FRONTAL WHITE MATTER CHANGES INDICATE RECOVERY WITH INPATIENT TREATMENT IN HEROIN ADDICTION.

Importance: Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. Distributed white matter (WM) impairments in individuals with heroin use disorder (iHUD) have been associated with increased drug craving, a reliable predictor of treatment outcomes. However, little is known about the extent of whole-brain structural connectivity changes with inpatient treatment and abstinence in iHUD. Objective: To assess WM microstructure and associations with drug craving changes with inpatient treatment in iHUD (effects of time/re-scan compared to controls; CTL). Design: Longitudinal cohort study (12/2020-09/2022) where iHUD and CTL underwent baseline magnetic resonance imaging (MRI#1) and follow-up (MRI#2) scans, (mean interval of 13.9 weeks in all participants combined). Setting: The iHUD and CTL were recruited from urban inpatient treatment facilities and surrounding communities, respectively. Participants: Thirty-four iHUD (42.1yo; 7 women), 25 age-/sex-matched CTL (40.5yo; 9 women). Intervention: Between scans, inpatient iHUD continued their medically-assisted treatment and related clinical interventions. CTL participants were scanned at similar time intervals. Main Outcomes and Measures: Changes in white matter diffusion metrics [fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivities (RD)] in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Results: Main findings showed HUD-specific WM microstructure changes encompassing mostly frontal major callosal, projection, and association tracts, characterized by increased FA (.949<1-p<.986) and decreased MD (.949<1-p<.997) and RD (.949<1-p<.999). The increased FA (r=-0.72, p<.00001) and decreased MD (r=0.69, p<.00001) and RD (r=0.67, p<.0001) in the genu and body of the corpus callosum and the left anterior corona radiata in iHUD were correlated with a reduction in baseline craving (.949<1-p<.999). No other WM correlations with outcome variables reached significance. Conclusions and Relevance: Our findings suggest whole-brain normalization of structural connectivity with inpatient medically-assisted treatment in iHUD encompassing recovery in frontal WM pathways implicated in emotional regulation and top-down executive control. The association with decreases in baseline craving further supports the relevance of these WM markers to a major symptom in drug addiction, with implications for monitoring clinical outcomes.

Association of Cortico-Striatal Engagement During Cue Reactivity, Reappraisal, and Savoring of Drug and Non-Drug Stimuli With Craving in Heroin Addiction.

OBJECTIVE: The authors investigated cortico-striatal reactivity to drug cues (as compared with neutral and food cues), drug cue reappraisal, food cue savoring, and their correlations with heroin craving in individuals with heroin use disorder compared with healthy control subjects. METHODS: Cross-sectional changes in functional MRI blood-oxygen-level-dependent signal during a novel cue reactivity task were assessed in 32 individuals with heroin use disorder (mean age, 40.3 years; seven women) and 21 age- and sex-matched healthy control subjects (mean age, 40.6 years; eight women). RESULTS: Drug cue reactivity (vs. neutral cues) was significantly higher in the nucleus accumbens in the heroin use disorder group compared with the control group and nominally significantly higher in the orbitofrontal cortex (OFC); ventromedial prefrontal cortex (vmPFC) activity positively correlated with drug craving. Drug cue reactivity (vs. salient food cues) was also higher in the inferior frontal gyrus (IFG) in the heroin use disorder group compared with the control group. Drug reappraisal and food savoring (vs. passive viewing) showed increased IFG and supplementary motor area activity in all participants; in the heroin use disorder group, higher IFG/dorsolateral PFC (dlPFC) activity during drug reappraisal and rostral anterior cingulate cortex (ACC) activity during food savoring were associated with lower drug cue-induced craving and longer treatment, respectively. A direct comparison of regulation of reactivity to both salient cues revealed widespread group differences such that drug reappraisal activity was higher in the heroin use disorder group and food savoring activity was higher in the control group in both cortical (e.g., OFC, IFG, ACC, vmPFC, and insula) and subcortical (e.g., dorsal striatum and hippocampus) regions. Higher drug reappraisal versus food savoring in the dlPFC was associated with higher self-reported methadone dosage in the heroin use disorder group. CONCLUSIONS: The results demonstrate cortico-striatal upregulation during drug cue exposure and impaired reactivity during processing of alternative non-drug rewards in the heroin use disorder group. Normalizing cortico-striatal function by reducing drug cue reactivity and enhancing natural reward valuation may inform therapeutic mechanisms for reducing drug craving and seeking in heroin addiction.

