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Schematic diagram of possible interventions on reconsolidation memory. Three possible approaches are described here. (a) Drug or other manipulations acting as metaplastic stimuli and/or on destabilization given before retrieval. (b) Drug treatment acting on molecular mechanisms of reconsolidation given at a time that guarantees plasma peak level during the 1–6-h temporal window of memory vulnerability. (c) Psycho-behavioral intervention acting as competing processes (e.g., post-retrieval extinction) given during the 1–6-h temporal window of memory vulnerability, and maybe on following hours. The consequences of memory manipulation could be assessed in the clinic or tested in an experiment as spontaneous recovery, renewal, or reinstatement (“TEST”; see Fig. 1 legend for description). Arrows indicate timeline of the different stages (segment length is not proportional to time duration). Abbreviations: dd = days; hrs = hours; min = minutes
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Rationale:
Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is bein...
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Citations
... Taking into consideration that ketamine's molecular and neural mechanisms of action are also involved in memory reconsolidation, Fattore et al. speculated that application of ketamine few hours prior to memory retrieval may trigger a metaplastic cascade. Increased synaptic plasticity and alterations in neural connectivity facilitate destabilization of memories and increases receptiveness to non-pharmacological interventions (136). Although there are concerns regarding increased risk of self-harm and suicidal behavior following trauma-focused treatments in BPD patients, a systematic review of psychotherapeutic approaches for comorbid BPD and PTSD treatment indicated that trauma-focused therapies may reduce both PTSD and BPD symptoms, whereas BPD-specific psychotherapies do not alleviate PTSD symptoms (137). ...
Borderline personality disorder (BPD) is diagnosed in 10-30% of patients with major depressive disorder (MDD), and the frequency of MDD among individuals with BPD reaches over 80%. The comorbidity of MDD and BPD is associated with more severe depressive symptoms and functional impairment, higher risk of treatment resistance and increased suicidality. The effectiveness of ketamine usage in treatment resistant depression (TRD) has been demonstrated in numerous studies. In most of these studies, individuals with BPD were not excluded, thus given the high co-occurrence of these disorders, it is possible that the beneficial effects of ketamine also extend to the subpopulation with comorbid TRD and BPD. However, no protocols were developed that would account for comorbidity. Moreover, psychotherapeutic interventions, which may be crucial for achieving a lasting therapeutic effect in TRD and BPD comorbidity, were not included. In the article, we discuss the results of a small number of existing studies and case reports on the use of ketamine in depressive disorders with comorbid BPD. We elucidate how, at the molecular and brain network levels, ketamine can impact the neurobiology and symptoms of BPD. Furthermore, we explore whether ketamine-induced neuroplasticity, augmented by psychotherapy, could be of use in alleviating core BPD-related symptoms such as emotional dysregulation, self-identity disturbances and self-harming behaviors. We also discuss the potential of ketamine-assisted psychotherapy (KAP) in BPD treatment. As there is no standard approach to the application of ketamine or KAP in individuals with comorbid TRD and BPD, we consider further research in the field as imperative. The priorities should include development of dedicated protocols, distinguishing subpopulations that may benefit most from such treatment and investigating factors that may influence its effectiveness and safety.
... Cannabinoids and dissociative anesthetics such as ketamine exert their psychedelic effects by activation of cannabinoid receptors and NMDA blockade, mechanisms eventually leading to an increased plasticity that may facilitate the integration Drug X Environment (Fattore et al., 2018). In the latter paper, we proposed that ketamine and cannabinoids may induce permissive mechanisms for subsequent plasticity, i.e., metaplastic effects that may facilitate the effect of the interaction with the environmental context (for metaplasticity as a model of integration of psychedelics into therapy see also Heifets & Olson, 2024). ...
