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.

'Nip it in the bud': Low-frequency rTMS of the prefrontal cortex disrupts threat memory consolidation in humans.

It is still unclear how the human brain consolidates aversive (e.g., traumatic) memories and whether this process can be disrupted. We hypothesized that the dorsolateral prefrontal cortex (dlPFC) is crucially involved in threat memory consolidation. To test this, we used low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) within the memory stabilization time window to disrupt the expression of threat memory. We combined a differential threat-conditioning paradigm with LF-rTMS targeting the dlPFC in the critical condition, and occipital cortex stimulation, delayed dlPFC stimulation, and sham stimulation as control conditions. In the critical condition, defensive reactions to threat were reduced immediately after brain stimulation, and 1 h and 24 h later. In stark contrast, no decrease was observed in the control conditions, thus showing both the anatomical and temporal specificity of our intervention. We provide causal evidence that selectively targeting the dlPFC within the early consolidation period prevents the persistence and return of conditioned responses. Furthermore, memory disruption lasted longer than the inhibitory window created by our TMS protocol, which suggests that we influenced dlPFC neural activity and hampered the underlying, time-dependent consolidation process. These results provide important insights for future clinical applications aimed at interfering with the consolidation of aversive, threat-related memories.

Family accommodation in obsessive-compulsive disorder: An updated systematic review and meta-analysis.

Family accommodation might play a crucial role in obsessive-compulsive disorder (OCD). Previous systematic reviews on family accommodation in OCD have focused on specific populations or variables or are outdated. We conducted a preregistered systematic review and meta-analysis on family accommodation in adults, children, and adolescents with OCD (CRD42021264461). We searched PubMed, Scopus, and Web of Science using the keywords "family accommodation" and "obsessive-compulsive disorder. One hundred-eight studies involving 8928 individuals with OCD were included. Our results indicate that levels of family accommodation in OCD are moderate, that there is a significant positive correlation between family accommodation and OCD severity (r = 0.42), that baseline family accommodation does not predict pre- to post-treatment change in OCD severity (g = -0.03), and that family accommodation decreases as a result of both individual and family-focused cognitive behavioral therapy for OCD (g = 2.00 and g = 1.17, respectively). Our findings highlight the relevance of family accommodation in OCD and may help guide assessment and treatment.

Trait anxiety is associated with attentional brain networks.

Trait anxiety is a well-established risk factor for anxiety and depressive disorders, yet its neural correlates are not clearly understood. In this study, we investigated the neural correlates of trait anxiety in a large sample (n = 179) of individuals who completed the trait and state versions of the State-Trait Anxiety Inventory and underwent resting-state functional magnetic resonance imaging. We used independent component analysis to characterize individual resting-state networks (RSNs), and multiple regression analyses to assess the relationship between trait anxiety and intrinsic connectivity. Trait anxiety was significantly associated with intrinsic connectivity in different regions of three RSNs (dorsal attention network, default mode network, and auditory network) when controlling for state anxiety. These RSNs primarily support attentional processes. Notably, when state anxiety was not controlled for, a different pattern of results emerged, highlighting the importance of considering this factor in assessing the neural correlates of trait anxiety. Our findings suggest that trait anxiety is uniquely associated with resting-state brain connectivity in networks mainly supporting attentional processes. Moreover, controlling for state anxiety is crucial when assessing the neural correlates of trait anxiety. These insights may help refine current neurobiological models of anxiety and identify potential targets for neurobiologically-based interventions.

Introduction to the special issue on the Neurobiology of Human Fear and Anxiety.

Pathological fear and anxiety are a leading cause of human misery and morbidity, afflicting millions of individuals worldwide. Yet existing treatments are inconsistently effective or associated with significant adverse effects, underscoring the urgency of developing a more complete understanding of the neural systems governing fear and anxiety in humans. This emphasis reflects the fact that fear and anxiety disorders are defined and diagnosed based on subjective symptoms, and human studies are essential for understanding the neural mechanisms that underlie the experience of fear and anxiety. Human studies are also crucial for identifying the features of animal models that are conserved and, hence, most relevant to human disease and treatment development ('forward translation'). Finally, human studies afford opportunities for developing objective biomarkers of disease or disease risk, accelerating the development of new diagnostic and treatment strategies, and generating novel hypotheses that can be mechanistically assessed in animal models ('reverse translation'). The present Special Issue-The Neurobiology of Human Fear and Anxiety-provides a concise survey of recent progress in this burgeoning area of research. Here we provide an Introduction to the Special Issue, highlighting some of the most significant and exciting advances.