Naturalistic drug cue reactivity in heroin use disorder: orbitofrontal synchronization as a marker of craving and recovery.

Movies captivate groups of individuals (the audience), especially if they contain themes of common motivational interest to the group. In drug addiction, a key mechanism is maladaptive motivational salience attribution whereby drug cues outcompete other reinforcers within the same environment or context. We predicted that while watching a drug-themed movie, where cues for drugs and other reinforcers share a continuous narrative context, fMRI responses in individuals with heroin use disorder (iHUD) will preferentially synchronize during drug scenes. Results revealed such drug-biased synchronization in the orbitofrontal cortex (OFC), ventromedial and ventrolateral prefrontal cortex, and insula. After 15 weeks of inpatient treatment, there was a significant reduction in this drug-biased shared response in the OFC, which correlated with a concomitant reduction in dynamically-measured craving, suggesting synchronized OFC responses to a drug-themed movie as a neural marker of craving and recovery in iHUD.

Reduced neural encoding of utility prediction errors in cocaine addiction.

Influential accounts of addiction posit alterations in adaptive behavior driven by deficient dopaminergic prediction errors (PEs), signaling the discrepancy between actual and expected reward. Dopamine neurons encode these error signals in subjective terms, calibrated by individual risk preferences, as "utility" PEs. It remains unclear, however, whether people with drug addiction have PE deficits or their computational source. Here, using an analogous task to prior single-unit studies with known expectancies, we show that fMRI-measured PEs similarly reflect utility PEs. Relative to control participants, people with chronic cocaine addiction demonstrate reduced utility PEs in the dopaminoceptive ventral striatum, with similar trends in orbitofrontal cortex. Dissecting this PE signal into its subcomponent terms attributed these reductions to weaker striatal responses to received reward/utility, whereas suppression of activity with reward expectation was unchanged. These findings support that addiction may fundamentally disrupt PE signaling and reveal an underappreciated role for perceived reward value in this mechanism.

Recovery of inhibitory control prefrontal cortex function in inpatients with heroin use disorder: a 15-week longitudinal fMRI study.

Importance: Heroin addiction and related mortality impose a devastating toll on society, with little known about the neurobiology of this disease or its treatment. Poor inhibitory control is a common manifestation of prefrontal cortex (PFC) impairments in addiction, and its potential recovery following treatment is largely unknown in heroin (or any drug) addiction. Objective: To study inhibitory control brain activity in iHUD and HC, before and after 15 weeks of inpatient treatment in the former. Design: A longitudinal cohort study (11/2020-03/2022) where iHUD and HC underwent baseline and follow-up fMRI scans. Average follow-up duration: 15 weeks. Setting: The iHUD and HC were recruited from treatment facilities and surrounding neighborhoods, respectively. Participants: Twenty-six iHUD [40.6±10.1 years; 7 (29.2%) women] and 24 age-/sex-matched HC [41.1±9.9 years; 9 (37.5%) women]. Intervention: Following the baseline scan, inpatient iHUD continued to participate in a medically-assisted program for an average of 15 weeks (abstinence increased from an initial 183±236 days by 65±82 days). The HC were scanned at similar time intervals. Main Outcomes and Measures: Behavioral performance as measured by the stop-signal response time (SSRT), target detection sensitivity (d', proportion of hits in go vs. false-alarms in stop trials), and brain activity (blood-oxygen level dependent signal differences) during successful vs. failed stops in the stop signal task. Results: As we previously reported, at time 1 and as compared to HC, iHUD exhibited similar SSRT but impaired d' [t(38.7)=2.37, p=.023], and lower anterior and dorsolateral PFC (aPFC, dlPFC) activity (p<.001). Importantly, at time 2, there were significant gains in aPFC and dlPFC activity in the iHUD (group*session interaction, p=.002); the former significantly correlated with increases in d' specifically in iHUD (p=.012). Conclusions and Relevance: Compared to HC, the aPFC and dlPFC impairments in the iHUD at time 1 were normalized at time 2, which was associated with individual differences in improvements in target detection sensitivity. For the first time in any drug addiction, these results indicate a treatment-mediated inhibitory control brain activity recovery. These neurobehavioral results highlight the aPFC and dlPFC as targets for intervention with a potential to enhance self-control recovery in heroin addiction.

Altered prefrontal signaling during inhibitory control in a salient drug context in cocaine use disorder.

