D-cycloserine-enhanced Exposure Therapy May Clarify The Role Of Fear In Blood-injection-injury Type Phobias

Running head: THE ROLE OF FEAR IN BII-TYPE PHOBIAS

D-Cycloserine-enhanced exposure therapy may clarify the role of fear in blood-injection-injury type phobias Brian C. Woolfrey University of Minnesota

Abstract There has been much debate over the years about the role of fear in Blood-Injection-Injury (BII) type phobias. This class of phobia is similar to other specific phobias except that there is often an acute fainting response in reaction to BII-relevant stimulus. In this paper an experiment is proposed to explore the specific role that fear conditioning plays in the etiology of BII-type phobias by using exposure therapy enhanced with injections of D-Cycloserine. D-Cycloserine (DCS) is a partial NDMA antagonist that has been shown to facilitate association learning in the amygdala at the cellular level and enhance extinction training for conditioned fear in both animals and humans. In the proposed study, BII-phobic participants will undergo DCS-enhanced extinction training in the form of modified BII-stimulus exposure therapy. Dependant measures of faintness will consist of self-reports of “pre-syncope auras” in the presence of BII stimulus, and fear states will be inferred using a standard eye-blink startle paradigm. Using these measures of fear and faintness, we expect do find that 1) DCS-enhanced exposure therapy reduces both measures of fear and faintness and 2) The effect on fear is much greater than the effect on faintness. If so, this would suggest that fear conditioning may indeed play only a supporting or mediating role in the tendency to faint and is not likely to be a primary etiological factor.

D-Cycloserine-enhanced exposure therapy clarifies the role of fear in blood-injectioninjury type phobias For many years researchers have debated the nature of Blood-Injection-Injury (BII) type specific phobias. Like other specific phobias, BII phobia is characterized by an irrational fear and avoidance of specific objects or situations related to the phobia (those that involve needle injections, injury or visible blood). Unlike other phobias, however, many people with BII phobia often faint in the presence of BII stimuli (Connolly, 1976). Early models of BII phobia tended to view the etiology of the disorder purely in terms of fear conditioning. According to this line of thinking, a child who has persistent negative experiences or who is involved in a particularly traumatic event relating to blood, injury or mutilation was thought to be at high risk for developing BII phobia in adolescence and adulthood. A more passive type of learning was even used to explain evidence that showed a greater familial concordance rate for BII phobia than other specific phobias. According to this logic, a child may be at risk for developing BII phobia after repeatedly observing fearful, anxious or neurotic behavior of a parent around BII-related stimuli (Bracha 2004). In recent years, however, evidence has suggested that the etiology of BII phobia may be more complicated than a simple case of fear conditioning. Many researchers have even started to claim that biologically-inherited traits such as disgust sensitivity or a type of autonomic dysregulation play a stronger role in the development of BII phobia than fear conditioning (Page, 1998 and Bracha, 2004). Although a substantial amount of research has been carried out regarding the role of disgust sensitivity, the results of these studies have been mixed at best (Gerlach, 2006). Autonomic dysregulation that predisposes a person to faint, on the other hand, seems to be more reliably correlated to BII phobia. The best evidence for this has come from

