Recall of Fear Extinction in Humans Activates the Ventromedial Prefrontal Cortex and Hippocampus in Concert

Milad, Mohammed R.; Wright, Christopher I.; Orr, Scott P.; Pitman, Roger K.; Quirk, Gregory J.; Rauch, Scott L.

doi:10.1016/j.biopsych.2006.10.011

Cited by 1,034 publications

(1,083 citation statements)

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“…Some design aspects are worth noting; in our experimental paradigm, extinction training was initiated within approximately 10 min after fear conditioning, which was done in order to allow comparison to previous studies (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007, 2008; van ‘t Wout et al., 2013). Prior research supports the presence of differences in extinction processes depending on their temporal relationship with fear conditioning (Myers, Ressler, & Davis, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The experimental protocol utilized a standardized 2‐day Pavlovian fear‐conditioning–extinction‐recall paradigm (Milad, Orr, Pitman, & Rauch, 2005; Milad et al., 2005, 2007, 2008; van ‘t Wout et al., 2013) using E‐Prime 2.0 software (Psychology Software Tools, Pittsburgh, PA). Participants were presented with photographs of two different rooms, one serving as the fear acquisition context (CX+; picture of an office) and one as the fear extinction context (CX−; picture of a bookcase) in which two conditioned stimuli (CS+; red and blue light) and one never‐to‐be conditioned stimulus (CS−; yellow light) were presented.…”

Section: Methodsmentioning

confidence: 99%

“…Two CS+ were included to allow comparison of results to previous studies on PTSD (Milad et al., 2009) and the effects of tDCS during fear extinction in healthy volunteers (van ‘t Wout et al., 2013), and lay the foundation for future sham‐controlled studies. For this same reason, we followed prior studies in the timing of habituation, conditioning, and extinction to occur on Day 1, and extinction recall on Day 2 approximately 24 hr later (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007, 2008; van ‘t Wout et al., 2013). …”

Section: Methodsmentioning

confidence: 99%

“…Skin conductance reactivity (SCR) for each trial was calculated by subtracting mean skin conductance level during the 3 s before CS onset (i.e., context alone was being presented) from the highest skin conductance level during the 6 s CS duration to reflect changes beyond any change produced by the presentation of context (McLaughlin et al., 2015; Milad et al., 2005, 2005, 2007; Orr et al., 2000; van ‘t Wout et al., 2013). SCR data were normalized using log transformation.…”

Section: Methodsmentioning

confidence: 99%

“…Animal models and human studies of PTSD have highlighted aberrations in neural circuitry including hyperactivity in the amygdala and dorsal anterior cingulate cortex, regions that promote fear responses, alongside hypoactivity in the ventromedial prefrontal cortex (vmPFC), a region that is thought to suppress fear responses (Milad & Quirk, 2012; Quirk, Garcia, & González‐Lima, 2006; VanElzakker et al., 2014). More specifically, vmPFC engagement during extinction learning predicts extinction success and is associated with “top‐down” modulation of amygdala‐driven fear expression (Do‐Monte, Manzano‐Nieves, Quiñones‐Laracuente, Ramos‐Medina, & Quirk, 2015; Lebrón, Milad, & Quirk, 2004; Milad et al., 2005, 2007; Phelps, Delgado, Nearing, & LeDoux, 2004; Quirk, Likhtik, Pelletier, & Paré, 2003; Rosenkranz, Moore, & Grace, 2003). Results from studies with PTSD patients revealed deficits in extinction recall (Milad et al., 2008), reduced vmPFC volume, and activation during fear extinction compared to controls (Bremner et al., 2005; Milad et al., 2009; Rauch et al., 2003; Rougemont‐Bücking et al., 2011; Shin, Rauch, & Pitman, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

