Conditioned Fear Associated Phenotypes as Robust, Translational Indices of Trauma-, Stressor-, and Anxiety-Related Behaviors

In the paper

“Walker et al. (64) found that d-cycloserine (DCS), an NMDA receptor partial agonist, facilitated extinction learning in rats; a finding that was later replicated by several other groups employing multiple types of fear learning paradigms in rodents [e.g., Ref. (65)] but not replicated using skin conductance and expectancy ratings in humans (66).”

What the sources say

• Supported

  The Abstract and Discussion report that DCS, an NMDA receptor partial agonist, facilitated conditioned fear extinction in rats. The later rodent replications and human findings are attributed to separate references (65 and 66), not to Walker et al. (LLM, conf=0.94)

  cites [64] Walker, 2002, Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats, J Neurosci source
• Supported

  The citation to this paper is offered as an example of rodent replication, not as support for the separate human finding cited to Ref. (66). In “Effects of Postextinction Administration of DCS” (page not provided), the authors explicitly say they replicated Walker et al.’s rat finding and extended it to freezing rather than potentiated startle. (LLM, conf=0.91)

  cites [65] Richardson, 2004, Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications, Learn Mem source
• Not checked yetcites [66] Guastella, 2007, A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans, Behav Res Ther source

In the paper

“trauma-, stressor-, and anxiety-related disorders have been shown to have a significant degree of heritability and more recently, it has become increasingly clear that genetic contributions include complex gene × environment interactions.”

What the sources say

• Not checked yetcites [36] Norrholm, 2013, Differential genetic and epigenetic regulation of catechol-O-methyltransferase is associated with impaired fear inhibition in posttraumatic stress disorder, Front Behav Neurosci source

In the paper

“High levels of conditioned fear remaining during late extinction are related to impaired inhibition, as it is best predicted by responses to the CS− (i.e., safety signal) at the end of acquisition (15).”

What the sources say

• Not checked yetcites [15] Norrholm, 2011, Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity, Biol Psychiatry source

In the paper

“Fear conditioning experiments have identified varying trajectories of the dimensions described, highlighting exciting new avenues of targeted, focused study.”

In the paper

“Morphine has also been studied as a possible intervention of fear memory consolidation; however, it is not clear whether morphine's analgesic properties act to reduce the potency of the CS+ or are acting through a separate mechanism (61, 62).”

What the sources say

• Not checked yetcites [61] Parsons, 2013, Implications of memory modulation for post-traumatic stress and fear disorders, Nat Neurosci source
• Not checked yetcites [62] Holbrook, 2010, Morphine use after combat injury in Iraq and post-traumatic stress disorder, N Engl J Med source

In the paper

“Both groups also discriminated between the CS+ and CS−; however, the auditory group exhibited discrimination on blocks 1, 2, and 3 of fear acquisition, while the visual CS+ group exhibited discrimination on blocks 2 and 3 of fear acquisition.”

What the sources say

• Not checked yetcites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

In the paper

“Specifically, several candidate gene studies have identified genetic differences and specific gene pathways involved in PTSD [for a review, see (53)].”

What the sources say

• Not checked yetcites [53] Skelton, 2012, PTSD and gene variants: new pathways and new thinking, Neuropharmacology source

In the paper

“Twenty-four hours later an extinction test was performed. This test showed that spontaneous recovery occurred in both groups and US-expectancy ratings increased in both groups regardless of modality as well (58).”

What the sources say

• Not checked yetcites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

In the paper

“Several recent translational studies have explored both pharmacological as well as non-pharmacological means of enhancing extinction of fear and preventing its re-emergence.”

In the paper

“Shortly thereafter, several groups reported that DCS administration before or after exposure therapy, a form of treatment based on the principles of fear extinction learning, was effective in alleviating the symptoms of acrophobia (67), panic disorder (68), social anxiety disorder (69, 70), and obsessive–compulsive disorder (71–73).”

What the sources say

• Not checked yetcites [67] Ressler, 2004, Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear, Arch Gen Psychiatry source
• Not checked yetcites [68] Otto, 2010, Efficacy of CBT for benzodiazepine discontinuation in patients with panic disorder: further evaluation, Behav Res Ther source
• Not checked yetcites [69] Hofmann, 2006, Augmentation of exposure therapy with D-cycloserine for social anxiety disorder, Arch Gen Psychiatry source
• Not checked yetcites [70] Hofmann, 2013, d-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder, Am J Psychiatry source

In the paper

“Ten minutes after this initial assessment, these groups were shown to also extinguish fear; however, the auditory group displayed a steeper slope of extinction, due in part to an initial increase in fear during extinction, than the visual group.”

