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Targeting memory processes with drugs to prevent or cure PTSD
Expert Opinion on Investigational Drugs
Abstract
Introduction:
Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed.
Areas covered:
Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized.
Expert opinion:
Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment.
... Induction of new learning and healthy memories and alteration of enduring TM is of crucial importance for treatment of PTSD. The administration of (R,S)ketamine has been shown to enhance synaptogenesis and synaptic plasticity in rat brain (Cain et al., 2012) which are the primary mechanisms underlying new learning and formation of new memories. It has also been suggested that this long-term memory is dependent on mammalian target of rapamycin (mTOR) biochemical pathway which the administration of (R,S)-ketamine and (2S,6S)hydroxynorketamine is known to influence (Cain et al., 2012;Paul et al., 2014). ...
... The administration of (R,S)ketamine has been shown to enhance synaptogenesis and synaptic plasticity in rat brain (Cain et al., 2012) which are the primary mechanisms underlying new learning and formation of new memories. It has also been suggested that this long-term memory is dependent on mammalian target of rapamycin (mTOR) biochemical pathway which the administration of (R,S)-ketamine and (2S,6S)hydroxynorketamine is known to influence (Cain et al., 2012;Paul et al., 2014). In chronic PTSD, the pathological TM remains as the major reason for prolonged symptoms and treatment resistance (Cain et al., 2012;Duman et al., 2012). ...
... It has also been suggested that this long-term memory is dependent on mammalian target of rapamycin (mTOR) biochemical pathway which the administration of (R,S)-ketamine and (2S,6S)hydroxynorketamine is known to influence (Cain et al., 2012;Paul et al., 2014). In chronic PTSD, the pathological TM remains as the major reason for prolonged symptoms and treatment resistance (Cain et al., 2012;Duman et al., 2012). Combination of psychotherapy and (R,S)-ketamine administration for targeting TM is an example of a novel strategy to bring possible long-term relief and has potential for curing PTSD. ...
Background and objectives: Trauma memories lay at the core in etiopathogenesis of post-traumatic stress disorder (PTSD). Using pharmacological and cognitive behavioral treatments that specifically target trauma memories can improve the outcome. Ketamine has been shown to rapidly improve symptoms in PTSD and comorbid depression, but unfortunately these effects are short-lived. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy is a type of mindfulness based cognitive behavioral therapy that targets the trauma memories. TIMBER psychotherapy in combination with (R,S)-ketamine are increasingly used to treat PTSD and comorbid depression. This study aims to determine if the combination of (R,S)-ketamine chemotherapy and TIMBER psychotherapy would produce a positive synergistic response in patients with PTSD.
Design: This is a randomized, placebo-controlled, cross-over clinical study.
Methods: Because response to ketamine alone is short-lived, this study combined TIMBER with a single infusion of 0.5 mg/kg (R,S)-ketamine to sustain its therapeutic effects. Ten patients with chronic and refractory PTSD were randomly assigned to two groups (n = 5 each): TIMBER-K group patients received ketamine infusion in combination with 12 TIMBER sessions (3 sessions in the first week followed by 9 sessions conducted on a weekly basis) and TIMBER-P group patients received placebo (normal saline infusion) in combination with 12 TIMBER sessions. The patients in the TIMBER-P group were switched to those in the TIMBER-K group after they experienced a sustained relapse.
Outcome measures: PTSD Checklist (PCL), Clinician Administered PTSD Scale for DSM-IV (CAPS), the 17-item Hamilton Rating Scale for Depression (Ham-D-17, clinician rated), Beck Anxiety Inventory (BAI), and Montreal Cognitive Assessment (MoCA) at baseline and 8 hours after infusion were used to investigate if ketamine selectively affected trauma memories leaving the general memory intact. The mindfulness interventions in TIMBER were personalized based on subject's scores on Assessment Scale for Mindfulness Interventions which was administered at baseline, and after 5 sessions and 9 sessions (completion) of TIMBER. In this study, scores on CAPS and PCL scales were the primary outcome measures.
Results: In the acute phase trial ( first 3 months after infusion), nine out of 10 subjects showed robust response in primary outcome measures (PCL and CAPS scores for PTSD) and in the secondary outcome measures (Ham-D-17 and Beck Anxiety Inventory for depression and anxiety respectively) with a sustained response of 31.78 ± 18.29 days. The TIMBER-K group had a more sustained response (33 ± 22.98 days) compared to the TIMBER-P group (25 ± 16.8 days, P = 0.545). After switch from TIMBER-P group to TIMBER-K, patients experienced significantly prolonged response (49 vs. 25 days, P = 0.028). There were no intolerable side effects or dropouts during the 18-month follow-up period.
Conclusion: TIMBER psychotherapy augmented with low dose (R,S)-ketamine prolongs the therapeutic effects of the later and may be a valuable treatment option for PTSD.
Trial registration: ClinicalTrials.gov identifier: NCT02766192
... In another study, scientists have revealed impairment in memory consolidation in PTSD individuals (Van Der Kolk et al., 1997). In fact, PTSD impairs a number of types of memory including implicit and explicit memories, part of which are hippocampus-based (Cain et al., 2012;McNally, 1997;Tsoory et al., 2008). Notably, relieving cognitive memory impairments in PTSD is important for treatment of other symptoms such as flashbacks, and avoidance behavior (Cain et al., 2012). ...
... In fact, PTSD impairs a number of types of memory including implicit and explicit memories, part of which are hippocampus-based (Cain et al., 2012;McNally, 1997;Tsoory et al., 2008). Notably, relieving cognitive memory impairments in PTSD is important for treatment of other symptoms such as flashbacks, and avoidance behavior (Cain et al., 2012). ...
Posttraumatic stress disorder (PTSD) is a disabling, prevalent and difficult-to-treat psychiatric disorder, which can develop after the exposure to severe traumatic events such as those occurring during wars and natural disasters. Despite the variety of pharmacological and psychological therapies, 30% of the patients are still symptomatic 10 years after initial diagnosis. Pentoxifylline (PTX) is a potent antioxidant, which has important role in treatment of vascular dementia and improves the cognitive function among the sleep deprived. In the present study, the effect of PTX on memory impairment induced by PTSD was investigated using rat animal model. PTSD was induced in animals using a single-prolonged stress rat model of PTSD (2h restrain, 20 min forced swimming, 15 min rest, 1-2 min diethyl ether exposure). PTX was administered intraperitoneally at a dose of 100mg/kg/day. Vitamin E was used as a positive control. Spatial learning and memory were assessed using the radial arm water maze (RAWM). Changes in oxidative stress biomarkers, brain derived neuroptrophic factor (BDNF), and epigenetics (histones) in the hippocampus following treatments were measured using enzymatic assays. The result revealed that PTSD impaired both short and long term memory (P<0.05). Use of PTX prevented memory impairment induced by PTSD. Furthermore, PTX normalized PTSD induced changes in the hippocampus GSH/GSSG ratio, activity of catalase, and glutathione peroxidase (GPx), BDNF, and certain histones levels. In conclusion, PTSD induced memory impairment, whereas PTX prevented this impairment possibly through normalizing antioxidant mechanisms, BDNF and epigenetic changes in the hippocampus.
... 3 Por supuesto, es importante que el sistema sea capaz de responder al estrés adaptativo a través de una red de activación fiable, pero lo suficientemente flexible como para producir diversas acciones de comportamiento, por lo que también debe ser transitoria, para proteger los recursos corporales críticos como la digestión, cuando la amenaza se desvanece. 4 Ante ello se reconoce la importancia adaptativa de la respuesta ante el estrés, pues recordar un evento estresante en la vida es esencial para la pervivencia de un organismo 5 , ya que esto admite una respuesta adaptativa apropiada en caso de que la misma situación se repita. Sin embargo, ante eventos extremos, el mismo proceso lleva a la formación de los recuerdos traumáticos que son perjudiciales para el organismo y conducen a trastornos psiquiátricos. ...
... La disfunción en NE también se ha implicado en la memoria asociativa. 4 A ello se agrega que el CRF inicia la respuesta del eje HHA al estrés, desde el hipotálamo que se une a los receptores en la pituitaria anterior, y causando la liberación de ACTH en la circulación. ACTH a su vez desencadena la liberación CORT de la corteza suprarrenal, que actúa sobre los receptores de glucocorticoides en la periferia y el cerebro; mientras que CRF se reconoce como un modulador potente de las respuestas defensivas al estrés, y la memoria. ...
Resumen El estrés es un estado fisiológico que prepara a los organismos para responder de manera defensiva, necesario para proceso cognitivos como el aprendizaje y la memoria; sin embargo, ante eventos extremos, el mismo proceso lleva a la formación de recuerdos traumáticos que son perjudiciales para el organismo y conducen a trastornos psiquiátricos. Tal es el caso del trastorno de estrés postraumático (TEPT), que puede inducir a una disfunción social profunda resultado de las respuestas al miedo que imitan la exposición al trauma original. Las personas con TEPT pueden experimentar dificultades para dormir, se asustan fácilmente y tienen problemas en la concentración y la memoria, lo cual comienza a manifestarse después de que la persona ha experimentado un evento traumático como la tortura, una violación, el secuestro, un asalto a mano armada, la muerte violenta de un familiar, o el embate de desastres naturales como inundaciones o terremotos, concomitante con factores a largo plazo como la violencia familiar, escolar, o situaciones de pobreza extrema, que se manifiesta en una desregulación del eje Hipotalámico-Hipofisiario-Adrenal (HHA) y su interacción con glucocorticoides. Ante ello, este artículo analiza los sistemas biológicos tanto a nivel molecular, endocrinológico neuronal, genético y epigenético, capaces de dar inicio al TEPT, en busca de biomarcadores que permitan la prevención del trastorno. Sin embargo, los mecanismos no son claros, pues se encuentran personas expuestas al trauma que no generan el trastorno, por lo que se desconoce si la regulación epigenética explica la actividad del eje, pues existen diferencias individuales en el número GR y el mecanismo por el cual los recursos genéticos influyen en el riesgo de trastorno. Surge de ello la epigenética intergeneracional, que analiza la sensibilización de la respuesta fisiológica al estrés en la descendencia de individuos altamente traumatizados debido a la activación inmune por la actividad materna. Palabras clave Trastorno de estrés post traumático, glucocorticoides, eje Hipotalámico-Hipofisiario-Adrenal, metilación, epigenética.
... Although the relationship between AMPA receptor subunit dynamics and the behavioral effects of CP-AMPAR blockade needs further studies, our findings suggest that this compound has clinical implications. Novel treatment strategies for acquired anxiety such as post-traumatic stress disorder recently shifted focus from symptom relief to the disruption of dysfunctional aversive memories either by exposure therapy, pharmacotherapy, or their combination (Cain et al. 2012;Fitzgerald et al. 2014;McNally 2007;Pape and Pare 2010). Extinction training in the laboratory is considered to model human exposure therapy, and compounds that enhance extinction learning can be used to enhance the efficacy of exposure therapy in humans (Cain et al. 2012;Davis 2011;Fitzgerald et al. 2014;Herry et al. 2010). ...
... Novel treatment strategies for acquired anxiety such as post-traumatic stress disorder recently shifted focus from symptom relief to the disruption of dysfunctional aversive memories either by exposure therapy, pharmacotherapy, or their combination (Cain et al. 2012;Fitzgerald et al. 2014;McNally 2007;Pape and Pare 2010). Extinction training in the laboratory is considered to model human exposure therapy, and compounds that enhance extinction learning can be used to enhance the efficacy of exposure therapy in humans (Cain et al. 2012;Davis 2011;Fitzgerald et al. 2014;Herry et al. 2010). IEM-1460 appears promising in this respect, particularly for patients with chronic symptoms. ...
Rationale:
Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far.
Methods:
The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala.
Results:
IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression.
Conclusions:
AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.
... Most studies probing MR/GR mechanisms have focused on their involvement during the initiation of stress, yet these receptors also have been implicated in memory consolidation mechanisms (de Kloet et al. 2005;Roozendaal et al. 2009). Considering that traumatic memories could be subject to disruption during the memory consolidation window (which begins immediately after the traumatic event), there also has been interest in understanding post-stress processes because their clarification could inform the development of early post-stressor therapeutic interventions (Cohen et al. 2008;Zohar et al. 2009;Cain et al. 2012). In line with this goal, previous research in our laboratory has interrogated the regulation of synaptic plasticity during the post-stress time domain. ...
... Thus, instead of addressing the mechanisms involved during the initiation of stress, our work pertains to the maintenance of AMPAR subunit phosphorylation during the post-stress interval. This time epoch was chosen for its relevance to developing post-trauma drug interventions (Cohen et al. 2008;Cain et al. 2012). ...
