This study tested whether aerobic exercise delivered during the consolidation window following fear extinction learning reduces the return of fear among women with posttraumatic stress disorder ...(PTSD). Participants (n=35) completed an initial clinical assessment followed by a 3-day fear acquisition, extinction, and recall protocol. On day 1, participants completed a fear acquisition training task in which one geometric shape (conditioning stimulus; CS+) was paired (with 50% probability) with a mild electric shock (unconditioned stimulus; US), while a different shape (CS-) was never paired with the US. On day 2 (24 h later), participants completed a fear extinction training task in which the CS+ no longer predicted administration of the US. Shortly following extinction, participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity exercise control (CON) condition. On day 3 (24 h later), participants completed fear recall tests assessing the return of fear (spontaneous recovery, renewal, and reinstatement). Fear responding was assessed via threat expectancy ratings and skin conductance responses (SCR). In the threat expectancy ratings, there were no significant differences between groups in spontaneous recovery; however, EX significantly (p=.02) reduced threat expectancy ratings following reinstatement relative to CON. In SCR measures, there were no significant differences between groups in spontaneous recovery, renewal, or reinstatement. These results support a role for moderate-intensity aerobic exercise during the consolidation window in reducing threat expectations following reinstatement in women with PTSD. Research should continue to examine exercise as a potential method for improving the efficacy of exposure-based therapies.
ClinicalTrials.gov Identifier: NCT04113798.
•Fear extinction paradigms are widely used as a model of exposure therapy in PTSD.•Women with PTSD completed exercise (or control) following fear extinction training.•24 h later, participants completed fear recall tests assessing return of fear.•Exercise during the consolidation window decreased threat expectancy ratings following reinstatement compared to control.•Exercise may be a promising candidate for improving exposure-based therapies in PTSD.
A major objective of experimental psychopathology research is to improve clinical practice via the experimental study of treatment mechanisms. The success of this endeavor depends on the external ...validity of the procedures used to model the treatment component in the laboratory. We propose a general framework and a set of specific criteria that will allow evaluating whether a certain laboratory procedure is a valid model for a certain clinical treatment. We illustrate this framework by evaluating the validity of extinction as a laboratory model for clinical exposure therapy. Although we acknowledge the merits of the extinction model, we argue that its validity might not be as firmly established as the research community assumes. We also use extinction as an example to demonstrate how considerations of the proposed criteria can stimulate further improvements to existing models of treatment. We conclude that the systematic assessment of external validity of treatment models is an important step towards bridging the gap between science and practice in the field of experimental psychopathology.
•A framework to evaluate the external validity of treatment models is proposed and applied to extinction research.•Using extinction, we illustrate how this framework can guide future research to optimize treatment models.•Improving external validity of treatment models can increase the clinical impact of experimental psychopathology research.
OBJECTIVES
To determine the prevalence of fear of falling (FOF) and fear‐related activity restriction (FAR) and their association with frailty, sarcopenia, gait speed and grip strength, cognitive ...impairment, depression, social isolation, self‐perceived health, and vision.
DESIGN
Observational cross‐sectional study.
SETTING
Community.
PARTICIPANTS
A total of 493 community‐dwelling older adults, 60 years and older.
MEASURES
FOF and FAR were assessed using validated single closed‐ended questions. Questionnaire was administered to evaluate frailty (FRAIL scale ‐ Fatigue, Resistance, Aerobic, Illness, and Loss of Weight), sarcopenia (SARC‐F ‐ lifting and carrying 10 pounds, walking across a room, transferring from bed/chair, climbing a flight of 10 stairs, and frequency of falls in the past 1 year), social isolation (six‐item Lubben Social Network Scale), depression (Even Briefer Assessment Scale), cognition (Chinese Mini‐Mental State Examination), and perceived general health and pain (The EuroQol‐5 Dimension (EQ‐5D)and EQ visual analogue scale (EQ VAS)) . Binary logistic regression was performed to determine the influence of sociodemographic, medical, functional, and cognitive variables on FOF with/without FAR.
RESULTS
Prevalence of FOF was 69.2%, and among them, 38.4% had FAR. Prevalence of FOF with or without FAR in those with sarcopenia was 93.3% and in prefrail/frail was 76.6%. FOF was significantly associated with prefrail/frail (odds ratio (OR) = 2.17; 95% confidence interval (CI) = 1.26–3.73), depression (OR = 4.90; 95% CI = 1.06–22.67), number of medications (OR = 1.28; 95% CI = 1.03–1.59), and female sex (OR = 3.54; 95% CI = 1.82–6.90). FOF + FAR was associated with depression (OR = 5.17; 95% CI = 1.84–14.54) and sarcopenia (OR = 8.13; 95% CI = 1.52–43.41).
CONCLUSION
FOF with/without FAR is highly prevalent among community‐dwelling older adults, especially in those with sarcopenia, prefrailty, and frailty, with significant negative impact on function, quality of life, social network, and mental health. Further research is needed to investigate the value of population‐level screening, causal relationship, and efficacy of comprehensive intervention strategies.
