure therapy. Fifty-five females with SAD received two exposure sessions during which fear levels were assessed. Session 1 was augmented with testosterone (0.50 mg) or placebo. Avoidance tendencies and symptom severity were assessed pre- and post-exposure. Participants showed stronger avoidance for social versus non-social stimuli and this tendency remained stable over time. Stronger pretreatment avoidance tendencies were associated with larger fear reduction in the testosterone but not the placebo condition. This effect did not transfer to the second non-enhanced session or symptom severity. The findings support the hypothesis that individuals suffering from SAD with relatively stronger pretreatment avoidance tendencies benefit more from testosterone-augmentation, pointing to a potential behavioral marker for testosterone enhancement of exposure therapy.

Anxious individuals shift emotion control from lateral frontal pole to dorsolateral prefrontal cortex.

Anxious individuals consistently fail in controlling emotional behavior, leading to excessive avoidance, a trait that prevents learning through exposure. Although the origin of this failure is unclear, one candidate system involves control of emotional actions, coordinated through lateral frontopolar cortex (FPl) via amygdala and sensorimotor connections. Using structural, functional, and neurochemical evidence, we show how FPl-based emotional action control fails in highly-anxious individuals. Their FPl is overexcitable, as indexed by GABA/glutamate ratio at rest, and receives stronger amygdalofugal projections than non-anxious male participants. Yet, high-anxious individuals fail to recruit FPl during emotional action control, relying instead on dorsolateral and medial prefrontal areas. This functional anatomical shift is proportional to FPl excitability and amygdalofugal projections strength. The findings characterize circuit-level vulnerabilities in anxious individuals, showing that even mild emotional challenges can saturate FPl neural range, leading to a neural bottleneck in the control of emotional action tendencies.

Studying additive effects of combining rTMS with cognitive control training: a pilot investigation.

Background: Repetitive transcranial magnetic stimulation (rTMS) on the dorsolateral prefrontal cortex (DLPFC) is an effective treatment for depression that has been proposed to work via the enhancement of cognitive control. Cognitive control training (CCT) can also alleviate depression by relying on DLPFC activation. As the additive effects of rTMS and CCT are unclear, we set out to conduct a within-subject pilot study in healthy controls. Methods: Seventeen participants received two sessions of individualized resting-state connectivity-guided high-frequency rTMS, while randomly performing CCT or a control task. After each session, a negative mood was induced. Results: We found effects on mood and cognitive control after rTMS + CCT as well as rTMS + control, which were indiscriminative between conditions. Based on the statistical evidence for the absence of an additive effect of CCT, we did not perform a full study. Conclusion: Our results demonstrate no differential effects of single sessions combining rTMS and CCT in a healthy population, even with the methodological improvement of individualized neuronavigation. The improvement in cognitive control seen in both conditions could indicate that a simple cognitive task is sufficient when studying additive rTMS effects. Future studies should focus on augmenting the effects of various cognitive tasks and compare the present interventions with rTMS or cognitive tasks alone.

Dynamic Modelling of Mental Resilience in Young Adults: Protocol for a Longitudinal Observational Study (DynaM-OBS).

BACKGROUND: Stress-related mental disorders are highly prevalent and pose a substantial burden on individuals and society. Improving strategies for the prevention and treatment of mental disorders requires a better understanding of their risk and resilience factors. This multicenter study aims to contribute to this endeavor by investigating psychological resilience in healthy but susceptible young adults over 9 months. Resilience is conceptualized in this study as the maintenance of mental health or quick recovery from mental health perturbations upon exposure to stressors, assessed longitudinally via frequent monitoring of stressors and mental health. OBJECTIVE: This study aims to investigate the factors predicting mental resilience and adaptive processes and mechanisms contributing to mental resilience and to provide a methodological and evidence-based framework for later intervention studies. METHODS: In a multicenter setting, across 5 research sites, a sample with a total target size of 250 young male and female adults was assessed longitudinally over 9 months. Participants were included if they reported at least 3 past stressful life events and an elevated level of (internalizing) mental health problems but were not presently affected by any mental disorder other than mild depression. At baseline, sociodemographic, psychological, neuropsychological, structural, and functional brain imaging; salivary cortisol and α-amylase levels; and cardiovascular data were acquired. In a 6-month longitudinal phase 1, stressor exposure, mental health problems, and perceived positive appraisal were monitored biweekly in a web-based environment, while ecological momentary assessments and ecological physiological assessments took place once per month for 1 week, using mobile phones and wristbands. In a subsequent 3-month longitudinal phase 2, web-based monitoring was reduced to once a month, and psychological resilience and risk factors were assessed again at the end of the 9-month period. In addition, samples for genetic, epigenetic, and microbiome analyses were collected at baseline and at months 3 and 6. As an approximation of resilience, an individual stressor reactivity score will be calculated. Using regularized regression methods, network modeling, ordinary differential equations, landmarking methods, and neural net-based methods for imputation and dimension reduction, we will identify the predictors and mechanisms of stressor reactivity and thus be able to identify resilience factors and mechanisms that facilitate adaptation to stressors. RESULTS: Participant inclusion began in October 2020, and data acquisition was completed in June 2022. A total of 249 participants were assessed at baseline, 209 finished longitudinal phase 1, and 153 finished longitudinal phase 2. CONCLUSIONS: The Dynamic Modelling of Resilience-Observational Study provides a methodological framework and data set to identify predictors and mechanisms of mental resilience, which are intended to serve as an empirical foundation for future intervention studies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39817.