The tuning of glutamatergic transmission is an essential mechanism for neuronal communication. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors that mediate fast synaptic transmission. The phosphorylation states of specific serine residues on the GluA1 and GluA2 AMPAR subunits are considered critical post-translational modifications that regulate AMPAR activity and subcellular trafficking. While behavioral stress, via stress hormones, exerts specific alterations on such glutamatergic processes, there have been conflicting data concerning the influence of stress on AMPAR phosphorylation in different brain regions, and the post-stress signaling mechanisms mediating these processes are not well delineated. Here, we examined the dynamics of phosphorylation at three AMPAR serine residues (ser831-GluA1, ser845-GluA1, and ser880-GluA2) in four brain regions [amygdala, medial prefrontal cortex (mPFC), dorsal hippocampus, and ventral hippocampus] of the rat during the hour following behavioral stress. We also tested the impact of post-stress corticosteroid receptor blockade on AMPAR phosphorylation. Both GluA1 subunit residues exhibited elevated phosphorylation after stress, yet post-stress administration of corticosteroid receptor antagonists curtailed these effects only at ser831-GluA1. In contrast, ser880-GluA2 displayed a time-dependent tendency for early decreased phosphorylation (that was selectively augmented by mifepristone treatment in the amygdala and mPFC of stressed animals) followed by increased phosphorylation later on. These findings show that the in vivo regulation of AMPAR phosphorylation after stress is a dynamic and subunit-specific process, and they provide support for the hypothesis that corticosteroid receptors have an ongoing role in the regulation of ser831-GluA1 phosphorylation during the post-stress interval.
... Although the relationship between AMPA receptor subunit dynamics and the behavioral effects of CP-AMPAR blockade needs further studies, our findings suggest that this compound has clinical implications. Novel treatment strategies for acquired anxiety such as post-traumatic stress disorder recently shifted focus from symptom relief to the disruption of dysfunctional aversive memories either by exposure therapy, pharmacotherapy, or their combination (Cain et al. 2012;Fitzgerald et al. 2014;McNally 2007;Pape and Pare 2010). Extinction training in the laboratory is considered to model human exposure therapy, and compounds that enhance extinction learning can be used to enhance the efficacy of exposure therapy in humans (Cain et al. 2012;Davis 2011;Fitzgerald et al. 2014;Herry et al. 2010). ...
... Novel treatment strategies for acquired anxiety such as post-traumatic stress disorder recently shifted focus from symptom relief to the disruption of dysfunctional aversive memories either by exposure therapy, pharmacotherapy, or their combination (Cain et al. 2012;Fitzgerald et al. 2014;McNally 2007;Pape and Pare 2010). Extinction training in the laboratory is considered to model human exposure therapy, and compounds that enhance extinction learning can be used to enhance the efficacy of exposure therapy in humans (Cain et al. 2012;Davis 2011;Fitzgerald et al. 2014;Herry et al. 2010). IEM-1460 appears promising in this respect, particularly for patients with chronic symptoms. ...
... Exposure to environmental cues alike the trauma ones, reinstates fear memories among individuals with PTSD. Therefore, adjunctive augmentation therapies to both facilitate extinction and prevent reinstatement of extinguished fear are required [39,[47][48][49][50][51]. ...
... The stimulation of the Akt/GSK3 pathway by modulators of the nicotinic and dopamine receptors in the brain has been proposed as a key mechanism of fear extinction by memory enhancers [47,106,107]. In agreement with this idea, cotinine stimulated Akt and inhibited GSK3 in the hippocampus and PFC, while decreasing depressive behavior and working memory impairment in mice subjected to restraint stress [97]. ...
Parkinson’s disease (PD) is a relatively common disorder of the Central Nervous System (CNS), whose etiology is characterized by a selective and progressive degeneration of dopaminergic neurons, and the presence of Lewy bodies in the pars compacta of the substantia nigra, thus dopamine depletion in the striatum. Patients with this disease suffer from tremors, slowness of movements, gait instability, rigidity, and may also present functional disability, reduced quality of life, and rapid cognitive decline. The prevalence of this disease is in a range of 107-187 per 100,000 inhabitants. Previous studies have shown that nicotine exerts beneficial effects in patients with PD and in in vitro and in vivo models of this disease. Astrocytes have an important role in the immune system, and that nicotine might be able to reduce inflammation-induced activation of pro-apoptotic signaling in PD. Nicotine might exert its effect through activation of α7 nicotinic acetylcholine receptors (α7-nAChRs) expressed in glial cells. Moreover, nicotine administration can protect dopaminergic neurons against degeneration by inhibiting astrocytes activation in the substantia nigra pars compacta (SNpc) and therefore reducing inflammation. Besides this beneficial effect of nicotine, its continuing use can induce toxicity and cause dependency. To counteract this effect, nicotine analogues have risen as an important therapeutic approach to maintain nicotine´s beneficial effects, but avoid its toxicity. Since astrocytes might drive chronic inflammatory processes in PD, therefore increasing neuronal vulnerability to damage, the administration of nicotine analogues in astrocytes is of interest to diminish neuronal death. In this work, we assess the role of different nicotine analogues in astrocytes following rotenone stimuli, and determine whether the possible beneficial effects of nicotine are via activation of α7-nAChRs.
... One of the potential strategies under investigation for PTSD management is to uncover/develop a safe method to uncouple, attenuate, or even erase the negative valence associated with aberrant and enduring aversive memories underlying the core of this psychiatric condition (Cain et al., 2012;Debiec, 2012;Parsons and Ressler, 2013). Of potential relevance to this matter is convergent evidence demonstrating that an established contextual fear memory, for instance, can again be rendered labile and susceptible to interference after its retrieval and reactivation (Alberini, 2011;Dudai, 2012). ...
... This result agrees with that seen in healthy humans after enhancing noradrenergic activity during aversive memory consolidation with yohimbine (Soeter and Kindt, 2012). As it also corresponds to results reported in PTSD patients (Milad et al., 2009;Cain et al., 2012), the current experimental design may be suitable to investigate pharmacological interventions able to maximize the effectiveness of the extinction approach, which in turn mimics the exposure therapy in humans, a key behavioral intervention for PTSD (Daskalakis et al., 2013). It may also allow further investigation of the noradrenergic system's role in brain regions, such as the amygdala, in which a dysfunctional activation has been associated with impaired extinction (Milad et al., 2009;Debiec et al., 2011). ...
Background:
Traumatic memories have been resilient to therapeutic approaches targeting their permanent attenuation. One of the potentially promising pharmacological strategies under investigation is the search for safe reconsolidation blockers. However, preclinical studies focusing on this matter have scarcely addressed abnormal aversive memories and related outcomes.
Methods:
By mimicking the enhanced noradrenergic activity reported after traumatic events in humans, here we sought to generate a suitable condition to establish whether some clinically approved drugs able to disrupt the reconsolidation of conditioned fear memories in rodents would still be effective.
Results:
We report that the α2-adrenoceptor antagonist yohimbine was able to induce an inability to restrict behavioral (fear) and cardiovascular (increased systolic blood pressure) responses to the paired context when administered immediately after acquisition, but not 6h later, indicating the formation of a generalized fear memory, which endured for over 29 days and was less susceptible to suppression by extinction. It was also resistant to reconsolidation disruption by the α2-adrenoceptor agonist clonidine or cannabidiol, the major non-psychotomimetic component of Cannabis sativa. Since signaling at N-methyl-D-aspartate (NMDA) receptors is important for memory labilization and because a dysfunctional memory may be less labile than is necessary to trigger reconsolidation on its brief retrieval and reactivation, we then investigated and demonstrated that pre-retrieval administration of the partial NMDA agonist D-cycloserine allowed the disrupting effects of clonidine and cannabidiol on reconsolidation.
Conclusions:
These findings highlight the effectiveness of a dual-step pharmacological intervention to mitigate an aberrant and enduring aversive memory similar to that underlying the post-traumatic stress disorder.
... However, about one-third to half of the patients remain symptomatic after treatment [6][7][8]. The prognosis of PTSD could be improved by developing targeted interventions to prevent consolidation, reconsolidation, or return of traumatic memory after extinction [9][10][11][12]. ...
Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this model, fear memory consolidation is thought to require synaptic remodeling, which is induced by signaling cascades involving matrix metalloproteinase 9 (MMP-9). Here we investigated the effect of the tetracycline antibiotic minocycline, an inhibitor of MMP-9, on fear memory retention. We conducted a pre-registered, randomized, double-blind, placebo-controlled trial in N = 105 healthy humans (N = 70 female), using a configural fear conditioning paradigm. We administered a single dose of minocycline before configural fear memory acquisition and assessed fear memory retention seven days later in a recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as the secondary outcome. As control indices of memory acquisition, we analyzed skin conductance responses (SCR) and pupil dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo, as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquisition or declarative contingency memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate further research into primary prevention, and given the short uptake time of minocycline, potentially also secondary prevention of PTSD after trauma.
... It is well known that the HPA plays an important role in the response to stress through the corticotropin-releasing factor (CRF) acting on CRF1 receptors that are present throughout the whole brain but mainly in the hypothalamus and amygdala [46] ( Figure 1). Clinical data indicate that dysfunction of the stress response system, excessive CRF activity, and possible excessive stimulation of CRF1 receptors are present in a wide range of stress-related disorders such as depression, anxiety, irritable bowel syndrome [47], and, not surprisingly, PTSD. The CRF1 receptor alteration might be particularly relevant in the most severe forms of these conditions, e.g., melancholic or psychotic depression or chronic PTSD, and/or when they are accompanied by a history of early life trauma [48][49][50]. ...
Post-traumatic stress disorder (PTSD) is a psychopathological condition with a heterogeneous clinical picture that is complex and challenging to treat. Its multifaceted pathophysiology still remains an unresolved question and certainly contributes to this issue. The pharmacological treatment of PTSD is mainly empirical and centered on the serotonergic system. Since the therapeutic response to prescribed drugs targeting single symptoms is generally inconsistent, there is an urgent need for novel pathogenetic hypotheses, including different mediators and pathways. This paper was conceived as a narrative review with the aim of debating the current pharmacological treatment of PTSD and further highlighting prospective targets for future drugs. The authors accessed some of the main databases of scientific literature available and selected all the papers that fulfilled the purpose of the present work. The results showed that most of the current pharmacological treatments for PTSD are symptom-based and show only partial benefits; this largely reflects the limited knowledge of its neurobiology. Growing, albeit limited, data suggests that the hypothalamic-pituitary-adrenal axis, opioids, glutamate, cannabinoids, oxytocin, neuropeptide Y, and microRNA may play a role in the development of PTSD and could be targeted for novel treatments. Indeed, recent research indicates that examining different pathways might result in the development of novel and more efficient drugs.
... Most anxiety and trauma-related disorders involve some form of associative learning. Pavlovian fear conditioning, therefore, has been used widely to study the mechanisms of associative learning and memory that form the basis for our understanding of specific aversive conditioning, as well as anxiety and trauma-related neural circuitry (Davis 2000;Maren 2008;Cain et al. 2012;Mahan and Ressler 2012;Steiger et al. 2015;Goode and Maren 2018). In Pavlovian fear conditioning, subjects are presented with a neutral conditional stimulus (CS; e.g., a tone), which is paired with an aversive unconditional stimulus (US; e.g., a footshock). ...
Anxiety and stress-related disorders are highly prevalent and are characterized by excessive fear to threatening and nonthreatening stimuli. Moreover, there is a large sex bias in vulnerability to anxiety and stress-related disorders—women make up a disproportionately larger number of affected individuals compared with men. Growing evidence suggests that an impaired ability to suppress fear in the presence of safety signals may in part contribute to the development and maintenance of many anxiety and stress-related disorders. However, the sex-dependent impact of stress on conditioned inhibition of fear remains unclear. The present study investigated sex differences in the acquisition and recall of conditioned inhibition in male and female mice with a focus on understanding how stress impacts fear suppression. In these experiments, the training context served as the “fear” cue and an explicit tone served as the “safety” cue. Here, we found a possible sex difference in the training requirements for safety learning, although this effect was not consistent across experiments. Reductions in freezing to the safety cue in female mice were also not due to alternative fear behavior expression such as darting. Next, using footshock as a stressor, we found that males were impaired in conditioned inhibition of freezing when the stress was experienced before, but not after, conditioned inhibition training. Females were unaffected by footshock stress when it was administered at either time. Extended conditioned inhibition training in males eliminated the deficit produced by footshock stress. Finally, exposing male and female mice to swim stress impaired safety learning in male mice only. Thus, we found sex × stress interactions in the learning of conditioned inhibition and sex-dependent effects of stress modality. The present study adds to the growing literature on sex differences in safety learning, which will be critical for developing sex-specific therapies for a variety of fear-related disorders that involve excessive fear and/or impaired fear inhibition.
... Rats were tested using a fear conditioning, extinction and recovery paradigm that is based on previously published studies (Smiley et al., 2020;Smiley et al., 2021b). As is depicted in Figure 1B, an "ABBAB" contextual design was used to assess conditioned fear acquisition, cued fear extinction, extinction recall (retention), context-dependent fear renewal, and spontaneous recovery (Cain et al., 2012;Vanelzakker et al., 2013). In this ABBAB timeline, initial fear conditioning occurred in context A, cued-fear extinction occurred in a novel context B (consisting of differently colored walls and grooved plexiglass flooring). ...
