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1.  Translational Research in the Neuroscience of Fear Extinction: Implications for Anxiety Disorders 
The American journal of psychiatry  2011;168(12):1255-1265.
In this review we propose that the fear extinction model can be used as an experimental tool to cut across symptom dimensions of multiple anxiety disorders to enhance our understanding of the psychopathology of these disorders, and potentially facilitate the detection of biomarkers for the same. We evaluate evidence for this proposition from studies examining the neurocircuitry underlying fear extinction in rodents, healthy humans and clinical populations. Furthermore, we assess the potential use of the fear extinction model to predict vulnerability for anxiety and treatment response, and to improve existing, or lead to developing novel, treatments. Finally, we suggest potential directions for future research that will help to further validate extinction as a biomarker for anxiety across diagnostic categories, and that will help to bridge the gap between basic neuroscience and clinical practice.
doi:10.1176/appi.ajp.2011.11040557
PMCID: PMC4118766  PMID: 21865528
2.  Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit 
The American journal of psychiatry  2012;169(4):415-423.
Objective
Individual differences in ability to control fear have been linked to activation of dorsal anterior cingulate cortex, ventromedial prefrontal cortex, and amygdala. This study investigated whether functional variance in this network can be predicted by resting metabolism in these same regions.
Methods
Healthy subject volunteers were studied with positron emission tomography using [18F]-deoxyglucose to measure resting brain metabolism. This was followed by a two-day fear conditioning and extinction training paradigm in a functional magnetic resonance imaging scanner to measure brain activation during fear extinction and its recall. Skin conductance response was used to index conditioned responding. Resting metabolism in amygdala, dorsal anterior cingulate cortex and ventromedial prefrontal cortex were used to predict responses during fear extinction and extinction recall.
Results
During extinction training, resting amygdala metabolism positively predicted ventromedial prefrontal cortex, and negatively predicted dorsal anterior cingulate cortex, activation. In contrast, during extinction recall, resting amygdala metabolism negatively predicted ventromedial prefrontal cortex, and positively predicted dorsal anterior cingulate cortex, activation. Resting dorsal anterior cingulate cortex metabolism predicted fear expression (skin conductance response) during extinction recall.
Conclusions
Brain metabolism at rest predicts neuronal reactivity and skin conductance changes associated with recall of the fear extinction memory.
doi:10.1176/appi.ajp.2011.10121780
PMCID: PMC4080711  PMID: 22318762
3.  Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women 
Biological psychiatry  2012;73(4):371-378.
Background
Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production, yet their effects on fear extinction are unknown.
Methods
We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n=140).
Results
Women using HCs exhibited significantly poorer extinction recall compared to naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists prior to fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories.
Conclusions
Together, these findings suggest that HCs may impact women’s ability to inhibit fear, but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.
doi:10.1016/j.biopsych.2012.09.018
PMCID: PMC3557577  PMID: 23158459
Estradiol; fear conditioning; anxiety; menstrual cycle; estrous cycle; gonadal hormones
4.  Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats 
Biological psychiatry  2011;70(10):920-927.
Background
Men and women differ in their ability to extinguish fear. Fear extinction requires the activation of brain regions including the ventromedial prefrontal cortex (vmPFC) and amygdala. Could estradiol modulate the activity of these brain regions during fear extinction?
Methods
All rat experiments were conducted in naturally cycling females. Rats underwent fear conditioning on day 1. On day 2, they underwent extinction training during the metestrus phase of the cycle (low estrogen and progesterone). Extinction recall was assessed on day 3. Systemic injections of estrogen-receptor beta and alpha agonists, and estradiol were administered at different time points to assess their influence on extinction consolidation and c-fos expression in the vmPFC and amygdala. In parallel, healthy naturally cycling women underwent an analogous fear conditioning extinction training while in a 3T fMRI scanner. Measurement of their estradiol levels and skin conductance responses were obtained throughout the experiment.
Results
In female rats, administration of the estrogen-receptor beta (but not alpha) agonist facilitated extinction recall. Immediate (but not delayed) post-extinction training administration of estradiol facilitated extinction memory consolidation and increased c-fos expression in the vmPFC while reducing it in the amygdala. In parallel, natural variance in estradiol in pre-menopausal cycling women modulated vmPFC and amygdala reactivity and facilitated extinction recall.
