INTERVIEW WITH JAAK PANKSEPP PhD.

Jaak Panksepp, Ph.D. is one of the leading theorists and researchers in the areas of biochemistry and Autism. Much of his work has focused on studying the brain mechanisms of emotionality and developing animal models of Autism and other childhood disorders. His research on beta-endorphins and naltrexone is a major contribution to both understanding and treating individuals with Autism. Dr. Panksepp (JP) was interviewed Dr. Stephen M. Edelson (SE) on March 11, 1997.

Could you describe your background?

My interest in this area goes back to graduate school when I was eager to be a clinical psychologist. As an undergrad at the Univ. of Pittsburgh, I worked in a child development clinic and the back wards of a mental hospital for several summers, and I became fascinated by these types of human problems. The real eye opener was when I went to graduate school at the University of Massachusetts. I realized that to be a clinical psychologist, more than anything else I would be learning a variety of pencil and paper tests that really did not relate to the human problems that I had encountered in my previous work. I had become interested in the severest forms of mental disorders but in grad school it did not seem I was going to be exposed to much more than the garden variety of everyday neuroses and depressions.

I decided that the level of knowledge was so meager in clinical psychology that I would be better off doing something else. Since I was much more interested in understanding the biological depths of human emotional problems, I decided to pursue psychology from the neuroscience side. I made one of those educational shifts that is quite rare these day - from clinical psychology to behavioral brain research. I became especially interested in fundamental brain functions - the basic emotions and motivations - that evolution has constructed in our brain rather than those that emerge from learning and individual experiences.

I have never regretted the move, and my impression is that the discipline of clinical psychology has changed very little in the intervening 30 years while brain research has undergone a remarkable revolution, with lots of useful new knowledge. At this point I strongly believe that all psychologists should be well trained in the brain sciences. Regrettably, they still are not.

Most psychologists are still working on 'top down' verbal-semantic approach to understanding the mind. I prefer the bottom-up approach. Many others feel they will understand basic mechanisms of mind by studying computers; but at some point, these strategies becomes comparatively unproductive. I think you have to tackle the nature of the organ of the mind rather directly, and it is remarkably difficult to really study brain functions at the human level in sufficient detail, even with the recent array of spectacular brain imagining technologies. Many of these techniques give only very global answers, and they can misinform one as easily as inform us about the many remaining mysteries of brain functions. This makes behavioral brain research one of the most important areas of psychology. But it remains one of the smallest areas. In any event, without incorporating brain research into psychological inquiry, psychology cannot become a solid science.

B.F. Skinner has always stressed that the underlying cause of behavior is psychological; but since our understanding of the brain is rather limited, we can only objectively measure behavior and the surrounding environment.

Well, certainly, but the brain also has many intrinsic functions that we have to infer from those behavioral studies. Skinner, who made so many seminal contributions, did little to promote such inquiries. As you know, research on genetics and personality has indicated that approximately half of our abilities are due to genetic/biological sources and half to social/environmental variables.

Although it is next to impossible to disentangle these influences, scientific psychology of the 20th century has largely focused its resources on studying the social/environmental variables while neglecting many of the innate potentials of the brain. During the tail end of this century, we have finally started to acknowledge the evolutionary nature of the human mind, and we are beginning to conceptualize the many intrinsic functions of the brain provided by nature. We are beginning to realize that behavior is only the tip of the iceberg, that it is controlled by many intrinsic brain functions that are only refined through nurture.

We are finally beginning to realize the nurture only refines and expands upon the many functions provided by nature. For instance, many of the emotional potentials of the nervous system are intrinsic to the organization of the brain, and if we do not understand those ancient value systems, we cannot have a satisfactory scientific understanding of behavior. For the past two decades, my aim has been to facilitate the development of a cross-species "Affective Neuroscience" that can tell us how internally experienced feelings, the psychological essence of our evolutionarily provided value systems, are constructed from neural activities.

Could you tell us more about your involvement in the areas of emotions and social behavior, and how they relate to Autism?

After I finished graduate school I spent about 10 years conducting research on energy balance and sleep/waking states. I was "paying my dues" so to speak, and I learned quite a bit about how the brain really works. Then I became intensely interested in trying to solve what seemed at the time to be an unsolvable problem - understanding the neural nature of all of our basic emotional processes. Most investigators, at least in my field, still regarded emotions as a pseudo-problem - as empirically untouchable.