... Trait and decisional impulsivity are relatively stable characteristics, while motor disinhibition can fluctuate naturally and improve with cognitive training (Houben, Nederkoorn, Wiers, & Jansen, 2011;Jones, Christiansen, Nederkoorn, Houben, & Field, 2013). Furthermore, neuroadaptive changes at glutamatergic synapses which appear to diminish responsivity to plasticity induction can potentially be counteracted with pharmacological agents (Chiamulera et al., 2021), such as NMDA channel blocker, ketamine (Fattore, Piva, Zanda, Fumagalli, & Chiamulera, 2018). Such agents − which are purported to amplify the malleability of neuronal circuits (Chiamulera et al., 2021)− have been combined with TMS protocols to treat symptoms of neuropsychiatric disorders in intractable states (Best, Pavel, & Haustrup, 2019;Pradhan, Parikh, Makani, & Sahoo, 2015). ...
... Such agents − which are purported to amplify the malleability of neuronal circuits (Chiamulera et al., 2021)− have been combined with TMS protocols to treat symptoms of neuropsychiatric disorders in intractable states (Best, Pavel, & Haustrup, 2019;Pradhan, Parikh, Makani, & Sahoo, 2015). Preliminary evidence indicates that improved response inhibition attenuates alcohol cue-induced craving (Papachristou et al., 2013) and intake (Houben et al., 2011); thus, future research is required to delineate the role of noninvasive neuromodulation − possibly paired with pharmacological agents which may increase responsivity to intervention (Fattore et al., 2018)− to enhance fronto-striatal integrity underlying inhibitory control and, in turn, mitigate adverse alcohol-related outcomes in AUD. ...
Background
Response inhibition − or the ability to withhold a suboptimal response − relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use.
Methods
Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26–74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27–73 years, 6[30%] females) within a larger sample of 35 HCs (23–84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions.
Results
HCs showed decreased stop signal reaction time in the excitation condition (t(19) = −3.01, p = 0.007, [CIs]:−35.6 to −6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: −68.64 to −14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:−3.34 to −0.55).
Conclusion
In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.
... 52 Reference to Curran et al. (2018); Zhang and Stackman (2015). Also Fattore et al. (2018) explores the link between psychedelics and reconsolidation. 53 For example, Frood (2012); Krebs and Johansen (2012); Johnson et al. (2014). ...
Scholarship has not so far raised the question whether the so-called Buddhist noble truths are actually true. The present article addresses this question in light of recent developments in neuroscience and psychology. It bases itself primarily on the theory proposed in some publications by Mark Solms, and on some other recent discoveries in psychology. Concentrating on the role of memories in the formation of personality, it draws attention to the potential effects of memory reconsolidation on those memories and shows how cessation of suffering and cessation of desire make sense in this context. Access to the relevant memories presents itself as a little understood process. Proposals are made as to how it may be attained.
... In contrast, Young et al. [46] report that, in mice, MDMA administered prior to cued fear extinction enhances fear extinction memory recall and reduces fear renewal induces spontaneous recovery. However, it is important to note that there is an interaction between the extinction and reconsolidation processes [39] and we cannot exclude that the MDMA may act on both processes [39,47,48]. Similar conclusions have been reported in clinical trials in humans [47,49]. ...
... However, it is important to note that there is an interaction between the extinction and reconsolidation processes [39] and we cannot exclude that the MDMA may act on both processes [39,47,48]. Similar conclusions have been reported in clinical trials in humans [47,49]. Interestingly, the beneficial behavioral effects of MDMA treatment paired with a trauma-cue were accompanied by a normalization of the dendritic cytoarchitecture of DG and BLA neurons. ...