Conclusion
We provide translational evidence that demonstrates the influence of endogenous and exogenous estradiol on the fear extinction network. Our data suggest that women’s endogenous hormonal status should be considered in future neurobiological research related to anxiety and mood disorders.
doi:10.1016/j.biopsych.2011.05.016
PMCID: PMC3197763  PMID: 21762880
Fear inhibition; fMRI; classical conditioning; menstrual cycle; estrogen; progesterone
5.  Ethnic Differences in Physiological Responses to Fear Conditioned Stimuli 
PLoS ONE  2014;9(12):e114977.
The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders.
doi:10.1371/journal.pone.0114977
PMCID: PMC4264849  PMID: 25501365
6.  The influence of gonadal hormones on conditioned fear extinction in healthy humans 
Neuroscience  2010;168(3):652-658.
Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.
doi:10.1016/j.neuroscience.2010.04.030
PMCID: PMC2881679  PMID: 20412837
estrogen; progesterone; sex difference; fear; menstrual cycle; learning and memory
7.  Estrous cycle phase and gonadal hormones influence conditioned fear extinction 
Neuroscience  2009;164(3):887-895.
Gonadal hormones modulate fear acquisition, but less is known about the influence of gonadal hormones on fear extinction. We assessed sex differences and the influence of gonadal hormone fluctuations and exogenous manipulations of estrogen and progesterone on acquisition, extinction learning and extinction recall in a 3-day auditory fear conditioning and extinction protocol. Experiments were conducted on males and naturally cycling female rats. Regarding female rats, significant differences in fear extinction were observed between subgroups of females, depending on their phase of the estrous cycle. Extinction that took place during the proestrus (high estrogen/progesterone) phase was more fully consolidated, as evidenced by low freezing during a recall test. This suggests that estrogen and/or progesterone facilitate extinction. In support of this, injection of both estrogen and progesterone prior to extinction learning in female rats during the metestrus phase of the cycle (low estrogen/progesterone) facilitated extinction consolidation, and blockade of estrogen and progesterone receptors during the proestrus phase impaired extinction consolidation. When comparing male to female rats without consideration of the estrous cycle phase, no significant sex differences were observed. When accounting for cycle phase in females, sex differences were observed only during extinction recall. Female rats that underwent extinction during the metestrus phase showed significantly higher freezing during the recall test relative to males. Collectively, these data suggest that gonadal hormones influence extinction behavior possibly by influencing the function of brain regions involved in the consolidation of fear extinction. Moreover, the elevated fear observed in female relative to male rats during extinction recall suggests that gonadal hormones may in part play a role in the higher prevalence of anxiety disorders in women.
doi:10.1016/j.neuroscience.2009.09.011
PMCID: PMC2783784  PMID: 19761818
estrous cycle; conditioned fear; anxiety; estrogen; progesterone
8.  Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder 
Biological psychiatry  2009;66(12):1075-1082.
Background:
A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC).
Methods:
Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response.
Results:
SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing.
Conclusions:
These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.
doi:10.1016/j.biopsych.2009.06.026
PMCID: PMC2787650  PMID: 19748076
conditioning, classical; stress disorders, post-traumatic; magnetic resonance imaging; amygdala; hippocampus; prefrontal cortex
9.  Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening 
Journal of psychiatric research  2013;47(11):1776-1784.
Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N=109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCR) to 2 differently colored lamps (CS+), but not a third color (CS−), within the computer image of a room (conditioning context). One CS+ (CS+E) but not the other (CS+U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 hr (within AM or PM), 12 hr (morning-to-evening or evening-to-morning) or 24 hr (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p=.002). Collapsing across CS+ type, there was smaller morning differential SCR at both extinction recall (p=.003) and fear renewal (p=.005). Morning extinction recall showed better generalization from the CS+E to CS+U with the response to the CS+U significantly larger than to the CS+E only in the evening (p=.028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicting better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear.
doi:10.1016/j.jpsychires.2013.07.027
PMCID: PMC3791331  PMID: 23992769
Sleep; fear conditioning; extinction; circadian rhythm; sleep homeostasis; cortisol; testosterone
10.  Presence and Acquired Origin of Reduced Recall for Fear Extinction in PTSD: Results of a Twin Study 
Journal of psychiatric research  2008;42(7):515-520.
Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) x combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.
doi:10.1016/j.jpsychires.2008.01.017
PMCID: PMC2377011  PMID: 18313695
Stress disorders, post-traumatic; Fear; Conditioning, classical; Galvanic skin response; Memory; Twins, monozygotic
11.  Cannabinoid facilitation of fear extinction memory recall in humans 
Neuropharmacology  2012;64(1):396-402.
A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing.
doi:10.1016/j.neuropharm.2012.06.063
PMCID: PMC3445738  PMID: 22796109
12.  Sex differences in fear conditioning in posttraumatic stress disorder 
Background
Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined.
Methods
Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task.
Results
Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD.
Conclusions
In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD.
doi:10.1016/j.jpsychires.2012.08.027
PMCID: PMC3806498  PMID: 23107307
Sex differences; Learning; Conditioning; Fear; Posttraumatic stress disorder; Galvanic skin response
13.  A parametric study of fear generalization to faces and non-face objects: relationship to discrimination thresholds 
Fear generalization is the production of fear responses to a stimulus that is similar—but not identical—to a threatening stimulus. Although prior studies have found that fear generalization magnitudes are qualitatively related to the degree of perceptual similarity to the threatening stimulus, the precise relationship between these two functions has not been measured systematically. Also, it remains unknown whether fear generalization mechanisms differ for social and non-social information. To examine these questions, we measured perceptual discrimination and fear generalization in the same subjects, using images of human faces and non-face control stimuli (“blobs”) that were perceptually matched to the faces. First, each subject’s ability to discriminate between pairs of faces or blobs was measured. Each subject then underwent a Pavlovian fear conditioning procedure, in which each of the paired conditioned stimuli (CS) were either followed (CS+) or not followed (CS−) by a shock. Skin conductance responses (SCRs) were also measured. Subjects were then presented with the CS+, CS− and five levels of a CS+-to-CS− morph continuum between the paired stimuli, which were identified based on individual discrimination thresholds. Finally, subjects rated the likelihood that each stimulus had been followed by a shock. Subjects showed both autonomic (SCR-based) and conscious (ratings-based) fear responses to morphs that they could not discriminate from the CS+ (generalization). For both faces and non-face objects, fear generalization was not found above discrimination thresholds. However, subjects exhibited greater fear generalization in the shock likelihood ratings compared to the SCRs, particularly for faces. These findings reveal that autonomic threat detection mechanisms in humans are highly sensitive to small perceptual differences between stimuli. Also, the conscious evaluation of threat shows broader generalization than autonomic responses, biased towards labeling a stimulus as threatening.
doi:10.3389/fnhum.2014.00624
PMCID: PMC4155784  PMID: 25249955
fear; faces; emotion; learning; generalization; perception
14.  Exaggerated Activation of Dorsal Anterior Cingulate Cortex During Cognitive Interference: A Monozygotic Twin Study of Posttraumatic Stress Disorder 
The American journal of psychiatry  2011;168(9):979-985.
Objective
Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of the current research was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or familial risk factor.
Method
Using a case-control twin design, we studied combat-exposed veterans with PTSD (n=12) and their identical combat-unexposed co-twins (n=12), as well as combat-exposed veterans without PTSD (n=14) and their identical combat-unexposed co-twins (n=14). Participants underwent functional magnetic resonance imaging during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate.
Results
Combat veterans with PTSD and their co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to non-PTSD veterans and their co-twins. Dorsal anterior cingulate activation in the exposed twins was positively correlated with their PTSD symptom severity. Dorsal anterior cingulate activation in the unexposed twins was positively correlated with their combat-exposed co-twins’ PTSD symptom severity, but not with depression or alcohol use severity in the combat-exposed co-twins.