At the time I started, most felt confident that no one could credibly address the underlying issues in mechanistic ways, for instance, emotions as neurochemical processes of the brain. However, in 1972, three reports were published indicating that an opiate receptor had been discovered. Everyone started thinking in functional terms as to what this newly discovered neurochemical system is doing in the brain. In line with traditional medical practice, the obvious ideas were that such neural systems controlled pain, coughing/respiratory and various gastric functions.

However, we decided to focus on the possibility that it was a prime mover in creating social feelings and regulating social behaviors. Many of my colleagues viewed this work rather skeptically, with a raised eyebrow, so to speak. Our guiding central idea was that there was a remarkable family resemblance between social bonding and narcotic addiction - from the initial attachment-dependence phase to the eventual tolerance-withdrawal phases.

When we final began studying this possibility empirically, it turned out to be a productive idea. It rapidly became clear that when we gave animals very tiny doses of opiates, they were not distressed by social isolation and they became comparatively unsocial (even though could exhibit increases in certain social activities such as rough-and-tumble play). When we gave them opiate antagonists, such as naltrexone, they were more disturbed by social isolation and they became more eager for gentle and friendly social contact. It was not a far step to imagine that these opiate effects on social behavior might reflect something that is happening in childhood disorders such as Autism.

For quite a while, we struggled with the two logical alternatives - whether such kids might have overactive opioid systems or underactive ones. It is easy to build a compelling logic around either view; but when we focused on the data, it was clear that only the animals given opiates became unsocial and less pain sensitive. Thus, it seemed more compelling to suggest that some kids with Autism might also have too much opioid activity in their brain. This was especially attractive since there were experimental drugs, such as naltrexone, that could reduce such brain activities. Still, in the back of my mind, I thought, and still do, that some of the kids, perhaps the insecure/anxious ones, have too little opioid activity.

Some have suggested that our thinking was only focused on the ß-endorphin system of the brain, but in fact we were open to any of a large number of opioids being imbalanced in Autism. At the present time, it is fairly certain that certain opioid systems are imbalanced, but the classic ß-endorphin system does not appear to be one of them. In Rett Syndrome, however, high ß-endorphin is present. Thus, right now we can be confident that some autistic children do have elevated opioid activities in their bodies.

Do you have any guess why that might be? Did something happen during the pregnancy or might it be genetically related?

I will not even take a position on the underlying reason at this point. We are nowhere close to specifying the exact nature of the imbalances. There are so many possibilities. There could be a genetic flaw whereby there is an overproduction of opioids. There may be too many receptors, or ones that are too sensitive. Conversely, there could be a deficit in an antagonistic system that shift overall brain balances. Alternatively, imbalanced opioids early in development may have promoted an unusual organizational pattern in the brain.

Also, we now know what a remarkable number of different opioids actually exist in the brain and body. Some are responsive to stress, most control pain, some create feelings of pleasure, and others have no known functions yet. Yet others are contained in dietary sources, such as the casomorphins from milk protein, and Karl Reichelt has shown that some of them enter the body, probably because of incomplete digestion and a leaky gut. Most of the hard work disentangling these influences still lies ahead, and some of the possibilities simply cannot be even tested in humans.

Perhaps different forms of Autism are expressed through different opioid systems. Also, it is highly likely that some forms of Autism have no major connection to the opioid systems of our bodies. I think everyone is beginning to accept the likelihood that Autism is a multi-factorial disorder. Margaret Bauman's work suggests the initial problems are manifested during the second trimester of pregnancy because of the abnormal patterns of brain development. There is not going to be a single gene which causes Autism, not a single brain chemical system, nor is it caused by a single environmental insult. It appears to be the result of many converging biological and stressful influences.

When you talk about stress - are you talking about physiological stress rather than psychological stress?

It is often hard to distinguish the two. Indeed stress has been hard to define psychologically, even though it is quite easy physiologically. Biologically stress is anything that activates the pituitary-adrenal system, and stress at certain times of life can have very long term consequences. For instance, excessive physiological stress responses during pregnancy appear to lead to some forms of male homosexuality, and the critical factor seems to be excessive exposure of the fetus to stress induced release of opioids.

