Joseph E. Dunsmoor’s research while affiliated with University of Texas at Austin and other places

Because extinction forms the empirical foundation of exposure therapy, strategies to enhance extinction could lead to more effective interventions for post-traumatic stress disorder (PTSD). Here, we used functional MRI to compare immediate and long-term efficacy of enhanced versus standard extinction in 54 adults with (n=32) and without (n=22) PTSD. In both control and PTSD groups, counterconditioning—an enhanced form of extinction that replaces threat with positive outcomes—was more effective than standard extinction. It reduced threat-related neural activity and promoted reinstatement of safety (extinction) patterns in the ventromedial prefrontal cortex (a region involved in learning and retrieving safety associations). However, the PTSD group continued to reinstate both threat- and safety-related neural patterns in the dorsal anterior cingulate cortex (a region involved in learning and retrieving threat associations). These findings represent novel evidence that enhanced extinction outperforms standard extinction in promoting more rapid and persistent neural representations of safety in PTSD.

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS-category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+-specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

The amygdala is considered crucial to the formation of emotional episodic memories, but causal evidence in humans is limited due to challenges in non-invasive neuromodulation of deep brain structures. In a double-blind, sham-controlled, repeated measures study, we examined whether transcranial low-intensity focused ultrasound (tFUS) targeting the left amygdala prior to the encoding of emotional and neutral pictures impacted memory for these pictures 24 hours later. We used a putative inhibitory tFUS protocol shown to attenuate amygdala blood-oxygenation- level-dependent signal, thus testing the hypothesis that pre-encoding amygdala inhibition diminishes emotional memory. Surprisingly, active vs. sham sonication enhanced multiple measures of neutral and emotional memory across two memory tests. A secondary test of amygdala function found that active sonication enhanced fear recognition in faces. Computational modeling further supported these results. These findings motivate a novel conceptualization of the amygdala’s role in emotional episodic memory. Rather than enhancing memory via amplification of salient stimuli, the amygdala may instead act as a filter that attenuates the maintenance of non-salient stimuli in long-term memory. Finally, the potential to enhance memory serves as an impetus to test tFUS of the amygdala in disorders such as depression and posttraumatic disorder that exhibit comorbid hyperreactive amygdalae and memory impairments.

Event boundaries help structure the content of episodic memories by segmenting continuous experiences into discrete events. Event boundaries may also serve to preserve meaningful information within an event, thereby actively separating important memories from interfering representations imposed by past and future events. Here, we tested the hypothesis that event boundaries organize emotional memory based on changing dynamics as events unfold. We developed a novel threat-reversal learning task whereby participants encoded trial-unique exemplars from two semantic categories across three phases: preconditioning, fear acquisition, and reversal. Shock contingencies were established for one category during acquisition (CS+) and then switched to the other during reversal (CS−). Importantly, reversal was either separated by a perceptible event boundary (Experiment 1) or occurred immediately after acquisition, with no perceptible context shift (Experiment 2). In a surprise recognition memory test the next day, memory performance tracked the learning contingencies from encoding in Experiment 1, such that participants selectively recognized more threat-associated CS+ exemplars from before (retroactive) and during acquisition, but this pattern reversed toward CS− exemplars encoded during reversal. By contrast, participants with continuous encoding—without a boundary between conditioning and reversal—exhibited undifferentiated memory for exemplars from both categories encoded before acquisition and after reversal. Further analyses highlight nuanced effects of event boundaries on reversing conditioned fear, updating mnemonic generalization, and emotional biasing of temporal source memory. These findings suggest that event boundaries provide anchor points to organize memory for distinctly meaningful information, thereby adaptively structuring memory based on the content of our experiences.

Emotional intensity can produce both optimal and suboptimal effects on learning and memory. While emotional events tend to be better remembered, memory performance can follow an inverted U-shaped curve with increasing intensity. The strength of Pavlovian conditioning tends to increase linearly with the intensity of the aversive outcome, but leads to greater stimulus generalization. Here, we combined elements of episodic memory and Pavlovian conditioning into a single paradigm to investigate the effects of varying outcome intensities on conditioned fear responses and episodic memory. Participants encoded trial-unique images from two semantic categories as conditioned stimuli (CS ⁺ and CS ⁻ ) before (preconditioning), during, and after (extinction) acquisition. We systematically varied the intensity of the unconditioned stimulus (US) during acquisition between-groups as a nonaversive tone, a low-intensity electrical shock, or a high-intensity electrical shock paired with a loud static noise. Results showed that conditioned skin conductance responses scaled linearly with US intensity during acquisition, with a high-intensity US leading to greater resistance to extinction and stronger 24 h fear recovery. However, 24 h recognition memory produced an inverted U-shaped relationship, with better recognition memory for CSs encoded before (retroactive), during, and following conditioning using a low-intensity US. These findings suggest a dissociation between optimal levels of emotional intensity on explicit and implicit learning and memory performance.

