1997 LECTURE SERIES

New Insights into Post-Traumatic Stress Disorder

Dr. Roger K. Pitman
Psychophysiology Laboratory/VA Research Service
Harvard University
May 21, 1997

Approximately 40% of the population are considered to have the kind of traumatic life experience that could potentially cause Postraumatic Stress Disorder. Approximately 25% of those are estimated to have suffered from the disorder some time in their life. So we may be talking about a disorder which has affected approximately 10% of the population.

I had the occasion to evaluate the unfortunate driver who was driving on the New York state freeway and got caught in a rock slide. A 20 ton boulder came down and landed on the passenger side of her car where her best friend sat in the passenger seat. Her best friend was instantly killed and she was trapped in the car for 20 minutes. She sat next to the body of her best friend while rocks covered the car before the fire department could come in and get her out. She suffered from a terrible case of Postraumatic Stress Disorder for several years. Eventually, she had a very good response to medication and she's doing pretty well now. Postraumatic Stress Disorder (PTSD) is defined in the diagnostic and statistical manual's 4th edition, which is often referred to as DSM 4. DSM 4 was written by the American Psychiatric Association.

The first criteria, according to DSM 4 which has been official since 1994, is that the person would have experienced, witnessed, or been confronted with an event or events that involved actual or threatened death or serious injury or threat to the physical integrity of self or others. Basically it is nearly a life threatening situation, or a situation in which a person has either exposed him or herself to the possibility of being seriously injured or killed, or has seen someone else in a similar situation.

The second part of the definition involves the response the person has at the time of the traumatic event, for example intense emotion of fear, helplessness, or horror. Now the next three criteria which are called B, C, and D are different symptoms that emerge as a part of the disorder. The B symptoms, or the B criteria, essentially involve re-experiencing the traumatic event, reliving it in one's mind, either involuntarily in the form of nightmares or flashbacks or distressing recollections that interfere with what one is doing at the time or becoming intensively distressed upon a reminder. The example given in DSM 4, is about a woman who was raped in an elevator and subsequently whenever she gets into an elevator, she becomes very fearful and may even experience physical symptoms, such as heart racing, nausea or dizziness. This is also one of the ways that the B criteria can be satisfied. It is physiological, bodily reactivity upon an exposure to an event which reminds the person of the traumatic event they experienced.

The next set of criteria are the avoidance or numbing criteria. The first part of this C criteria is that if a person is upset at being reminded of the traumatic event, it's natural for them to try to avoid being reminded. For example, the woman might choose to climb 15 flights to get up to work every morning instead of having to ride in the elevator. This also includes trying to push thoughts of the event out of one's mind, trying to avoid thinking about it, or avoiding televisions shows that might be related to rape. The second part of the C criteria is a general sense of numbing which is emotional constriction. It boils down to having difficulty getting involved emotionally in the present world and what's going on in the present, because the sufferer from Postraumatic Stress Disorder spends so much of his or her time living in the horrible past.

Finally, the last set of the triad of symptomtology are the arousal symptoms. These are various ways that the person shows that they are overly aroused, either overly nervous in the form of insomnia, irritability, difficulty concentrating, excessive alertness to things that might go wrong in the environment, hypervilagence, a heightened startle response, or being very jumpy.

The criteria B5 is the physiological reactivity on exposure to internal or external cues that symbolize, or resemble, an aspect of the traumatic event. In other words, a cue is a reminder, and the reminder can be external, such as the sight of an elevator, or it can be an internal memory. When a Postraumatic Stress Disorder sufferer has such exposure, either internally or externally, they may develop various kinds of physiological or physical response.

A theory which is pretty widely endorsed about the Postraumatic Stress Disorder draws from the conditioning theory. Pavlovian or classical conditioning might help to explain what we see in Postraumatic Stress Disorder. In Pavlovian conditioning, there is an event which is referred to as to the unconditional stimulus, or UCS, that leads to a certain form of memory that Pavlov called the conditional reflex. In Postraumatic Stress Disorder, applying Pavlovian conditioning theory, we think of the traumatic event. That is to say that when the rock fell on the car, it was the unconditioned stimulus that evoked the person to experience a traumatic response. The criterion A1, which is always the traumatic event, and criterion A2, which is intense fear, helplessness, or horror, is the response to the unconditioned stimulus. This is called the unconditioned response.