Conclusions
Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.
doi:10.1176/appi.ajp.2011.09121812
PMCID: PMC3773363  PMID: 21724666
magnetic resonance imaging; limbic system; stress disorders; post-traumatic; twins; monozygotic; gyrus cinguli; Multi-Source Interference Task
15.  Failure of Neural Responses to Safety Cues in Schizophrenia 
Archives of general psychiatry  2012;69(9):893-903.
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.
doi:10.1001/archgenpsychiatry.2011.2310
PMCID: PMC3767036  PMID: 22945619
16.  Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder 
Archives of general psychiatry  2009;66(10):1099-1107.
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.
doi:10.1001/archgenpsychiatry.2009.138
PMCID: PMC3752096  PMID: 19805700
stress disorders; post-traumatic; twins; monozygotic; positron-emission tomography; fluorodexoyglucose F18; metabolism; cingulate gyrus
17.  Extinction memory is impaired in schizophrenia 
Biological psychiatry  2008;65(6):455-463.
Background
Schizophrenia is associated with abnormalities in emotional processing and social cognition, which may result from disruption of the underlying neural mechanism(s) governing emotional learning and memory. To investigate this possibility, we measured the acquisition and extinction of conditioned fear responses and delayed recall of extinction in schizophrenia and control subjects.
Methods
28 schizophrenia and 18 demographically-matched control subjects underwent a two-day fear conditioning, extinction learning and extinction recall procedure, in which skin conductance response (SCR) magnitude was used as the index of conditioned responses.
Results
During fear acquisition, 83% of the controls and 57% of the patients showed autonomic responsivity (‘responders’), and the patients showed larger SCRs to the stimulus that was not paired with the unconditioned stimulus (CS−) than the controls. Within the responder group, there was no difference between the patients and controls in levels of extinction learning; however, the schizophrenia patients showed significant impairment, relative to the controls, in context-dependent recall of the extinction memory. In addition, delusion severity in the patients correlated with baseline skin conductance levels.
Conclusions
These data are consistent with prior evidence for a heightened neural response to innocuous stimuli in schizophrenia and elevated arousal levels in psychosis. The finding of deficient extinction recall in schizophrenia patients who showed intact extinction learning suggests that schizophrenia is associated with a disturbance in the neural processes supporting emotional memory.
doi:10.1016/j.biopsych.2008.09.017
PMCID: PMC3740529  PMID: 18986648
schizophrenia; fear; conditioning; extinction; emotion; memory
18.  Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning 
Biological Psychology  2011;89(2):450-459.
We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning.
doi:10.1016/j.biopsycho.2011.12.012
PMCID: PMC3269527  PMID: 22207247
19.  Correlations between psychological tests and physiological responses during fear conditioning and renewal 
Background
Anxiety disorders are characterized by specific emotions, thoughts and physiological responses. Little is known, however, about the relationship between psychological/personality indices of anxiety responses to fear stimuli.
Methods
We studied this relationship in healthy subjects by comparing scores on psychological and personality questionnaires with results of an experimental fear conditioning paradigm using a visual conditioned stimulus (CS). We measured skin conductance response (SCR) during habituation, conditioning, and extinction; subsequently testing for recall and renewal of fear 24 hours later.
Results
We found that multiple regression models explained 45% of the variance during conditioning to the CS+, and 24% of the variance during renewal of fear to the CS+. Factors that explained conditioning included lower levels of conscientiousness, increased baseline reactivity (SCL), and response to the shock (UCR). Low levels of extraversion correlated with greater renewal. No model could be found to explain extinction learning or extinction recall to the CS+.
Conclusions
The lack of correlation of fear extinction with personality and neuropsychological indices suggests that extinction may be less determined by trait variables and cognitive state, and may depend more on the subject’s current emotional state. The negative correlation between fear renewal and extraversion suggests that this personality characteristic may protect against post-treatment relapse of symptoms of anxiety disorders.
doi:10.1186/2045-5380-2-16
PMCID: PMC3511243  PMID: 22985550
Fear; Conditioning; Extinction; Anxiety; Skin conductance; Personality traits
20.  Unconditioned responses and functional fear networks in human classical conditioning 
Behavioural brain research  2011;221(1):237-245.
