Adolescents flexibly adapt action selection based on controllability inferences.

From early in life, we encounter both controllable environments, in which our actions can causally influence the reward outcomes we experience, and uncontrollable environments, in which they cannot. Environmental controllability is theoretically proposed to organize our behavior. In controllable contexts, we can learn to proactively select instrumental actions that bring about desired outcomes. In uncontrollable environments, Pavlovian learning enables hard-wired, reflexive reactions to anticipated, motivationally salient events, providing "default" behavioral responses. Previous studies characterizing the balance between Pavlovian and instrumental learning systems across development have yielded divergent findings, with some studies observing heightened expression of Pavlovian learning during adolescence and others observing a reduced influence of Pavlovian learning during this developmental stage. In this study, we aimed to investigate whether a theoretical model of controllability-dependent arbitration between learning systems might explain these seemingly divergent findings in the developmental literature, with the specific hypothesis that adolescents' action selection might be particularly sensitive to environmental controllability. To test this hypothesis, 90 participants, aged 8-27, performed a probabilistic-learning task that enables estimation of Pavlovian influence on instrumental learning, across both controllable and uncontrollable conditions. We fit participants' data with a reinforcement-learning model in which controllability inferences adaptively modulate the dominance of Pavlovian versus instrumental control. Relative to children and adults, adolescents exhibited greater flexibility in calibrating the expression of Pavlovian bias to the degree of environmental controllability. These findings suggest that sensitivity to environmental reward statistics that organize motivated behavior may be heightened during adolescence.

Sensitivity to the Instrumental Value of Choice Increases Across Development.

Across development, people tend to demonstrate a preference for contexts in which they have the opportunity to make choices. However, it is not clear how children, adolescents, and adults learn to calibrate this preference based on the costs and benefits of agentic choice. Here, in both a primary, in-person, reinforcement-learning experiment (N = 92; age range = 10-25 years) and a preregistered online replication study (N = 150; age range = 8-25 years), we found that participants overvalued agentic choice but also calibrated their agency decisions to the reward structure of the environment, increasingly selecting agentic choice when choice had greater instrumental value. Regression analyses and computational modeling of participant choices revealed that participants' bias toward agentic choice-reflecting its intrinsic value-remained consistent across age, whereas sensitivity to the instrumental value of agentic choice increased from childhood to early adulthood.

Reward Enhances Memory via Age-Varying Online and Offline Neural Mechanisms across Development.

Reward motivation enhances memory through interactions between mesolimbic, hippocampal, and cortical systems, both during and after encoding. Developmental changes in these distributed neural circuits may lead to age-related differences in reward-motivated memory and the underlying neural mechanisms. Converging evidence from cross-species studies suggests that subcortical dopamine signaling is increased during adolescence, which may lead to stronger memory representations of rewarding, relative to mundane, events and changes in the contributions of underlying subcortical and cortical brain mechanisms across age. Here, we used fMRI to examine how reward motivation influences the "online" encoding and "offline" postencoding brain mechanisms that support long-term associative memory from childhood to adulthood in human participants of both sexes. We found that reward motivation led to both age-invariant enhancements and nonlinear age-related differences in associative memory after 24 h. Furthermore, reward-related memory benefits were linked to age-varying neural mechanisms. During encoding, interactions between the prefrontal cortex (PFC) and ventral tegmental area (VTA) were associated with better high-reward memory to a greater degree with increasing age. Preencoding to postencoding changes in functional connectivity between the anterior hippocampus and VTA were also associated with better high-reward memory, but more so at younger ages. Our findings suggest that there may be developmental differences in the contributions of offline subcortical and online cortical brain mechanisms supporting reward-motivated memory.SIGNIFICANCE STATEMENT A substantial body of research has examined the neural mechanisms through which reward influences memory formation in adults. However, despite extensive evidence that both reward processing and associative memory undergo dynamic change across development, few studies have examined age-related changes in these processes. We found both age-invariant and nonlinear age-related differences in reward-motivated memory. Moreover, our findings point to developmental differences in the processes through which reward modulates the prioritization of information in long-term memory, with greater early reliance on offline subcortical consolidation mechanisms and increased contribution of systems-level online encoding circuitry with increasing age. These results highlight dynamic developmental changes in the cognitive and neural mechanisms through which motivationally salient information is prioritized in memory from childhood to adulthood.