These opioids are released probably in the body's attempt to counteract various stress responses, but if this occurs during the middle of pregnancy, it disrupts the metabolism of testosterone which normally induces male-typical patterns of brain organization. Thus, baby boys from stressed mothers will tend to have a brain organization similar to girls, while bodily they still look like normal boys. This has been experimentally well demonstrated in other mammals, and some of us believe the lessons apply to humans as well. If one gives the opiate antagonist naltrexone to the mother at the same time the stress is applied, so as to block the physiological influences of the stress-activated opioids, the demasculinizing effect of the stress is blocked.

If all this applies to humans, we would expect that such boys would grow up to be normal men. Anyway, all these stress effects seem to operate at a physiological level. There is every reason to believe that naltrexone should increase the perceived level of psychological stress in the mother. Thus, it seems likely that it is the physiological rather than the psychological stress response that initiates the cascade of events that impairs the masculinization of the brain during infancy. The psychological stress without the physiological components, simply should not disrupt normal development.

I would assume that the body reacts differently to various types of stress.

Certainly. For example, mild stress responses are typically highly adaptive, while extreme forms can be pathological, actually killing brain tissue. Also there is a distinct sympathetic nervous system response pathway and a separate pituitary-adrenal stress pathway, whereby cortisol is secreted from the adrenal gland as the brain and pituitary respond to intense emotional events. There are many physiological components to each of these distinct responses, and in different situations, and different times of life, the responses can be orchestrated in different ways. The underlying brain systems can also learn, so we still have a great deal to learn about the details of the underlying mechanisms.

Do you have any thoughts regarding a link between social problems in Autism and the communication problems?

I think they are closely related. There has to be a social motive for communication, but its relation to language remains poorly understood. If one were to select an brain area where social motivation for language originates, one reasonable candidate would be the anterior cingulate area. When this area is damaged, humans lose their motivation to speak. This is also one of the highest brain area in which social emotions are organized, and even though no one has looked closely, maybe autistic people have impaired neural connections in those brain circuits.

Indeed, certain animals have wonderfully enriched anterior cingulate areas compared to human. In whales and dolphins this area is much larger than in our brains. If we just look at their remarkable levels of social spontaneity, cooperation and group coordination, dolphins appear to have more sophisticated social emotional abilities than we do. Perhaps they can read each others minds much better than we can. As you know, this 'theory in mind' concept is presently very popular in Autism research. Many investigators believe that autistic kids simply can't manage to fathom what other people are thinking and feeling.

Obviously, if we cannot intuit the thoughts and emotions of others, we cannot really understand what moves them to behave the way they do. If we could represent the workings of other minds, our desire to communicate with others would surely be diminished, and the entire flow of communication would be distorted.

Endorphins seem to be directly linked to social behavior, which in turn, is linked to communication as well as emotions. These three areas - socialization, communication, emotion - can be thought of as three core features of Autism. What are some of your observations with naltrexone?

This whole idea of there being a brain emotional system that control social motivation, which then provides a reason for communication, connects up nicely with possible benefits that can be seen in some children following naltrexone. This medicine can increase the desire to communicate in some children. Presumably those that are responders, which is no more than half the kids, have high internal opioid levels which might be making them aloof by reducing their social desires.

However, naltrexone does not activate linguistic competence by itself. It seems to promote the quality of verbal communication only in those children who already have language competence but who seem to have a diminished motivation to communicate. However, if the child is basically mute, as many are, naltrexone does not increase language. It can increase nonverbal communication somewhat, but by itself, it does not seem to contribute directly to language competence.

Is there a 'best candidate' for naltrexone?

Our impression is that young children who have some interactive skills and who have highly engaged and emotionally supportive parents do the best. Naltrexone can decrease activity and increase social desire, but the behaviors need to be noticed, reinforced and hopefully consolidated via parental support. If we simply focus on the child's traits, the number one feature which comes to mind is pain insensitivity. This, of course, would be the clearest indicator that the internal opioid systems might be too active.

However, there have been no studies that have examined naltrexone in kids who are and who are not pain sensitive in order to see if the above hunch really holds. However, Chris Gillberg did measure opiate-like activities in the cerebrospinal fluids (CSF) of a group of autistic children, and about half had elevated opioid levels and they were the ones that exhibited the most pain insensitivity. However, recently similar results have not been found by a Japanese group that actually measured CSF ß-endorphin levels.