The present study used auditory fear conditioning to assess the impact of repeated binge-like episodes of alcohol exposure during adolescence on conditioned fear in adulthood. Male and female Long-Evans rats were subjected to adolescent intermittent ethanol (AIE) exposure by vapor inhalation between post-natal day 28 and 44. After aging into adulthood, rats then underwent fear conditioning by exposure to a series of tone-shock pairings. This was followed by cued-tone extinction training, and then testing of fear recovery. In male rats, AIE exposure enhanced conditioned freezing but did not alter the time-course of extinction of cued-tone freezing. During subsequent assessment of fear recovery, AIE exposed rats exhibited less freezing during contextual fear renewal, but greater freezing during extinction recall and spontaneous recovery. Compared to males, female rats exhibited significantly lower levels of freezing during fear conditioning, more rapid extinction of freezing behavior, and significantly lower levels of freezing during the tests of fear recovery. Unlike males that were all classified as high conditioners; female rats could be parsed into either a high or low conditioning group. However, irrespective of their level of conditioned freezing, both the high and low conditioning groups of female rats exhibited rapid extinction of conditioned freezing behavior and comparatively low levels of freezing in tests of fear recovery. Regardless of group classification, AIE had no effect on freezing behavior in female rats during acquisition, extinction, or fear recovery. Lastly, exposure of male rats to the mGlu5 positive allosteric modulator CDPPB prevented AIE-induced alterations in freezing. Taken together, these observations demonstrate sex-specific changes in conditioned fear behaviors that are reversible by pharmacological interventions that target mGlu5 receptor activation.
... Auditory fear conditioning procedures began 9 days after surgery to allow for recovery. Similar protocols have been previously used by our lab (Smiley et al. 2020;Gass et al. 2014a;Gass et al. 2017;Gass and Olive 2009) and others (Singewald et al. 2014;Singewald and Holmes 2019;VanElzakker et al. 2013) as a preclinical model of stress exposure used to evaluate fear learning and memory (Cain et al. 2012;VanElzakker et al. 2013). A 60-s habituation period occurred at the start of each session, and each tone/shock pairing was separated by a ten second inter-stimulus interval. ...
Rationale and objectivePost-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are disorders of learning and memory that often occur comorbidly. Exposure to trauma-related cues can increase alcohol intake in PTSD patients that are using alcohol to self-medicate. The recurrence of anxiety symptoms with subsequent alcohol use may initiate a destructive cycle where stress and alcohol exposure impair the function of the prefrontal cortex (PFC). While the incidence of these disorders has steadily increased, current therapies and treatments often lack efficacy. Thus, investigation into the underlying neurocircuitry responsible for the establishment and maintenance of these disorders is necessary to develop novel treatment targets.Methods
The present study examined the effects of ethanol exposure on the ability to create new learned associations around previously conditioned fear cues in a rat model. Animals were exposed to fear conditioning followed by chronic intermittent ethanol to translationally model trauma exposure followed by alcohol abuse. Optogenetics was used to inhibit the prelimbic (PrL) or infralimbic (IfL) cortex during fear memory reconsolidation, and fear behaviors were measured during subsequent extinction and spontaneous recovery tests.Results and conclusionChronic ethanol exposure led to deficits in fear extinction learning and increased freezing during spontaneous recovery, both of which were prevented following inhibition of the PrL, but not the IfL, during memory reconsolidation. These results support the involvement of the PrL in fear learning and memory, and strongly suggest that the PrL could serve as a potential target for the treatment of the learning and memory deficits that occur following exposure to stress and alcohol.
... Excessive associative fear and the inability to extinguish learned fear are some of the major hallmarks of several disabling anxiety disorders and trauma disorders such as post-traumatic stress disorder (PTSD) (Rothbaum and Davis, 2003;Cain et al., 2012;Mahan and Ressler, 2012). In a clinical setting, anxiety disorders, apart from a broad spectrum of co-existing symptoms, are also highly comorbid with substance abuse (Merikangas et al., 1998;Lai et al., 2015;Stewart et al., 2016). ...
The nucleus accumbens (NAc), consisting of core (NAcC) and shell (NAcS) sub-regions, has primarily been studied as a locus mediating the effects of drug reward and addiction. However, there is ample evidence that this region is also involved in regulating aversive responses, but the exact role of the NAc and its subregions in regulating associative fear processing remains unclear. Here, we investigated the specific contribution of the NAcC and NAcS in regulating both fear expression and fear extinction in C57BL/6J mice. Using Arc expression as an indicator of neuronal activity, we first show that the NAcC is specifically active only in response to an associative fear cue during an expression test. In contrast, the NAcS is specifically active during fear extinction. We next inactivated each subregion using lidocaine and demonstrated that the NAcC is necessary for fear expression, but not for extinction learning or consolidation of extinction. In contrast, we demonstrate that the NAcS is necessary for the consolidation of extinction, but not fear expression or extinction learning. Further, inactivation of mGluR1 or ERK signaling specifically in the NAcS disrupted the consolidation of extinction but had no effect on fear expression or extinction learning itself. Our data provide the first evidence for the importance of the ERK/MAPK pathway as the underlying neural mechanism facilitating extinction consolidation within the NAcS. These findings suggest that the NAc subregions play dissociable roles in regulating fear recall and the consolidation of fear extinction, and potentially implicate them as critical regions within the canonical fear circuit.
... Most anxiety and trauma-related disorders involve dysfunctional associative learning. For decades, Pavlovian fear conditioning has been used extensively to study the neural underpinnings of associative learning and memory that form the basis for our understanding of specific aversive conditioning and anxiety circuitry (Cain et al. 2012;Davis 2000;Fendt et al. 1999;Kim and Jung 2006;Mahan and Ressler 2012;Steiger et al. 2015). In Pavlovian fear conditioning, subjects are presented with a neutral conditional stimulus (CS; e.g., a tone), which is paired with an aversive unconditional stimulus (US; e.g., a foot shock). ...
Anxiety and trauma-related disorders are highly prevalent worldwide, and are associated with altered associative fear learning. Despite the effectiveness of exposure therapy, which aims to reduce associative fear responses, relapse rates remain high. This is due, in part, to the context specificity of exposure therapy, which is a form of extinction. Many studies show that fear relapses when mice are tested outside the extinction context, and this is known as fear renewal. Using Pavlovian fear conditioning and extinction, we can study the mechanisms underlying extinction and renewal. The aim of the current experiment was to identify the role of presynaptic GABAB receptors in these two processes. Previous work from our lab showed that genetic deletion or pharmacological inhibition of GABAB(1a) receptors that provide presynaptic inhibition on glutamatergic terminals reduces context specificity and leads to generalization. We therefore hypothesized that inactivation of these presynaptic GABAB receptors could be used to reduce the context specificity associated with fear extinction training and suppress renewal when mice are tested outside of the extinction context. Using CGP 36216, an antagonist specific for presynaptic GABAB receptors, we blocked presynaptic GABAB receptors using intracerebroventricular injections during various time points of extinction learning in male and female mice. Results showed that blocking these receptors pre- and post-extinction training led to enhanced extinction learning in male mice only. We also found that post-extinction infusions of CGP reduced renewal rates in male mice when they were tested outside of the extinction context. In an attempt to localize the function of presynaptic GABAB receptors within regions of the extinction circuit, we infused CGP locally within the basolateral amygdala or dorsal hippocampus. We failed to reduce renewal when CGP was infused directly within these regions, suggesting that presynaptic inhibition within these regions per se may not be necessary for driving context specificity during extinction learning. Together, these results show an important sex-dependent role of presynaptic GABAB receptors in extinction and renewal processes and identify a novel receptor target that may be used to design pharmacotherapies to enhance the effectiveness of exposure therapy.
... This destabilization-reconsolidation process after retrieval appears to occur only with the availability of new information (Rodriguez-Ortiz et al., 2005;Hupbach et al., 2007;Tronson and Taylor, 2007). It allows memories to change adaptively and can offer an opportunity for adjusting potentially detrimental features of maladaptive emotional memories (Cain et al., 2012;Parsons and Ressler et al., 2013;Beckers and Kindt, 2017;Walsh et al., 2018). Both pharmacological and behavioral interventions carried out within this period have been shown to attenuate the aversive content of memories upon reactivation in animal and human studies (Przybyslawski et al., 1999;Monfils et al., 2009;Schiller et al., 2010;Schwabe et al., 2012;Steckler and Risbrough, 2012). ...
Upon retrieval, an aversive memory can undergo destabilization and reconsolidation. A traumatic-like memory, however, may be resistant to this process. The present study sought to contribute with a strategy to overcome this potential issue by investigating whether generalized fear retrieval is susceptible to destabilization-reconsolidation that can be pharmacologically modified. We hypothesized that exposure to a context that elicits moderate generalization levels would allow a malleable memory state. We developed a fear conditioning protocol in context A (cxt-A) paired with yohimbine administration to promote significant fear to a non-conditioned context B (cxt-B) in rats, mimicking the enhanced noradrenergic activity reported after traumatic events in humans. Next, we attempted to impair the reconsolidation phase by administering clonidine (CLO) immediately after exposure to cxt-A, cxt-B, or a third context C (cxt-C) neither conditioned nor generalized. CLO administered post-cxt-B exposure for two consecutive days subsequently resulted in decreased freezing levels in cxt-A. CLO after cxt-B only once, after cxt-A or cxt-C in two consecutive days, or independently of cxt-B exposures did not affect fear in a later test. A 6-h-delay in CLO treatment post-cxt-B exposures produced no effects, and nimodipine administered pre-cxt-B exposures precluded the CLO action. We then quantified the Egr1/Zif268 protein expression following cxt-B exposures and CLO treatments. We found that these factors interact to modulate this memory destabilization-reconsolidation mechanism in the basolateral amygdala but not the dorsal CA1 hippocampus. Altogether, memory destabilization can accompany generalized fear expression; thus, we may exploit it to potentiate reconsolidation blockers' action.
... Each tone/ shock pairing was separated by a 10-second inter-stimulus interval. These 5-minute sessions occurred daily for 3 days and served to model characteristics of PTSD (Cain et al. 2012;Vanelzakker et al. 2013). Rats were considered to have reached "conditioning criteria" when they displayed freezing behavior at least 80% of the time during the presentation of the CS. ...
Rationale and objectivesAlcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) often occur comorbidly. While the incidence of these disorders is increasing, there is little investigation into the interacting neural mechanisms between these disorders. These studies aim to identify cognitive deficits that occur as a consequence of fear and ethanol exposure, implement a novel pharmaceutical intervention, and determine relevant underlying neurocircuitry. Additionally, due to clinical sex differences in PTSD prevalence and alcohol abuse, these studies examine the nature of this relationship in rodent models.Methods
Animals were exposed to a model of PTSD+AUD using auditory fear conditioning followed by chronic intermittent ethanol exposure (CIE). Then, rats received extinction training consisting of multiple conditioned stimulus presentations in absence of the shock. Extinction recall and context-induced freezing were measured in subsequent tests. CDPPB, a metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulator, was used to treat these deficits, and region-specific effects were determined using microinjections.ResultsThese studies determined that CIE exposure led to deficits in fear extinction learning and heightened context-induced freezing while sex differences emerged in fear conditioning and extinction cue recall tests. Furthermore, using CDPPB, these studies found that enhancement of infralimbic (IfL) mGlu5 activity was able to recover CIE-induced deficits in both males and females.Conclusions
These studies show that CIE induces deficits in fear-related behaviors and that enhancement of IfL glutamatergic activity can facilitate learning during extinction. Additionally, we identify novel pharmacological targets for the treatment of individuals who suffer from PTSD and AUD.
... Fear conditioning is established when a neutral or conditioned stimulus is paired with an aversive or unconditioned stimulus. This pairing changes the plasticity of the fear system and hence the fear response of the individual (3). Another important PTSD-related process is called fear of extinction. ...
Background and purpose:
Neurobiological changes in memory processes seem to play a role in the pathophysiology of post-traumatic stress disorder (PTSD). Memory itself is influenced by PTSD, too. Histone deacetylase inhibitors (HDAIs) have shown promising results in the extinction of fear-related memories in animals and hence they seem to be important for the treatment of PTSD. Data are scarce about the effect of HDAIs in spatial memory formation/extinction in PTSD models. The main goal of the present work is to find the effect of sodium butyrate (NaBu), as an HDAI, on spatial memory and spatial memory extinction in rats exposed to single prolonged stress procedure (SPS).
Experimental approach:
Different doses of NaBu were administered subcutaneously for 7 days in different groups of rats after SPS procedure. Learning, memory, and extinction of memory were evaluated in the Morris water maze test of spatial memory in 6 consecutive days.
Findings / results:
The results show that NaBu (0.5 mg/kg) alleviates impaired learning and memory in SPS rats. It also facilitates the extinction of newly formed memory in the animals.
Conclusion and implications:
Our data suggest that the administration of HDAIs after a traumatic experience can prevent the aversive effects of SPS on spatial memory. It also reinforces the notion that extinction of spatial memory involves the same or similar brain circuitry that is involved in the extinction of fear memories in PTSD patients.
... The current findings suggest a mechanism for emotional regulation in health and disease. Specifically, the LC→CeA circuit may underlie exaggerated reactions to stimuli and may explain the efficacy of β-AR antagonists like propranolol in fear and anxiety disorders [78][79][80]. for advice and comments on the manuscript. We thank the University of Pennsylvania Vector Core for packaging the AAV vectors. ...
Norepinephrine (NE) plays a central role in the acquisition of aversive learning via actions in the lateral nucleus of the amygdala (LA) [1, 2]. However, the function of NE in expression of aversively-conditioned responses has not been established. Given the role of the central nucleus of the amygdala (CeA) in the expression of such behaviors [3–5], and the presence of NE axons projections in this brain nucleus [6], we assessed the effects of NE activity in the CeA on behavioral expression using receptor-specific pharmacology and cell- and projection-specific chemogenetic manipulations. We found that inhibition and activation of locus coeruleus (LC) neurons decreases and increases freezing to aversively conditioned cues, respectively. We then show that locally inhibiting or activating LC terminals in CeA is sufficient to achieve this bidirectional modulation of defensive reactions. These findings support the hypothesis that LC projections to CeA are critical for the expression of defensive responses elicited by conditioned threats.