INTRODUCTION: Drug addiction is characterized by impaired response inhibition and salience attribution (iRISA), where the salience of drug cues is postulated to overpower that of other reinforcers with a concomitant decrease in self-control. However, the neural underpinnings of the interaction between the salience of drug cues and inhibitory control in drug addiction remain unclear. METHODS: We developed a novel stop-signal functional magnetic resonance imaging task where the stop-signal reaction time (SSRT-a classical inhibitory control measure) was tested under different salience conditions (modulated by drug, food, threat, or neutral words) in individuals with cocaine use disorder (CUD; n = 26) versus demographically matched healthy control participants (n = 26). RESULTS: Despite similarities in drug cue-related SSRT and valence and arousal word ratings between groups, dorsolateral prefrontal cortex (dlPFC) activity was diminished during the successful inhibition of drug versus food cues in CUD and was correlated with lower frequency of recent use, lower craving, and longer abstinence (Z > 3.1, P < 0.05 corrected). DISCUSSION: Results suggest altered involvement of cognitive control regions (e.g. dlPFC) during inhibitory control under a drug context, relative to an alternative reinforcer, in CUD. Supporting the iRISA model, these results elucidate the direct impact of drug-related cue reactivity on the neural signature of inhibitory control in drug addiction.

The Neural Signature of Impaired Inhibitory Control in Individuals with Heroin Use Disorder.

Heroin addiction imposes a devastating toll on society, with little known about its neurobiology. Excessive salience attribution to drug over nondrug cues/reinforcers, with concomitant inhibitory control decreases, are common mechanisms underlying drug addiction. Although inhibitory control alterations generally culminate in prefrontal cortex (PFC) hypoactivations across drugs of abuse, patterns in individuals with heroin addiction (iHUDs) remain unknown. We used a stop-signal fMRI task designed to meet recent consensus guidelines in mapping inhibitory control in 41 iHUDs and 24 age- and sex-matched healthy controls (HCs). Despite group similarities in the stop-signal response time (SSRT; the classic inhibitory control measure), compared with HCs, iHUDs exhibited impaired target detection sensitivity (proportion of hits in go vs false alarms in stop trials; p = 0.003). Additionally, iHUDs exhibited lower right anterior PFC (aPFC) and dorsolateral PFC (dlPFC) activity during successful versus failed stops (the hallmark inhibitory control contrast). Lower left dlPFC/supplementary motor area (SMA) activity was associated with slower SSRT specifically in iHUDs and lower left aPFC activity with worse target sensitivity across all participants (p < 0.05 corrected). Importantly, in iHUDs, lower left SMA and aPFC activity during inhibitory control was associated with shorter time since last use and higher severity of dependence, respectively (p < 0.05 corrected). Together, results revealed lower perceptual sensitivity and hypoactivations during inhibitory control in cognitive control regions (e.g., aPFC, dlPFC, SMA) as associated with task performance and heroin use severity measures in iHUDs. Such neurobehavioral inhibitory control deficits may contribute to self-control lapses in heroin addiction, constituting targets for prevention and intervention efforts to enhance recovery.SIGNIFICANCE STATEMENT Heroin addiction continues its deadly impact, with little known about the neurobiology of this disorder. Although behavioral and prefrontal cortical impairments in inhibitory control characterize addiction across drugs of abuse, these patterns remain underexplored in heroin addiction. Here, we illustrate a significant behavioral impairment in target discrimination in individuals with heroin addiction compared with matched healthy controls. We further show lower engagement during inhibitory control in the anterior and dorsolateral prefrontal cortex (key regions that regulate cognitive control) as associated with slower stopping, worse discrimination, and heroin use measures. Mapping the neurobiology of inhibitory control in heroin addiction for the first time, we identify potential treatment targets inclusive of prefrontal cortex-mediated cognitive control amenable for neuromodulation en route to recovery.

Common and distinct fronto-striatal volumetric changes in heroin and cocaine use disorders.