MDMA (3,4-methylenedioxymethamphetamine), a synthetic ring-substituted amphetamine, combined with psychotherapy has demonstrated efficacy for the treatment of chronic posttraumatic stress disorder (PTSD) patients. This controlled prospective study aimed to assess the bio-behavioral underpinnings of MDMA in a translational model of PTSD. Rats exposed to predator-scent stress (PSS) were subjected to a trauma-cue at day 7 shortly after single-dose MDMA injection (5 mg/kg). The elevated plus maze and acoustic startle response tests were assessed on day 14 and served for classification into behavioral response groups. Freezing response to a further trauma-reminder was assessed on Day 15. The morphological characteristics of the dentate gyrus (DG) and basolateral amygdala (BLA) were subsequently examined. Hypothalamic–pituitary–adrenal axis and 5-hydroxytryptamine involvement were evaluated using: (1) corticosterone measurements at 2 h and 4 h after MDMA treatment, (2) Lewis strain rats with blunted HPA-response and (3) pharmacological receptor-blockade. MDMA treatment was effective in attenuating stress behavioral responses only when paired with memory reactivation by a trauma-cue. The effects of the treatment on behavior were associated with a commensurate normalization of the dendritic cytoarchitecture of DG and BLA neurons. Pretreatment with RU486, Ketanserin, or Pindolol prevented the above improvement in anxiety-like behavioral responses. MDMA treatment paired with memory reactivation reduced the prevalence rate of PTSD-phenotype 14 days later and normalized the cytoarchitecture changes induced by PSS (in dendritic complexities) compared to saline control. MDMA treatment paired with a trauma-cue may modify or update the original traumatic memory trace through reconsolidation processes. These anxiolytic-like effects seem to involve the HPA axis and 5-HT systems.
... What are the implications of the effects of psychedelics on working memory with regards to how these substances are used to treat diseases? For example, psychedelics are proposed for treating PTSD but it is unclear whether they would have an effect on destabilizing maladaptive memories as per different reconsolidation paradigms (Fattore et al., 2018), or whether they would affect non-maladaptive memories recalled during therapy in any way. Further, there are uncertainties about the permanency of possible memory impairment, and whether the process of remembering something during a trip causes disruption of processes such as memory reconsolidation, and what this means for long-term memory integrity. ...
Psychedelic compounds hold the promise of changing the face of neuroscience and psychiatry as we know it. There have been numerous proposals to use them to treat a range of neuropsychiatric conditions such as depression, anxiety, addiction and PTSD; and trials to date have delivered positive results in favor of the novel therapeutics. Further to the medical use, the wider healthy population is gaining interest in these compounds. We see a surge in personal use of psychedelic drugs for reasons not limited to spiritual enhancement, improved productivity, aiding the management of non-pathological anxiety and depression, and recreational interests. Notably, microdosing—the practice of taking subacute doses of psychedelic compounds—is on the rise. Our knowledge about the effects of psychedelic compounds, however, especially in naturalistic settings, is still fairly limited. In particular, one of the largest gaps concerns the acute effects on cognition caused by psychedelics. Studies carried out to date are riddled with limitations such as having disparate paradigms, small sample sizes, and insufficient breadth of testing on both unhealthy and healthy volunteers. Moreover, the studies are majoritarily limited to laboratory settings and do not assess the effects at multiple dosages within the same paradigm nor at various points throughout the psychedelic experience. This review aims to summarize the studies to date in relation to how psychedelics acutely affect different domains of cognition. In the pursuit of illuminating the current limitations and offering long-term, forward-thinking solutions, this review compares and contrasts findings related to how psychedelics impact memory, attention, reasoning, social cognition, and creativity.
... Ces études suggèrent que ces éléments traumatiques pourraient être spécifiquement retravaillés pendant l'administration aiguë, ou pendant les séances de débriefing, sans la présence de flash-back ou d'hyperactivation neurovégétative [76]. La kétamine pourrait également être utilisée au cours de protocole de reconsolidation mnésique, favorisant l'extinction des mémoires aversives [77]. Toutefois, d'autres essais cliniques randomisés contre placebo sont encore nécessaires avant de conclure à l'efficacité de la kétamine dans cette indication [78,79], et pour déterminer de quelle manière les techniques psychothérapeutiques pourraient être combinées à l'effet pharmacologique. ...