Our impression is that adults generally do less well than children, and this may be a real developmental effect or perhaps older people simply have too many habits to break down. Also, there may be dosage issues. Our experience in children is that quite low doses (0.5 mg/kg every other day or even lower) are the best.

How soon will a parent know whether his son or daughter is a responder to naltrexone?

If nothing happens during the first couple of hours after the first few medications, you probably have a child that will not be a responder. We always tell parents to pay special attention during the initial two to three hours after the first medication. If the child does not have excess opioid activity, you should not see anything at all. If the child has a high opioid level, you will likely observe some kind of withdrawal or "come-down" response; and this initial indication that the child might be a responder is unlikely to be a pleasant or desired response. The child may become mopey or tired. Some actually show some emotional distress as if something is bothering them. a few hours after receiving naltrexone, we say 'great.'

We believe these initial negative signals, which soon disappear, tend to indicate that you have a potential responder, but then one still need to find the optimal maintenance dose. Also, it is important to remember that naltrexone is quite bitter and needs to be disguised in food, otherwise the child may learn to reject the medication because of taste alone.

Besides pain threshold, are there any other characteristics that may predict responsiveness to naltrexone?

We think a kid who really likes hot, spicy or salty foods may be a responder because this measure may also be tapping into the pain issue. Other potential indicates may be - if the child never cries or cries only rarely, and without tears. The brain opioid system controls crying behavior in animals. If you give opiates to animals, they do not cry at all. Perhaps another feature is when the child is socially aloof. We suspect that the more social and emotional autistic children are less likely to respond.

When you say 'socially aloof,' do you mean asocial, where they can take it or leave it?

Exactly. They appear to be the classical Kanner-type children. They are the ones who prefer to be by themselves and appear self-satisfied. They are not the anxious types. If anything, naltrexone may intensify anxiety symptoms, so one should use the medication with special care, or very, very low doses, in those children.

Another characteristic may be those kids who are aggressive but in a playfully nasty manner. In other words, naltrexone can reduce a teasing type of aggression, such as pulling hair - where the kids are doing things to provoke attention or attempting to see how far they can go. In our animal models, naltrexone reduces this type of play-fighting quite well. However, when it comes to real anger types of aggression, naltrexone may actually increase that in certain children.

Could this type of playful aggression release endorphins?

Yes, we have some evidence that rough-housing play releases opioids in the brain of experimental animals. We can even intensify playful kinds of aggression in animals by giving them small injections of opiates. Also, Lorna Wing claims that if a child desires rough and tumble play, but practically no other type of social activity, it may indicated the presence of Autism. Thus, the high desire for rough-housing in an autistic child might be a reasonable indicator that naltrexone might provide some desirable benefits. What is now very clear is that the brain's own opioids clearly control rough-and-tumble play urges in animals, and I am sure the lesson also applies to humans.

You were one of the first ones to speculate the importance of oxytocin and Autism. What are your current thoughts on this matter?

It certainly appears that oxytocin is a player, but precisely how it is involved remains unknown. Clearly, oxytocin controls a lot of social processes, including loneliness, amount of social interaction, motherly feelings and sexual ones as well. However, just as with the opioids, you can play the logic in several ways. Maybe the kids have too much or too little. Maybe it is not levels of oxytocin, but brain receptor distributions and sensitivities. At several scientific meetings, Hollander has reported seeing some improvements after autistic adults received oxytocin sprayed into their noses - a route of administration whereby some gets into the brain.

On the other hand, a Japanese obstetric study has suggested that the administration of oxytocin to mothers during birth may actually contribute to autistic problems later in life. We are presently conducting a large developmental study where we administered newborn rat pups very high doses of oxytocin directly into the brain for the first few days of life. We have yet seen anything that give us any reason for concern about this causing autistic-like behavior pattern. There were no changes in pain sensitivity, overall activity, fearfulness, nor basic playfulness. There were some tiny effect on competitiveness during play but the effects were tiny. Thus, if you take willing to accept such data for what oxytocin might do to human children developmentally, there appears to be little reason for concern.

However, there are reasons to believe that abnormalities of the sister hormone, vasopressin, may be more important, since interesting brain and behavioral changes can be induced by manipulating this hormone. Still, I have a gut-feeling that there is an oxytocin component to Autism. The Hollander result makes perfect sense to me based on the animal data, where increases in certain social behaviors have seen following oxytocin administration by many investigators. Still, I think the bottom line is bound to be more complex than any of the simple ideas we presently have.