recent findings by Accurso (2001), who used a “tilt table” to demonstrate that BII phobics were more likely to lose consciousness even under non-phobic conditions than a control group. This recent evidence supports the ideas of researchers such Page (1998) and Kleinecht (1989) who theorized that fear may be only a secondary development in BII phobia. According to this line of thinking, the avoidance and acute anxiety behaviors that are characteristic of specific phobias develop after the first few fainting responses because fainting is such an unpleasant experience. In this view, BII phobia begins as a predisposition to faint around BIIrelated stimulus that is caused by an inherited autonomic dysregulation interacting with high disgust sensitivity. The role of fear in BII phobia in this view, therefore, is reduced to a side effect. Although this theory seems to offer a promising explanation for the tendency for BIIphobics to faint, it is not a fully sufficient explanation for the phenomenon. The fact that a person with BII phobia is more likely to lose consciousness under tilt-table conditions than non-BII phobics doesn’t disprove the role of fear as a causal factor altogether. All it tells us is that some type of autonomic dysregulation is common in many people with BII-type phobia. A purely autonomic explanation, however, does not explain the roughly 25% of BII-phobics who do not have a history of fainting (DSM-IV-TR) or the findings that extinction training is helpful in reducing fainting in certain BII phobics. It seems reasonable, therefore, to assume that fear conditioning plays some role in the etiology of BII-phobia, but the exact nature of its role is still unknown. One way to better understand the role of fear would be to simply remove it from the equation and observe what happens. Until recently this might have seemed like a pointless endeavor because a deeply-ingrained phobia is not something that is easily extinguished. There

has been moderate success at extinguishing phobias using classic exposure therapy, but in most cases this simply reduces the fear to a manageable level. There are also anxiolytic drugs available that can reduce an even eliminate fearful behavior, but most of these rely in some way on diffuse inhibitory neurotransmitter systems such as GABA that tend to effect more than just fear systems. Using this type of “shotgun” method of reducing fear and anxiety poses a problem in research because one of the many other neural systems that are affected by GABA might also play a role in BII-phobia. How, then, do we specifically target and remove fear from the equation? Fortunately, a relatively new drug in the arsenal of researchers called D-Cycloserine (DCS) may be able to provide the means. DCS is a partial NMDA-receptor agonist that acts to enhance long-term potentiation (LTP) in amygdalar neurons that are important for the acquisition of fear associations (Ressler 2001). Recently it has been demonstrated by Walker and colleagues (2002) that injecting DCS into the amygdale of rats just before extinction training acts to enhance its effects. To date, the positive effects of DCS injections on extinction training has been replicated many times in animal models (Ledgerwood 2003; Davis 2005) and even shown to increase the generalization of extinguished fear (Vervliet 2008). More recently, some researchers have begun applying the idea of DCS-enhanced extinction training to human subjects with certain psychological disorders in which dysfunctional learning is thought to be of etiological relevance. A recent study by Hoffman and colleagues (2004), for example, showed that DCS administered with exposure treatment augmented extinction in subjects with social phobia. Ressler and colleagues (2004) applied DCS-enhanced extinction training to human subjects with acrophobia and found similar results.

Based on experimental evidence that indicates DCS-enhanced exposure therapy may enhance the extinction of conditioned fear in both animals and humans (Vervliet 2008), we propose to use a form of DCS-enhanced exposure therapy as a way to experimentally manipulate the role of conditioned fear in BII-phobia. We hypothesize that DCS-enhanced exposure therapy will reduce both measures of fear and faintness in participants, but that the effect of exposure therapy will be far greater on fear than it is for faintness. If so, this evidence would support the idea that fear plays at least some role in the etiology of blood phobia but that it may be more of a mediating function than a core cause in BII phobics with a history of fainting. Method Participants All participants in this study will have been previously diagnosed with blood-injectioninjury type phobia and would be recruited though local clinics and newspaper ads. The total number of participants in our sample should be greater than 30 and each would be compensated for their tame with an appropriate monetary reward. As this study would take place in Minnesota, it is likely that the majority would be Caucasian. Consistent with BII-phobia prevalence rates, we would expect there to be more female participants than males. We would also expect that the majority of our participants would have a history of fainting. Measures The two dependant variables that would be measured in this study are fear and faintness. The operational measure of fear would be based off of acoustic fear-potentiated startle paradigm. To infer fear states in our study, eye-blink magnitude in response to a sudden burst of white noise in the presence of BII-related stimuli would be measured and compared to eye-blink magnitude