... The current findings suggest a mechanism for emotional regulation in health and disease. Specifically, the LC→CeA circuit may underlie exaggerated reactions to stimuli and may explain the efficacy of β-AR antagonists like propranolol in fear and anxiety disorders [78][79][80]. ...
Norepinephrine (NE) plays a central role in the acquisition of aversive learning via actions in the lateral nucleus of the amygdala (LA). However, the function of NE in expression of aversively-conditioned responses has not been established. Given the role of the central nucleus of the amygdala (CeA) in the expression of such behaviors, and the presence of NE projections in this brain nucleus, we assessed the effects of NE activity in the CeA on behavioral expression using receptor-specific pharmacology and cell- and projection-specific chemogenetic manipulations. We found that inhibition and activation of locus coeruleus (LC) neurons decreases and increases freezing to aversively conditioned cues, respectively. We then show that locally inhibiting or activating LC terminals in CeA is sufficient to achieve this bidirectional modulation of defensive reactions. These findings support the hypothesis that LC projections to CeA are required for the expression of defensive responses elicited by conditioned threats.
... Pavlovian conditioning contributes to disorders like PTSD (Rau and Fanselow 2009;Cain et al. 2012;Mahan and Ressler 2012). Using this task, we have found that NE enhances memory by acting during learning. ...
The creation of auditory threat Pavlovian memory requires an initial learning stage in which a neutral conditioned stimulus (CS), such as a tone, is paired with an aversive one (US), such as a shock. In this phase, the CS acquires the capacity of predicting the occurrence of the US and therefore elicits conditioned defense responses. Norepinephrine (NE), through β-adrenergic receptors in the amygdala, enhances threat memory by facilitating the acquisition of the CS-US association, but the nature of this effect has not been described. Here we show that NE release, induced by the footshock of the first conditioning trial, promotes the subsequent enhancement of learning. Consequently, blocking NE transmission disrupts multitrial but not one-trial conditioning.We further found that increasing the time between the conditioning trials eliminates the amplificatory effect of NE. Similarly, an unsignaled footshock delivered in a separate context immediately before conditioning can enhance learning. These results help define the conditions under which NE should and should not be expected to alter threat processing and fill an important gap in the understanding of the neural processes relevant to the pathophysiology of stress and anxiety disorders.
... Pavlovian conditioning contributes to disorders like PTSD (Rau and Fanselow 2009;Cain et al. 2012;Mahan and Ressler 2012). Using this task, we have found that NE enhances memory by acting during learning. ...
The creation of auditory threat Pavlovian memory requires an initial learning stage in which a neutral conditioned stimulus (CS), such as a tone, is paired with an aversive one (US), such as a shock. In this phase, the CS acquires the capacity of predicting the occurrence of the US and therefore elicits conditioned defense responses. Norepinephrine (NE), through β-adrenergic receptors in the amygdala, enhances threat memory by facilitating the acquisition of the CS-US association, but the nature of this effect has not been described. Here we show that NE release, induced by the footshock of the first conditioning trial, promotes the subsequent enhancement of learning. Consequently, blocking NE transmission disrupts multitrial but not one-trial conditioning. We further found that increasing the time between the conditioning trials eliminates the amplificatory effect of NE. Similarly, an unsignaled footshock delivered in a separate context immediately before conditioning can enhance learning. These results help define the conditions under which NE should and should not be expected to alter threat processing and fill an important gap in the understanding of the neural processes relevant to the pathophysiology of stress and anxiety disorders.
... Because PTSD is characterized by a failure to recover from a normal fear response (Rothbaum & Davis, 2003), animal studies utilizing Pavlovian fear conditioning paradigms can be used to gain insight into the development and maintenance of PTSD-like symptoms. Such animal models have facilitated a greater understanding of the neurobiological mechanisms underlying the pathological fear response that characterizes PTSD (Johansen, Cain, Ostroff, & LeDoux, 2011;Maren, 2001;Parsons & Ressler, 2013), allowing for the development of pharmacological treatments intended to reduce symptoms following trauma (Cain, Maynard, & Kehne, 2012;Steckler & Risbrough, 2012). However, little progress has been made in prospective identification of the individuals most likely to develop a pathological fear response following exposure to trauma (Yehuda & LeDoux, 2007). ...
Although a large portion of the population is exposed to a traumatic event at some point, only a small percentage of the population develops post-traumatic stress disorder (PTSD), suggesting the presence of predisposing factors. Abnormal acoustic startle response (ASR) has been shown to be associated with PTSD, implicating it as a potential predictor of the development of PTSD-like behavior. Since poor extinction and retention of extinction learning are characteristic of PTSD patients, it is of interest to determine if abnormal ASR is predictive of development of such deficits. To determine whether baseline ASR has utility in predicting the development of PTSD-like behavior, the relationship between baseline ASR and freezing behavior following Pavlovian fear conditioning was examined in a group of adult, male Sprague-Dawley rats. Baseline acoustic startle response (ASR) was assessed preceding exposure to a Pavlovian fear conditioning paradigm where freezing behavior was measured during fear conditioning, extinction training, and extinction testing. Although there was no relationship between baseline ASR and fear memory following conditioning, rats with low baseline ASR had significantly lower magnitude of retention of the extinction memory than rats with high baseline ASR. The results suggest that baseline ASR has value as a predictive index of the development of a PTSD-like phenotype.
... Because the present results correspond to the above-mentioned clinical findings, they might shed light on the neurobiology of this psychiatric condition and related behavioral outcomes. Furthermore, as higher dACC activation could predict poor responses to treatment in humans suffering from PTSD (van Rooij, Kennis, Vink, & Geuze, 2016), the current experimental design could be suitable for investigating single or combined pharmacological interventions that are able to maximize the effectiveness of the extinction approach, a key behavioral intervention for PTSD (Daskalakis, Yehuda, & Diamond, 2013;Singewald, Schmuckermair, Whittle, Holmes, & Ressler, 2015;VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014), as well as those focusing on traumatic memory reconsolidation disruption (Cain, Maynard, & Kehne, 2012;Gazarini et al., 2015;Parsons & Ressler, 2013;Schwabe, Nader, & Pruessne, 2014). Of note, the rodent anterior cingulate (AC) cortex has been shown to have a corresponding role with the PL cortex in learned fear, its extinction and generalization (Choi et al., 2010;Courtin et al., 2014;Cullen et al., 2015;Einarsson & Nader, 2012;Einarsson et al., 2015;Stern et al., 2014;Vetere et al., 2011;Zhang et al., 2011), which supports the idea that altered activity in these two medial prefrontal subregions could underlie PTSD-related behavioral outcomes. ...
... Melatonin has also been shown to influence circadian clock gene expression in hippocampal neurons (see above) and to protect these neurons from oxidative stress, by preventing GC-related toxicity and inhibition of hippocampal neurogenesis and cell proliferation through decrease of receptor translocation to nuclei in models of SD and chronic stress [260,[334][335][336]. Melatonergic action has been shown to resemble sleep effects and prevent and/or reverse stress-, SD-and agingrelated cognitive impairment and memory deterioration [334, 335,[337][338][339][340], as well as facilitate conditional cued fear extinction [341], without leading to next-day cognitive impairment, as seen with other hypnotics [342]. Reports suggest that interventions aimed at restoring normal hippocampal function, disrupting dysfunctional aversive memories and enhancing extinction of conditional cued fear may serve future treatment strategies for PTSD [320, 341, 343]. ...
Loss of circadian rhythmicity fundamentally affects the neuroendocrine, immune and autonomic system, similar to chronic stress and may play a central role in the development of stress-related disorders. Recent articles have focused on the role of sleep and circadian disruption in the pathophysiology of posttraumatic stress disorder (PTSD), suggesting that chronodisruption plays a causal role in PTSD development. Direct and indirect human and animal PTSD research suggests circadian-system-linked neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Recent experimental findings also support a specific role of the fundamental synchronizing pineal hormone melatonin in mechanisms of sleep, cognition and memory, metabolism, pain, neuroimmunomodulation, stress endocrinology and physiology, circadian gene expression, oxidative stress and epigenetics, all processes affected in PTSD. In the current paper, we review available literature underpinning a potentially beneficiary role of an add-on melatonergic treatment in PTSD pathophysiology and PTSD-related symptoms. The literature is presented as a narrative review, providing an overview on the most important and clinically relevant publications. We conclude that adjuvant melatonergic treatment could provide a potentially promising treatment strategy in the management of PTSD and especially PTSD-related syndromes and comorbidities. Rigorous pre-clinical and clinical studies are needed to validate this hypothesis. This article is protected by copyright. All rights reserved.
... In addition, it has been found that cortisol-augmented CBT has efficacy in acrophobia (de Quervain et al., 2011), arachnophobia (Soravia et al., 2006(Soravia et al., , 2014 and social phobia [ (Soravia et al., 2006) see Table 8A for a summary]. Whether cortisol augmented CBT for non-phobic anxiety disorders, including also GAD, facilitates fear inhibition is currently being investigated in ongoing clinical studies (see Cain et al., 2012). Furthermore, future studies may implement more selective GC agonists than cortisol (which is also acting on MRs) to avoid nonspecific side effects. ...
... However, it is still unknown whether THC could also alleviate, in a long-lasting manner, the outcome of an aversive memory through reconsolidation disruption when taken either separately or in conjunction with CBD. If so, it could encourage further investigation of their efficacy in PTSD patients, whose dysfunctional memories are usually resilient to therapeutic approaches targeting their permanent attenuation (Cain et al., 2012;Debiec, 2012;Pitman et al., 2012). ...
Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.
Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
... Whether cortisol augmented CBT for non-phobic anxiety disorders, including also GAD, facilitates fear inhibition is currently being investigated in ongoing clinical studies (see (Cain et al., 2012). ...
Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example D-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.
... Conditioned fear responses (CRs) also consist of changes in autonomic reactivity, including the release of stress hormones and endogenous opioids (Antov et al. 2013;Davis 1979;Fanselow and Bolles 1979;Fanselow et al. 1989;Kull et al. 2012;Merz et al. 2013a;Przewłocka 1990;Soeter and Kindt 2011). As will be discussed later, pharmacological interventions for posttraumatic stress disorder (PTSD) and anxiety often target autonomic responding (Bailey et al. 2013;Cain et al. 2012). Fear acquisition in rodents is remarkably similar to that of the general human population (Galatzer-Levy et al. 2013), allowing Pavlovian fear conditioning to serve as a translational model (Milad and Quirk 2012;VanElzakker et al. 2013). ...
Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible
to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce
only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse
of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal,
spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused
on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological
research are examined in light of treatment of pathological fear in humans.
... In summary, we report in an animal model of PTSD that 25% Xe administered within the reconsolidation window after fear memory reactivation substantially reduced subsequent fear memory expression. This anxiolytic-like effect in rats has translational application to current clinical research aimed at modulating memory processes as a therapy for fear and anxiety disorders [50][51][52][53]. People with PTSD experience intrusive, persistent traumatic memories [54], impaired fear memory extinction [55], and may be locked in reconsolidation mode [56]. ...
Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation - a state in which recalled memories become susceptible to modification - we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.
... The strength of available evidence underlines that some drugs may mediate some positive effects by altering the autonomic hyperarousal and emotional distress related to trauma and traumatic memories. The database having been established so far, however, is still insufficient to correctly assess the proper preventive potential of any of these drugs regarding the incidence of later PTSD.50-54 On an empirically informed level of assessment one has to keep in mind that several psychological preventive strategies are also far from being conclusive in their efficacy to reduce the risk of PTSD after trauma exposure and their acceptance by affected patients in an emergency setting.55,36 ...
Post-traumatic stress disorder (PTSD) may be associated with long-lasting psychological suffering, distressing psychosocial disability, markedly reduced health-related quality of life, and increased morbidity and mortality in a subgroup of individuals in the aftermath of serious traumatic events. Both etiopathogenesis and treatment modalities of PTSD are best conceptualized within a biopsychosotial model. Pharmacotherapy may lay claim to a major role in the multimodal treatment approaches. Here we outline two different pharmacotherapeutic trends that aim to modify the encoding, consolidation, and rehearsal of traumatic memory in order to reduce the risk of PTSD immediately after trauma exposure on the one hand, and that endeavor to treat the clinical state of PTSD on the other. The theoretical rationales of both pharmacological strategies are the complex neurobiological underpinnings that characterize traumatic memory organization and clinical PTSD. Meanwhile, promising data from randomized controlled trials have been obtained for both approaches. Empirical evidence may inform clinicians in their clinical efforts for this special group of patients. The efficacy of several classes of drugs that have been investigated within a context of research should be evaluated critically and still have to stand the test of effectiveness in daily clinical practice. From a patient perspective, empirical results may serve as a psychoeducative guideline to what pharmacotherapeutic approaches may realistically achieve, what their risks and benefits are, and what their limits are in contributing to reducing the often major chronic suffering caused by serious traumatic events. Ethical issues have to be considered, particularly in the context of pharmacological strategies projected to prevent PTSD in the aftermath of traumatic exposure.