What the sources say

• Not checked yetcites [58] Norrholm, 2011, Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear, Front Behav Neurosci source

In the paper

“More recently, GWAS data, which is obtained when expression levels of the whole genome are analyzed in the context of PTSD, have been used to identify novel gene pathways involved in the mechanisms underlying complex disorders such as PTSD [see Ref. (54) for a review].”

What the sources say

• Not checked yetcites [54] Almli, 2014, Genetic approaches to understanding post-traumatic stress disorder, Int J Neuropsychopharmacol source

In the paper

“Specifically, when DCS was administered prior to virtual reality exposure therapy subjects showed earlier, enhanced symptom reduction and greater PTSD remission rates (78).”

What the sources say

• Not checked yetcites [78] Difede, 2014, D-cycloserine augmentation of exposure therapy for post-traumatic stress disorder: a pilot randomized clinical trial, Neuropsychopharmacology source

In the paper

“Initial reports by Litz et al. (75) suggested that DCS + exposure therapy was not as effective as placebo + exposure in a population of combat veterans with PTSD (75)”

What the sources say

• Not checked yetcites [75] Litz, 2012, A randomized placebo-controlled trial of D-cycloserine and exposure therapy for posttraumatic stress disorder, J Psychiatr Res source

In the paper

“Fear-potentiated startle is observed across species and is ideal for studying translational models of fear-related phenotypes (27).”

What the sources say

• Not checked yetcites [27] Lissek, 2008, Generalization of conditioned fear-potentiated startle in humans: experimental validation and clinical relevance, Behav Res Ther source

In the paper

“Fear extinction, as a translational tool, is an important area of study due to its relevance to the limbic neural circuitry believed to underlie fear psychopathology and also due to its role as an experimental homolog to exposure therapy, which is currently recognized as the most effective treatment for fear and anxiety.”

In the paper

“Fear conditioning is a robust, translational experimental paradigm that can be employed to elucidate these mechanisms by allowing for the study of fear-related dimensions of PTSD (e.g., fear extinction, fear inhibition, and generalization of fear) across multiple units of analysis.”

In the paper

“Post-traumatic stress disorder is a heterogeneous disorder in which symptoms span four primary symptom clusters according to the recent Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5; (9)].”

What the sources say

• Not checked yetcites [9] 2013

In the paper

“The dysregulated fear learning commonly observed in anxious and traumatized populations can be modeled by fear-conditioning paradigms, which can provide a translational framework.”

In the paper

“Using the RDoC approach, fear-conditioning studies can identify intermediate phenotypes, which represent specific components of a disorder and allow for a more direct examination of brain–behavior relationships.”

In the paper

“The presence of divergent extinction trajectories as described above represents an exciting new avenue of study and has recently been introduced in the rodent literature (43), which may be analogous to heterogeneous responses to trauma in PTSD (44).”

What the sources say

• Not checked yetcites [43] Galatzer-Levy, 2013, Heterogeneity in threat extinction learning: substantive and methodological considerations for identifying individual difference in response to stress, Front Behav Neurosci source
• Not checked yetcites [44] Galatzer-Levy, 2013, Early PTSD symptom trajectories: persistence, recovery, and response to treatment: results from the Jerusalem Trauma Outreach and Prevention Study (J-TOPS), PLoS One source

In the paper

“While PTSD symptom clusters provide a useful set of diagnostic criteria and could be used to discern the most effective treatment [for a comprehensive review, see Ref. (10)], they represent broad categories of behavior and do not easily reflect common underlying mechanisms.”

What the sources say

• Not checked yetcites [10] Norrholm, 2010, Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters, Neuropsychiatr Dis Treat source

In the paper

“Further, PTSD has long been associated with intrinsic [e.g., age and gender (48, 49)], environmental (e.g., exposure to trauma, rearing environment, degree of social support), and genetic factors (50–52).”

