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"Anderson, Michael C."
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Prefrontal-hippocampal interactions supporting the extinction of emotional memories: the retrieval stopping model
Neuroimaging has revealed robust interactions between the prefrontal cortex and the hippocampus when people stop memory retrieval. Efforts to stop retrieval can arise when people encounter reminders to unpleasant thoughts they prefer not to think about. Retrieval stopping suppresses hippocampal and amygdala activity, especially when cues elicit aversive memory intrusions, via a broad inhibitory control capacity enabling prepotent response suppression. Repeated retrieval stopping reduces intrusions of unpleasant memories and diminishes their affective tone, outcomes resembling those achieved by the extinction of conditioned emotional responses. Despite this resemblance, the role of inhibitory fronto-hippocampal interactions and retrieval stopping broadly in extinction has received little attention. Here we integrate human and animal research on extinction and retrieval stopping. We argue that reconceptualising extinction to integrate mnemonic inhibitory control with learning would yield a greater understanding of extinction’s relevance to mental health. We hypothesize that fear extinction spontaneously engages retrieval stopping across species, and that controlled suppression of hippocampal and amygdala activity by the prefrontal cortex reduces fearful thoughts. Moreover, we argue that retrieval stopping recruits extinction circuitry to achieve affect regulation, linking extinction to how humans cope with intrusive thoughts. We discuss novel hypotheses derived from this theoretical synthesis.
Journal Article
Inducing forgetting of unwanted memories through subliminal reactivation
Processes that might facilitate the forgetting of unwanted experiences typically require the actual or imagined re-exposure to reminders of the event, which is aversive and carries risks to people. But it is unclear whether awareness of aversive content is necessary for effective voluntary forgetting. Disrupting hippocampal function through retrieval suppression induces an amnesic shadow that impairs the encoding and stabilization of unrelated memories that are activated near in time to people’s effort to suppress retrieval. Building on this mechanism, here we successfully disrupt retention of unpleasant memories by subliminally reactivating them within this amnesic shadow. Critically, whereas unconscious forgetting occurs on these affective memories, the amnesic shadow itself is induced by conscious suppression of unrelated and benign neutral memories, avoiding conscious re-exposure of unwelcome content. Combining the amnesic shadow with subliminal reactivation may offer a new approach to voluntary forgetting that bypasses the unpleasantness in conscious exposure to unwanted memories.
Classical forgetting methods typically re-expose people to reminders of their unwanted memories. Here, the authors disrupt unpleasant memories by subliminally reactivating them as participants suppress retrieval of unrelated neutral memories, avoiding the need for conscious exposure.
Journal Article
Dynamic targeting enables domain-general inhibitory control over action and thought by the prefrontal cortex
Over the last two decades, inhibitory control has featured prominently in accounts of how humans and other organisms regulate their behaviour and thought. Previous work on how the brain stops actions and thoughts, however, has emphasised distinct prefrontal regions supporting these functions, suggesting domain-specific mechanisms. Here we show that stopping actions and thoughts recruits common regions in the right dorsolateral and ventrolateral prefrontal cortex to suppress diverse content, via dynamic targeting. Within each region, classifiers trained to distinguish action-stopping from action-execution also identify when people are suppressing their thoughts (and vice versa). Effective connectivity analysis reveals that both prefrontal regions contribute to action and thought stopping by targeting the motor cortex or the hippocampus, depending on the goal, to suppress their task-specific activity. These findings support the existence of a domain-general system that underlies inhibitory control and establish Dynamic Targeting as a mechanism enabling this ability.
The authors use fMRI to show that the ability to stop unwanted actions and thoughts arises from a common stopping mechanism that flexibly inhibits activity in diverse, content-specific brain areas.
Journal Article
Reducing future fears by suppressing the brain mechanisms underlying episodic simulation
Imagining future events conveys adaptive benefits, yet recurrent simulations of feared situations may help to maintain anxiety. In two studies, we tested the hypothesis that people can attenuate future fears by suppressing anticipatory simulations of dreaded events. Participants repeatedly imagined upsetting episodes that they feared might happen to them and suppressed imaginings of other such events. Suppressing imagination engaged the right dorsolateral prefrontal cortex, which modulated activation in the hippocampus and in the ventromedial prefrontal cortex (vmPFC). Consistent with the role of the vmPFC in providing access to details that are typical for an event, stronger inhibition of this region was associated with greater forgetting of such details. Suppression further hindered participants’ ability to later freely envision suppressed episodes. Critically, it also reduced feelings of apprehensiveness about the feared scenario, and individuals who were particularly successful at down-regulating fears were also less trait-anxious. Attenuating apprehensiveness by suppressing simulations of feared events may thus be an effective coping strategy, suggesting that a deficiency in this mechanism could contribute to the development of anxiety.
Journal Article
Hippocampal GABA enables inhibitory control over unwanted thoughts
Intrusive memories, images, and hallucinations are hallmark symptoms of psychiatric disorders. Although often attributed to deficient inhibitory control by the prefrontal cortex, difficulty in controlling intrusive thoughts is also associated with hippocampal hyperactivity, arising from dysfunctional GABAergic interneurons. How hippocampal GABA contributes to stopping unwanted thoughts is unknown. Here we show that GABAergic inhibition of hippocampal retrieval activity forms a key link in a fronto-hippocampal inhibitory control pathway underlying thought suppression. Subjects viewed reminders of unwanted thoughts and tried to suppress retrieval while being scanned with functional magnetic resonance imaging. Suppression reduced hippocampal activity and memory for suppressed content.
