代做PSYC3241: Psychobiology of Memory代写C/C++语言

日期：2024-04-08 04:28

Too Much of a Good Thing: Estradiol Administration and Extinction Retention in Spider Phobic Women

PSYC3241: Psychobiology of Memory

Exposure therapy is the recommended psychological treatment for anxiety disorders (Hofmann & Smits, 2008) but some individuals who receive this treatment relapse or fail to achieve full symptom remission (DiMauro et al., 2013). Therefore, it is crucial to identify mechanisms that enhance the effectiveness of exposure therapy. This is especially important for women as they experience greater prevalence of anxiety and poorer therapeutic outcomes (Krzikalla et al., 2023).

Fear extinction offers a laboratory model of exposure therapy (Forcadell et al., 2017) and has been employed to examine the influence of sex hormones like estradiol. Estradiol fluctuates across the menstrual cycle and may moderate women’s heightened vulnerability to anxiety (Milad et al., 2009). Traditionally, a median split based on serum analysis has been used to class women as low or high estradiol. Research with healthy women demonstrates that extinction learning is impaired when estradiol is low, indicated by persistent fear responses when re-exposed to an extinguished conditioned stimuli (CS) during retention tests (Milad et al., 2010; Graham & Milad, 2013). This pattern may be explained via neural mechanisms as low estradiol women exhibit less activation of brain areas involved in fear extinction including the ventromedial prefrontal cortex and left amygdala, compared to high estradiol women (Zeidan et al., 2011).

It is important to further investigate the relationship between estradiol and extinction  retention in clinical populations as deficits in fear extinction contribute to the maintenance of anxiety and fear-based disorders (Mineka & Oehlberg, 2008). In support of this, PTSD women with low estradiol show persistent fear during extinction training (Glover et al., 2012). Additionally, trauma-exposed women with low estradiol exhibit an inability to discriminate between safety and threat cues and impaired fear inhibition compared to high estradiol women (Glover et al., 2013). More recently, a similar pattern was replicated with spider phobic women as relative to the high estradiol group, the low estradiol women demonstrated significantly more fear during extinction retention (Li & Graham, 2016). Importantly, high estradiol anxious women perform. comparably to high estradiol healthy controls (Glover et al., 2012; Li & Graham, 2016), suggesting that high estradiol may be protective against fear extinction deficits in anxiety disorders.

These findings indicate that low endogenous estradiol may reduce the effectiveness of exposure therapy and thus estradiol may be a pharmacological agent to augment retention of extinction learning. In light of this, one study found that when women naturally low in estradiol receive estradiol treatment, they have superior extinction retention to placebo controls (Graham & Milad 2013). However, the current literature has not considered the impact of estradiol administration when estradiol is naturally high. Work with cycling female rats offers some insight as a high dosage of estradiol administered during proestrus (high estradiol phase) resulted in poor retention whilst a low dose during proestrus had no effect.  Conversely a low dose during metestrus (low estradiol phase) enhanced retention (Graham & Scott, 2018). Furthermore, ovariectomised rats show more anxiety-like behaviours when treated with high doses of estradiol (Tomihara et al., 2009) but reduced fear responses when receiving lower doses (Barha et al., 2010). This suggests that high levels of estradiol have anxiogenic effects whilst lower levels may be anxiolytic.

It remains to be elucidated if systematically elevated levels of estradiol will have the same impairing effect in women. Graham and Scott (2018) proposed that even though women demonstrate greater extinction retention when estradiol is high, it may be possible to optimise responses further. Furthermore, no study to date has examined the effect of estradiol administration on fear extinction in a clinical population. To improve the effectiveness of exposure therapy and evaluate the use of estradiol as a therapeutic adjunct, the conditions under which estradiol can enhance extinction learning must be clarified. Consequently, the present study aims to investigate the effects of estradiol administration on extinction retention in anxious women with varying levels of natural estradiol.

By administering estradiol when natural levels are both low and high, my research will build upon work from Li and Graham (2016) by examining the relationship between endogenous and exogenous estradiol in spider phobic women. The effect of endocrine products often forms an inverted U-shaped curve (Tomihara et al., 2009), where very low levels have no effect whilst extremely high levels impair. It is plausible that the effects of estradiol levels on extinction retention shall operate in a similar manner. Given that very high estradiol levels had an impairing effect in female rodents (Graham & Scott, 2018), I hypothesis that amongst spider phobic women, extinction retention will be poorest for naturally high estradiol women who receive estradiol treatment, indicated by high fear responses. Based on the effect previously found in healthy females (Graham and Milad 2013), I also predict that estradiol administration will enhance learning for naturally low  estradiol women with spider phobia, meaning that this group will demonstrate less fear responses during the retention test than low estradiol placebo treated women.

Method

Participants

Our study shall recruit 80 regular cycling females who meet DSM-V criteria for spider phobia. Inclusion criteria will remain consistent with previous literature (Milad et al. 2010) and eligible participants will be aged 18-45, non-pregnant and not using hormonal contraceptives.

Design

Our study will utilise a 2 x 2 mixed factorial design. The first factor shall be participants’ endogenous estradiol levels, classified as low or high according to a median split of blood results. The second factor is pharmacological treatment (estradiol or placebo).  The dependent variable will be extinction retention, operationalised as a percent recovery of skin conductance levels (SCLs) during retention.

Materials

Conditioned and Unconditioned Stimuli

The CS+ and CS- will consist of spider pictures adapted from Li and Graham (2016).

The CS+ will be paired with a mild electric shock US delivered to the participant’s hand.

Physiological Assessment

SCLs will quantify the conditioned response and will be measured using the ADInstruments system employed by Li and Graham (2016). Extinction retention shall be calculated according to the approach used by Graham and Milad (2013) which involves dividing average SCLs during recall by the largest SCL to CS+ trials at conditioning for each participant.

Estradiol Administration

Estradiol treatment will be adapted from Graham and Milad (2013) and one dose of   Femtrace (1.8mg, estradiol tablets) shall be used. Half of the women in each group (low and high estradiol) will receive Femtrace whilst half will receive placebo.

Procedure

All eligible participants will attend the lab on Day 1 to provide an initial blood sample. A median split based on serum results will group participants as low or high estradiol. Next participants will be habituated to the CS+ and CS- as the two pictures will be presented twice without any shock. The conditioning phase will follow which involves displaying the CS+ and CS- eight times each. The CS- will never be followed by shock whereas the CS+ shall be 62.5% partially reinforced with shock as this causes differential fear conditioning (Graham & Milad, 2013).  On Day 2, estradiol or placebo will be administered 30 minutes before extinction training to ensure estradiol levels are elevated during memory consolidation (Zeidan et al., 2011). During extinction training, the CS+ and CS- will be displayed seven times each with no shock. Participants will then provide a second blood sample to validate that the drug increased estradiol levels. On Day 3 participants shall return to the lab for a retention test which will be identical to extinction training. SCRs will be recorded throughout all experimental trials and used to calculate a percent recovery of fear as an index of extinction retention.