The nature and neurobiology of fear and anxiety: State of the science and opportunities for accelerating discovery.

Fear and anxiety play a central role in mammalian life, and there is considerable interest in clarifying their nature, identifying their biological underpinnings, and determining their consequences for health and disease. Here we provide a roundtable discussion on the nature and biological bases of fear- and anxiety-related states, traits, and disorders. The discussants include scientists familiar with a wide variety of populations and a broad spectrum of techniques. The goal of the roundtable was to take stock of the state of the science and provide a roadmap to the next generation of fear and anxiety research. Much of the discussion centered on the key challenges facing the field, the most fruitful avenues for future research, and emerging opportunities for accelerating discovery, with implications for scientists, funders, and other stakeholders. Understanding fear and anxiety is a matter of practical importance. Anxiety disorders are a leading burden on public health and existing treatments are far from curative, underscoring the urgency of developing a deeper understanding of the factors governing threat-related emotions.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

Common neural correlates of vestibular stimulation and fear learning: an fMRI meta-analysis.

BACKGROUND: A bidirectional functional link between vestibular and fear-related disorders has been previously suggested. OBJECTIVE: To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps. METHODS: By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers. RESULTS: Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2. CONCLUSIONS: The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.

Development and Validation of a Smartphone-Based App for the Longitudinal Assessment of Anxiety in Daily Life.

Current methods to assess human anxiety often ignore that anxiety is a dynamic process and have limitations such as high recall bias and low generalizability to real life. Smartphone apps using ecological momentary assessment (EMA) may overcome such limitations. We developed a smartphone app for the longitudinal evaluation of anxiety symptoms using EMA. We assessed the feasibility (retention and compliance) and psychometric properties (reliability and validity) of the app over 6 months in a sample of 99 participants with different levels of anxiety. The EMA-based smartphone app was highly feasible. It showed excellent within-person and between-person reliability, high convergent and moderate discriminant validity, and significant incremental validity. Assessing anxiety longitudinally using a smartphone and following EMA principles is feasible and can be reliable and valid. Studies combining EMA-based anxiety longitudinal assessments with other assessment methods deserve further research and may offer novel insights into human anxiety.

Neural predictors of cognitive-behavior therapy outcome in anxiety-related disorders: a meta-analysis of task-based fMRI studies.

BACKGROUND: Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent. METHODS: We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442). RESULTS: Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome. CONCLUSIONS: Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.

Editorial: Thalamic Subregions Are Differentially Associated With Obsessive-Compulsive Symptoms in Children.

Weeland et al.1 discuss the relationship between subregional thalamic volumes and obsessive-compulsive symptoms (OCS) in children from the general population. The thalamus is the last relay node of the so-called corticostriatal-thalamocortical (CSTC) circuits before information reenters the cortex. There are different CSTC circuits involved in motor, cognitive, and affective/motivational processes whose information is conveyed in parallel through different thalamic nuclei.2 Studies have shown that patients with obsessive-compulsive disorder (OCD) show pervasive alterations in these circuits.3 Indeed, such alterations are central to prevailing neurobiological models of OCD, which are largely based on the results from neuroimaging research conducted with clinical OCD samples over the last 3 decades.3 This research includes magnetic resonance imaging studies identifying a range of structural changes in relay nodes within CSTC circuits. In one of the earliest reports, Gilbert et al.4 identified enlarged thalamic volumes in a small sample of treatment-naïve children with OCD, which normalized after treatment with paroxetine. Although treatment effects have not been replicated, recent research with larger datasets from the ENIGMA international consortium confirmed these initial findings in unmedicated children with OCD.5 Likewise, in a previous study conducted with children from the population-based birth cohort Generation R, the same sample used in the study by Weeland et al.,1 total thalamic volume was also associated with OCS.6.