in response to the same noise in the presence of neutral stimuli. The difference between eyeblink magnitude would become our operational measure of fear. Since no reliable physiological measure of “faintness” exists, this study must rely on participants’ self-reports of feelings of faintness or “auras” that typically occur just before fainting. Self-reports would take the form of the participant verbally reporting a feeling of faintness to the researcher. To avoid medical complications with fainting, participants would be asked to report the first signs of faintness or pre-syncope auras and such a report would be grounds for immediate cessation of stimulus presentation. These reports of faintness or lack thereof would be recorded as a categorical measure of “faintness” or “no faintness” for each stimulus set. We would then use the total number of times a participant reported faintness across all stimulus sets as a quantification of the tendency to faint in the presence of BII-related stimuli. Stimulus This study would make use two different contexts in order to maximize the potential for fear and faintness in the participants. The first set of stimuli would consist of BII-related media displayed on a computer screen. This media would include several sets of pictures or video clips, each of which would be highly relevant to BII-related fears such as injections, bleeding, severe mutilation and vascular surgery. The white noise stimulus would be presented randomly during one of the pictures in each of the sets in order to measure eye-blink magnitude. After each set the participant would be given a 2 minute horizontal rest period so that those who reported feelings of faintness could fully recover. In order to increase the likelihood of reporting faintness we would also include a second situation in which the stimulus was personally salient to the participant. To do this we would instruct a registered nurse take a small blood sample from the participants while they are in an

upright position. In this condition the white noise would be presented after the nurse verbally indicated that she was about to begin the procedure. Procedure This study would include several different phases that would take place over a period of about 9 weeks. The first phase would be the initial recording of measurements of fear and faintness in response to BII stimulus using the stimuli and response measures that are described above. The second phase of the study would be a period of extinction training. In this phase all participants would undergo 4 weeks of highly structured exposure therapy performed by certified, experienced clinicians. Each session would take an hour to complete and take place every other day. To control for individual therapy styles, the clinicians would administer the therapy in a highly structured way and use identical stimuli on all participants. In order to encourage generalization the clinicians would use a wide variety of highly salient stimuli (including media exposure, live O.R. observations, handling needles and even the dissection of animals) in a wide variety of settings (doctor’s office, psych labs, classrooms and etc). Our hope is that this extensive exposure therapy will successfully overwrite previously conditioned BIIrelated fear associations with new, less threatening associations and effectively extinguishing learned BII-related fears. To maximize the effectiveness of the exposure therapy, 20 of the 30 subjects will be given injections of 500 mg of D-Cycloserine (DCS) before each extinction training session. The remaining 10 participants will receive saline injections as a control. The third and final phase of the experiment would be post-extinction measurements of fear and faintness using the same procedures as the initial base-line measurements.

Data Reduction and Analysis The goal of our analysis would be to determine the size of the effect that DCS-enhanced extinction training had on our dependant variables of fear and faintness. To do this we would first have to quantify our “before” and “after” data for each variable into average scores and standard deviations. For the variable of fear, the group data would reflect the average and standard deviations of the average change in eye-blink magnitude between neutral and fearful stimuli for each participant. Data for faintness would reflect the average and standard deviations of the total number of times each participant reported feeling faint across all stimuli sets. Once average scores and standard deviations are determined for each group, we can then run statistical tests to determine the precise effects of exposure therapy on each variable. To determine if there was a significant change in each variable after exposure therapy we would run independent samples ttests. To determine the nature of this change we would use Cohen’s d as a measure of effect size. Results The results of our statistical tests should look something like the following. First, we anticipate finding a significant difference between pre- and post-therapy conditions in our measures of both fear and faintness in the DCS-enhanced group (p < .01). Also, because previous research that tells us that DCS-enhanced exposure therapy is more effective at extinguishing fear than exposure therapy alone, we would expect to see a comparatively weaker effect (if any) on both variables in the saline-injected control group. Although we would expect to find a significant change in both fear and faintness after exposure therapy in the DCS-enhanced group, we do not expect this change to be equal. Using Cohen’s d as a statistical test of effect size, we would expect the d-value to be much higher for fear (ex. d = .8) than it is for fainting (ex. d = .3). In other words we would expect the DCS-