The neurocircuitry mechanisms underlying recall of traumatic memories remain unclear. This study investigated whether traumatic memory recall engages neurocircuitry representations that mirror activity patterns engaged during generalized threat stimulus processing in Post Traumatic Stress Disorder (PTSD). Multivariate pattern analysis was used to train 3 decoders. A "trauma" decoder was trained on fMRI patterns during idiographic trauma versus neutral narratives in a sample of 73 adult women with PTSD. A separate cohort of 125 adult participants completed a reward and threat learning task, from which "shock" and "reward loss" decoders were trained on neural patterns during threat or reward outcome delivery, respectively. These decoders were then cross-tested on the alternative datasets, allowing analyses of the degree to which traumatic memory recall engaged neurocircuitry representations that overlap with more general aversive stimuli. Decoders were trained and tested in four networks related to salience processing as well bilateral amygdala and hippocampal masks. The shock decoder trained in a midcingulate / posterior insula network demonstrated elevated predictions for shock during traumatic versus neutral memory recall. Similarly, the trauma decoder made elevated predictions about trauma recall during shock versus no shock delivery across multiple networks related to salience processing. There was no overlap between reward loss decoder predictions and trauma memory recall or vice versa. PTSD participants with elevated re-experiencing symptoms demonstrated the highest engagement of shock activity patterns during trauma memory recall. These results suggest that trauma memory recall engages neurocircuitry representations that overlap with threat, specifically painful, stimulus delivery.

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS- category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+- specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

Counterconditioning (CC) aims to enhance extinction of threat memories by establishing new associations of opposite valence. While its underlying neurocognitive mechanisms remain largely unexplored, previous studies suggest qualitatively different mechanisms from regular extinction. In this functional MRI study, participants underwent categorical threat conditioning (CS+/CS-: images of animals/tools), followed by either CC (CS+ images reinforced with monetary rewards, n=24) or regular extinction (n=24). The following day, we assessed spontaneous recovery of threat responses and episodic memory for CS+ and CS- category exemplars. While the ventromedial prefrontal cortex (vmPFC) was activated during regular extinction, participants undergoing CC showed persistent CS+- specific deactivation of the vmPFC and hippocampus, and CS+-specific activation of the nucleus accumbens (NAcc). The following day, physiological threat responses returned in the regular extinction group, but not in the CC group. Counterconditioning furthermore strengthened episodic memory for CS+ exemplars presented during CC, and retroactively also for CS+ exemplars presented during the threat conditioning phase. Our findings confirm that CC leads to more persistent extinction of threat memories, as well as altered consolidation of the threat conditioning episode. Crucially, we show a qualitatively different activation pattern during CC versus regular extinction, with a shift away from the vmPFC and towards the NAcc.

Theoretical and methodological research on threat conditioning provides important neuroscience-informed approaches to studying fear and anxiety. The threat conditioning framework is at the vanguard of physiological and neurobiological research into core mechanistic symptoms of anxiety-related psychopathology, providing detailed models of neural circuitry underlying variability in clinically relevant behaviors (e.g., decreased extinction, heightened generalization) and heterogeneity in clinical anxiety presentations. Despite the strengths of this approach in explaining symptom and syndromal heterogeneity, the vast majority of psychopathology-oriented threat conditioning work has been conducted using Diagnostic and Statistical Manualof Mental Disorders (DSM) diagnostic categories, which fail to capture the symptom-level resolution that is afforded by threat conditioning indices. Furthermore, relations between fine-grained neurobehavioral measures of threat conditioning and anxiety traits and symptoms are substantially attenuated by within-category heterogeneity, arbitrary boundaries, and inherent comorbidity in the DSM approach. Conversely, the Hierarchical Taxonomy of Psychopathology (HiTOP) is a promising approach for modeling anxiety symptoms relevant to threat conditioning work and for relating threat conditioning to broader anxiety-related constructs. To date, HiTOP has had a minimal impact on the threat conditioning field. Here, we propose that combining the HiTOP and neurobehavioral threat conditioning approaches is an important next step in studying anxiety-related pathology. We provide a brief review of prominent DSM critiques and how they affect threat conditioning studies and review relevant research and suggest solutions and recommendations that flow from the HiTOP perspective. Our hope is that this effort serves as both an inflection point and practical primer for HiTOP-aligned threat conditioning research that benefits both fields.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder with defining abnormalities in memory, and psychedelics may be promising candidates for the treatment of PTSD given their effects on multiple memory systems. Most PTSD and psychedelic research has investigated memory with fear conditioning and extinction. While fruitful, conditioning and extinction provide a limited model of the complexity of PTSD and phenomenology of psychedelics, thereby limiting the refinement of therapies. In this review, we discuss abnormalities in fear conditioning and extinction in PTSD and review 25 studies testing psychedelics on these forms of memory. Perhaps the most reliable effect is that the acute effects of psychedelics can enhance extinction learning, which is impaired in PTSD. However, the post-acute effects may also enhance extinction learning, and the acute effects can also enhance fear conditioning. We then discuss abnormalities in episodic and semantic memory in PTSD and review current knowledge on how psychedelics impact these memory systems. Although PTSD and psychedelics acutely impair the formation of hippocampal-dependent episodic memories, psychedelics may acutely enhance cortical-dependent learning of semantic memories that could facilitate the integration of trauma memories and disrupt maladaptive beliefs. More research is needed on the acute effects of psychedelics on episodic memory consolidation, retrieval, and reconsolidation and post-acute effects of psychedelics on all phases of episodic memory. We conclude by discussing how targeting multiple memory mechanisms could improve upon the current psychedelic therapy paradigm for PTSD, thereby necessitating a greater emphasis on assessing diverse measures of memory in translational PTSD and psychedelic research.