Over the past years, numerous studies have provided a clear understanding of the neuronal circuits and mechanisms involved in the formation, expression and extinction phases of conditioned cued fear ...memories. Yet, despite a strong clinical interest, a detailed understanding of these memory phases for contextual fear memories is still missing. Besides the well‐known role of the hippocampus in encoding contextual fear behavior, growing evidence indicates that specific regions of the medial prefrontal cortex differentially regulate contextual fear acquisition and storage in both animals and humans that ultimately leads to expression of contextual fear memories. In this review, we provide a detailed description of the recent literature on the role of distinct prefrontal subregions in contextual fear behavior and provide a working model of the neuronal circuits involved in the acquisition, expression and generalization of contextual fear memories.
This review provides a detailed description of our current knowledge of the neuronal circuits mediating contextual fear conditioning.
Purpose
Research to date on fear of cancer recurrence (FCR) shows that moderate to high FCR affects 22–87 % of cancer survivors and is associated with higher psychological morbidity (Simard et al J ...Cancer Surviv 7:300–322,
2013
). Despite growing research interest in FCR, the lack of consensus on its definition and characteristics when it reaches a clinical level has impeded knowledge transfer into patient services.
Methods
In order to address these gaps, expert researchers, policy makers, trainees, and patient advocates attended a 2-day colloquium at the University of Ottawa in August 2015. A Delphi method was used to identify the most relevant definition of FCR, and the attendees generated possible diagnostic characteristics of clinical FCR.
Results
After three rounds of discussion and voting, the attendees reached consensus on a new definition of FCR: “Fear, worry, or concern relating to the possibility that cancer will come back or progress.” Regarding clinical FCR, five possible characteristics were proposed: (1) high levels of preoccupation, worry, rumination, or intrusive thoughts; (2) maladaptive coping; (3) functional impairments; (4) excessive distress; and (5) difficulties making plans for the future.
Conclusions
The new proposed definition of FCR reflects the broad spectrum in which patients experience FCR. A consensual definition of FCR and the identification of the essential characteristics of clinical FCR are necessary to accurately and consistently measure FCR severity and to develop effective interventions to treat FCR. We hope this broad definition can encourage further research and the development of inclusive policies for all cancer patients and survivors who are struggling with this issue.
Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed ...for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.
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•vHC projects to the BA and the CEA via separate pathways with distinct behavioral roles•vHC inputs to the CEA contact output cells that target PAG and NST•vHC projection to the BA is required for contextual fear memory retrieval•vHC projection to the CEA is necessary for context-dependent cue fear memory retrieval
Two parallel hippocampal circuits link sensory memories with the context in which they are formed, helping the selection of appropriate behavioral responses to fear.
When faced with threat, the survival of an organism is contingent upon the selection of appropriate active or passive behavioural responses. Freezing is an evolutionarily conserved passive fear ...response that has been used extensively to study the neuronal mechanisms of fear and fear conditioning in rodents. However, rodents also exhibit active responses such as flight under natural conditions. The central amygdala (CEA) is a forebrain structure vital for the acquisition and expression of conditioned fear responses, and the role of specific neuronal sub-populations of the CEA in freezing behaviour is well-established. Whether the CEA is also involved in flight behaviour, and how neuronal circuits for active and passive fear behaviour interact within the CEA, are not yet understood. Here, using in vivo optogenetics and extracellular recordings of identified cell types in a behavioural model in which mice switch between conditioned freezing and flight, we show that active and passive fear responses are mediated by distinct and mutually inhibitory CEA neurons. Cells expressing corticotropin-releasing factor (CRF
) mediate conditioned flight, and activation of somatostatin-positive (SOM
) neurons initiates passive freezing behaviour. Moreover, we find that the balance between conditioned flight and freezing behaviour is regulated by means of local inhibitory connections between CRF
and SOM
neurons, indicating that the selection of appropriate behavioural responses to threat is based on competitive interactions between two defined populations of inhibitory neurons, a circuit motif allowing for rapid and flexible action selection.
Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying ...relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.
Can mental imagery rather than external stimulation reactivate an aversive conditioned memory for the purposes of attenuating fear with subsequent extinction training? To answer this question ...participant underwent a three-day protocol: Day 1 entailed fear acquisition training in which two conditioned stimuli were paired with mild shock (US), while a CS− never was; day 2 included imagery-based reactivation of only one of the two CS+ followed by standard extinction training within the reconsolidation ten minutes later; day 3 included reinstatement by the unsignaled presentation of the US followed by a re-extinction phase. We observed no evidence of fear recovery on the first trial of re-extinction for the reminded, mentally imaged, CS+, whereas fear returned for the non-reminded CS+. Thus, mental imagery was sufficient to reactivate a fear memory thereby opening the reconsolidation window and facilitating fear suppression via extinction training. The clinical implications of this are potentially far-reaching as it allows for in vivo reconsolidation procedures in exposure therapy.
Rationale
3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these ...effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA’s broad pharmacological profile, further investigation is warranted before moving to a complex clinical population.
Objectives
We aimed to inform clinical research by providing a translational model of MDMA’s effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction.
Methods
We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training.
Results
MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA’s effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA’s effect by 5-HTT inhibition also downregulated 5-HT
2A
-mediated behavior, and 5-HT
2A
antagonism disrupted MDMA’s effect on extinction.
Conclusions
We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT
2A
receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.
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