Background
Extracting research of domain criteria (RDoC) from high-risk populations like those with post-traumatic stress disorder (PTSD) is crucial for positive mental health improvements and policy enhancements. The intricacies of collecting, integrating, and effectively leveraging clinical notes for this purpose introduce complexities.
Methods
In our study, we created a natural language processing (NLP) workflow to analyze electronic medical record (EMR) data and identify and extract research of domain criteria using a pre-trained transformer-based natural language model, all-mpnet-base-v2. We subsequently built dictionaries from 100,000 clinical notes and analyzed 5.67 million clinical notes from 38,807 PTSD patients from the University of Pittsburgh Medical Center. Subsequently, we showcased the significance of our approach by extracting and visualizing RDoC information in two use cases: (i) across multiple patient populations and (ii) throughout various disease trajectories.
Results
The sentence transformer model demonstrated high F1 macro scores across all RDoC domains, achieving the highest performance with a cosine similarity threshold value of 0.3. This ensured an F1 score of at least 80% across all RDoC domains. The study revealed consistent reductions in all six RDoC domains among PTSD patients after psychotherapy. We found that 60.6% of PTSD women have at least one abnormal instance of the six RDoC domains as compared to PTSD men (51.3%), with 45.1% of PTSD women with higher levels of sensorimotor disturbances compared to men (41.3%). We also found that 57.3% of PTSD patients have at least one abnormal instance of the six RDoC domains based on our records. Also, veterans had the higher abnormalities of negative and positive valence systems (60% and 51.9% of veterans respectively) compared to non-veterans (59.1% and 49.2% respectively). The domains following first diagnoses of PTSD were associated with heightened cue reactivity to trauma, suicide, alcohol, and substance consumption.
Conclusions
The findings provide initial insights into RDoC functioning in different populations and disease trajectories. Natural language processing proves valuable for capturing real-time, context dependent RDoC instances from extensive clinical notes.
Background
Extracting research of domain criteria (RDoC) from high-risk populations like those with post-traumatic stress disorder (PTSD) is crucial for positive mental health improvements and policy enhancements. The intricacies of collecting, integrating, and effectively leveraging clinical notes for this purpose introduce complexities.
Methods
In our study, we created an NLP workflow to analyze electronic medical record (EMR) data, and identify and extract research of domain criteria using a pre-trained transformer-based natural language model, all-mpnet-base-v2. We subsequently built dictionaries from 100,000 clinical notes and analyzed 5.67 million clinical notes from 38,807 PTSD patients from the University of Pittsburgh Medical Center. Subsequently, we showcased the significance of our approach by extracting and visualizing RDoC information in two use cases: (i) across multiple patient populations and (ii) throughout various disease trajectories.
Results
The sentence transformer model demonstrated superior F1 macro scores across all RDoC domains, achieving the highest performance with a cosine similarity threshold value of 0.3. This ensured an F1 score of at least 80% across all RDoC domains. The study revealed consistent reductions in all six RDoC domains among PTSD patients after psychotherapy. Women had the highest abnormalities of sensorimotor systems, while veterans had the highest abnormalities of negative and positive valence systems. The domains following first diagnoses of PTSD were associated with heightened cue reactivity to trauma, suicide, alcohol, and substance consumption.
Conclusions
The findings provide initial insights into RDoC functioning in different populations and disease trajectories. Natural language processing proves valuable for capturing real-time, context dependent RDoC instances from extensive clinical notes.
Translational neuroscience for anxiety has had limited success despite great progress in understanding the neurobiology of Pavlovian fear conditioning and extinction. This chapter explores the idea that conditioning paradigms have had a modest impact on translation because studies in animals and humans are misaligned in important ways. For instance, animal conditioning studies typically use imminent threats to assess short-duration fear states with single behavioral measures (e.g., freezing), whereas human studies typically assess weaker or more prolonged anxiety states with physiological (e.g., skin conductance) and self-report measures. A path forward may be more animal research on conditioned anxiety phenomena measuring dynamic behavioral and physiological responses in more complex environments. Exploring transitions between defensive brain states during extinction, looming threats, and post-threat recovery may be particularly informative. If care is taken to align paradigms, threat levels, and measures, this strategy may reveal stable patterns of non-conscious defense in animals and humans that correlate better with conscious anxiety. This shift in focus is also warranted because anxiety is a bigger problem than fear, even in disorders defined by dysfunctional fear or panic reactions.KeywordsFearAnxietyTranslationThreatExtinctionFreezing
Background and objectives:
Evidence indicates that positive memory processes play a role in the etiology and maintenance of posttraumatic stress symptoms (PTSS) and related posttrauma health indicators. To extend this research, the current pilot study examined if repeated retrieval of positive vs. neutral memories was associated with (1) less PTSS and depression severity; and (2) improved affect and cognitions (fewer posttrauma cognitions, more positively-valenced affect, less negatively-valenced affect, less negative affect interference, less anhedonia, retrieval of more positive specific memories, retrieval of fewer negative specific memories).
Methods:
Twenty-five trauma-exposed participants were randomly assigned to a positive or neutral memory task condition. They participated in four weekly experimental sessions facilitated by an experimenter virtually; each consecutive session was separated by 6-8 days. We conducted mixed between-within subjects ANOVAs to examine study hypotheses.
Results:
No interaction effects were significant. There were significant main effects of time on PTSS and depression severity, posttrauma cognitions, positively-valenced and negatively-valenced affect, and negative affect interference.
Limitations:
We used self-report measures, small and non-clinical sample with limited demographic diversity, and virtual format; did not record memory narratives; and did not have a trauma memory condition.
Conclusions:
Based on pilot data, our findings suggest that individuals who retrieve positive or neutral memories repeatedly may report less PTSS and depression severity, fewer posttrauma cognitions, and improved affect. Results provide an impetus to examine impacts of and mechanisms underlying memory interventions (beyond a sole focus on negatively-valenced memories) in trauma work.
This volume explores the latest experimental techniques in animal models of PTSD and humans affected by PTSD. The methods discussed in this book cover topics such as translational research; addressing sex differences; highlighting the state-of-the-art of biomarker discovery in the development and maintenance of PTSD; and looks at new promising agents to enhance fear extinction retention that may help millions of individuals that suffer from this debilitating disorder worldwide. In the Neuromethods series style, chapters include the kind of detail and key advice from the specialists needed to get successful results in your laboratory.
Post-traumatic stress disorder is associated with highly threatening and stressful events. The underlying memory is overconsolidated, leading to generalized fear expression and overall resistance to extinction- and reconsolidation-based interventions. Fear conditioning and avoidance protocols commonly used in laboratory settings induce specific and moderate-intensity aversive memories, but traumatic ones differ in quantitative and qualitative aspects. It would be appropriate to reproduce their abnormal features for studying PTSD neurobiology and assessing potential new therapeutics. After discussing the mnemonic basis of PTSD, its memory-related symptoms, and neurochemical findings underlying the traumatic memory, we aimed to review and discuss studies addressing the abovementioned question in rats and mice. Because of its potential translational value, the focus was on procedures associating an aversive task with single or combined post-training pharmacological interventions. Nearly 200 studies published since 1975 report that this protocol enhances aversive memory strength. The parallel assessment of abnormal features related to traumatic memories, such as altered specificity and susceptibility to extinction and drug-induced reconsolidation blockade, started more recently. Systemically administered drugs potentiating noradrenergic or glucocorticoid mechanisms have predominated, probably because of PTSD’s physiopathology. Other options and discrete brain infusions have provided complementary information. Currently available data indicate that aversive task exposure followed by adequate drug interference during consolidation generates more intense and generalized memories, which are less prone to modulation by behavioral and pharmacological strategies. These findings based on the bedside-to-bench approach are instructive for future analyses to advance our understanding of the underlying neurobiological mechanisms and develop more effective treatments for PTSD.Key wordsMemory consolidationTranslational researchPTSD model
Adverse situations that challenge an individual’s physical or psychological integrity are frequent throughout the lifespan. However, some situations go beyond the adaptive capacity and are considered traumatic, leading, in some individuals, to the development of post-traumatic stress disorder (PTSD), a condition characterized by persistent recollection of the trauma, avoidance of trauma-related cues, increased arousal, and fear generalization and sensitization. Some of these symptoms indicate that fear conditioning (cue or context-based) plays a major role in this disorder. Because individual variability is a major feature of PTSD, it is crucial to understand the psychological and biological factors that confer vulnerability and resilience to the development of this disorder. Animal models based on fear conditioning, which incorporates individual variability and sex differences, could, therefore, increase the translational value and validity of these models for testing of potential pharmacological and non-pharmacological treatments. In the present chapter, we will present the behavioral and neurobiological outcomes of animal models of PTSD based on paradigms of fear conditioning and the putative systems that may be involved with vulnerability and resilience. We will close the chapter by presenting the gaps in the literature and propose future directions on how to fill them in.Key wordsTraumatic stressAnimal modelsFear conditioningBehaviorFear extinctionIndividual variability
Post-traumatic stress disorder (PTSD) and other stress-related mood disorders are a major public health burden. Psychotherapy and SSRIs, the only pharmacological treatment currently approved for PTSD, are only partially treatments. Validated PTSD animal models could provide a better understanding of PTSD neurobiology via discovery of new pharmacologic targets to facilitate resilience after trauma. However, the complexity of PTSD makes the development of adequate animal models a challenge. To mimic the endophenotypes underlying the pathophysiology of PTSD, several trauma-focused rodent models have been assessed. The protracted social isolation paradigm used in our laboratory results in a time-dependent reduction in the synthesis of neurosteroids, such as allopregnanolone and its isomer, pregnanolone, which is consistent with PTSD clinical findings. Neurosteroids act at membrane receptors to regulate neuronal excitability and the stress response. Neurosteroids, allopregnanolone and pregnanolone are potent positive allosteric modulators of extrasynaptic GABAA receptors. Several alterations in the GABAergic system, both in GABA levels and GABAA receptor subunit composition, have been shown in PTSD. Following social isolation, changes in GABAergic receptor sensitivity and receptor conformation have been observed in corticolimbic areas that correlate with receptor pharmacology changes, and relative lack of sensitivity to anxiolytic benzodiazepines. Allopregnanolone plays a crucial role in the pathophysiology of PTSD and depression, mainly by potentiating GABAergic neurotransmission. Several agents have recently been shown to mimic the pharmacology of GABAergic neurosteroids and offer novel treatments for PTSD. In a translational approach, allopregnanolone, allopregnanolone analogs, SSRIs at low doses, and the endocannabinoid-like molecule, N-palmitoylethanolamine (PEA) have been shown to stimulate allopregnanolone biosynthesis and be effective in reducing PTSD-like behavioral alterations in rodent stress models and thus, provide potential candidates for clinical testing.
The paper explores the menace of drug tourism on the hummus trail of India. The study unfolds Israeli tourists’ socio-psychological background, motivations for escape and transformation, and drug use behaviour in India. A qualitative research design was applied to understand travel experiences. The finding highlights three significant themes supported by textual descriptions of narratives produced as evidence. Schmoll’s tourism consumer choice model was used to understand the travel decision-making process. The study proposes curating spiritual experiences through tourism for people’s mental health and well-being by replacing drug abuse on the hummus trail of India.
Trauma-related psychopathology, most notably posttraumatic stress disorder (PTSD), poses unique challenges for psychiatric nosology due to the wide range of symptoms and diagnoses associated with trauma and challenges representing the impact of trauma exposure on psychopathology. In this paper, we review the literature on categorical (i.e., Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases systems) versus dimensional conceptualizations of trauma-related symptoms with an emphasis on the Research Domain Criteria (RDoC) and the Hierarchical Taxonomy of Psychopathology (HiTOP) frameworks. We identify strengths of each approach and challenges in accommodating the full range of trauma-related psychopathology and the clinical implications thereof. We discuss several potential approaches for improving the representation of traumatic stress, including the use of PTSD subtypes, trauma-related specifiers for psychiatric diagnoses, and the development of a dimension that we call the traumatic stress spectrum, which spans both adaptive and adverse reactions to trauma. These approaches to representing traumatic stress can be evaluated empirically and further refined. We also discuss how the use of an integrated RDoC-HiTOP approach to reconceptualize traumatic stress might maximize the ability to model valid and reliable trauma-related phenotypes, which would aid in the investigation of clinically relevant biological correlates.
Torture is the purposeful infliction of severe pain on an individual by a public official (Section 2340(1) of title 18, United States Code). It is an act that dates back to early civilization, and, unfortunately, it continues well into the twenty-first century. Each year, the number of people seeking refugee or asylum status as a result of torture rises. The impact of such interpersonal trauma that encompasses both physical as well as psychological pain can be profound and long-lasting. Survivors may present for medical care and not disclose torture as part of their history, which may be just one component to their trauma experience. The most effective care for a survivor of torture is embedded in a provider’s awareness of the history and training that allows for a trauma-informed, team-oriented approach emphasizing a survivor’s resilience. This chapter will discuss the psychiatric manifestations and sequelae of torture survival and provide recommendations for treatment planning.
