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DISCOVERY! |
Research Centre for Human Movement Control, The University of Adelaide, Adelaide SA 5005, Australia; timothy.miles{at}adelaide.edu.au
Martin Taubman, Editor
KEY WORDS: trigeminal • stretch reflex • motor control
My pathway into research was considered to be unusual in the early 1970s, although now it would be considered to be entirely conventional. As an undergraduate dental student at The University of Adelaide, I explored the possibility of interrupting my course for a year to gain a research-based Honors degree. However, Professor Whelan, the Head of Physiology at the time, told me that if I wanted to have a research career in this field, I would need "a license to kill", namely, a medical degree (!). This advice arose from the nature of physiological research in Adelaide at the time, which was conducted almost exclusively by medical graduates using human subjects as their experimental models. Hindsight shows, of course, that Whelan’s advice was diametrically wrong, since research in medicine (but, curiously, less so in dentistry) is now conducted primarily by people with backgrounds in various biomedical sciences, but usually without clinical training. The undoubted rewards of a research career are apparently less tempting than the material rewards of clinical practice.
I therefore completed my dental studies without interruption, and, after graduating in 1969, practiced clinical dentistry for a year or so as an intern and then privately. However, I remained in contact with a popular undergraduate teacher, Peter Dellow, who had recently moved from Adelaide to the University of Western Ontario, in Canada. He wrote seductively of the joys of research and of life in Canada generally. In fact, he had already attracted two other young Adelaide dentists, Jim Lund and John Barker, to become PhD students in his laboratory at UWO. Jim went on to have a distinguished academic career in Canada, culminating in his appointment as Dean of Dentistry at McGill University. So, newly married to Janet, I sold my beloved MG TF car to pay for our fares to Canada, and we moved to London, Ontario, to begin a new life and new career.
Our time in Canada was extremely stimulating and enjoyable, both socially and professionally. My first research project in the Department of Physiology involved a chemical called capsaicin, an extract of chili peppers. This has subsequently become a powerful agent for research into pain, but my interest in it was sparked by a report that it interfered with temperature regulation. Despite a lot of work, some of which I now regret, since it undoubtedly caused unnecessary suffering in my experimental rats and rabbits, this project went nowhere, and I abandoned it.
At about this time, a new professor was appointed to the Physiology Department. Mario Wiesendanger was recruited from Switzerland as a ’rising star’ in the field of motor control, so I approached him for advice. He pointed out that the sensory and motor functions of the cranial nerves had not been investigated to the same extent as those of the spinal nerves, so that field was ripe for exploration. I therefore changed research supervisors and joined his lab to investigate the projections from the trigeminal nerve to the cerebellum in the cat. The experiments were gruelling. I was fortunate to have the advice of a distinguished neurosurgeon, John Girvin, on the surgical techniques, which were complex and time-consuming. The experiments themselves lasted for up to 24 hours, and generated vast quantities of data which were stored on photographic film. I vividly recall my most successful experiment that finished at about 6 a.m. I left a message for Mario describing my success, and, in a fit of enthusiasm, he decided, when he found it, to take the film from the camera and develop it himself, to see these great results. He was not very experienced with photography, however, and called (and awoke) me at home to tell me, to my horror, that he had put the film directly into fixer, without first developing it. Crushing news indeed, but it ensured his willing assistance with the rest of my candidature!
My doctoral dissertation was the first from UWO to be in the form of a series of scientific papers, based on two major papers in the Journal of Physiology (Miles et al., 2004), which were then retyped into thesis format. This apparently radical approach delayed the dissertation’s final acceptance, since, even after the successful completion of my oral defense, the University Librarian refused to endorse acceptance of the thesis, since the bound-papers format did not satisfy the Library’s inflexible prescription for theses.
I had been funded throughout my doctoral studies by the Medical Research Council of Canada, which then generously funded my post-doctoral appointment at the University of Zürich, Switzerland, where I had the privilege of working with Volker Henn, a brilliant scientist and a skilled neurologist at the Kantonsspital. I spent about a year mastering the difficult art of recording single-neurone activity in various areas of the conscious monkey brain, and relating it to eye movements. My aim was to continue in this field, but when I accepted a position as Lecturer in Physiology at my alma mater, I found, to my naïve surprise, that, in Australia, in contrast to Canada, the large sums of money required for work of this nature were not available to junior scientists like myself.