Different drugs of abuse impact the morphology of fronto-striatal dopaminergic targets in both common and unique ways. While dorsal striatal volume tracks with addiction severity across drug classes, opiates impact ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAcc) neuroplasticity in preclinical models, and psychostimulants alter inhibitory control, rooted in cortical regions such as the inferior frontal gyrus (IFG). We hypothesized parallel grey matter volume changes associated with human heroin or cocaine use disorder: lower grey matter volume of vmPFC/NAcc in heroin use disorder and IFG in cocaine use disorder, and putamen grey matter volume to be associated with addiction severity measures (including craving) across both. In this cross-sectional study, we quantified grey matter volume (P < 0.05-corrected) in age/sex/IQ-matched individuals with heroin use disorder (n = 32, seven females), cocaine use disorder (n = 32, six females) and healthy controls (n = 32, six females) and compared fronto-striatal volume between groups using voxel-wise general linear models and non-parametric permutation-based tests. Overall, individuals with heroin use disorder had smaller vmPFC and NAcc/putamen volumes than healthy controls. Bilateral lower IFG grey matter volume patterns were specifically evident in cocaine versus heroin use disorders. Correlations between addiction severity measures and putamen grey matter volume did not reach nominal significance level in this sample. These results indicate alterations in dopamine-innervated regions (in the vmPFC and NAcc) in heroin addiction. For the first time we demonstrate lower IFG grey matter volume specifically in cocaine compared with heroin use disorder, suggesting a signature of reduced inhibitory control, which remains to be tested directly using select behavioural measures. Overall, results suggest substance-specific volumetric changes in human psychostimulant or opiate addiction, with implications for fine-tuning biomarker and treatment identification by primary drug of abuse.

Altered functional connectivity during performance feedback processing in multiple sclerosis.

Effective learning from performance feedback is vital for adaptive behavior regulation necessary for successful cognitive performance. Yet, how this learning operates in clinical groups that experience cognitive dysfunction is not well understood. Multiple sclerosis (MS) is an autoimmune, degenerative disease of the central nervous system characterized by physical and cognitive dysfunction. A highly prevalent impairment in MS is cognitive fatigue (CF). CF is associated with altered functioning within cortico-striatal regions that also facilitate feedback-based learning in neurotypical (NT) individuals. Despite this cortico-striatal overlap, research about feedback-based learning in MS, its associated neural underpinnings, and its sensitivity to CF, are all lacking. The present study investigated feedback-based learning ability in MS, as well as associated cortico-striatal function and connectivity. MS and NT participants completed a functional magnetic resonance imaging (fMRI) paired-word association task during which they received trial-by-trial monetary, non-monetary, and uninformative performance feedback. Despite reporting greater CF throughout the task, MS participants displayed comparable task performance to NTs, suggesting preserved feedback-based learning ability in the MS group. Both groups recruited the ventral striatum (VS), caudate nucleus, and ventromedial prefrontal cortex in response to the receipt of performance feedback, suggesting that people with MS also recruit cortico-striatal regions during feedback-based learning. However, compared to NT participants, MS participants also displayed stronger functional connectivity between the VS and task-relevant regions, including the left angular gyrus and right superior temporal gyrus, in response to feedback receipt. Results indicate that CF may not interfere with feedback-based learning in MS. Nonetheless, people with MS may recruit alternative connections with the striatum to assist with this form of learning. These findings have implications for cognitive rehabilitation treatments that incorporate performance feedback to remediate cognitive dysfunction in clinical populations.

The neurobiology of drug addiction: cross-species insights into the dysfunction and recovery of the prefrontal cortex.

A growing preclinical and clinical body of work on the effects of chronic drug use and drug addiction has extended the scope of inquiry from the putative reward-related subcortical mechanisms to higher-order executive functions as regulated by the prefrontal cortex. Here we review the neuroimaging evidence in humans and non-human primates to demonstrate the involvement of the prefrontal cortex in emotional, cognitive, and behavioral alterations in drug addiction, with particular attention to the impaired response inhibition and salience attribution (iRISA) framework. In support of iRISA, functional and structural neuroimaging studies document a role for the prefrontal cortex in assigning excessive salience to drug over non-drug-related processes with concomitant lapses in self-control, and deficits in reward-related decision-making and insight into illness. Importantly, converging insights from human and non-human primate studies suggest a causal relationship between drug addiction and prefrontal insult, indicating that chronic drug use causes the prefrontal cortex damage that underlies iRISA while changes with abstinence and recovery with treatment suggest plasticity of these same brain regions and functions. We further dissect the overlapping and distinct characteristics of drug classes, potential biomarkers that inform vulnerability and resilience, and advancements in cutting-edge psychological and neuromodulatory treatment strategies, providing a comprehensive landscape of the human and non-human primate drug addiction literature as it relates to the prefrontal cortex.