Developmental shifts in computations used to detect environmental controllability.

Accurate assessment of environmental controllability enables individuals to adaptively adjust their behavior-exploiting rewards when desirable outcomes are contingent upon their actions and minimizing costly deliberation when their actions are inconsequential. However, it remains unclear how estimation of environmental controllability changes from childhood to adulthood. Ninety participants (ages 8-25) completed a task that covertly alternated between controllable and uncontrollable conditions, requiring them to explore different actions to discover the current degree of environmental controllability. We found that while children were able to distinguish controllable and uncontrollable conditions, accuracy of controllability assessments improved with age. Computational modeling revealed that whereas younger participants' controllability assessments relied on evidence gleaned through random exploration, older participants more effectively recruited their task structure knowledge to make highly informative interventions. Age-related improvements in working memory mediated this qualitative shift toward increased use of an inferential strategy. Collectively, these findings reveal an age-related shift in the cognitive processes engaged to assess environmental controllability. Improved detection of environmental controllability may foster increasingly adaptive behavior over development by revealing when actions can be leveraged for one's benefit.

Neural effects of controllability as a key dimension of stress exposure.

Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants (N = 56; Mage = 23.74, range = 18-30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.

Reward-motivated memories influence new learning across development.

Previously rewarding experiences can influence choices in new situations. Past work has demonstrated that existing reward associations can either help or hinder future behaviors and that there is substantial individual variability in the transfer of value across contexts. Developmental changes in reward sensitivity may also modulate the impact of prior reward associations on later goal-directed behavior. The current study aimed to characterize how reward associations formed in the past affected learning in the present from childhood to adulthood. Participants completed a reinforcement learning paradigm using high- and low-reward stimuli from a task completed 24 h earlier, as well as novel stimuli, as choice options. We found that prior high-reward associations impeded learning across all ages. We then assessed how individual differences in the prioritization of high- versus low-reward associations in memory impacted new learning. Greater high-reward memory prioritization was associated with worse learning performance for previously high-reward relative to low-reward stimuli across age. Adolescents also showed impeded early learning regardless of individual differences in high-reward memory prioritization. Detrimental effects of previous reward on choice behavior did not persist beyond learning. These findings indicate that prior reward associations proactively interfere with future learning from childhood to adulthood and that individual differences in reward-related memory prioritization influence new learning across age.

Antibody Response of Heterologous vs Homologous Messenger RNA Vaccine Boosters Against the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant: Interim Results from the PRIBIVAC Study, a Randomized Clinical Trial.

BACKGROUND: Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity have raised the need for booster vaccinations. However, which combination of coronavirus disease 2019 (COVID-19) vaccines offers the strongest immune response against the Omicron variant is unknown. METHODS: This randomized, participant-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. A total of 100 BNT162b2-vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; "BBB") or heterologous messenger RNA (mRNA) (BNT162b2 + BNT162b2 + mRNA-1273; "BBM") booster vaccine. The primary end point was the level of neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wild-type and VOCs at day 28. RESULTS: A total of 51 participants were allocated to BBB and 49 to BBM; 50 and 48, respectively, were analyzed for safety and immunogenicity outcomes. At day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22 382 IU/mL; 95% confidence interval [CI], 18 210 to 27 517) vs BBM (29 751 IU/mL; 95% CI, 25 281 to 35 011; P = .034) as was the median level of neutralizing antibodies: BBB 99.0% (interquartile range [IQR], 97.9% to 99.3%) vs BBM 99.3% (IQR, 98.8% to 99.5%; P = .021). On subgroup analysis, significant higher mean spike antibody titer, median surrogate neutralizing antibody level against all VOCs, and live Omicron neutralization titer were observed only in older adults receiving BBM. Both vaccines were well tolerated. CONCLUSIONS: Heterologous mRNA-1273 booster vaccination compared with homologous BNT123b2 induced a stronger neutralizing response against the Omicron variant in older individuals. CLINICAL TRIALS REGISTRATION: NCT05142319.