Résumé
La kétamine, un antagoniste non compétitif du récepteur NMDA, est utilisée aujourd’hui comme traitement antidépresseur d’action rapide dans les troubles dépressifs. Ce traitement provoque des effets psychodysleptiques dissociatifs associant une déréalisation et une dépersonnalisation, et déclenche des modifications synaptogéniques favorisant la plasticité cérébrale. Malgré plusieurs études préliminaires suggérant l’utilité de son association avec la psychothérapie, l’administration de kétamine n’est généralement pas combinée à des protocoles de psychothérapie per- et postperfusion dans le cadre de son utilisation clinique à visée antidépressive. Pourtant, la phénoménologie des expériences psychodysleptiques et l’effet synaptogénique pourraient potentialiser l’effet des psychothérapies cognitives et comportementales. Dans cet article, nous proposons un guide pratique de psychothérapie augmentée sous kétamine (KAP) synthétisant les données contemporaines de la littérature et notre expérience clinique. Nous détaillons des propositions de bonne pratique clinique et proposons quatre étapes importantes pour l’utilisation d’une molécule psychodysleptique à visée antidépressive : la préparation, l’administration, l’intégration, et la prolongation. Enfin, nous discutons les limites et les perspectives de cette combinaison dans la prise en charge des troubles de l’humeur.
... Ces études suggèrent que ces éléments traumatiques pourraient être spécifiquement retravaillés pendant l'administration aiguë, ou pendant les séances de débriefing, sans la présence de flash-back ou d'hyperactivation neurovégétative [76]. La kétamine pourrait également être utilisée au cours de protocole de reconsolidation mnésique, favorisant l'extinction des mémoires aversives [77]. Toutefois, d'autres essais cliniques randomisés contre placebo sont encore nécessaires avant de conclure à l'efficacité de la kétamine dans cette indication [78,79], et pour déterminer de quelle manière les techniques psychothérapeutiques pourraient être combinées à l'effet pharmacologique. ...
Ketamine, a non-competitive NMDA receptor antagonist, is used as a fast-acting antidepressant therapy in depressive disorders. This treatment provokes dissociative effects associating derealization and depersonalization, and a synaptogenic signaling cascade promoting brain plasticity. Despite several preliminary studies suggesting the usefulness of its combination with psychotherapy, administration of ketamine isn’t generally combined with per- and post-infusion psychotherapy protocols in its clinical antidepressant use. However, the phenomenology of psychodysleptic experiences, and the synaptogenic effect associated with ketamine, could potentiate the effect of cognitive and behavioral therapies. In this article, we purpose a practical guide to augmented psychotherapy with ketamine (KAP) synthesizing contemporary data from the literature and our clinical experience. We detail four important steps for the use of a psychodysleptic molecule for antidepressant purposes: preparation, administration, integration and prolongation. Finally we discuss the limits and prospects of this combination in the management of mood disorders.
... Although the mechanism by which ketamine alleviates mood and stress-related psychopathology is not fully understood, it is thought that this may include promoting synaptogenesis in the prefrontal cortex and hippocampus: thereby reversing characteristic structural deficits observed in these brain regions following chronic stress [3][4][5][6][7]. Further, it has recently been proposed that ketamine administration results in a window of increased neuroplasticity that may support the un-or re-learning of maladaptive associations that contribute to longer-term symptom maintenance in these disorders-for example via facilitating the extinction of fear memories [8,9]. Previous studies in individuals with treatmentresistant depression suggest that improvements in depressive symptom severity following ketamine are associated with changes in neural connectivity during emotional processing (e.g. ...
... Specifically, we suggest that improvement in PTSD symptom severity following ketamine is accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat-brain circuitry that has previously been implicated in emotional regulation and extinction learning. If confirmed in future studies, this finding has implications for the potential utility of combining plasticity-promoting agents such as ketamine with psychological therapies that directly encourage reconsolidation and extinction of trauma memories [8,9,18]. ...