Determining the effects of training duration on the behavioral expression of habitual control in humans: a multilaboratory investigation.

It has been suggested that there are two distinct and parallel mechanisms for controlling instrumental behavior in mammals: goal-directed actions and habits. To gain an understanding of how these two systems interact to control behavior, it is essential to characterize the mechanisms by which the balance between these systems is influenced by experience. Studies in rodents have shown that the amount of training governs the relative expression of these two systems: Behavior is goal-directed following moderate training, but the more extensively an instrumental action is trained, the more it becomes habitual. It is less clear whether humans exhibit similar training effects on the expression of goal-directed and habitual behavior, as human studies have reported contradictory findings. To tackle these contradictory findings, we formed a consortium, where four laboratories undertook a preregistered experimental induction of habits by manipulating the amount of training. There was no statistical evidence for a main effect of the amount of training on the formation and expression of habits. However, exploratory analyses suggest a moderating effect of the affective component of stress on the impact of training over habit expression. Participants who were lower in affective stress appeared to be initially goal-directed, but became habitual with increased training, whereas participants who were high in affective stress were already habitual even after moderate training, thereby manifesting insensitivity to overtraining effects. Our findings highlight the importance of the role of moderating variables such as individual differences in stress and anxiety when studying the experimental induction of habits in humans.

Demonstrating and disrupting well-learned habits.

Researchers have exerted tremendous efforts to empirically study how habits form and dominate at the expense of deliberation, yet we know very little about breaking these rigid habits to restore goal-directed control. In a three-experiment study, we first illustrate a novel approach of studying well-learned habits, in order to effectively demonstrate habit disruption. In Experiment 1, we use a Go/NoGo task with familiar color-response associations to demonstrate outcome-insensitivity when compared to novel, more flexible associations. Specifically, subjects perform more accurately when the required mapping is the familiar association of green-Go/red-NoGo than when it is red-Go/green-NoGo, confirming outcome-insensitive, habitual control. As a control condition, subjects show equivalent performance with unfamiliar color-response mappings (using the colors blue and purple mapped to Go and NoGo responses). Next, in Experiments 2 and 3, we test a motivation-based feedback manipulation in varying magnitudes (i.e., performance feedback with and without monetary incentives) to break the well-established habits elicited by our familiar stimuli. We find that although performance feedback prior to the contingency reversal test is insufficient to disrupt outcome-insensitivity in Experiment 2, a combination of performance feedback and monetary incentive is able to restore goal-directed control in Experiment 3, effectively breaking the habits. As the first successful demonstration of well-learned habit disruption in the laboratory, these findings provide new insights into how we execute and modify habits, while fostering new and translational research avenues that may be applicable to treating habit-based pathologies.

The neurobehavioral mechanisms of motivational control in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) poses debilitating impairments in the neurobehavioral systems governing reward-related processes-key to the control of motivated behaviors. Individuals with ADHD may rely on a motivational control system that favors cue-driven habits-rooted in the posterior putamen-over caudate and prefrontal cortex-driven goal-directed behaviors. We examined the neurobehavioral correlates of motivational control in ADHD. Twenty-five adults with ADHD and 25 neurotypicals underwent fMRI while training on two stimulus-response-outcome associations. A devaluation procedure followed, whereby they were selectively satiated on one of the snack outcomes, decreasing its value. A subsequent extinction test determined outcome-sensitivity (i.e., whether responses towards devalued snack diminished). Despite behavioral similarities, the ADHD group displayed a distinct neural signature marked by enhanced posterior putamen activation as a function of training. This region also displayed diminished functional connectivity with the dorsal anterior cingulate cortex, which is associated with top-down control. Our whole-brain analysis yielded ADHD-specific posterior putamen and opercular/insular cortex activity over the course of training-regions associated with stimulus-sensitivity and maladaptively rigid behaviors, respectively. Neural comparisons also identified hyper-recruitment of the hippocampus in the ADHD group. These results highlight corticostriatal discrepancies in ADHD, possibly serving as a biomarker of the disorder.

Effects of Expressive Writing on Neural Processing During Learning.