Antidepressants overuse in primary care: Prescription trends between 2010 and 2019 in Catalonia.

INTRODUCTION: There has been an increase in the prescription of antidepressants (AD) in primary care (PC). However, it is unclear whether this was explained by a rise in diagnoses with an indication for AD. We investigated the changes in frequency and the variables associated with AD prescription in Catalonia, Spain. METHODS: We retrieved AD prescription, sociodemographic, and health-related data using individual electronic health records from a population-representative sample (N=947.698) attending PC between 2010 and 2019. Prescription of AD was calculated using DHD (Defined Daily Doses per 1000 inhabitants/day). We compared cumulative changes in DHD with cumulative changes in diagnoses with an indication for AD during the study period. We used Poisson regression to examine sociodemographic and health-related variables associated with AD prescription. RESULTS: Both AD prescription and mental health diagnoses with an indication for AD gradually increased. At the end of the study period, DHD of AD prescriptions and mental health diagnoses with an indication for AD reached cumulative increases of 404% and 49% respectively. Female sex (incidence rate ratio (IRR)=2.83), older age (IRR=25.43), and lower socio-economic status (IRR=1.35) were significantly associated with increased risk of being prescribed an AD. CONCLUSIONS: Our results from a large and representative cohort of patients confirm a steady increase of AD prescriptions that is not explained by a parallel increase in mental health diagnoses with an indication for AD. A trend on AD off-label and over-prescriptions in the PC system in Catalonia can be inferred from this dissociation.

Neural correlates of fear conditioning and fear extinction and its association with cognitive-behavioral therapy outcome in adults with obsessive-compulsive disorder.

Recent neurobiological models of obsessive-compulsive disorder (OCD) have highlighted the potential role of abnormalities in fear learning processes. We compared brain activation -as assessed with whole-brain functional magnetic resonance imaging- during fear conditioning, fear extinction learning, and fear extinction recall in patients with OCD (n = 18) and healthy controls (n = 18). We also investigated whether brain activation during any of these processes was associated with exposure-based cognitive-behavioral therapy (CBT) outcome in patients. Patients with OCD showed significantly lower brain activation in the right insulo-opercular region and the dorsal anterior cingulate cortex during fear conditioning in comparison to healthy controls. Moreover, brain activation in the right insula predicted CBT outcome, with lower activation predicting a better outcome. Brain activation during extinction learning or recall did not differ between patients and controls or predicted CBT outcome in patients. Our results suggest that neural activations during fear conditioning in patients with OCD are abnormal and predict CBT outcome.

Can we increase the subjective well-being of the general population? An umbrella review of the evidence

Introduction: Subjective well-being (SWB) refers to being satisfied with one's life, having positive affect and having little negative affect. We may understand it as a subjective definition of good life, or in colloquial terms “happiness”, and it has been associated with several important benefits such as lower mortality. In the last decades, several randomized controlled trials (RCT) have investigated the efficacy of several interventions in increasing SWB in the general population but results from different disciplines have not been integrated.MethodsWe conducted an umbrella review of systematic reviews and meta-analyses of RCT that assess the efficacy of any kind of interventions in increasing SWB in the general population, including both positive psychology interventions (PPI) and other interventions. We (re)calculated the meta-analytic statistics needed to objectively assess the quality of the evidence of the efficacy of each type of intervention in improving each component of SWB according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.ResultsThere was moderate-quality evidence that PPI might induce small decreases of negative affect, and low-quality evidence that they might induce moderate increases of positive affect. We found similar results for those PPI specifically consisting in conducting acts of kindness (especially spending money on or giving items to others), for which there was low-quality evidence that they might induces small increases of life satisfaction, but not for PPI specifically consisting in practicing gratitude. Quality of the evidence of the efficacy for the other interventions included in the umbrella review (yoga, resilience training, physical activity, leisure, control enhancement, psychoeducation, and miscellaneous) was very low. (AU)