Reinforcement learning with associative or discriminative generalization across states and actions: fMRI at 3 T and 7 T.

The model-free algorithms of "reinforcement learning" (RL) have gained clout across disciplines, but so too have model-based alternatives. The present study emphasizes other dimensions of this model space in consideration of associative or discriminative generalization across states and actions. This "generalized reinforcement learning" (GRL) model, a frugal extension of RL, parsimoniously retains the single reward-prediction error (RPE), but the scope of learning goes beyond the experienced state and action. Instead, the generalized RPE is efficiently relayed for bidirectional counterfactual updating of value estimates for other representations. Aided by structural information but as an implicit rather than explicit cognitive map, GRL provided the most precise account of human behavior and individual differences in a reversal-learning task with hierarchical structure that encouraged inverse generalization across both states and actions. Reflecting inference that could be true, false (i.e., overgeneralization), or absent (i.e., undergeneralization), state generalization distinguished those who learned well more so than action generalization. With high-resolution high-field fMRI targeting the dopaminergic midbrain, the GRL model's RPE signals (alongside value and decision signals) were localized within not only the striatum but also the substantia nigra and the ventral tegmental area, including specific effects of generalization that also extend to the hippocampus. Factoring in generalization as a multidimensional process in value-based learning, these findings shed light on complexities that, while challenging classic RL, can still be resolved within the bounds of its core computations.

Real-World Exploration Increases Across Adolescence and Relates to Affect, Risk Taking, and Social Connectivity.

Cross-species research suggests that exploratory behaviors increase during adolescence and relate to the social, affective, and risky behaviors characteristic of this developmental stage. However, how these typical adolescent behaviors manifest and relate in real-world settings remains unclear. Using geolocation tracking to quantify exploration-variability in daily movement patterns-over a 3-month period in 58 adolescents and adults (ages 13-27) in New York City, we investigated whether daily exploration varied with age and whether exploration related to social connectivity, risk taking, and momentary positive affect. In our cross-sectional sample, we found an association between daily exploration and age, with individuals near the transition to legal adulthood exhibiting the highest exploration levels. Days of higher exploration were associated with greater positive affect irrespective of age. Higher mean exploration was associated with greater social connectivity in all participants but was linked to higher risk taking selectively among adolescents. Our results highlight the interplay of exploration and socioemotional behaviors across development and suggest that societal norms may modulate their expression in naturalistic contexts.

Flexibility in valenced reinforcement learning computations across development.

Optimal integration of positive and negative outcomes during learning varies depending on an environment's reward statistics. The present study investigated the extent to which children, adolescents, and adults (N = 142 8-25 year-olds, 55% female, 42% White, 31% Asian, 17% mixed race, and 8% Black; data collected in 2021) adapt their weighting of better-than-expected and worse-than-expected outcomes when learning from reinforcement. Participants made choices across two contexts: one in which weighting positive outcomes more heavily than negative outcomes led to better performance, and one in which the reverse was true. Reinforcement learning modeling revealed that across age, participants shifted their valence biases in accordance with environmental structure. Exploratory analyses revealed strengthening of context-dependent flexibility with increasing age.

Tissue-Specific Immunopathology in Fatal COVID-19.

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Squamous cell carcinoma complicating chronic osteomyelitis: A systematic review and case series.