What are your thoughts on melatonin?

I think melatonin is certainly a god-send to many families right now. There is no question that low doses of melatonin can promote sleepiness and stabilize daily rhythms, but it must be given only once a day and at the right time, which is about half an hour before bed-time. We have seen many children where melatonin has had remarkable benefits for stabilizing the sleep patterns of kids, and if kids sleep well, they are bound to be better during the day. It is unfortunate that there is no proper scientific documentation of these issues yet, but the ready availability of the medication allows parents to evaluate it for their own child. This is not the case with either naltrexone or oxytocin.

Could you describe some of the other ongoing studies in your laboratory?

We are very interested in attention deficit/hyperactivity disorders. Although there are some kids that have real brain problems, I suspect the majority being diagnosed right now do not. They are simply too rambunctious, exhibiting many childish behaviors that cannot be tolerated in a well-run educational system. However, it seems scandalous that so many normal kids are being placed on heavy duty drugs that may have life-long consequences.

Such as Ritalin?

Yes, Ritalin, Dexedrine, and others. I think these drugs have a place in childhood medicine - there should be no question about that - but I doubt if they should be used as widely as is presently being done, especially since such drugs can permanently "sensitize" certain neural circuits, such as the dopamine systems of the brain. What this "sensitization" means is that a brain system become chronically over-responsive, and since dopamine controls our eagerness, individuals that have been sensitized should want more of everything than is normal.

From animal work, we know such creatures want more food, more sex, and more drugs. It's very scary if these types of changes are being produced in kids, but no one has yet really evaluated the matter empirically Even worse, practically no one is really talking about such issues. It may all come back to haunt us one day. There is no question in my mind that the symptoms which lead to the diagnosis of ADHD are caused by the brain differences, but I am not convinced that it is usually caused by a medically certifiable abnormality of the brain. Often it may simply be the slow maturation of certain executive systems of the brain such as those in the frontal lobes that give us the ability to have foresight and self-control.

Anyway, we are beginning to model ADHD in animals. The best MRI data today suggests that these kids have slightly smaller frontal lobes on the right sides of their brains. We have recently found that we can produce striking hyperactive symptoms in laboratory animals by damaging one their frontal lobes, and it does not matter whether it is on the right or the left. We still need to determine whether Ritalin and Dexedrine can reduce hyperactive symptoms in these animals. The bigger question in our minds is whether other treatments might do the same. One approach we want to eventually pursue is to see whether the excessive activity can be controlled by various patterns of dietary ingredients and forms of bodily exercise.

Do you know about Mary Coleman's study? She investigated the effectiveness of Ritalin as well as vitamin B6 on hyperactive children. One group was given Ritalin; a second group was given vitamin B6, and a third group was given a placebo. Both the vitamin B6 and Ritalin groups improved significantly as compared to the placebo group, and there was no difference between the Vitamin B6 and Ritalin groups. The study was published in Biological Psychiatry, 1979.

That's marvelous. We should also try to evaluate amino acid precursors for dopamine, such as phenylalanine and tyrosine, as well as those that promote glutamate activity in the brain. Another direction we hope to take is to see if rough and tumble play can reduce ADHD symptoms. I think half of these kids diagnosed with ADHD are simply highly energized kids who need to blow off some playful steam early in the morning before classes. It's amazing that no one has yet tried an intervention as straightforward as that.

I would not be surprised if play activates various "growth factors" in the brain such as BDNF (Brain Derived Neurotrophic Factor) so that lots of normal play would have long-term benefits on the development of the brain. In this same vein, I would not be surprised if many of the problems of Autism emerge from deficiencies of certain neurotrophins. We can now produce animals missing certain growth factors, and they exhibit specific deficits in hearing, vision and touch - in many of those systems where problems are seen in Autism.

Very interesting. Do you have any final comments?

Just to come back to one of my pet peeves - that psychology needs to become biologically-oriented. We have this wonderful discipline, but one where people seem to be doing the same thing over and over again, especially with the many verbal and pencil and paper approaches. Psychology departments have very few people that really understand the way the brain operates, and that is a great shortcoming of the area. If we all knew much more about the brain, we would be able to help kids with problems, as well as adults with problems, much better. We could finally become a solid science.

Thank you for the time, and keep up the great work!

Thanks Steve, and I am sure you will do the same.

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