Introducción: El bienestar subjetivo (BS) se refiere a estar satisfecho con la vida, tener afecto positivo y tener poco afecto negativo. Podemos entenderlo como una definición subjetiva de la buena vida, o en términos coloquiales, como «felicidad», y se ha asociado con varios beneficios importantes, como una menor mortalidad. En las últimas décadas, varios ensayos controlados aleatorizados (ECA) han investigado la eficacia de varias intervenciones para aumentar el BS en la población general, pero los resultados de las diferentes disciplinas no se han integrado.MétodosRealizamos una revisión paraguas de revisiones sistemáticas y metaanálisis de ECA que evaluasen la eficacia de cualquier tipo de intervención para aumentar el BS en la población general, incluidas tanto las intervenciones de psicología positiva (IPP) como otras intervenciones. (Re)calculamos los estadísticos metaanalíticos necesarios para evaluar objetivamente la calidad de la evidencia de la eficacia de cada tipo de intervención para mejorar cada componente del BS de acuerdo con el Grading of Recommendations Assessment, Development and Evaluation (GRADE).ResultadosHubo evidencia de moderada calidad de que las IPP podrían inducir pequeñas disminuciones de afecto negativo, así como evidencia de baja calidad de que podrían inducir aumentos moderados de afecto positivo. Encontramos resultados similares para aquellas IPP que consistían específicamente en realizar actos de bondad (especialmente gastar dinero en o dar artículos a otros), para las cuales había evidencia de baja calidad de que podrían inducir pequeños aumentos de satisfacción con la vida, pero no para las IPP que consistían específicamente en practicar la gratitud. La calidad de la evidencia de la eficacia para las otras intervenciones incluidas en la revisión paraguas (yoga, entrenamiento de resiliencia, actividad física, ocio, mejora del control, psicoeducación y miscelánea) fue muy baja. (AU)

Can we increase the subjective well-being of the general population? An umbrella review of the evidence.

INTRODUCTION: Subjective well-being (SWB) refers to being satisfied with one's life, having positive affect and having little negative affect. We may understand it as a subjective definition of good life, or in colloquial terms "happiness", and it has been associated with several important benefits such as lower mortality. In the last decades, several randomized controlled trials (RCT) have investigated the efficacy of several interventions in increasing SWB in the general population but results from different disciplines have not been integrated. METHODS: We conducted an umbrella review of systematic reviews and meta-analyses of RCT that assess the efficacy of any kind of interventions in increasing SWB in the general population, including both positive psychology interventions (PPI) and other interventions. We (re)calculated the meta-analytic statistics needed to objectively assess the quality of the evidence of the efficacy of each type of intervention in improving each component of SWB according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: There was moderate-quality evidence that PPI might induce small decreases of negative affect, and low-quality evidence that they might induce moderate increases of positive affect. We found similar results for those PPI specifically consisting in conducting acts of kindness (especially spending money on or giving items to others), for which there was low-quality evidence that they might induces small increases of life satisfaction, but not for PPI specifically consisting in practicing gratitude. Quality of the evidence of the efficacy for the other interventions included in the umbrella review (yoga, resilience training, physical activity, leisure, control enhancement, psychoeducation, and miscellaneous) was very low. CONCLUSION: There is some evidence that PPI, and specially conducting acts of kindness such as spending money on others, may increase the SWB of the general population. The quality of the evidence of the efficacy for other interventions (e.g., yoga, physical activity, or leisure) is still very low. Registration number: PROSPERO CRD42020111681.

Threat and safety reversal learning in social anxiety disorder - an fMRI study.

Social anxiety disorder (SAD) has been linked to maladaptive forms of fear regulation, including flexibly distinguishing between learned threat and safety signals. Few studies have examined this in young, unmedicated SAD patients, including its neural basis. We aimed to characterize the neural, subjective, and autonomic correlates of reversal learning in patients with SAD and compare them to matched patients with major depressive disorder and to healthy control participants. All participants completed a threat-safety reversal learning task during functional magnetic resonance imaging. Successful threat-safety updating was associated with significant activation of primary regions of interest (anterior cingulate, insula and ventromedial prefrontal cortex), however, no significant differences were observed between them, consistent with subjective reports of task-evoked anxiety and affect. Contrary to expectations, we did not observe threat and safety reversal learning to be significantly impaired in young people with SAD.