Subsequently, reminders of the traumatic event, which are referred to as condition stimuli, or stimuli that may have no special emotional meaning in themselves, come to have emotional meaning because of their association with the traumatic event. For example, an elevator for most of us is not a very emotionally meaningful thing, or not one that is especially upsetting, but for a woman who has been raped in an elevator, it takes on new meaning. It becomes a condition stimulus and when exposed to the condition stimulus, the Postraumatic Stress Disorder sufferer will have a response which consists of primarily fear, but also other negative emotions, possibly including anger or sadness. We can think of this as a conditioned response to reminders. These include the condition stimuli of the traumatic event, the unconditioned stimulus and the response, the time of intense fear, helplessness, or horror. This is a model that we have been applying and many other people have been applying to Postraumatic Stress Disorder. There is a second leg of the conditioning model which is referred to as the two factory learning factor. This time honored principle of psychology and operand element of the conditioning model of Postraumatic Stress Disorder explains how being exposed to reminders of the traumatic event is so upsetting that a person will naturally try to avoid them. For example, the lady who climbs the stairs instead of going up the elevator. This is an example of operating conditioning. The operating condition would potentially explain the avoidance of symptoms of PTSD. The classical Pavolian's conditioning theory would potentially explain the re-experiencing symptoms of the disorder, especially the intense psychological distress and physiological reactivity upon exposure to reminder her of the event.

In 1980, Post Traumatic Street Disorder was skeptically reviewed by a large part of the general public, as well as by the psychiatric community. The psychiatric community tended to think that Postraumatic Stress Disorder did not have a valid independent standing apart from other anxiety and depressive disorders. A large part of the general public thought that Postraumatic Stress Disorder was simply a political concession to Vietnam veterans, and not really a mental disorder, but something that people tried to put on so they could get compensation from the VA. We began trying to utilize more objective ways of measuring changes in patients that might help to test the validity of Postraumatic Stress Disorder as legitimate and as an independent psychiatric or mental disorder. We decided to try to measure physiological responses during the recollections, or during exposure to cues resembling the traumatic event. We decided to utilize a method which had been designed by psychologist Peter Lange at the University of Florida, which involved using internal stimuli instead of administering external stimulus. The internal stimuli used were the research subject's own internal memories which were presented to the research subject within the laboratory. This was done using, what Peter Lange called, scripts. A script is a 30-second description of a person's past personal experience.

We can write scripts for people who have served in Vietnam and other wars or other traumatic events, but who were fortunate enough to escape without Postraumatic Stress Disorder. We can also write scripts describing other life events including stressful events unrelated to the Postraumatic Stress Disorder, for example the worse thing that ever happened to a person besides their traumatic experience that caused the PTSD. We can also write positive scripts as well. The Lange method that we adopted involved making tape recordings of these scripts, and having the subject go into the psycho physiology laboratory. There the subject is wired to listen to a tape recorder playing scripts of his own life events, one at a time. The subject is instructed to sit quietly for a 30-second period during which baseline measures of three variables are recorded. The three variables are heart rate, sweat gland activity in the palm of the hands measured by a technique called skin conductance, and muscle tension in the forehead measured by an electromyagram. The computer is then programmed to turn the tape recorder on and to play whichever randomly chosen script happens to be the next in sequence. When the recording stops playing, the subject is instructed to imagine that event in their minds as vividly as possibly, as if it were happening again. A little buzzer sounds indicating the recovery period in which the subject stops thinking about the event. Then another buzzer sounds indicating the subject to relax. The subject gives self reports via the computer and a joystick their emotions they experienced. A rest period follows, which lasts from one to three minutes where the physiological variables return to the previous level and then the computer automatically turns on the next script and runs through about 10 or 11 of scripts in the course of an hour.