Expressive writing about past negative events has been shown to lead to a slew of positive outcomes. However, little is known about why writing about something negative would have positive effects. While some have posited that telling a narrative of a past negative event or current anxiety "frees up" cognitive resources, allowing individuals to focus more on the task at hand, there is little neural evidence suggesting that expressive writing has an effect on cognitive load. Moreover, little is known about how individual differences in the content of expressive writing could affect neural processing and the cognitive benefits writing confers. In our experiment, we compared brain activity in a group that had engaged in expressive writing vs. a control group, during performance on a feedback-based paired-associate word-learning task. We found that across groups, differential activation in the dorsal striatum in response to positive vs. negative feedback significantly predicted better later memory. Moreover, writing about a past failure resulted in more activation relative to the control group during the learning task in the mid-cingulate cortex (MCC), an area of the brain crucial to processing negative emotion. While our results do not provide support for the assertion that expressive writing alters attentional processing, our findings suggest that choosing to write about particularly intense past negative experiences like a difficult past failure may have resulted in changes in neural activation during task processing.

Habit Expression and Disruption as a Function of Attention-Deficit/Hyperactivity Disorder Symptomology.

Attention-deficit/hyperactivity disorder (ADHD) is associated with neurobehavioral reward system dysfunctions that pose debilitating impairments in adaptive decision-making. A candidate mechanism for such anomalies in ADHD may be a compromise in the control of motivated behaviors. Thus, demonstrating and restoring potential motivational control irregularities may serve significant clinical benefit. The motivational control of action guides goal-directed behaviors that are driven by outcome value, and habits that are inflexibly cue-triggered. We examined whether ADHD symptomology within the general population is linked to habitual control, and whether a motivation-based manipulation can break well-learned habits. We obtained symptom severity scores from 106 participants and administered a Go/NoGo task that capitalizes on familiar, well-learned associations (green-Go and red-NoGo) to demonstrate outcome-insensitivity when compared to newly learned Go/NoGo associations. We tested for outcome-insensitive habits by changing the Go and NoGo contingencies, such that Go signals became NoGo signals and vice versa. We found that generally, participants responded less accurately when green and red stimuli were mapped to color-response contingencies that were incongruent with daily experiences, whereas novel Go/NoGo stimuli evoked similar accuracy regardless of color-response mappings. Thus, our Go/NoGo task successfully elicited outcome-insensitive habits (i.e., persistent responses to familiar stimuli without regard for consequences); however, this effect was independent of ADHD symptomology. Nevertheless, we found an association between hyperactivity and congruent Go response latency, suggesting heightened pre-potency to perform habitual Go actions as hyperactivity increases. To examine habit disruption, participants returned to the lab and underwent the familiar version of the Go/NoGo task, but were given mid-experiment performance tracking information and a monetary incentive prior to contingency change. We found that this motivational boost via dual feedback prevented the incongruency-related accuracy impairment, effectively breaking the habit, albeit independent of ADHD symptomology. Our findings present only a modest link between ADHD symptomology and motivational control, which may be due to compensatory mechanisms in ADHD driving goal-directed control, or our task's potential insensitivity to individual differences in ADHD symptomology. Further investigations may be crucial for determining whether ADHD is related to motivational impairments.

Novelty-facilitated extinction: providing a novel outcome in place of an expected threat diminishes recovery of defensive responses.

BACKGROUND: Experimental extinction serves as a model for psychiatric treatments based on associative learning. However, the effects of extinction are often transient, as evidenced by postextinction return of defensive behaviors. From a therapeutic perspective, an inherent problem with extinction may be that mere omission of threat is not sufficient to reduce future threat uncertainty. The current study tested an augmented form of extinction that replaced, rather than merely omitted, expected threat outcomes with novel nonthreat outcomes, with the goal of reducing postextinction return of defensive behaviors. METHODS: Thirty-two healthy male Sprague-Dawley rats and 47 human adults underwent threat conditioning to a conditioned stimulus paired with an electrical shock. Subjects then underwent a standard extinction protocol with shock omitted or an augmented extinction protocol wherein the shock was replaced by a surprising tone. Tests of postextinction recovery occurred 24 hours later in the absence of the tone. RESULTS: Replacing the shock with a novel nonthreat outcome, as compared with shock omission, reduced postextinction recovery (freezing in rats and anticipatory skin conductance responses in humans) when tested 24 hours later. Self-reported intolerance of uncertainty was positively correlated with recovery following standard extinction in humans, providing new evidence that postextinction recovery is related to sensitivity to future threat uncertainty. CONCLUSIONS: These findings provide cross-species evidence of a novel strategy to enhance extinction that may have broad implications for how to override associative learning that has become maladaptive and offer a simple technique that could be straightforwardly adapted and implemented in clinical situations.