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H magnetic resonance spectroscopy revealed that greater resting concentrations of hippocampal GABA predicted better mnemonic control. Higher hippocampal, but not prefrontal GABA, predicted stronger fronto-hippocampal coupling during suppression, suggesting that interneurons local to the hippocampus implement control over intrusive thoughts. Stopping actions did not engage this pathway. These findings specify a multi-level mechanistic model of how the content of awareness is voluntarily controlled.
It is not fully understood how intrusive or unwanted memories are regulated. Here the authors show that hippocampal GABA concentrations, and coupling between the dorsolateral prefrontal cortex and hippocampus, predict how well subjects can suppress unwanted memories when presented with a reminder.
Journal Article
Suppressing unwanted memories reduces their unconscious influence via targeted cortical inhibition
Suppressing retrieval of unwanted memories reduces their later conscious recall. It is widely believed, however, that suppressed memories can continue to exert strong unconscious effects that may compromise mental health. Here we show that excluding memories from awareness not only modulates medial temporal lobe regions involved in explicit retention, but also neocortical areas underlying unconscious expressions of memory. Using repetition priming in visual perception as a model task, we found that excluding memories of visual objects from consciousness reduced their later indirect influence on perception, literally making the content of suppressed memories harder for participants to see. Critically, effective connectivity and pattern similarity analysis revealed that suppression mechanisms mediated by the right middle frontal gyrus reduced activity in neocortical areas involved in perceiving objects and targeted the neural populations most activated by reminders. The degree of inhibitory modulation of the visual cortex while people were suppressing visual memories predicted, in a later perception test, the disruption in the neural markers of sensory memory. These findings suggest a neurobiological model of how motivated forgetting affects the unconscious expression of memory that may be generalized to other types of memory content. More generally, they suggest that the century-old assumption that suppression leaves unconscious memories intact should be reconsidered.
Journal Article
Inducing amnesia through systemic suppression
Hippocampal damage profoundly disrupts the ability to store new memories of life events. Amnesic windows might also occur in healthy people due to disturbed hippocampal function arising during mental processes that systemically reduce hippocampal activity. Intentionally suppressing memory retrieval (retrieval stopping) reduces hippocampal activity via control mechanisms mediated by the lateral prefrontal cortex. Here we show that when people suppress retrieval given a reminder of an unwanted memory, they are considerably more likely to forget unrelated experiences from periods surrounding suppression. This amnesic shadow follows a dose-response function, becomes more pronounced after practice suppressing retrieval, exhibits characteristics indicating disturbed hippocampal function, and is predicted by reduced hippocampal activity. These findings indicate that stopping retrieval engages a suppression mechanism that broadly compromises hippocampal processes and that hippocampal stabilization processes can be interrupted strategically. Cognitively triggered amnesia constitutes an unrecognized forgetting process that may account for otherwise unexplained memory lapses following trauma.
Suppressing an unwanted memory reduces hippocampal activity and makes people more likely to forget the experience. Here, the authors show that suppressing past events induces an \"amnesic shadow\" for experiences near in time to suppression, consistent with a global disruption to hippocampal function.
Journal Article
On the role of inhibition in suppression-induced forgetting
Suppressing retrieval of unwanted memories can cause forgetting, an outcome often attributed to the recruitment of inhibitory control. This suppression-induced forgetting (SIF) generalizes to different cues used to test the suppressed content (cue-independence), a property taken as consistent with inhibition. But does cue-independent forgetting necessarily imply that a memory has been inhibited? Tomlinson et al. (Proc Natl Acad Sci 106:15588–15593, 2009) reported a surprising finding that pressing a button also led to cue-independent forgetting, which was taken as support for an alternative interference account. Here we investigated the role of inhibition in forgetting due to retrieval suppression and pressing buttons. We modified Tomlinson et al.’s procedure to examine an unusual feature they introduced that may have caused memory inhibition effects in their experiment: the omission of explicit task-cues. When tasks were uncued, we replicated the button-press forgetting effect; but when cued, pressing buttons caused no forgetting. Moreover, button-press forgetting partially reflects output-interference effects at test and not a lasting effect of interference. In contrast, SIF occurred regardless of these procedural changes. Collectively, these findings indicate that simply pressing a button does not induce forgetting, on its own, without confounding factors that introduce inhibition into the task and that inhibition likely underlies SIF.
Journal Article
Trans-synaptic molecular context of NMDA receptor nanodomains
Tight coordination of spatial relationships between protein complexes is required for cellular function. In neuronal synapses, proteins responsible for neurotransmission form subsynaptic nanoclusters whose trans-cellular alignment modulates synaptic signal propagation. However, the spatial relationships between these proteins and NMDA receptors (NMDARs), which are required for learning and memory, remain undefined. Here, we mapped key NMDAR subunits relative to active zone and post-synaptic density reference proteins using multiplexed super-resolution DNA-PAINT microscopy in rat hippocampal neurons. GluN2A and GluN2B subunits formed diverse nanoclusters that, surprisingly, were not localized near presynaptic vesicle release sites marked by Munc13-1. However, a subset of release sites was enriched with NMDARs, and modeling indicated this nanotopography promotes NMDAR activation. These enriched sites were internally denser with Munc13-1, aligned with PSD-95, and closely associated with specific NMDAR nanodomains. NMDAR activation rapidly reorganized this relationship, suggesting a structural mechanism for tuning NMDAR-mediated synaptic transmission. These findings suggest synaptic functional architecture depends on assembly of and trans-cellular spatial relationships between multiprotein nanodomains.
Spatial relationships between clustered proteins within synapses shape neurotransmission. Here, NMDA receptors are shown to align with only a subset of presynaptic release sites, suggesting a structural mechanism controls NMDAR-mediated synaptic transmission.
Journal Article