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Bridging the Gap - Opioid Peptides and Executive Function





Paul Shattock & Paul Whiteley
Autism Research Unit, University of Sunderland, UK


“The cobbler should stick to his last”. Old English Proverb



One of the main objectives of conferences is that people with differing background and understanding can come together and not only promote their own studies and points of view but also learn from the experience of others. This is particularly important in the study of autism where so many disciplines are involved. Courchesne & Courchesne (1997) discussed this issue with regard to the differing needs of clinicians and practitioners, and scientific researchers and have pointed out the commonalities and dichotomies inherent in their approaches. There is an additional difficulty within the field of autism in that a number of apparently totally different and, at first sight, incompatible sets of understanding and experience are required. Although the syllabi for modern degrees in psychology require a basic appreciation of neurology, graduates cannot be expected to be comfortable with more complex biological and neurological processes. Even worse, those with a physiological or pharmacological training are often dismissive of concepts, which involve measuring elements, which cannot be seen, weighed or quantified by physical methods.


One of the most intractable divides, within the field of autism at least, is that which separates brain biochemistry and the psychological theories, which underlie the symptoms by which autism is still defined. This paper represents an attempt to explore some aspect of that gap. Given that no one really understands the neurochemical workings involved in the central nervous system especially when they may well be abnormal, as in the case of autism, the task is a difficult one. The speculations contained in the following pages, are offered and can be accepted as no more than that.



Basic Principles


a) Biological


We subscribe to the opioid excess theory for the causation of autism. The theory has been expounded on a number of occasions (Shattock et al, 1990; Shattock & Lowdon, 1991). In brief, we suspect that peptides and other related compounds, some with opioid (morphine-like) activity, resulting from the incomplete digestion of certain foods in particular gluten from wheat and certain other cereals and from casein from milk and dairy produce, find their way into the bloodstream from the lumen of the intestine. Once in the bloodstream a proportion will cross into the brain. They will either act directly as neuroregulators by mimicking the bodies own natural opioids (such as the enkephalins or endorphins) or act as ligands to the enzymes which would break down these naturally occurring compounds. In either case, the consequence is an increase in opioid and other activities.


In the brain the opioids act in a variety of ways at a variety of specific receptors but their effects are basically neuromodulatory. They do not, usually, act as direct neurotransmitters (such as 5-HT (serotonin) or dopamine) but they regulate their activity usually in a diminutive manner. Details will be discussed in the course of the specific examples described later in this paper.


b) Psychological


There are a number of psychological models, which have been presented as capable of explaining the symptoms of autism. Each theory has its proponents and detractors. Each theory has strengths and weaknesses but it is beyond the scope of this presentation to discuss each of these in detail. In particular, in the UK at least, much attention is given to the “Theory of Mind” deficit ideas (as proposed by Baron-Cohen, Leslie & Frith, 1985) and of “Weak Central Coherence” as advocated by, for example, Hobson (1991; 1995). This study will concentrate upon the ideas of deficits in “Executive Function” as described by Ozonoff (1991) and elaborated by Hughes (1993; 1994; 1996). It is readily conceded that this has been done because the concepts of the theory fit happily with the theories we espouse rather than for any quarrels with the other proposals.


Executive Function Deficits


There seems, to us, to be one problem inherent with theories based around these concepts: how “autism specific” these deficits would be [see reference]. A case could be made for abnormalities in this process being relevant in many forms of learning difficulty as well as autism spectrum disorders. However, we remain of the opinion that possible links are worthy of exploration.


Hughes has listed these deficits as including the following:


- planning;
- impulse control;
- inhibition of pre-potent but incorrect responses;
- set maintenance;
- organised search;
- flexibility of thought and action;
- ability to disengage from control by the external context;
- ability to guide behaviour by mental models or internal representations.


It would seem to us, that these could be summarised in terms of deficits in the process by which the “clever” elements of “the brain” tell the “thick bits” what to do. It is characteristic of scientists, including psychologists (such as Ozonoff and Hughes), to concentrate on some of the more interesting and complex of the deficits which are possible and to ignore some of the very basic systems to which the same principles are known to apply but which would not attract and hold the attention of the trained specialist.


We would start by exploring a couple of these simpler systems.