Early life stress (ELS) is one of the most critical factors that could modify brain plasticity, memory and learning abilities, behavioral reactions, and emotional response in adulthood leading to development of different mental disorders. Prenatal and early postnatal periods appear to be the most sensitive periods of brain development in mammals, thereby action of various factors at these stages of brain development might result in neurodegeneration, memory impairment, and mood disorders at later periods of life. Deciphering the processes underlying aberrant neurogenesis, synaptogenesis, and cerebral angiogenesis as well as deeper understanding the effects of ELS on brain development will provide novel approaches to prevent or to cure psychiatric and neurological deficits caused by stressful conditions at the earliest stages of ontogenesis. Neuropeptide oxytocin serves as an amnesic, anti-stress, pro-angiogenic, and neurogenesis-controlling molecule contributing to dramatic changes in brain plasticity in ELS. In the current review, we summarize recent data on molecular mechanisms of ELS-driven changes in brain plasticity with the particular focus on oxytocin-mediated effects on neurogenesis and angiogenesis, memory establishment, and forgetting.
Die letzten beiden Dekaden neurowissenschaftlicher und hier vor allem bildgebender Forschung haben eindrücklich belegen können, dass psychotherapeutische Interventionen zu funktionellen und strukturellen Veränderungen des Gehirns und damit zu Korrekturen im Erleben und Verhalten führen können (Schiepek 2011). Auch wenn im Erwachsenenalter die Dynamik eines Neugeborenen oder eines Jugendlichen in der Pubertät nicht mehr erreicht wird, so bleibt das Gehirn bis ins hohe Alter plastisch und damit veränderbar (neuronale Plastizität). Man geht davon aus, dass sich neuronale Netzwerke in erfahrungsabhängiger Weise verändern können und dass stimulierende Bedingungen in Form von z. B. körperlichen, sozialen oder kognitiven Anreizen die Voraussetzung dafür bilden (Greifzu et al. 2014). Auf das therapeutische Setting übertragen: Sobald also zwei Personen miteinander kommunizieren und dies über einen gewissen Zeitraum und unter Anwendung verschiedener therapeutischer Techniken und Interventionen tun, werden sie gewissermaßen zu Neurobiologen, die mit ihrem Handeln bis auf molekulare Ebene wirksam sind. Jeder Psychotherapeut sollte sich darüber im Klaren sein, dass er es neben dem Klienten oder dem Paar auch mit nahezu 100.000.000.000 Nervenzellen zu tun hat, von denen jede einzelne Nervenzelle über etwa 10.000 Synapsen in intensivem Austausch mit anderen Neuronen steht. Welche Herausforderung und Komplexität und zugleich Trost für die vielen Phänomene, die für Therapeuten wie Klienten nicht immer verstehbar sind. Die „sprechende Medizin“ und ihre intensive Weiterentwicklung hinsichtlich störungsübergreifender und störungsspezifischer Techniken haben sich von einem belächeltem Nischendasein zu einer in Wissenschaft und Gesellschaft anerkannten und bei Patienten intensiv nachgefragten Therapieform entwickelt. Klinische und experimentelle Studien haben zeigen können, dass die Effektstärken von pharmakologischen und psychotherapeutischen Interventionen vergleichbar sind und dass die Kombination beider Verfahren oftmals den größtmöglichen Nutzen für Patienten herbeiführt (Aigner und Lenz 2011; De Maat et al. 2007). Gleichzeitig wird klar, dass mit biologischen und psychologischen Therapieformen nicht immer die gleichen Zielstrukturen angesteuert werden, sondern dass hier durchaus Unterschiede existieren. So scheint vereinfachend gesagt, die Wirksamkeit von z. B. Antidepressiva bei Depressionen mehrheitlich über eine Modulation subkortikaler Strukturen wie der Amygdala, Hirnstamm und limbischem System erklärbar zu sein (bottom-up), während eine kognitive Verhaltenstherapie zunächst vor allem kortikale und hier vor allem präfrontale Prozesse anspricht und erst darüber Einfluss auf emotionale Prozesse bzw. die Aktivität der Amygdala und assoziierten Strukturen ausübt (top-down) (DeRubeis et al. 2008; Hartley und Phelps 2010). Bei emotions- und erlebnisfokussierten Ansätzen könnte dies wiederum anders sein, sodass hier angesichts der Vielzahl unterschiedlicher Therapiemethoden vorschnelle Verallgemeinerungen problematisch sind.
Ein Trauma ist ein äußeres Ereignis, das bei den Betroffenen das Gefühl einer überwältigenden Bedrohung und Katastrophe vermittelt und Todesangst, Panik, Ohnmacht und Hilflosigkeit auslöst. Eine akute Traumaexposition geht mit einer psychischen und psychosomatischen Erschütterung einher, von der sich aber in der Regel die meisten Menschen innerhalb absehbarer Zeit wieder gut erholen. Bei manchen traumatisierten Personen können in der Folge jedoch zahlreiche psychische Störungen auftreten. Die akute Belastungsstörung (ABS) und die posttraumatische Belastungsstörung (PTBS) stellen prägnanztypische Traumafolgestörungen dar, die sowohl im ICD- als auch im DSM-Klassifikationssystem gesondert thematisiert werden. Für die komplizierte Trauer existiert im DSM-5 kein eigener diagnostischer Status, jedoch wird die ICD-11 die Diagnose einer anhaltenden Trauer führen. Die extremen und meist entwicklungspsychopathologischen Traumatisierungen werden innerhalb des DSM-5 unter der PTBS subsumiert, in der künftigen ICD-11-Revision werden sie hingegen einen eigenständigen diagnostischen Status einnehmen. Die PTBS wird im DSM-5 mit der ABS und den Anpassungsstörungen neu unter den trauma- und stressbezogenen Störungen zusammengefasst. Die ICD-11 wird sich diesbezüglich analog verhalten. Die ABS deckt die ersten vier Wochen nach einer Traumaexposition ab, eine PTBS kann erst nach dieser Zeitspanne diagnostiziert werden. Beide zeichnen sich syndromal durch ein intrusives Wiedererleben der Traumaerfahrung, ein traumabezogenes Vermeidungsverhalten sowie durch eine autonome Hyperaktivität oder aber durch prominente dissoziative Symptome aus. Für eine differenzielle Behandlung existieren empirisch validierte psychotherapeutische und psychopharmakologische Ansätze. Die Verläufe von PTBS sind aber nach wie vor häufig chronisch und behindernd. Darum werden derzeit intensive Forschungsbestrebungen unternommen, um zu günstigeren Therapieoptionen zu gelangen.
Many posttraumatic stress disorder (PTSD) symptoms relate to associative memory for the traumatic experience. Safety conditioning (extinction and conditioned inhibition) can reduce fear responding post-trauma. This chapter discusses the neurobiological mechanisms of fear and safety conditioning, focusing first on findings from studies in adult rodents and then the ontogenetic emergence of fear in early life. It features the amygdala, as this brain region is critical for conditioned fear. The chapter discusses the potential role that dysfunctional threat processing plays in PTSD. There are two major hypotheses regarding dysfunctional fear conditioning (FC) processes in adult PTSD (resulting from adult trauma): PTSD occurs because the FC memory is excessively strong; and PTSD occurs because safety conditioning processes important for coping are deficient. Developmental work also raises an exciting new treatment possibility for PTSD: reopening critical periods to recruit early-life fear expression and extinction mechanisms.
Arousal and stress critically regulate memory formation and retention. Increasing levels of stress produce an inverted U-shaped effect on cognitive performance, including the retention of explicit memories, and experiencing a severe stress during a traumatic event may lead to posttraumatic stress disorder (PTSD). The molecular mechanisms underlying the impairing effect of a severe stress on memory and the key contribution of traumatic experiences toward the development of PTSD are still unknown. Here, using increasing footshock intensities in an inhibitory avoidance paradigm, we reproduced the inverted U-shaped curve of memory performance in rats. We then show that the inverted U profile of memory performance correlates with an inverted U profile of corticosterone level in the circulation and of brain-derived neurotrophic factor, phosphorylated tropomyosin-receptor kinase B, and methyl CpG binding protein in the dorsal hippocampus. Furthermore, training with the highest footshock intensity (traumatic experience) led to a significant elevation of hippocampal glucocorticoid receptors. Exposure to an unpredictable, but not to a predictable, highly stressful reminder shock after a first traumatic experience resulted in PTSD-like phenotypes, including increased memory of the trauma, high anxiety, threat generalization, and resistance to extinction. Systemic corticosterone injection immediately after the traumatic experience, but not 3 d later, was sufficient to produce PTSD-like phenotypes. We suggest that, although after a first traumatic experience a suppression of the corticosterone- dependent response protects against the development of an anxiety disorder, experiencing more than one trauma (multiple hits) is a critical contributor to the etiology of PTSD.
Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after experiencing trauma. Actual therapies do not help majority of patients with PTSD. Moreover, extinguished fear memories usually reappear in the individuals when exposed to trauma cues. New drugs to reduce the impact of conditioned cues in eliciting abnormal fear responses are urgently required. Cotinine, the main metabolite of nicotine, decreased anxiety and depressive-like behavior, and enhanced fear extinction in mouse models of PTSD. Cotinine, considered a positive modulator of the α7 nicotinic acetylcholine receptor (α7nAChR), enhances fear extinction in rodents in a manner dependent on the activity of the nAChRs. Cotinine stimulates signaling pathways downstream of α7nAChR including the protein kinase B (Akt)/glycogen synthase kinase 3β (GSK3β pathway and the extracellular signal-regulated kinases (ERKs). The stimulation of these factors promotes synaptic plasticity and the extinction of fear. In this review, we discuss the hypothesis that cotinine relieves PTSD symptoms and facilitates fear memory extinction by promoting brain plasticity through the positive modulation of presynaptic nAChRs and its effectors in the brain.
Background:
Civilian posttraumatic stress disorder (PTSD) and combat PTSD are major public health concerns. Although a number of psychosocial risk factors have been identified related to PTSD risk, there are no accepted, robust biological predictors that identify who will develop PTSD or who will respond to early intervention following trauma. We wished to examine whether genetic risk for PTSD can be mitigated with an early intervention.
Method:
65 emergency department patients recruited in 2009-2010 at Grady Memorial Hospital in Atlanta, Georgia, who met criterion A of DSM-IV PTSD received either 3 sessions of an exposure intervention, beginning in the emergency department shortly after trauma exposure or assessment only. PTSD symptoms were assessed 4 and 12 weeks after trauma exposure. A composite additive risk score was derived from polymorphisms in 10 previously identified genes associated with stress-response (ADCYAP1R1, COMT, CRHR1, DBH, DRD2, FAAH, FKBP5, NPY, NTRK2, and PCLO), and gene x treatment effects were examined. The intervention included 3 sessions of imaginal exposure to the trauma memory and additional exposure homework. The primary outcome measure was the PTSD Symptom Scale-Interview Version or DSM-IV-based PTSD diagnosis in patients related to genotype and treatment group.
Results:
A gene x intervention x time effect was detected for individual polymorphisms, in particular the PACAP receptor, ADCYAP1R1, as well as with a combined genotype risk score created from independent SNP markers. Subjects who did not receive treatment had higher symptoms than those who received intervention. Furthermore, subjects with the "risk" genotypes who did not receive intervention had higher PTSD symptoms compared to those with the "low-risk" or "resilience" genotypes or those who received intervention. Additionally, PTSD symptoms correlated with level of genetic risk at week 12 (P < .005) in the assessment-only group, but with no relationship in the intervention group, even after controlling for age, sex, race, education, income, and childhood trauma. Using logistic regression, the number of risk alleles was significantly associated with likelihood of PTSD diagnosis at week 12 (P < .05).
Conclusions:
This pilot prospective study suggests that combined genetic variants may serve to predict those most at risk for developing PTSD following trauma. A psychotherapeutic intervention initiated in the emergency department within hours of the trauma may mitigate this risk. The role of genetic predictors of risk and resilience should be further evaluated in larger, prospective intervention and prevention trials.
Trial registration:
ClinicalTrials.gov identifier: NCT00895518.
Isolation for several hours after fear conditioning reduces contextual but not auditory-cue fear conditioning (J. W. Rudy, 1996). This isolation effect is reversed by both centrally and peripherally acting opioid receptor antagonists. As in isolation, systemically administered morphine given immediately after conditioning also reduces contextual fear conditioning. Morphine's effect is also reversed by both centrally and peripherally acting opioid receptor antagonists. Exposure to the conditioning context has been shown to eliminate the effect of isolation on contextual fear conditioning (J. W. Rudy, 1996). Context preexposure also eliminated the effect of morphine on contextual fear conditioning. These results imply that opioids released in the periphery play an important role in producing the isolation effect and that they do so by disrupting the postconditioning memory consolidation processes.
Four experiments with rats were run to investigate whether fear extinction conducted under the influence of a benzodiazepine transfers to the undrugged state. Fear was conditioned by pairing an experimental chamber with footshock and was assessed by observing freezing, a characteristic response of the rat to stimuli associated with shock. In Experiment 1, extinction of the chamber cues under chlordiazepoxide (librium) or diazepam (valium) was compared with extinction under a placebo; both drugs interfered with extinction in a dose-dependent manner as indicated by freezing during an undrugged test. Further results with chlordiazepoxide suggested that the effect depended on the drug’s specific combination with extinction and that it occurred even though the extinction procedure otherwise eliminated fear completely (Experiment 2). Repeated preexposure to the drug, and the development of partial tolerance to its sedative effects, did not weaken the interference effect (Experiment 3). Other evidence suggested that the drug signaled or retrieved extinction instead of disrupting learning or consolidation (Experiment 4). The results are consistent with research suggesting that extinguished fear can be “renewed” if the exteroceptive contextual stimuli are changed after extinction. Extinction combined with either unique exteroceptive or interoceptive cues may be specific to its context.