et al. 2017

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BackgroundAbnormalities in fear extinction and recall are core components of posttraumatic stress disorder (PTSD). Data from animal and human studies point to a role of the ventromedial prefrontal cortex (vmPFC) in extinction learning and subsequent retention of extinction memories. Given the increasing interest in developing noninvasive brain stimulation protocols for psychopathology treatment, we piloted whether transcranial direct current stimulation (tDCS) during extinction learning, vs. during consolidation of extinction learning, might improve extinction recall in veterans with warzone‐related PTSD.MethodsTwenty‐eight veterans with PTSD completed a 2‐day Pavlovian fear conditioning, extinction, and recall paradigm. Participants received one 10‐min session of 2 mA anodal tDCS over AF3, intended to target the vmPFC. Fourteen received tDCS that started simultaneously with extinction learning onset, and the remaining 14 participants received tDCS during extinction consolidation. Normalized skin conductance reactivity (SCR) was the primary outcome measure. Linear mixed effects models were used to test for effects of tDCS on late extinction and early extinction recall 24 hr later.ResultsDuring early recall, veterans who received tDCS during extinction consolidation showed slightly lower SCR in response to previously extinguished stimuli as compared to veterans who received tDCS simultaneous with extinction learning (p = .08), generating a medium effect size (Cohen's d = .38). There was no significant effect of tDCS on SCR during late extinction.ConclusionsThese preliminary findings suggest that testing the effects of tDCS during consolidation of fear extinction may have promise as a way of enhancing extinction recall.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

et al. 2017

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Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder

Shin¹,

Lasko²,

Macklin³

et al. 2009

Arch Gen Psychiatry

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127

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Context Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala and hippocampus in posttraumatic stress disorder (PTSD). Objective To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors. Design Cross-sectional design including identical twins discordant for trauma exposure. Setting Academic medical center. Participants Combat-exposed veterans with PTSD (n=14) and their identical, combat-unexposed co-twins (n=14), as well as combat-exposed veterans without PTSD (n=19) and their identical, combat-unexposed co-twins (n=19). Main Outcome Measures We used positron emission tomography and [18F]-fluorodeoxyglucose to examine resting regional cerebral metabolic rates for glucose (rCMRglu). Results Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in dorsal anterior cingulate/mid cingulate cortex (dACC/MCC) compared to non-PTSD veterans and their co-twins. Resting rCMRglu in dACC/MCC in the combat-unexposed co-twins was positively correlated with combat exposure severity, PTSD symptom severity, and alcohol use in their exposed twins. Conclusions Enhanced resting metabolic activity in dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.

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Failure of Neural Responses to Safety Cues in Schizophrenia

Holt

Coombs²,

Zeidan³

et al. 2012

Arch Gen Psychiatry

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108

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Context Abnormalities in associative memory processes, such as Pavlovian fear conditioning and extinction, have been observed in schizophrenia. The retrieval of fear extinction memories (‘safety signals’) may be particularly affected; although schizophrenia patients can extinguish conditioned fear, they show a deficit in retrieving fear extinction memories after a delay. The neurobiological basis of this abnormality is unknown, but clues have emerged from studies in rodents and humans demonstrating that the ventromedial prefrontal cortex (vmPFC) is a key mediator of extinction memory retrieval. Objective To measure autonomic and neural responses during the acquisition and extinction of conditioned fear and the delayed recall of fear and extinction memories in patients with schizophrenia and healthy controls. Design Cross-sectional case-control, functional magnetic resonance imaging study. Setting Academic medical center. Participants Twenty patients with schizophrenia and 17 healthy control participants, demographically-matched to the patient group. Main Outcome Measures Skin conductance and blood oxygen level dependent (BOLD) responses. Results During fear conditioning, patients with schizophrenia showed blunted autonomic responses and abnormal BOLD responses, relative to controls, within the posterior cingulate gyrus, hippocampus and other regions. Several of these abnormalities were linked to negative symptoms. During extinction learning, patients with schizophrenia and controls showed comparable autonomic and neural responses. Twenty-four hours after the learning phases, the control subjects exhibited decreased fear and increased vmPFC responses in the extinction (safe) context as expected, indicating successful retention of the extinction memory. In contrast, the schizophrenia patients showed inappropriately elevated fear and poor vmPFC responses in the safe context. Conclusion Failure of extinction memory retrieval in schizophrenia is associated with vmPFC dysfunction. In future studies, abnormalities in fear learning and extinction recall may serve as quantitative phenotypes that can be linked to genetic, symptom or outcome profiles in schizophrenia and those at risk for the disorder.

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Recall of Fear Extinction in Humans Activates the Ventromedial Prefrontal Cortex and Hippocampus in Concert

Cited by 1,034 publications

References 48 publications

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder

Failure of Neural Responses to Safety Cues in Schizophrenia

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