Let's talk about sex … differences in human fear conditioning

doi:10.1016/j.cobeha.2018.01.021

Current Opinion in Behavioral Sciences

Volume 23, October 2018, Pages 7-12

https://doi.org/10.1016/j.cobeha.2018.01.021 Get rights and content

Highlights

•
Men and women differ in their ability to acquire and to extinguish fear.
•
Sex hormones play a critical role in the modulation of fear conditioning processes.
•
Low estrogen levels are associated with an enhanced return of fear.
•
The influence of oral contraceptives is in need for further research.

Fear conditioning represents an experimental paradigm ideally suited to investigate aversive learning and memory mechanisms that are fundamental to the development, maintenance and treatment of mental disorders. Men and women seem to differ in their capability to learn and retrieve fear and extinction memories. This review outlines how sex may influence human fear conditioning, with an emphasis on the sex hormones and oral contraceptives. Available evidence suggests women with high estrogen levels to acquire fear more readily, but also to extinguish fear more easily, leading to an enhanced extinction memory trace. By contrast, women with low estrogens (e.g. due to oral contraceptives) seem to show deficits in extinction recall. These findings are highly relevant for future basic and applied studies alike.

Introduction

Anxiety and stress-related disorders occur twice as likely and with a higher severity in women compared to men [1•, 2, 3]. Fear conditioning represents an important model for the development, maintenance and treatment of these disorders [4, 5, 6]. However, surprisingly few fear conditioning studies have been conducted in females questioning the generalizability of the obtained results [1•, 7]. Proper research in females faces some methodological challenges such as the fluctuation of sex hormones over the menstrual cycle or the intake of hormonal contraceptives [cf. 8], which requires multiplying the sample sizes per experiment when compared to a study conducted in men only. For this reason, such a strategy has not been pursued systematically as evident by a substantially reduced number of fear conditioning studies investigating female compared to male brains [9].

In this review, we will selectively focus on the available literature reporting sex differences in human fear conditioning. We present evidence for sex and sex hormone effects on the different phases of fear conditioning, separated into fear acquisition, extinction and the return of fear. After that, current trends will be highlighted and an outlook will be given before coming to concluding remarks.

Section snippets

Sex differences in fear acquisition

During fear acquisition training, the paired presentation of a stimulus (conditioned stimulus, CS+) with an innately aversive event (unconditioned stimulus, UCS, e.g. an electrical stimulation) leads to fear learning as indexed by conditioned fear responses to the CS+ on different outcome measures [for methodological details, see 10]. Most human studies employ differential fear conditioning designs, in which a second CS (CS−) is added without coupling with the UCS, usually acting as a safety

Sex differences in extinction and the return of fear

During extinction training, repeated presentations of the CS without further pairings with the UCS lead to decreasing conditioned fear responses (cf. Figure 1). Extinction learning is considered to mediate exposure-based treatments in cognitive-behavioral therapy [24, 25].

However, even after successful extinction, conditioned responding may reoccur (cf. Figure 1) as a function of time (spontaneous recovery), after a contextual change (renewal) or unsignalled presentations of the UCS or other

Methodological considerations

Important methodological considerations need to be taken into account when trying to draw a conclusive picture of the presented results. First, we provided a selective overview of recent fear conditioning studies reporting sex differences. However, while available data are still limited due to the overrepresentation of results derived from research including males only [1^•], the existing literature including both sexes with null or not reported results concerning sex differences is hard to

Sex differences in fear conditioning: current trends and outlook

Stress is another important risk factor for the development, maintenance and relapse of anxiety disorders [38, 39]. In response to stress, the adrenal cortex releases glucocorticoids (GCs), which typically enhance memory consolidation but impair memory retrieval [40, 41]. These effects might explain why stress is often associated with symptom relapse [38]. At the same time, GCs appear to be able to boost the success of exposure based therapy presumably by impairing the retrieval of previously

Conclusion

The present review highlights sex hormones as an important modulator of different fear conditioning processes. Whereas high estrogen levels are associated with enhanced extinction and extinction memory recall, they also seem to facilitate initial fear acquisition. Thus, it might be assumed that high estrogens play an essential role in emotional learning processes in general, ultimately leading to unfavorable effects during fear acquisition, whereas being beneficial during extinction processes.