Post-traumatic stress disorder (PTSD) has its believers and non-believers, but the balance appears to be moving in favour of the former. Despite numerous descriptions of the disorder since the First World War (and before), it was not a formally recognised clinical diagnosis until fairly recently.
This book has something to offer almost anyone interested in the effects of psychological trauma on individuals and communities. It is crafted to integrate knowledge of trauma responses across the disciplines of neurobiology, clinical science, and anthropology and is organized by sections primarily associated with each discipline. The conceptualization of the book emerged from a series of workshops organized and funded by the Foundation for Psychosocial Research in 2001 and 2002. The editors acknowledge that “In modest ways this integration occurred” (p 475) and that “Each discipline used markedly different styles of reasoning, rhetoric, and presentation” (pp 476-477). The greatest degree of integration occurred between the neuroscientists and the clinicians. During the conference discussions—and as is evident in the style of the chapters—“the anthropologists seemed nonplussed at the inevitability of bullet points, graphs, and tables in the neuroscience presentations, whereas the neuroscientists were frustrated by the uncharted narratives that unfolded as the anthropologists read their papers.”
the predatory imminence continuum / pre-encounter defensive behavior / post-encounter defensive behavior / circa-strike defensive behavior / recuperation and the return to the preferred activity pattern / temporal and spatial aspects of predatory imminence (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Emotional arousal has been shown to enhance memory, an effect that is blocked by propranolol suggesting that the noradrenergic system is important in the mechanism action. Because PTSD has as prominent features heightened arousal and distressing memories, the current study was undertaken to examine whether PTSD subjects differed from controls in emotional enhancement of memory. Seventeen subjects with PTSD and 21 controls received either placebo or 40 mg of propranolol prior to exposure to either an emotionally arousing or emotionally neutral, narrated slide story. Recall, measured 1 wk later, for the arousing story was enhanced and this effect was reduced by propranolol. PTSD and control subjects did not differ in the acquisition and retention of memories under emotionally arousing or emotionally neutral conditions, nor were differential effects of propranolol observed between the two groups.
I propose a reconceptualization of key phenomena important in the study of emotion-those phenomena that reflect functions and circuits related to survival, and that are shared by humans and other animals. The approach shifts the focus from questions about whether emotions that humans consciously feel are also present in other animals, and toward questions about the extent to which circuits and corresponding functions that are present in other animals (survival circuits and functions) are also present in humans. Survival circuit functions are not causally related to emotional feelings but obviously contribute to these, at least indirectly. The survival circuit concept integrates ideas about emotion, motivation, reinforcement, and arousal in the effort to understand how organisms survive and thrive by detecting and responding to challenges and opportunities in daily life.
Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.
Hypoxia-inducible factors (HIFs) are broadly expressed in human cancers, and HIF1α and HIF2α were previously suspected to promote tumour progression through largely overlapping functions. However, this relatively simple model has now been challenged in light of recent data from various approaches that reveal unique and sometimes opposing activities of these HIFα isoforms in both normal physiology and disease. These effects are mediated in part through the regulation of unique target genes, as well as through direct and indirect interactions with important oncoproteins and tumour suppressors, including MYC and p53. As HIF inhibitors are currently undergoing clinical evaluation as cancer therapeutics, a more thorough understanding of the unique roles performed by HIF1α and HIF2α in human neoplasia is warranted.
The noradrenergic system plays a critical role in the 'consolidation' of emotional memory. If we are to target 'reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α(2)-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively 'neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders.
Selective serotonin reuptake inhibitors (SSRIs) are often recommended in combination with established cognitive-behavioral therapies (CBTs) for posttraumatic stress disorder (PTSD), but combined initial treatment of PTSD has not been studied under controlled conditions. There are also few studies of either SSRIs or CBT in treating PTSD related to terrorism. The authors compared prolonged exposure therapy (a CBT) plus paroxetine (an SSRI) with prolonged exposure plus placebo in the treatment of terrorism-related PTSD.
Adult survivors of the World Trade Center attack of September 11, 2001, with PTSD were randomly assigned to 10 weeks of treatment with prolonged exposure (10 sessions) plus paroxetine (N=19) or prolonged exposure plus placebo (N=18). After week 10, patients discontinued prolonged exposure and were offered 12 additional weeks of continued randomized treatment.
Patients treated with prolonged exposure plus paroxetine experienced significantly greater improvement in PTSD symptoms (incidence rate ratio=0.50, 95% CI=0.30-0.85) and remission status (odds ratio=12.6, 95% CI=1.23-129) during 10 weeks of combined treatment than patients treated with prolonged exposure plus placebo. Response rate and quality of life were also significantly more improved with combined treatment. The subset of patients who continued randomized treatment for 12 additional weeks showed no group differences.
Initial treatment with paroxetine plus prolonged exposure was more efficacious than prolonged exposure plus placebo for PTSD related to the World Trade Center attack. Combined treatment medication and prolonged exposure therapy deserves further study in larger samples with diverse forms of PTSD and over longer follow-up periods.
This is a review of the relevant empirical literature concerning the DSM-IV-TR diagnostic criteria for PTSD. Most of this work has focused on Criteria A1 and A2, the two components of the A (Stressor) Criterion. With regard to A1, the review considers: (a) whether A1 is etiologically or temporally related to the PTSD symptoms; (b) whether it is possible to distinguish "traumatic" from "non-traumatic" stressors; and (c) whether A1 should be eliminated from DSM-5. Empirical literature regarding the utility of the A2 criterion indicates that there is little support for keeping the A2 criterion in DSM-5. The B (reexperiencing), C (avoidance/numbing) and D (hyperarousal) criteria are also reviewed. Confirmatory factor analyses suggest that the latent structure of PTSD appears to consist of four distinct symptom clusters rather than the three-cluster structure found in DSM-IV. It has also been shown that in addition to the fear-based symptoms emphasized in DSM-IV, traumatic exposure is also followed by dysphoric, anhedonic symptoms, aggressive/externalizing symptoms, guilt/shame symptoms, dissociative symptoms, and negative appraisals about oneself and the world. A new set of diagnostic criteria is proposed for DSM-5 that: (a) attempts to sharpen the A1 criterion; (b) eliminates the A2 criterion; (c) proposes four rather than three symptom clusters; and (d) expands the scope of the B-E criteria beyond a fear-based context. The final sections of this review consider: (a) partial/subsyndromal PTSD; (b) disorders of extreme stress not otherwise specified (DESNOS)/complex PTSD; (c) cross- cultural factors; (d) developmental factors; and (e) subtypes of PTSD.
Introduction:
Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments.
Areas covered:
A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad - although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission.
Expert opinion:
So far, the mental health field has tended to focus on either biological or psychological targets. We propose that maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Exciting new developments reflecting this perspective include psychopharmacologic augmentation strategies that enhance the mechanisms of psychotherapy.
This review examines the question of whether there should be a cluster of disorders, including the adjustment disorders (ADs), acute stress disorder (ASD), posttraumatic stress disorder (PTSD), and the dissociative disorders (DDs), in a section devoted to abnormal responses to stress and trauma in the DSM-5. Environmental risk factors, including the individual's developmental experience, would thus become a major diagnostic consideration. The relationship of these disorders to one another is examined and also their relationship to other anxiety disorders to determine whether they are better grouped with anxiety disorders or a new specific grouping of trauma and stressor-related disorders. First how stress responses have been classified since DSM-III is reviewed. The major focus is on PTSD because it has received the most attention, regarding its proper placement among the psychiatric diagnoses. It is discussed whether PTSD should be considered an anxiety disorder, a stress-induced fear circuitry disorder, an internalizing disorder, or a trauma and stressor-related disorder. Then, ASD, AD, and DD are considered from a similar perspective. Evidence is examined pro and con, and a conclsion is offered recommending inclusion of this cluster of disorders in a section entitled "Trauma and Stressor-Related Disorders." The recommendation to shift ASD and PTSD out of the anxiety disorders section reflects increased recognition of trauma as a precipitant, emphasizing common etiology over common phenomenology. Similar considerations are addressed with regard to AD and DD.
Evidence for reconsolidation in non-human animals has accumulated rapidly in the last decade, providing compelling` demonstration for this phenomenon across species and memory paradigms. In vast contrast, scant evidence exists for human reconsolidation to date. A major reason for this discrepancy is the invasive nature of current techniques used to investigate reconsolidation, which are difficult to apply in humans. Pharmacological blockade of reconsolidation, for example, has been typically used in animals as a proof of concept. However, most compounds used in these studies are toxic for humans, and those compounds that are safe target related, but not direct mechanisms of reconsolidation. Thus, although human reconsolidation has been hypothesized, there is limited evidence it actually exists. The best evidence for human reconsolidation emerges from non-invasive techniques that "update" memory during reconsolidation rather than block it, a technique only rarely used in animal research. Here we discuss the current state of human reconsolidation and the challenges ahead. We review findings on reconsolidation of emotional associative, episodic, and procedural memories, using invasive and non-invasive techniques. We discuss the possible interpretation of these results, attempt to reconcile some inconsistencies, and suggest a conceptual framework for future research.
Context No large-scale posttraumatic stress disorder drug trials have been conducted to evaluate treatment effects beyond 12 weeks outside of those with selective serotonin reuptake inhibitors. Objective To evaluate the efficacy of venlafaxine extended release (ER), a serotonin norepinephrine reuptake inhibitor, in posttraumatic stress disorder. Design 6-month, double-blind, placebo-controlled trial. Setting International study at 56 sites. Patients Adult outpatients (N = 329) with a primary diagnosis of posttraumatic stress disorder as defined in the DSM-IV, symptoms for 6 months or longer, and a 17-item Clinician-Administered Posttraumatic Stress Disorder Scale score of 60 or higher. Intervention Patients randomly assigned to receive flexible doses of venlafaxine ER (37.5-300 mg/d) or placebo for 24 weeks. Main Outcome Measures Primary measure was the change from baseline in the Clinician-Administered Posttraumatic Stress Disorder Scale score. Secondary measures included remission, defined as a Clinician-Administered Posttraumatic Stress Disorder Scale score of 20 or lower, and changes in symptom cluster scores, frequency of remission, and time to remission. Measures of stress vulnerability, resilience, depression, quality of life, functioning, and global illness severity were also taken. Results Mean changes from baseline in Clinician-Administered Posttraumatic Stress Disorder Scale total scores at end point were –51.7 for venlafaxine ER and –43.9 for placebo (P = .006). Improvement was significantly greater for the venlafaxine ER group than for the placebo group in cluster scores for reexperiencing (P = .008) and avoidance/numbing (P = .006), but not for hyperarousal. Remission rates were 50.9% for venlafaxine ER and 37.5% for placebo (P = .01). The venlafaxine ER group also showed significantly greater improvement at end point than the placebo group (P<.05) on all other reported outcome measures. The mean maximum daily dose of venlafaxine ER was 221.5 mg/d. Withdrawal rates were similar between groups with no significant difference in dropouts attributable to adverse events. Conclusion In this study, venlafaxine ER was effective and well tolerated in short-term and continuation treatment of patients with posttraumatic stress disorder.
Although most people will gradually recover from the psychological effects of a traumatic event, PTSD will develop in a substantial proportion. PTSD appears to represent a failure to recover from a nearly universal set of emotions and reactions and is typically manifested as distressing memories or nightmares related to the traumatic event, attempts to avoid reminders of the trauma, and a heightened state of physiological arousal. Studies of the biologic mechanisms of PTSD have delineated circumscribed alterations in brain regions, such as the amygdala and hippocampus, that are associated with fear and memory, as well as changes in hormonal, neurochemical, and physiological systems involved in coordinating the body's response to stress. The treatment of PTSD involves educating the patient about the nature of the disorder, providing a safe and supportive environment for discussing traumatic events and their impact, and relieving the distress associated with memories and reminders of the event. A variety of approaches, such as exposure therapy, cognitive therapy, and pharmacotherapy, have been found to be effective in the treatment of PTSD.
Immediately after experiencing a traumatic event, many people have symptoms of posttraumatic stress disorder (PTSD). If trauma victims restrict their routine and systematically avoid reminders of the incident, symptoms of PTSD are more likely to become chronic. Several clinical studies have shown that programs of cognitive-behavioral therapy (CBT) can be effective in the management of patients with PTSD. Prolonged exposure (PE) therapy-a specific form of exposure therapy-can provide benefits, as can stress inoculation training (SIT) and cognitive therapy (CT). PE is not enhanced by the addition of SIT or CT. PE therapy is a safe treatment that is accepted by patients, and benefits remain apparent after treatment programs have finished. Nonspecialists can be taught to practice effective CBT. For the treatment of large numbers of patients, or for use in centers where CBT has not been routinely employed previously, appropriate training of mental health professionals should be performed. Methods used for the dissemination of CBT to nonspecialists need to be modified to meet the requirements of countries affected by the Asian tsunami. This will entail the use of culturally sensitive materials and the adaptation of training methods to enable large numbers of mental health professionals to be trained together.