... hypothesis, preclinical evidence suggests that, under some conditions, administration of ketamine improves fear extinction learning in rodents [73][74][75]. It is therefore possible that extinction of maladaptive fear responses related to trauma memories may contribute to symptom improvement in individuals who responded to ketamine [7,9]. In trial participants' own words when discussing their trauma, "I made peace, I could go past it, I could, can let it go"; "Before, talking about it used to make me feel a terrible feeling…[but now] I have to dig out the memory as if from an attic" [2]. ...
Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N = 21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures from a target neural circuit were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models (regions of interest in the target circuit consisted of the dorsal and rostral anterior cingulate cortex, ventromedial prefrontal cortex, anterior hippocampus, anterior insula, and amygdala). Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β] = 2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β = 0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β = 0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs = −2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.
... Although the mechanism by which ketamine alleviates mood and stress-related psychopathology is not fully understood, it is thought that this may include promoting synaptogenesis in the prefrontal cortex and hippocampus: thereby reversing characteristic structural deficits observed in these brain regions following chronic stress [3][4][5][6][7]. Further, it has been proposed that this window of increased neuroplasticity may support the (re-)learning of maladaptive associations that contribute to longerterm symptom maintenance in these disorders [8,9]. Previous studies in individuals with treatmentresistant depression suggest that improvements in depressive symptom severity following ketamine are associated with changes in neural connectivity during emotional processing (e.g., [10][11][12]). ...
... Specifically, we suggest that improvement in PTSD symptom severity following ketamine is accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat -brain circuitry which has previously been implicated in extinction learning and emotional regulation. If confirmed in future studies, this finding has implications for the potential utility of combining plasticity-promoting agents such as ketamine with psychological therapies that directly encourage reconsolidation and extinction of trauma memories [8,9,18]. ...
... Consistent with this hypothesis, preclinical evidence suggests that under some conditions administration of ketamine improves fear extinction learning in rodents [69][70][71]. It is therefore possible that extinction of maladaptive fear responses related to trauma memories may contribute to symptom improvement in individuals who responded to ketamine [7,9]. In trial participants' own words when discussing their trauma, "I made peace, I could go past it, I could, can let it go"; "Before, talking about it used to make me feel a terrible feeling…[but now] I have to dig out the memory as if from an attic" [2]. ...
Promising initial data indicate that the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist ketamine may be beneficial in post-traumatic stress disorder (PTSD). Here, we explore the neural correlates of ketamine-related changes in PTSD symptoms, using a rich battery of functional imaging data (two emotion-processing tasks and one task-free scan), collected from a subset of participants of a randomized clinical trial of repeated-dose intravenous ketamine vs midazolam (total N =21). In a pre-registered analysis, we tested whether changes in an a priori set of imaging measures were predictive of improvement in PTSD symptoms, using leave-one-out cross-validated elastic-net regression models. Improvements in PTSD severity were associated with increased functional connectivity between the ventromedial prefrontal cortex (vmPFC) and amygdala during emotional face-viewing (change score retained in model with minimum predictive error in left-out subjects, standardized regression coefficient [β]=2.90). This effect was stronger in participants who received ketamine compared to midazolam (interaction β=0.86), and persisted following inclusion of concomitant change in depressive symptoms in the analysis model (β=0.69). Improvement following ketamine was also predicted by decreased dorsal anterior cingulate activity during emotional conflict regulation, and increased task-free connectivity between the vmPFC and anterior insula (βs=-2.82, 0.60). Exploratory follow-up analysis via dynamic causal modelling revealed that whilst improvement in PTSD symptoms following either drug was associated with decreased excitatory modulation of amygdala→vmPFC connectivity during emotional face-viewing, increased top-down inhibition of the amygdala by the vmPFC was only observed in participants who improved under ketamine. Individuals with low prefrontal inhibition of amygdala responses to faces at baseline also showed greater improvements following ketamine treatment. These preliminary findings suggest that, specifically under ketamine, improvements in PTSD symptoms are accompanied by normalization of hypofrontal control over amygdala responses to social signals of threat.