Role of the funding source

This work was supported by a grant from the German Research Foundation (DFG; SFB 1280 Extinction Learning; project A09 to CJM and OTW). The DFG had no further role in interpretation of data, in the writing of the report and in the decision to submit the paper for publication.

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Disgust can be acquired via evaluative conditioning; a process by which a neutral stimulus (conditioned stimulus; CS) comes to be evaluated as disgusting due to its pairing with an inherently disgusting stimulus (unconditioned stimulus; US). Research has shown that conditioned disgust responses are resistant to extinction which may have implications for disorders (i.e., contamination-based obsessive-compulsive disorder, specific phobias, and post-traumatic stress disorder) in which heightened disgust has been implicated. Importantly, extinction is the primary mechanism by which exposure therapies are thought to achieve symptom reduction for these disorders. Exposure therapies were originally modeled on fear extinction, whereas disgust extinction was largely overlooked until recently. Accordingly, differences in the degree to which learned disgust and fear can be attenuated via extinction learning remains unclear. The present investigation was a meta-analysis directly comparing the degree of extinction of conditioned disgust (n = 14) and conditioned fear (n = 14) in laboratory paradigms. Extinction was operationalized as the standardized mean difference (SMD) in evaluative ratings between the CS+ (the CS paired with the US) and CS- (the unpaired CS) after extinction training. Results of a subgroup analysis indicated that disgust (SMD = 0.52) was significantly more resistant to extinction than fear (SMD = 0.37). Additionally, a series of meta-regression analyses indicated that extinction was not influenced by important study characteristics (e.g., sex, age, number of conditioning and extinction trials). The findings suggest that extinction-based approaches may be less effective at attenuating learned disgust and research is needed to better optimize treatments for disgust-related disorders.
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Sex hormones can cross the blood-brain barrier and access brain regions underlying higher-order cognition. Containing synthetic sex hormones, oral contraceptives (OC) have been found to modulate visuospatial and verbal abilities, though inconsistencies have been found in the literature. Among possible explanations, certain OC use parameters (progestin androgenicity, synthetic hormone levels, duration of use) have not received consistent consideration. Thus, the objectives were to (1) examine group differences between men, combined OC users, and naturally cycling women (NC women; not using OC) in visuospatial abilities, verbal fluency, and verbal memory and (2) investigate the contribution of endogenous and exogenous sex hormones on these effects. We also aimed to (3) identify OC use parameters relevant to cognitive outcomes. In total, 70 combined OC users, 53 early follicular (EF) women, 43 pre-ovulatory (PO) women, and 47 men underwent cognitive tests. Performance was compared based on hormonal milieus (OC, EF, PO, men) and OC users' contraceptive androgenicity (anti, low, high). Correlations between performance, hormone levels and OC use duration were also conducted. OC use dampened the sex difference that typically favors men in 3D visuospatial abilities, whereas its duration of use positively predicted verbal fluency. Androgenicity and hormone levels did not predict performance in any task. These results highlight the importance of considering OC use duration. Results also did not support a role for androgenicity in cognition. Importantly, combined OC use (including prolonged use) does not impair visuospatial, verbal, and memory functions in a healthy young sample.
Cross-paradigm integration shows a common neural basis for aversive and appetitive conditioning
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Sharing imaging data and comparing them across different psychological tasks is becoming increasingly possible as the open science movement advances. Such cross-paradigm integration has the potential to identify commonalities in findings that neighboring areas of study thought to be paradigm-specific. However, even the integration of research from closely related paradigms, such as aversive and appetitive classical conditioning is rare – even though qualitative comparisons already hint at how similar the ‘fear network’ and ‘reward network’ may be. We aimed to validate these theories by taking a multivariate approach to assess commonalities across paradigms empirically. Specifically, we quantified the similarity of an aversive conditioning pattern derived from meta-analysis to appetitive