What the sources say

• Not checked yetcites [48] Bokszczanin, 2007, PTSD symptoms in children adolescents 28 months after a flood: age gender differences, J Trauma Stress source
• Not checked yetcites [49] Iwadare, 2014, Posttraumatic symptoms in elementary and junior high school children after the 2011 Japan earthquake and tsunami: symptom severity and recovery vary by age and sex, J Pediatr source
• Not checked yetcites [50] True, 1993, A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms, Arch Gen Psychiatry source
• Not checked yetcites [51] Binder, 2008, Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults, JAMA source
• Not checked yetcites [52] Yehuda, 2008, Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors, J Psychiatr Res source

In the paper

“Fear-potentiated startle can be used in several mammalian species (57); however, in animal models the CSs are typically auditory, whereas visual CSs are used in human studies.”

What the sources say

• Not checked yetcites [57] Myers, 2009, Measurement of fear inhibition in rats, monkeys, and humans with or without posttraumatic stress disorder, using the AX+, BX– paradigm

In the paper

“Not surprisingly, treatment approaches aimed at reducing the fear-related symptoms of PTSD (e.g., re-experiencing and intrusive memories) have focused on the disruption of fear memory consolidation/reconsolidation, facilitation of extinction learning, and the prevention of the return of fear.”

In the paper

“The use of these intermediate phenotypes not only enhances the ability to identify complex gene interactions but also allows for these gene pathways to be more readily studied.”

In the paper

“The advantage of this versatility is that it can be used in patients with visual impairment with equivalent results and also lends itself to the use of “cross-over” longitudinal studies in which practice effects can be minimized.”

In the paper

“These conditions include, but are not limited to, the type of psychophysiological measure employed, the schedule of reinforcement used during acquisition, the fear-relevancy of the conditioned stimuli presented, the strength of the fear memory following acquisition, and the presence or absence of on-line measures of expectancy or fear ratings [see Ref. (37, 91–93)].”

What the sources say

• Not checked yetcites [37] Warren, 2013, Human fear extinction and return of fear using reconsolidation update mechanisms: the contribution of on-line expectancy ratings, Neurobiol Learn Mem source
• Not checked yetcites [91] Golkar, 2012, Are fear memories erasable?-reconsolidation of learned fear with fear-relevant and fear-irrelevant stimuli, Front Behav Neurosci source
• Not checked yetcites [92] Oyarzun, 2012, Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli, PLoS One source
• Not checked yetcites [93] Kindt, 2013, Reconsolidation in a human fear conditioning study: a test of extinction as updating mechanism, Biol Psychol source

In the paper

“For example, PTSD is known to affect women more commonly than men (1, 94), and fear-conditioning paradigms are useful for characterizing the sex differences underlying different neuronal, endocrine, and behavioral responses to trauma and other stressors.”

What the sources say

• Not checked yetcites [1] Kessler, 1995, Posttraumatic stress disorder in the National Comorbidity Survey, Arch Gen Psychiatry source
• Not checked yetcites [94] Breslau, 1997, Sex differences in posttraumatic stress disorder, Arch Gen Psychiatry source

In the paper

“This work was furthered by Gunduz-Cinar et al. (84, 85) who showed that inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes the endogenous cannabinoid anandamide, enhances extinction learning in rodents and could represent a risk variant for stressor-related psychiatric disorders (84, 85).”

What the sources say

• Not checked yetcites [84] Gunduz-Cinar, 2013, Amygdala FAAH and anandamide: mediating protection and recovery from stress, Trends Pharmacol Sci source
• Not checked yetcites [85] Gunduz-Cinar, 2013, Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity, Mol Psychiatry source

In the paper

“While the present review summarized the current progress of interfacing fear conditioning-related intermediate phenotypes and genetic (54), behavioral (47), symptomatic (15, 45), and clinical studies (78), further characterization of these intermediate phenotypes will enhance the utility of fear-conditioning studies.”

In the paper

“By identifying these intermediate phenotypes, we can create specific testable measures, which can then be used to examine the effectiveness of treatment interventions.”

In the paper

“Ultimately, potential breakthroughs will increase the utility of fear-conditioning studies as a translational platform for studying the intermediate phenotypes underlying dysregulated fear learning, a central tenant of trauma-, stressor-, and anxiety-related disorders.”

In the paper

“Understanding these phenotypes (i.e., fear inhibition, high fear load, fear generalization, etc.) and the divergent manifestations of these responses in the context of a broader etiology (i.e., genetic, behavioral, symptomatic, and clinical studies) may lead to more effective treatment and preventative strategies for PTSD and other trauma-, stressor-, and anxiety-related disorders.”