Human imaging studies examining fear conditioning have mainly focused on the neural responses to conditioned cues. In contrast, the neural basis of the unconditioned response and the mechanisms by which fear modulates inter-regional functional coupling have received limited attention. We examined the neural responses to an unconditioned stimulus using a partial-reinforcement fear conditioning paradigm and functional MRI. The analysis focused on: (1) the effects of an unconditioned stimulus (an electric shock) that was either expected and actually delivered, or expected but not delivered, and (2) on how related brain activity changed across conditioning trials, and (3) how shock expectation influenced inter-regional coupling within the fear network. We found that: (1) the delivery of the shock engaged the red nucleus, amygdale, dorsal striatum, insula, somatosensory and cingulate cortices, (2) when the shock was expected but not delivered, only the red nucleus, the anterior insular and dorsal anterior cingulate cortices showed activity increases that were sustained across trials, and (3) psycho-physiological interaction analysis demonstrated that fear led to increased red nucleus coupling to insula but decreased hippocampus coupling to the red nucleus, thalamus and cerebellum. The hippocampus and the anterior insula may serve as hubs facilitating the switch between engagement of a defensive immediate fear network and a resting network.
doi:10.1016/j.bbr.2011.02.045
PMCID: PMC3092385  PMID: 21377494
fMRI; conditioning; psychophysiological interaction; connectivity; insula; PPI
21.  Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry 
Background
The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction.
Methods
Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8.
Results
Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall.
Conclusions
These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.
doi:10.1186/2045-5380-2-7
PMCID: PMC3416700  PMID: 22738021
Sex differences; Fear extinction; Fear conditioning; fMRI; Stress response circuitry
22.  Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders 
Convergent data from rodents and human studies have led to the development of models describing the neural mechanisms of fear extinction. Key components of the now well-characterized fear extinction network include the amygdala, hippocampus, and medial prefrontal cortical regions. These models are fueling novel hypotheses that are currently being tested with much refined experimental tools to examine the interactions within this network. Lagging far behind, however, is the examination of sex differences in this network and how sex hormones influence the functional activity and reactivity of these brain regions in the context of fear inhibition. Indeed, there is a large body of literature suggesting that sex hormones, such as estrogen, do modulate neural plasticity within the fear extinction network, especially in the hippocampus.
After a brief overview of the fear extinction network, we summarize what is currently known about sex differences in fear extinction and the influence of gonadal hormones on the fear extinction network. We then go on to propose possible mechanisms by which sex hormones, such as estrogen, may influence neural plasticity within the fear extinction network. We end with a discussion of how knowledge to be gained from developing this line of research may have significant ramifications towards the etiology, epidemiology and treatment of anxiety disorders.
doi:10.1186/2045-5380-2-3
PMCID: PMC3384233  PMID: 22738383
menstrual cycle; sex hormones; estrogen; progesterone; estrus cycle; fear extinction
23.  An fMRI study of unconditioned responses in post-traumatic stress disorder 
Background
Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response.
Results
Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD.
Conclusions
Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased.
doi:10.1186/2045-5380-1-8
PMCID: PMC3384234  PMID: 22738227
24.  Hemispheric differences in amygdala contributions to response monitoring 
Neuroreport  2009;20(4):398-402.
The amygdala detects aversive events and coordinates with rostral anterior cingulate cortex to adapt behavior. We assessed error-related activation in these regions and its relation to task performance using functional MRI and a saccadic paradigm. Both amygdalae showed increased activation during error versus correct antisaccade trials that was correlated with error-related activation in the corresponding rostral anterior cingulate cortex. Together, activation in right amygdala and right rostral anterior cingulate cortex predicted greater accuracy. In contrast, left amygdala activation predicted a higher error rate. These findings support a role for amygdala in response monitoring. Consistent with proposed specializations of right and left amygdala in aversive conditioning, we hypothesize that right amygdala-rostral anterior cingulate cortex interactions mediate learning to avoid errors, while left error-related amygdala activation underpins detrimental negative affect.
doi:10.1097/WNR.0b013e328324edb8
PMCID: PMC2650381  PMID: 19218865
response monitoring; reinforcement learning; emotion; amygdala; anterior cingulate cortex; antisaccade; errors; limbic system

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