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D-Cycloserine-enhanced exposure therapy may clarify the role of fear in blood-injection-injury

type phobias

Brian C. Woolfrey

University of Minnesota

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-injection-

injury 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 BII-

related 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


Although this theory seems to offer a promising explanation for the tendency for BII-

phobics 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


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.



All participants in this study will have been previously diagnosed with blood-injection-

injury 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.


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 eye-

blink 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.


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.


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


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 BII-

related 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 t-

tests. To determine the nature of this change we would use Cohen’s d as a measure of effect size.


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.


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 BII-

phobia 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.

Accurso, V., Winnicki, M., Shamsuzzaman, A., Wenzel, A., Johnson, A., Somers, V. (2001).
Predisposition to vasovagal syncope in subjects with blood/injury phobia. Circulation, 104, 903-

Bracha, S. (2004). Freeze, flight, fight, fright, faint: adaptionist perspectives on the acute stress
response spectrum. CNS Spectrums, 9, 697-685.

Connolly, J., Hallam. R.S., Marks, I.M. (1976). Selective association of fainting with blood-
injury-illness fear. Behavior Therapy, 8.

Davis, et al (2002). Role of NMDA receptors and MAP kinase in the amygdala in extinction of
fear: clinical implications for exposure therapy. European Journal of Neuroscience, 16.

Davis, M. (2005). Facilitation of extinction of conditioned fear by d-cycloserine. Current

Directions in Psychological Science, 14.

Davis, M., Ressler, K., Rothbaum, B.O., Richardson, R. (2006). Effects of d-cycloserine on
extinction: translation from preclinical to clinical work. Biological Psychiatry, 60, 369-

Diagnostic and Statistical Manual of Mental Disorders (2000). 4th ed, revised. Washington, DC.

Gerlach, A., Spellmeyer, G., Vogele, C., Huster, R., Stevens, S., Hetzel, G., Deckert, J. (2006).
Blood-injury phobia with and without a history of fainting: disgust sensitivity does not explain
the fainting response. Psychosomatic Medicine, 68, 331-339.

Hoffman, S.G., Meuret, A.E., Smits, J.A., Simon, N.M., Pollack, M.H., Eisenmenger, K. (2004).
Augmentation of exposure therapy with d-cycloserine for social anxiety disorder. Archives of
General Psychiatry, 63, 298–304.

Kleinknecht, R., Lenz, J. (1989). Blood/injury fear, fainting and avoidance of medically related
situations: a family correspondence study. Behavior Research and Therapy, 27, 527-547.

Kushner, M.G., Kim, S.W., Donahue, C., Thuras, P., Adson, D., Kotlyar. M., McCabe, J.,
Peterson, J., Foa, E.B. (2007). D-cycloserine augmented exposure therapy for obsessive-
compulsive disorder. Biological Psychiatry.

Ledgerwood, L. (2003) Effects of d-cycloserine on extinction of conditioned freezing.

Behavioral Neuroscience, 117, 341

Page, A., Martin, N. (1998). Testing a genetic structure of blood-injury-injection fears. American
Journal of Medical Genetics, 81, 377-384

Parnas (2005) Effects of multiple exposures to d-cycloserine on extinction of conditioned fear in

rats. Neurobiology of Learning & Memory, 83
Ressler, K. (2001) Extinction of conditioned fear is facilitated by d-cycloserine, a partial NMDA
agonist. Society for Neuroscience Abstracts, 27

Ressler, K.J., Rothbaum, B.O., Tannenbaum L, Anderson P, Graap K, Zimand E (2004).

Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to
facilitate extinction of fear. Archives of General Psychiatry, 61 1136–1144

Rogan, M.T. (1997). Fear conditioning induces associative long-term potentiation in the
amygdala. Nature, 390, 604-607

Vervliet, B. (2008). Learning and memory in conditioned fear extinction: effect of d-cycloserine.
Acta Psychologica, 127, 601-613

Walker, D.L., Ressler, K.J., Lu, K.T., Davis, M. (2002). Facilitation of conditioned fear
extinction by systemic administration or intra-amygdala infusions of d-
cycloserine as assessed with fear-potentiated startle in rats. Journal of Neuroscience, 22, 2343-

Weber (2007). Effects of D-cycloserine on extinction of learned fear to an olfactory cue.

Neurobiology of Learning and Memory, 87