conditioning fMRI data. We tested pattern expression in three independent appetitive conditioning studies with 29, 76 and 38 participants each. During fMRI scanning, participants in each cohorts performed an appetitive conditioning task in which a CS+ was repeatedly rewarded with money and a CS- was never rewarded. The aversive pattern was highly similar to appetitive CS+ > CS- contrast maps across samples and variations of the appetitive conditioning paradigms. Moreover, the pattern distinguished the CS+ from the CS- with above-chance accuracy in every sample. These findings provide robust empirical evidence for an underlying neural system common to appetitive and aversive learning. We believe that this approach provides a way to empirically integrate the steadily growing body of fMRI findings across paradigms.
Estradiol during (analogue-)trauma: Risk- or protective factor for intrusive re-experiencing?
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The cerebellum contributes to context-effects during fear extinction learning: A 7T fMRI study
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The cerebellum is involved in the acquisition and consolidation of learned fear responses. Knowledge about its contribution to extinction learning, however, is sparse. Extinction processes likely involve erasure of memories, but there is ample evidence that at least part of the original memory remains. We asked the question whether memory persists within the cerebellum following extinction training. The renewal effect, that is the reoccurrence of the extinguished fear memory during recall in a context different from the extinction context, constitutes one of the phenomena indicating that memory of extinguished learned fear responses is not fully erased during extinction training. We performed a differential AB-A/B fear conditioning paradigm in a 7-Tesla (7T) MRI system in 31 young and healthy men. On day 1, fear acquisition training was performed in context A and extinction training in context B. On day 2, recall was tested in contexts A and B. As expected, participants learned to predict that the CS+ was followed by an aversive electric shock during fear acquisition training. Skin conductance responses (SCRs) were significantly higher to the CS+ compared to the CS- at the end of acquisition. Differences in SCRs vanished in extinction and reoccurred in the acquisition context during recall indicating renewal. Fitting SCR data, a deep neural network model was trained to predict the correct shock value for a given stimulus and context. Event-related fMRI analysis with model-derived prediction values as parametric modulations showed significant effects on activation of the posterolateral cerebellum (lobules VI and Crus I) during recall. Since the prediction values differ based on stimulus (CS+ and CS-) and context during recall, data provide support that the cerebellum is involved in context-related recall of learned fear associations. Likewise, mean β values were highest in lobules VI and Crus I bilaterally related to the CS+ in the acquisition context during early recall. A similar pattern was seen in the vermis, but only on a trend level. Thus, part of the original memory likely remains within the cerebellum following extinction training. We found cerebellar activations related to the CS+ and CS- during fear acquisition training which likely reflect associative and non-associative aspects of the task. Cerebellar activations, however, were not significantly different for CS+ and CS-. Since the CS- was never followed by an electric shock, the cerebellum may contribute to associative learning related to the CS, for example as a safety cue.
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View full text

Let's talk about sex … differences in human fear conditioning

Highlights

Introduction

Section snippets

Sex differences in fear acquisition

Sex differences in extinction and the return of fear

Methodological considerations

Sex differences in fear conditioning: current trends and outlook

Conclusion

Role of the funding source

Conflict of interest statement

References and recommended reading

Am Psychol

J Psychiatr Neurosci

Pain

Pharmacol Rev

J Psychiatr Res

Dev Psychobiol

Behav Neurosci

Behav Res Ther

Learn Mem

Annu Rev Clin Psychol

Q J Exp Psychol

Soc Cogn Affect Neurosci

Neurobiol Learn Mem

Neurobiol Learn Mem

Psychol Rev

Psychol Bull

Curr Opin Behav Sci

Psychoneuroendocrinology

Neuroimage

Psychoneuroendocrinology

Neuroimage

Front Behav Neurosci

Transl Psychiatry

Neuroscience

Trends Cogn Sci

Reprod Biomed Online

Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology

Transl Psychiatry

National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria

J Trauma Stress

Post-traumatic stress disorder in women — epidemiological and treatment issues

CNS Drugs