Reappraisal is less effective than distraction in downregulation of neural responses to physical threats-An event-related potential investigation.

Evolutionary threats (ETs), such as predatory animals and heights, elicit stronger fear responses and are more often the subject of specific phobias, as compared to modern threats (MTs, such as guns and motorcycles). Since processing of ET depends on lower-order, phylogenetically conserved neural fear circuits, it may be less susceptible to higher-order (vs. simpler) cognitive emotion regulation. Given the relevance for treatment of specific phobias, we tested this hypothesis in an ERP study. Sixty-one female participants passively watched high- and low-threat pictures of evolutionary (snakes, lizards) and modern (guns, water-guns) origin, and downregulated responses to the high-threat pictures (snakes and guns) using either cognitive reappraisal or a simpler cognitive distraction strategy. ET elicited stronger early (EPN) and sustained (LPP) attention processing compared to MT. Both strategies successfully downregulated subjective and LPP (but not EPN) responses compared to passive watching. Although reappraisal was more effective subjectively, distraction downregulated the LPP earlier and stronger than reappraisal, irrespective of the threat type. These findings provide novel evidence that neural responses to physical threat might be less susceptible to cognitive emotion regulation via higher-order (reappraisal) versus simpler (distraction) strategies, irrespective of the evolutionary or modern relevance of threat. Combining both strategies could be beneficial for the emotion regulation-enhancing interventions for specific phobias. Distraction could be used during initial exposure, to reduce immediate emotion responding and help endure the contact with the feared stimulus, whereas reappraisal could be used subsequently, when emotions are less intense, to change maladaptive thoughts about the stimulus for future encounters.

Age differences in intertemporal choice among children, adolescents, and adults.

When choosing between sooner-smaller and later-larger rewards (i.e., intertemporal choices), adults typically prefer later-larger rewards more often than children. Intertemporal choice preferences have been implicated in various impulsivity-related psychopathologies, making it important to understand the underlying mechanisms not only in terms of how reward magnitude and delay affect choice but also in terms of how these mechanisms develop across age. We administered an intertemporal choice paradigm to 60 children (8-11 years), 79 adolescents (14-16 years), and 60 young adults (18-23 years). The paradigm systematically varied amounts and delays of the available rewards, allowing us to identify mechanisms underlying age-related differences in patience. Compared with young adults, both children and adolescents made fewer later-larger choices. In terms of underlying mechanisms, variation in delays, absolute reward magnitudes, and relative amount differences affected choice in each age group, indicating that children showed sensitivity to the same choice-relevant factors as young adults. Sensitivity to both absolute reward magnitude and relative amount differences showed a further monotonic age-related increase, whereas no change in delay sensitivity occurred. Lastly, adolescents and young adults weakly displayed a present bias (i.e., overvaluing immediate vs. future rewards; nonsignificant and trend, respectively), whereas children showed a nonsignificant but opposite pattern, possibly indicating that specifically dealing with future rewards changed with age. These findings shed light on the underlying mechanisms that contribute to the development of patience. By decomposing overt choices, our results suggest that the age-related increase in patience may be driven specifically by stronger sensitivity to amount differences with age.