INTRODUCTION: Squamous cell carcinoma (SCC) is a rare but serious complication of chronic osteomyelitis. This study aimed to determine an optimum approach to diagnosis and management. METHODS: A systematic review was performed using Medline, Embase, CINAHL and Web of Science, from 1999-present. Additional cases, meeting the eligibility criteria, were added from our hospital database. Patient demographics (age, gender, co-morbidities), osteomyelitis diagnosis (location, duration), diagnosis of SCC (method, imaging, extent of disease) and management (amputation versus wide local excision versus palliation) as well as outcome at one and five years were collected. RESULTS: Nineteen studies involving 106 patients met strict inclusion criteria. All published studies were case reports or case series. Chronic osteomyelitis had been present for a mean of 31 years (range 3-67) prior to SCC diagnosis. SCC was most commonly treated by amputation (81%). A poorer outcome occurred in those with metastatic disease (p = 0.006 at one year; p = 0.032 at five years), an incidental diagnosis at surgery for osteomyelitis (p = 0.052; p = 0.021) and SCC after pelvic osteomyelitis (p < 0.001; p = 0.002). CONCLUSIONS: SCC should be suspected in all cases of chronic osteomyelitis with skin changes, particularly if the duration of sinus drainage exceeds 3 years. Histological biopsy for malignancy should be taken in all suspected cases, as well as routinely during excision of osteomyelitis when chronic skin changes are present. Staging computed tomography (CT) scanning is recommended to guide adjunctive therapy. Amputation, where possible, may be considered as the definitive surgical management, after discussion with the patient.

Gender Differences in Concerns About Participating in Cancer Research During the COVID-19 Pandemic.

INTRODUCTION: The ongoing SARS-CoV-2 pandemic is having major effects on cancer research, including major reductions in participant accrual to cancer clinical trials. Existing research has indicated that these steep drops in accrual rates to cancer clinical trials may be disproportionately affecting women. We sought to determine if there were gender differences in a dataset collected to examine participants' concerns about taking part in cancer research during the pandemic. METHODS: Between 5-19 June 2020, we distributed a fully anonymized survey via social media. We contacted 85 UK cancer patient organizations/charities and asked them to share our questionnaire on their platforms, of which 26 obliged. Patients aged 18 with a cancer diagnosis were eligible to participate and asked about their clinical and demographic characteristics, concerns about research participation given the COVID-19 pandemic, anxiety levels measured using the Generalized Anxiety Disorder-7 (GAD-7) scale, amongst other questions. Anxiety levels and concerns about participating were compared between men and women using univariate and multivariate analyses. RESULTS: 93 individuals, comprising n = 37 women and n = 56 men of various cancer types, provided survey responses. Independent t-tests showed that women reported higher anxiety scores, and concerns about participating in cancer research during COVID-19, than men. Linear regression analyses showed that anxiety scores predicted concerns about research participation in women but not men (pinteraction = 0.002). CONCLUSIONS: Cancer patients have concerns about participating in research during the COVID-19 pandemic that range from mild to serious. Furthermore, the relationship between general anxiety and concerns about research participation may be both more relevant and more pronounced in women than in men. Future work should examine the reasons why women are less likely to enrol in cancer trials during the COVID-19 pandemic.

Associative memory persistence in 3- to 5-year-olds.

Adults struggle to recollect episodic memories from early life. This phenomenon-referred to as "infantile" and "childhood amnesia"-has been widely observed across species and is characterized by rapid forgetting from birth until early childhood. While a number of studies have focused on infancy, few studies have examined the persistence of memory for newly learned associations during the putative period of childhood amnesia. In this study, we investigated forgetting in 137 children ages 3-5 years old by using an interactive storybook task. We assessed associative memory between subjects after 5-min, 24-h, and 1-week delay periods. Across all delays, we observed a significant increase in memory performance with age. While all ages demonstrated above-chance memory performance after 5-min and 24-h delays, we observed chance-level memory accuracy in 3-year-olds following a 1-week delay. The observed age differences in associative memory support the proposal that hippocampal-dependent memory systems undergo rapid development during the preschool years. These data have the potential to inform future work translating memory persistence and malleability research from rodent models to humans by establishing timescales at which we expect young children to forget newly learned associations.