enhanced exposure therapy to reduce fear far more than it reduces the propensity to faint. Again, this effect should be smaller or non-existent in the saline group (ex. d < .2) for both variables. Discussion We expect our data to show two important relationships. The first is that DCS-enhanced exposure therapy should reduce both measures of fear and faintness in a statistically significant way. This would indicate that conditioned fear is somehow involved in the fainting response in BII phobia. We can be confident of this because DCS-enhanced exposure therapy is only thought to target conditioned fear. Any reduction in the propensity to faint, therefore, should be attributable to this reduction in conditioned fear. The second important relationship we expected to find is that DCS-enhanced exposure therapy reduces fear far more than it reduces the propensity to faint. This would suggest that fear is not likely to be primary cause of fainting in BII phobia. If it were, fainting would show an equally strong decline after DCS-enhanced exposure therapy as measures of fear. It is also important to note that these results would suggest that it is possible for someone with BII phobia to faint in the presence of BII-related stimulus even without the influence of conditioned fear. The role of fear, therefore, may indeed be a secondary development in the overall etiology of BII phobia similar to what Page and colleagues had envisioned. But because we expect the data to show at least some reduction of fainting propensity after DCS-enhanced exposure therapy, we can also make the argument that the role of fear is likely to be more complicated than that. Aside from not discounting the possibility that conditioned fear is somehow involved in the etiology of many BII phobia cases (particularly those that show little or no fainting response), the expected results of this study would also suggest that fear can act as a mediating variable in the fainting response. Even if one develops a fear of BII-related stimuli

after the first few fainting responses, this fear may act as a type of positive feedback loop that enhances or even triggers future fainting responses. It is also possible that DCS-mediated exposure therapy may have different effects on fear and fainting than we expect to find. Fear extinction, for example, may not have any effect at all on self-reports of faintness. Something like this could happen if the fainting response in BIIphobia is in fact entirely independent from fear as Page had theorized. Another alternative outcome could be that DCS-enhanced exposure therapy does not have a significant effect on fear conditioning at all in BII phobia. There could be several different explanations for a finding like this. One could be that DCS-enhanced emotional learning does not act in the same way for BII-related fears than it does for fears of spiders. This could be because the specific fears in BII-phobia are more instinctive and inheritable than conditioned. One theory even goes so far as to suggested that a fainting response to the sight of blood may have played an adaptive role in the course of human evolution because the corresponding reduction in blood pressure would reduce bleeding after a serious injury (Bracha 2004). Another reason why DCS might fail to enhance exposure therapy might be that the clinician administering the therapy fails to demonstrate that a subject’s fears are irrational. In some cases of severe autonomic dysregulation the subjects fears may actually be reinforced by exposure to BII-related stimulus because it triggers feelings of faintness that the clinician can not control. If this study were to be successfully run and the expected results obtained, this would have several implications for future research. The first would be to encourage future research of BII phobia to study conditioned fear as an important mediating variable or part of a positive feedback loop that reinforces fainting. Current research tends to ignore the role of fear altogether

in favor of other possible causes that may be more relevant to medical treatment than psychological treatment. It may also be prudent for future research to begin to make a distinction between different subtypes of BII-phobia based on the possibility of different etiologies. It may be that the commonality between BII-related phobias is just an illusion that different etiologies or subtypes have been confounding the results of previous BII phobia studies. Do date no research has made this type of distinction in any meaningful way and it is possible that fear conditioning has a greater role to play in certain subtypes. Based on the hypothetical results of this study, for example, a future research project could use DCS-enhanced exposure therapy to test the specific role of fear in BII-phobia subjects with strong histories of fainting and with no history of fainting. This could lead to even more discoveries about how fear conditioning is involved in BII phobia and provide the rationale for a meaningful new type of treatment.

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