1. Extra-Pyramidal Movements and Dyskinesias


One of the features of autism which is well known but which has not been the subject of intensive investigation is the constant movement, which some (but not all) subjects show. Many children appear completely unable to keep still; to sit at a table or to take a meal without standing up and walking around. However much parents and teachers attempt to stop this movement the child will find difficulty. There appears to be a severe, but variable inner drive directed towards this constant movement. To an observer it seems this drive and many of the associated movements are very similar to the constant activity seen in people, diagnosed with schizophrenia but who are taking neuroleptic (anti-dopaminergic) medications. People taking medications such as thioridazine (Melleril), chlorpromazine (Largactil) or haloperidol (Serenace; Haldol) are nearly always given other medications (e.g. orphenadrine (Disipal)) to eradicate or minimise these side effects.


It is likely that the movements induced by these medications are in fact the same as those seen in people with autism because they are the result of the same causal mechanism. These neuroleptic drugs act by inhibiting transmission in dopaminergic systems; we are proposing that in autism the dopaminergic system is inhibited not by medications but by the opioid peptides. The consequence is, however, the same. Impulses from the system make use of acetylcholine as their transmitter and such impulses will cause “movement” in many parts of the body. Under normal circumstances, these movements are inhibited by a system (the nigrostriatal system) utilising dopamine as its transmitter. If, therefore, these inhibitory systems are themselves inhibited, the constant movements described above will become evident. The usual medical response is then to give further medications, which are anticholinergic. The phenomenon does bring into question the practice of using neuroleptic drugs, which are basically anti-dopaminergic in their action) in cases where dopaminergic systems are already inhibited. This example is, perhaps, stretching the original description of “executive function” into an area not considered by those who originally proposed the ideas but the principle is entirely analogous.



(Medical note: Some neuroleptic drugs, such as haloperidol and sulpiride when used at low doses and risperidone at low or moderate doses, have a selective activity in blocking the pre-synaptic receptors. The net result would be an increase in transmission and amelioration of these particular symptoms)



2) Control of Aggression


Being aggressive is “normal” for humans under certain circumstances. Theories of aggression being a basic drive receive support from studies (e.g. Smuts, 1986) showing a biological basis of aggression in other mammalian animals. Whether in response to a stressor (i.e. an aggressive response to a conflict situation), or as a result of frustration (i.e. inability to reach a goal), animal studies have shown that aggression is a primary motivator of behaviour. In humans, the exhibition of aggression is described in many terms, some acceptable and justifiable (e.g. during periods of human conflict as seen in the world wars of the twentieth century) and others deemed socially unacceptable (e.g. committing murder). Often the justification for aggression is defined in terms of factors such as cultural and communicative processes and according to individual perspectives (e.g. attributing the aggressive behaviour of others as being “aggressive” or “assertive” and the aggressive behaviour of ourselves as being “defensive”). Humans need to be prepared to act in this way and the mechanisms to do so are already in place (i.e. fight-or-flight response). However under normal circumstances, they are “inhibited” by other systems and in particular by systems under serotonergic (using serotonin (5-HT) as their transmitter) control. If these systems are themselves inhibited the tendency towards aggressive activity will become evident and more difficult to control. Opioid peptides will inhibit these systems.



Regulation of Aggression by Serotonergic System



Medical note: Drugs such as fluoxetine (Prozac), which increase the availability of serotonin are frequently given to minimise aggression. Eltoprazine is, unfortunately, no longer available but its “serenic” activity is said to be due to its ability to stimulate the postsynaptic receptors. Risperidone will inhibit the presynaptic receptors and so result in a net increase in serotonin availability and decrease in aggression. Note that risperidone will, at appropriate doses, increase dopaminergic transmission in the nigro-striatal system whilst, as the same time, increase serotonergic transmission in these systems. Both of these effects would be predicted as being beneficial.)


Taken together these two functions of being primed for immediate movement (dopaminergic system) and being mentally appeared to fight (serotonergic system) are important for the preservation of the individual and normal physiological and behavioural responses to environmental stress. It is well known that under conditions of stress, opioids such as beta-endorphin are released in the brain. These consequences are characteristic of the fear – “fight-or-flight” response and are part of the overall requirement for self-preservation. The same responses would be anticipated as resulting from the presence of opioids from exogenous sources such as food.