The relationships between rugby union, and health and well-being: a scoping review.

OBJECTIVE: To scope the relationships between rugby union, and health and well-being. DESIGN: Scoping review. DATA SOURCES: Published and unpublished reports of any age, identified by searching electronic databases, platforms and reference lists. METHODS: A three-step search strategy identified relevant published primary, secondary studies and grey literature, which were screened using a priori inclusion criteria. Data were extracted using a standardised tool, to form (1) a numerical analysis and (2) a thematic summary. RESULTS AND DISCUSSION: 6658 records were identified, and 198 studies met the inclusion criteria. All forms of rugby union can provide health-enhancing physical activity (PA). 'Non-contact' and wheelchair rugby in particular provide a wide range of physical and mental health and well-being benefits. The evidence is either mixed or unclear in relation to 'contact' rugby union and its effects on a range of physical health domains. Injury and concussion incidence rates are high for contact rugby union relative to other sports. CONCLUSIONS: A wide range of stakeholders as well as existing and potential participants can use this information to make a more informed decision about participating in and promoting rugby union as a health-enhancing activity. Industry and policy-makers can use this review to inform policies and strategies that look to increase participation rates and use rugby union as a vehicle to contribute positively to population health. Further research understanding rugby union's contribution to PA as well as to muscle-strengthening and balance is indicated, as well as research examining more health and well-being outcomes across more diverse cohorts.

Stress attenuates the flexible updating of aversive value.

In a dynamic environment, sources of threat or safety can unexpectedly change, requiring the flexible updating of stimulus-outcome associations that promote adaptive behavior. However, aversive contexts in which we are required to update predictions of threat are often marked by stress. Acute stress is thought to reduce behavioral flexibility, yet its influence on the modulation of aversive value has not been well characterized. Given that stress exposure is a prominent risk factor for anxiety and trauma-related disorders marked by persistent, inflexible responses to threat, here we examined how acute stress affects the flexible updating of threat responses. Participants completed an aversive learning task, in which one stimulus was probabilistically associated with an electric shock, while the other stimulus signaled safety. A day later, participants underwent an acute stress or control manipulation before completing a reversal learning task during which the original stimulus-outcome contingencies switched. Skin conductance and neuroendocrine responses provided indices of sympathetic arousal and stress responses, respectively. Despite equivalent initial learning, stressed participants showed marked impairments in reversal learning relative to controls. Additionally, reversal learning deficits across participants were related to heightened levels of alpha-amylase, a marker of noradrenergic activity. Finally, fitting arousal data to a computational reinforcement learning model revealed that stress-induced reversal learning deficits emerged from stress-specific changes in the weight assigned to prediction error signals, disrupting the adaptive adjustment of learning rates. Our findings provide insight into how stress renders individuals less sensitive to changes in aversive reinforcement and have implications for understanding clinical conditions marked by stress-related psychopathology.

Aversive learning strengthens episodic memory in both adolescents and adults.

Adolescence is often filled with positive and negative emotional experiences that may change how individuals remember and respond to stimuli in their environment. In adults, aversive events can both enhance memory for associated stimuli as well as generalize to enhance memory for unreinforced but conceptually related stimuli. The present study tested whether learned aversive associations similarly lead to better memory and generalization across a category of stimuli in adolescents. Participants completed an olfactory Pavlovian category conditioning task in which trial-unique exemplars from one of two categories were partially reinforced with an aversive odor. Participants then returned 24 h later to complete a recognition memory test. We found better corrected recognition memory for the reinforced versus the unreinforced category of stimuli in both adults and adolescents. Further analysis revealed that enhanced recognition memory was driven specifically by better memory for the reinforced exemplars. Autonomic arousal during learning was also related to subsequent memory. These findings build on previous work in adolescent and adult humans and rodents showing comparable acquisition of aversive Pavlovian conditioned responses across age groups and demonstrate that memory for stimuli with an acquired aversive association is enhanced in both adults and adolescents.