Fortunately, most people eventually will get over PTSD, but there is a substantial minority in which time has not helped them. What could there be that created such lasting conditioned responses in the brains of the Postraumatic Stress Disorder patients that could seem to last almost forever? We sought brain mechanisms from basic science that might help us understand the durability of these conditioned responses in PTSD and we also feel that psychiatry has something to offer basic science. It is sometimes the study of mental disorders, as Darwin knew 100 years ago, that sheds light on normal human behavior, normal mechanisms, or brain mechanisms. For example, emotion and memory because they are presented in higher relief, more dramatic forms in mentally disordered people. Postraumatic Stress Disorder may be an example of illustrating this in an exaggerated form of basic mechanisms of human memory and emotion.

An hypothesized theory about PTSD is that an extremely stressful event, like military combat, over stimulates stress hormones, such as adrenaline, and they mediate an over learning or an intense consolidation of the memory of that event which manifests itself in the intrusive re-experiencing, or recollections, of the conditioned stimulus in Postraumatic Stress Disorder. The unwanted recollection of a traumatic event may cause more release of stress hormones which may in turn engrave the memory even more deeply into a kind of a positive cycle. The unfortunate outcome may be Postraumatic Stress Disorder. This is a hypothesis. It is not a fact, but some evidence suggests that it may be a good hypothesis or theory of PTSD. Hormones can excerpt their effects two times. They can excerpt their effect at the time that the person is learning about the experience which is called memory consolidation, when the memory is getting engraved into the brain. They can also act at the time of retrieval, when the person is exposed to something that reminds them, which is a condition stimulus. Hormones can also potentate the conditioned response at the time of memory retrieval. Because we deal with people who already have Postraumatic Stress Disorder, it's been easiest to look at the retrieval part of this mechanism.

We have recently done research using the script and imagery technique, but instead of doing it in the psychology laboratory, the research is conducted in the positron emission tomography, or the PET laboratory at the Massachusetts General Hospital. A PET scan has a positron which is a radioactive particle produced in a psychotron which decays very rapidly and emits two photons, or electromagnetic beams, which go out in opposite directions, 180 degrees form each other. It decays in a matter of minutes if positrons attached to an oxygen molecule are injected. If the subject is injected via radioactive water into their veins, or they breath a gas containing positron labeled oxygen, not so much that it would be dangerous to expose them, they are exposed to an acceptable level of radioactivity. Wherever the blood goes containing these positron oxygen atoms, there will be radioactivity. We know from research that the more an area of the brain is working, the more blood it needs, and the more oxygen it uses. Blood flow in various areas of the brain is a good measure of the amount of activity the nerve cells in that area of the brain. These studies are called PET activation studies. The person in the PET laboratory inhales the radioactive oxygen with positrons and has a camera around their head. As the photons are omitted, the camera takes pictures by tomography, which means slicing in three dimensions. This very expensive $2 million - $3 million camera can localize the areas of the brain from which the radioactivity is coming, or which areas have increased blood flow and increased brain activity. The scriptive and imagery study was conducted under two conditions in the PET laboratory at the Mass General in a group of subjects with Postraumatic Stress Disorder. It was conducted under neutral imagery condition when subjects were thinking of a neutral personal event, for example taking out the garbage in the morning or doing the dishes, and also when the subjects went through scripting and imagery of their traumatic events that led to their PTSD. A statistical subtraction was performed. Each area, each tiny little cube in the brain, which is referred to as a voxel or a pixel, depending on whether you're talking about three or two dimensions. The radioactivity is measured in a voxel, which represents the smallest area of the brain that the camera is able to measure. The blood flow, or the radioactivity in each voxel, was studied during the neutral imagery when the person was remembering taking out the garbage and when the person was remembering their personal traumatic experience that led to their PTSD. Using a computer to subtract the baseline flow during the neutral imagery from the flow during the traumatic image, one can determine how much the blood flow increased in each voxel of the brain when people relive or remember their traumatic events that led to the PTSD. A technique called statistically parametric mapping is then used to make a colored picture of the brain which corresponds to the areas of the brain based on their degree of activation. The most significant area of activation in the brain is labeled in a color code white. Red would be very highly activated, but not quite as much as white, and yellow would be a little bit less. This is known as a statistical parametric map. This study suggests that the medulla is becoming activated during the conditioned fear that is associated with the recollection of traumatic events. It was also found that another area of the brain, called Brokea's area, which is the area of speech, is deactivated during traumatic recollection. This has been described as the speechless terror of Postraumatic Stress Disorder, when a subject relives the traumatic event and becomes speechless. It's a figurative interpretation, but there have been about a half a dozen PET activation studies in PTSD, for traumatized people and reliably, and the speech area is always deactivated.