Defensive behaviors are evolved responses to threat, common to most mammalian species. Specific defenses may be differentiated anatomically at some brain sites and by responsivity to antianxiety drugs. Over-(or inappropriate) expression of specific defenses may contribute to the phenomenology of particular anxiety disorders.
This book analyzes the individual and collective experience of and response to trauma from a wide range of perspectives including basic neuroscience, clinical science, and cultural anthropology. Each perspective presents critical and creative challenges to the other. The first section reviews the effects of early life stress on the development of neural systems and vulnerability to persistent effects of trauma. The second section of the book reviews a wide range of clinical approaches to the treatment of the effects of trauma. The final section of the book presents cultural analyses of personal, social, and political responses to massive trauma and genocidal events in a variety of societies. This work goes well beyond the neurobiological models of conditioned fear and clinical syndrome of post-traumatic stress disorder to examine how massive traumatic events affect the whole fabric of a society, calling forth collective responses of resilience and moral transformation.
Post-traumatic stress disorder (PTSD) is a prevalent psychiatric disorder that may result in significant social and occupational debilitation unless symptoms are recognized and treated appropriately. Considerable research effort has been devoted over the last 20years to developing effective pharmacological treatments for this illness. At this time, the bulk of the agents investigated include antidepressants, anticonvulsants, atypical antipsychotics, benzodiazepines, and antiadrenergic agents. Herein, we review the existing evidence base for these different classes of psychotropics in PTSD. Emphasis is placed on discussion of evidence stemming from randomized placebo-controlled clinical trials wherever possible. A brief description of novel agents that have shown initial promise for PTSD treatment is also provided.
There is a strong consensus that the amygdala is involved in mediating influences of emotional arousal and stress on learning and memory. There is extensive evidence that the basolateral amygdala (BLA) is a critical locus of integration of neuromodulatory influences regulating the consolidation of several forms of memory. Many drug and stress hormone influences converge in activating the release of norepinephrine (NE) within the BLA. Evidence from studies using in vivo microdialysis and high-performance liquid chromatography indicates that increases in amygdala NE levels assessed following inhibitory avoidance training correlate highly with subsequent retention. Other evidence indicates that NE influences on memory consolidation require muscarinic cholinergic activation within the BLA provided by projections from the nucleus basalis magnocellularis (NB). Evidence from several experiments indicates that activation of the BLA plays an essential role in modulating memory consolidation processes involving other brain regions. These findings provide strong support for the hypothesis that the BLA plays a critical role in regulating the consolidation of lasting memories of significant experiences.
BACKGROUND: The efficacy and safety of risperidone was evaluated in veteran patients with chronic combat-related posttraumatic stress disorder (PTSD) who were referred to a residential treatment program. METHODS: Seventy-three subjects volunteered to participate in this double-blind, placebo-controlled study, which comprised of a 5 week residential program followed by a 3-month outpatient follow-up. Risperidone was added to a stable psychotropic medication regimen in 92% of subjects. Primary outcome measures were the Clinician-Administered PTSD scale (CAPS-total) and its three subscales; B (Re-experiencing), C (Avoidance) and D (Arousal). Secondary outcome measures were the Hamilton Anxiety (HAM-A) and Depression (HAM-D) scales, and the Positive and Negative Syndrome Scale, Positive Subscale (PANSS-P). RESULTS: Sixty-five subjects were randomized and 48 completed the 4-month study. Significantly greater improvement in symptoms was observed in subjects receiving risperidone compared to placebo on the CAPS-total and CAPS-D subscale scores and also on HAM-A and PANSS-P. Numerically greater improvements in all the remaining measures were noted with risperidone, but the differences did not reach statistical significance. Risperidone was well tolerated. CONCLUSIONS: These results suggest that adjunctive risperidone improved a broad range of psychiatric symptoms in patients with chronic combat-related PTSD. The data support the concept that atypical antipsychotic medications may have a wider therapeutic spectrum that goes beyond the treatment of psychosis.
Activation of central 5-HT 2A receptor signaling and its subsequent alterations have been implicated in the pathophysiological response to stress and the pathogenesis of stress-associated psychiatric disorders. To further examine the association between alterations in central 5-HT2A receptor signaling and the occurrence of stress-induced psychiatric symptoms, the present study, utilizing a learned helplessness stress model in rats, determined whether 5-HT2A receptor signaling blockade during stress could prevent the occurrence of stress-induced physical and behavioral abnormalities. Rats subjected to restraint/tail shock for three days developed long-lasting elevated acoustic startle response (ASR) and reduced body weight, compared to non-stressed control animals. However, administration of the selective 5-HT2A receptor antagonist, MDL 11,939 (α-phenyl-1-(2-phenylethyl)-4-piperidinemethanol), 30 min prior to exposure of the animals to the stress protocol prevented the subsequent occurrence of elevated ASR and reduced body weight in a dose-dependent manner in stressed subjects. Administration of MDL 11,939 to the animals immediately after exposure to the stress protocol also prevented the occurrence of exaggerated ASR, but was not able to normalize body weight. These findings suggest a critical role of the central 5HT2A receptor activation in developing the pathophysiology associated with elevated ASR and reduced body weight during stress. The differential effects of MDL 11,939 on startle response and body weight and its potential clinical significance are discussed.
Human responses to stress and trauma vary widely. Some people develop trauma-related psychological disorders, such as posttraumatic
stress disorder (PTSD) and depression; others develop mild to moderate psychological symptoms that resolve rapidly; still
others report no new psychological symptoms in response to traumatic stress. Individual variability in how animals and humans
respond to stress and trauma depends on numerous genetic, developmental, cognitive, psychological, and neurobiological risk
and protective factors.
The revised Department of Veterans Affairs (VA) and Department of Defense Clinical Practice Guideline for Management of Post-Traumatic Stress recommends against long-term use of benzodiazepines to manage posttraumatic stress disorder (PTSD). An analysis of recent trends among veterans receiving care for PTSD in the VA noted a decreasing proportion receiving benzodiazepines. The authors examined prescribing patterns for other medications to better understand the general context in which the changes in benzodiazepine prescribing have occurred in the VA.
Administrative VA data from fiscal years 1999 through 2009 were used to identify veterans with PTSD using ICD-9 codes extracted from inpatient discharges and outpatient encounters. Prescribing of antidepressants, antipsychotics, and hypnotics was determined for each fiscal year using prescription drug files.
The proportion of veterans receiving either of the 2 Clinical Practice Guideline-recommended first-line pharmacotherapy treatments for PTSD, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, increased from 49.7% in 1999 to 58.9% in 2009. In addition to reduced benzodiazepine prescriptions, the overall frequency of antipsychotic use declined 6.1%, from 20.0% in 1999 to 13.9% in 2009. Nonbenzodiazepine hypnotic prescribing tripled when zolpidem was added to the VA national formulary in 2008. Buspirone prescribing decreased steadily, while prazosin prescribing expanded nearly 7-fold.
This work highlights several clinically important trends in prescribing over the past decade among veterans with PTSD that are generally consistent with the revised VA/Department of Defense Clinical Practice Guideline recommendations. However, the findings illustrate the limitations of administrative data and point to a need to supplement this work with a qualitative examination of PTSD prescribing from interviews with providers to better understand the strategies used to make medication management decisions.
Fear learning can be broadly divided into two categories: the acquisition of fear reactions, modeled by Pavlovian conditioning, and the acquisition of fear actions, modeled by instrumental avoidance/escape conditioning. Brain research on Pavlovian conditioning has been especially successful at delineating the cellular and molecular mechanisms of fear-reaction learning. Instrumental conditioning research is beginning to shed light on fear-action learning at the brain systems level. In the present chapter we review recent advances in both fields and suggest that the Escape from Fear (EFF) paradigm is an excellent model for studying how these two types of learning interact to subserve fear behavior. The mechanisms of such learning may be related to passive versus active coping strategies in humans suffering from pathological fear and understanding these mechanisms may have important treatment implications.
A common approach to the clinical treatment of Posttraumatic Stress Disorder (PTSD) has focused on the facilitation of fear extinction through cognitive behavioural therapy that involves both safe exposure to the trauma-related cues and subsequent changes in conditioned stimulus–unconditioned stimulus (CS–US) contingency expectations. PTSD symptoms can be tracked back to pathologically modified associative fear, hyperarousal and a time-dependent fear generalization. We have used a mouse model of PTSD that is based on a brief exposure to an inescapable foot shock in order to investigate the influence of early (starting 1 day after the shock) and late (starting 1 month after the shock) extinction training. Both early and late extinction training led to a long-lasting reduction of contextual and generalized fear, but only early extinction caused an amelioration of hyperarousal. Consequently, our results suggest early post-shock intervention as a successful strategy for reducing hyperarousal in the aftermath of a trauma.
Anxiety disorders, characterized by anxiety and fearfulness, are found to be able to cause abnormal emotional responses' associated with memories of negative events, which implicate pressure on society with an increasingly large burden. Better treatment has been of concern to the community. Venlafaxine (VEN), a nonclassical antidepressant agent, is applied in the treatment of social phobia, major depression (MD) and general anxiety disorder (GAD) and, to a certain extent, posttraumatic stress disorder (PTSD), which improves working memory and spatial memory as well as ameliorates emotion by affecting specified brain regions. In this study, we committed to seek a new way for using VEN on treatment of anxiety disorders. To investigate the effect of VEN on extinction of auditory-cue conditioned fear, conditioned rats received a treatment with VEN before extinction training and tests for freezing level of within-session and between-session extinction. To investigate the effect of VEN on reinstatement, all conditioned rats received a treatment with VEN over a period for 21 days. After a rest for 7 days, two tests for freezing level were conducted. We found that: (1) VEN (40mg/kg) treatment at 30min prior to extinction training significantly facilitated the between-session extinction, but not the within-session extinction; (2) chronic administration with VEN (40mg/kg) prevented the return of extinguished auditory-cue fear. These data elucidate the critical role of VEN in auditory-cue fear memory, suggesting that VEN may be an ideal choice for the exposure-based drug treatment and maintenance treatment in patients with GAD, SAD and PTSD.
The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in both animals and humans. Progress during this period has been facilitated by a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.
The brain and body need to adapt constantly to changing social and physical environments. A key mechanism for this adaptation is the 'stress response', which is necessary and not negative in and of itself. The term 'stress', however, is ambiguous and has acquired negative connotations. We argue that the concept of allostasis can be used instead to describe the mechanisms employed to achieve stability of homeostatic systems through active intervention (adaptive plasticity). In the context of allostasis, resilience denotes the ability of an organism to respond to stressors in the environment by means of the appropriate engagement and efficient termination of allostatic responses. In this review, we discuss the neurobiological and organismal factors that modulate resilience, such as growth factors, chaperone molecules and circadian rhythms, and highlight its consequences for cognition and behavior.
Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β-adrenergic blocker propranolol, to reduce this overconsolidation.
In this randomized, placebo-controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty-one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post-trauma, PTSD symptoms were assessed. One week later, participants engaged in script-driven imagery of their traumatic event while psychophysiological responses were measured.
Physiological reactivity during script-driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5-week posttrauma assessment, physiological reactivity was significantly lower during script-driven imagery in the propranolol than in the placebo subjects.
The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.
Pavlovian fear conditioning is a particularly useful behavioral paradigm for exploring the molecular mechanisms of learning and memory because a well-defined response to a specific environmental stimulus is produced through associative learning processes. Synaptic plasticity in the lateral nucleus of the amygdala (LA) underlies this form of associative learning. Here, we summarize the molecular mechanisms that contribute to this synaptic plasticity in the context of auditory fear conditioning, the form of fear conditioning best understood at the molecular level. We discuss the neurotransmitter systems and signaling cascades that contribute to three phases of auditory fear conditioning: acquisition, consolidation, and reconsolidation. These studies suggest that multiple intracellular signaling pathways, including those triggered by activation of Hebbian processes and neuromodulatory receptors, interact to produce neural plasticity in the LA and behavioral fear conditioning. Collectively, this body of research illustrates the power of fear conditioning as a model system for characterizing the mechanisms of learning and memory in mammals and potentially for understanding fear-related disorders, such as PTSD and phobias.
Among drugs that act on serotonergic neurotransmission, selective serotonin (5-HT) reuptake inhibitors (SSRIs) are now the gold standard for the treatment of anxiety disorders. The precise mechanisms of the anxiolytic actions of SSRIs are unclear. We reviewed the literature related to the effects of SSRIs and the neurochemical changes of 5-HT in conditioned fear. Acute SSRIs and 5-HT(1A) receptor agonists reduced the acquisition and expression of contextual conditioned fear. Chronic SSRI administration enhanced anxiolytic-like effects. Microinjection studies revealed the amygdala as the target brain region of both classes of serotonergic drugs, and the hippocampus as the target of 5-HT(1A) receptor agonists. These findings highlight the contribution of post-synaptic 5-HT receptors, especially 5-HT(1A) receptors, to the anxiolytic-like effects of serotonergic drugs. These results support the new 5-HT hypothesis of fear/anxiety: the facilitation of 5-HT neurotransmission ameliorates fear/anxiety. Furthermore, these behavioral data provide a new explanation of neurochemical adaptations to contextual conditioned fear: increased 5-HT transmission seems to decrease, not increase, fear.
Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).
To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.
A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure.
Risperidone (up to 4 mg once daily) or placebo.
The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V).
Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.
Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms.
clinicaltrials.gov Identifier: NCT00099983.