Neurocognitive Development of Motivated Behavior: Dynamic Changes across Childhood and Adolescence.

The ability to anticipate and respond appropriately to the challenges and opportunities present in our environments is critical for adaptive behavior. Recent methodological innovations have led to substantial advances in our understanding of the neurocircuitry supporting such motivated behavior in adulthood. However, the neural circuits and cognitive processes that enable threat- and reward-motivated behavior undergo substantive changes over the course of development, and these changes are less well understood. In this article, we highlight recent research in human and animal models demonstrating how developmental changes in prefrontal-subcortical neural circuits give rise to corresponding changes in the processing of threats and rewards from infancy to adulthood. We discuss how these developmental trajectories are altered by experiential factors, such as early-life stress, and highlight the relevance of this research for understanding the developmental onset and treatment of psychiatric disorders characterized by dysregulation of motivated behavior.

Developing a 3D intestinal epithelium model for livestock species.

The in vitro 3D culture of intestinal epithelium is a valuable resource in the study of its function. Organoid culture exploits stem cells' ability to regenerate and produce differentiated epithelium. Intestinal organoid models from rodent or human tissue are widely available whereas large animal models are not. Livestock enteric and zoonotic diseases elicit significant morbidity and mortality in animal and human populations. Therefore, livestock species-specific models may offer novel insights into host-pathogen interactions and disease responses. Bovine and porcine jejunum were obtained from an abattoir and their intestinal crypts isolated, suspended in Matrigel, cultured, cryopreserved and resuscitated. 'Rounding' of crypts occurred followed by budding and then enlargement of the organoids. Epithelial cells were characterised using immunofluorescent staining and confocal microscopy. Organoids were successfully infected with Toxoplasma gondii or Salmonella typhimurium. This 3D organoid model offers a long-term, renewable resource for investigating species-specific intestinal infections with a variety of pathogens.

Active Avoidance: Neural Mechanisms and Attenuation of Pavlovian Conditioned Responding.

Patients with anxiety disorders often experience a relapse in symptoms after exposure therapy. Similarly, threat responses acquired during Pavlovian threat conditioning often return after extinction learning. Accordingly, there is a need for alternative methods to persistently reduce threat responding. Studies in rodents have suggested that exercising behavioral control over an aversive stimulus can persistently diminish threat responses, and that these effects are mediated by the amygdala, ventromedial prefrontal cortex, and striatum. In this fMRI study, we attempted to translate these findings to humans. Subjects first underwent threat conditioning. We then contrasted two forms of safety learning: active avoidance, in which participants could prevent the shock through an action, and yoked extinction, with shock presentation matched to the active condition, but without instrumental control. The following day, we assessed subjects' threat responses (measured by skin conductance) to the conditioned stimuli without shock. Subjects next underwent threat conditioning with novel stimuli. Yoked extinction subjects showed an increase in conditioned response to stimuli from the previous day, but the active avoidance group did not. Additionally, active avoidance subjects showed reduced conditioned responding during novel threat conditioning, but the extinction group did not. We observed between-group differences in striatal BOLD responses to shock omission in Avoidance/Extinction. These findings suggest a differential role for the striatum in human active avoidance versus extinction learning, and indicate that active avoidance may be more effective than extinction in persistently diminishing threat responses.SIGNIFICANCE STATEMENT Extinguished threat responses often reemerge with time, highlighting the importance of identifying more enduring means of attenuation. We compared the effects of active avoidance learning and yoked extinction on threat responses in humans and contrasted the neural circuitry engaged by these two processes. Subjects who learned to prevent a shock through an action maintained low threat responses after safety learning and showed attenuated threat conditioning with novel stimuli, in contrast to those who underwent yoked extinction. The results suggest that experiences of active control over threat engage the striatum and promote a shift from expression of innate defensive responses toward more adaptive behavioral responses to threatening stimuli.