As mentioned earlier, we're better at measuring memory retrieval in people that already have Postraumatic Stress Disorder because we don't see them until they come into the clinic. We have started to take a look at people who don't have Postraumatic Stress Disorder yet. A study was conducted with people as they came into the Emergency Room having just experienced a very psychologically traumatic event. The patients who went on to develop Postraumatic Stress Disorder had significantly higher heart rates after their traumatic event than the ones who had also been through a traumatic event but didn't get PTSD. Interestingly, the difference in heart rate was greater than the difference in blood pressure systolic and there was no difference at all in diastolic blood pressure and activation of heart rate. The absence of blood pressure activation tends to implicate the hormone adrenaline. It suggests that these people had a higher release of adrenaline when they were in the Emergency Room and it raises the distinct possibility that the higher level of adrenaline at the time, is incremental in their developing the lasting memory of this traumatic event that a month later manifested itself as Postraumatic Stress Disorder. To build on this research, we will not only take a look at their heart rates but draw blood from the people who come into the Emergency Room and measure their adrenaline levels as well as a number of other things. We're also thinking about administering an anti-adrenaline drug which has shown to be effective in blocking the consolidating effect of adrenaline in recollection of a stressful stimulus in normal human subjects. There's a possibility that there is a higher release of adrenaline. This leads to the acquisition of the memory which is Postraumatic Stress Disorder. If one were to be able to get to these people in time, and give them a drug which blocked adrenaline, it might be possible to prevent the development of Postraumatic Stress Disorder.

Shifting gears, groups of investigators have looked the hippocampus and found that it's smaller in people with Postraumatic Stress Disorder compared to people who don't have Postraumatic Stress Disorder. This is a potentially exciting finding because a lot of animal research has shown that stress in animals can damage the hippocampus and can actually lead to the death of nerve cells. The current rage about this finding in the smaller hippocampi in Postraumatic Stress Disorder, is the possibility that what we're looking at is the ability of an intense physiological stressor to actually damage human brain tissue, sort of bridging the cartesian duality between mind and body and showing physical brain effects of psychological events or stressful events. If this is what is happening, there are several drugs which have been shown in animals to be able to prevent this from happening. Dialian is one of them. This raises the possibility that, if stress is damaging the hippocampus that a drug called dialian, given to people shortly after traumatic events, over a period of time, could prevent them from developing this hippocampus damage and possibly prevent Postraumatic Stress Disorder. There is a relationship between the amount of combat exposure a the person experienced in Vietnam and the size of the hippocampus. The greater the combat exposure, the smaller their hippocampi, which suggests that the stress of combat may be damaging people's brains. This is the explanation which is hanging from the balcony. It is the obvious explanation, but there are a number of explanations which are hiding in the refrigerator. One is that the abnormality may have already been there before the person ever went to Vietnam. People who have smaller hippocampi to begin with are more likely to be affected by a traumatic event because we know the hippocampus is involved in memory. People who may have poor memory to begin with, may not be good at avoiding bad things happening to them. Another possibility is that people who have pre-existing small hippocampi upon exposure to a stressful event may be more likely to develop Postraumatic Stress Disorder. These are two alternative explanations which are hiding in the refrigerator which have to be tested before we can conclude that stress is damaging the brain. Studies are currently being conducted in Israel by taking MRIs of people within a week of their coming to the Emergency Room after a traumatic event, before there is any chance of showing any gross brain deterioration. The patients are brought back six months later for MRIs again. If the people who develop Postraumatic Stress Disorder have smaller hippocampi over the six month period, then there is good evidence suggesting that the trauma may damage the brain. If, on the other hand, the hippocampi were smaller to begin with, then it may be good data supporting smaller hippocampi as a risk factor for Postraumatic Stress Disorder.