3) Sensory Filtration


Moving up the scale of complexity from these comparatively simple examples consideration should be given to the effects on sensory systems. The human sensory system comprises of a complex set of devices and channels, which deliver to us the ability to explore the outside world. The properties of this system are made up through a complex association between biological and psychological processes, drawing on information from our five senses and the subsequent coding, organisation and retention of this information. Because of the vast amount of information made available to us from our sensory organs and our finite ability to process this information, we undertake a process of filtration to separate the information, which is meaningful to us from the background information. Cognitive psychological investigation has suggested various theories as to the nature of this filtration process (e.g. Deutsch & Deutsch, 1963; Johnston & Heinz, 1979). Evidence of unusual sensory responses throughout the range of sensory mediums in autism has been catalogued both through psychological research (Courchesne, Akshoomoff & Townsend, 1990) and through various self-report measures by people with autism (Williams, 1996). Studies carried out at the Autism Research Unit have also provided supportive evidence (Taylor, 1998). The presence of opioid peptides will affect transmission in all of the sensory or perceptual systems of the CNS. At the same time as affecting the transmission of signals from the sense organs (sight; sound; gustation; touch; pain; proprioception) these same chemicals will affect the filtration of these signals. As described earlier, under normal circumstances, a perceiver will be able to automatically filter out those sensations which are deemed to be of no interest but which are fairly constant. Thus, the background noise in a classroom or of the traffic; the feel of ones clothing; the constant bombardment by visual stimuli can be ignored and we can concentrate on the task or point of particular interest.


In biological terms, this “filtration” is achieved by the intelligent (cortical) areas of the brain sending messages to the more automatic areas to cut down on those impulses. If these inhibitory signals are themselves inhibited then the filtration processes will be inhibited and all of these phenomena will have equal significance. It is not possible to focus on particular areas without unusual effort and concentration. The Attention Deficit Disorder (ADD) problems are explicable in these terms. Similarly, if combined with the problems described above, we would see the additional problems of hyperactivity as shown in Attention-Deficit Hyperactivity Disorder (ADHD) and which so frequently accompany symptoms of dyslexia the symptoms of which are also explicable in terms of perceptual and cognitive abnormalities of this type.



4) Attention Switching


Many people with autism have described the difficulties that they experience in switching from one sensory mode to another. For example (Williams 1996), whilst concentrating on processing visual stimuli which may be arriving in overwhelming quantities, they find it difficult, if not impossible, to make sense of auditory inputs. Many people with autism have described themselves as “visual learners”


Courchesne (1994), by means of electrophysiological measurements, has provided very convincing evidence that people with autism do have great difficulty in switching their attention from one perceptual mode to another. Once in “visual mode” the time lag before switching to “auditory mode” is very much greater. The control of this switching system could, once again, be described as an “Executive Function” and, once again, could be the consequence of opioid activity within the CNS.



5) Higher Executive Functions


The theorists (such as Ozonoff and Hughes) mentioned previously, have concentrated upon activities, which are more complex than the simple examples described here but by extending the explanation to more complex systems one can see how the same principles could apply and how these biochemical abnormalities could result in irregularities in functioning.


For example, children with autism find it especially difficult to make choices. When presented with an array of sweets such as is seen in sweet shops and told to choose something the child will appear to “choose” in an arbitrary fashion. Alternatively, (s)he may choose the same thing every time (whether or not (s)he actually likes the chosen entity) or, sometimes, always choose the product nearest to the hand. Making choices is about filtering through options and if, as described above this filtration is affected such processes are far from easy for the subject.


Psychologists have drawn attention to the problems people with autism have in planning future activities. Once again, planning involves a consideration of a variety of possible activities. In this case it is even harder than simply choosing sweets as the possibilities are imaginary rather than real. Thus filtering through a range of possibilities; visualising; considering and rejecting possibilities and making choices is asking too much from people where the basic processes are impaired by the presence of these comparatively simple chemicals.



Conclusions and General Observations


It is not necessary to explain how the other deficits in Executive Functioning, referred to earlier, are explicable in terms of this process but it can be done. In the same way, it may be possible to extend the process further to explain the perceived difficulties in “Theory of Mind” or Central Coherence” tasks. We do not see these psychological abnormalities as being “the cause” of autism although they are sometimes described in these terms. Rather, they are symptoms of underlying psychological abnormalities, which may themselves result, in particular difficulties, which will modify the semi-automatic behaviours described above, or behaviours which are not otherwise directly related to these basic biochemically inspired phenomena.


Finally, we totally accept that each person with autism is different. The symptoms described above are superimposed upon the characters of individual human beings who have their own personalities and characteristics, foibles, preferences and inconsistencies. In no way are we attempting to define real people in terms of chemically driven automata. We must also consider how each and every one of us is affected to a greater or lesser extent by such forces, which are difficult to explain.





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