However, this setback had a valuable side-effect. Because I was unable to purchase electronic equipment like amplifiers and filters, I made them myself. Fortunately, I had had a good tutor in Switzerland in the form of Vito Corti, a superb electronics technician: I am forever in his debt. Some of this 30-year-old equipment is still in use today. Having to build all of my own apparatus taught me a great deal that has been valuable throughout my career as an electrophysiologist.
When my laboratory was established, I began to carry out some preliminary experiments with cats. However, a former dental classmate of mine, Tom Wilkinson, expressed an interest in carrying out some experiments on human subjects. This chance encounter eventually resulted in the abandonment of my animal experiments, to be succeeded by the application, to humans, of the meticulous techniques that I had used previously. I suggested to him that he might investigate a rather intriguing problem, namely, the mechanisms that prevent the teeth from snapping together after one bites through a brittle object, like a nut. Tom enrolled as a MSc candidate, and I built a Heath Robinson-like device to examine this problem. The device consisted of upper and lower bite bars. The lower one was hinged, but was held in position by a glass rod, which then snapped when the experimental subject bit down hard enough. The yielding, while satisfyingly sudden, could be quite dramatic, and often sprayed shards of glass rod around the lab. (Safety was less of an issue in those days!) We were able to show, convincingly, that a hitherto-undescribed mechanism was responsible for holding the teeth apart in this situation. During forceful bites, when there is a possibility that the resistance might yield, the antagonist muscles (digastrics in this case) are co-activated with the agonist (jaw-closing) muscles. The contracting digastric then functions like a seat belt when the jaw begins to move rapidly upward (Miles and Wilkinson, 1982).
These experiments led me into a long series of experiments into the human masticatory system, in which I was ably assisted for many years by my post-doctoral fellow, Kemal Türker, a dentist who came from Turkey to work with me.
One area in which our research group achieved considerable eminence was experiments in which we recorded the activity of single motor units in the masticatory and other muscles. In Montréal, Jim Lund had shown me that it was quite easy to record single motor units (in cat muscles), and, happily, it proved quite simple to record in the human masseter as well. I soon realized that, while being interesting in itself, this method gave direct, quantitative insights into the activity of single motor neurones in the brainstem (in the trigeminal system) or in the spinal cord in limb muscles. Accordingly, we devoted a great deal of effort to exploiting this experimental model. This included the development of the first computer-based system for classifying motor units online, which was subsequently marketed as the SPS8701. Another dentist, Mike Nordstrom, enrolled as a PhD student and performed some superb experiments in which we characterized the mechanical properties of the muscle fibers in single human masseter motor units. Among other achievements, we were the first to demonstrate mechanical fatigue in a single motor unit (Nordstrom and Miles, 1990). In fact, this was the first incontrovertible demonstration of mechanical fatigue in any muscle in a conscious human. Our collaborative relationship has continued since, and remains the source of great satisfaction.
My next step was to examine the reflex responses of single motor units in both masticatory and limb muscles. Kemal Türker and I first looked at the reflex responses of masseter motor units to electrical stimulation of the lip. In this interesting reflex, the response in the whole muscle (recorded with surface electromyography) consists of an unusual biphasic inhibition, and there was much debate about whether there was also an excitatory component within it. We had collected quite a bit of data on this when I left to spend a year in the Physiological Laboratory at Oxford University with Peter Matthews, the world authority on stretch reflexes. Shortly before I left Oxford, I gave a seminar describing my single motor unit reflex data, and in the following discussion, Stuart Judge casually suggested that it should be possible to use my data to infer or calculate the shape of the synaptic potential in the parent motor neurone that was responsible for the reflex. I went straight back to my office to try to do just that. The answer came to me in a "Eureka!" moment. On a sheet of graph paper, I sketched the shape of the membrane potential of a tonically active neuron (known from animal experiments), then cut a bit of cardboard into the shape of a simple excitatory synaptic potential and slid it along the membrane potential trajectory. The answer became immediately and blindingly obvious. When the synaptic potential, added to the membrane trajectory, reached the firing threshold potential of the neurone, it would discharge an action potential. Because the latency of the reflex synaptic response was constant, the timing of a reflex spike in the motor neurone was determined by the timing of the preceding spike and the leading edge of the synaptic potential (Miles et al., 1989).
I immediately FAXed this insight, together with my graphs, back to my research group in Adelaide. To my disappointment, they were distinctly ’underwhelmed’ by my revelation—perhaps because, in my excitement, I had not explained it properly. When I returned to Adelaide, we carried out several experiments to exploit this new idea that one could directly estimate the shape of a synaptic potential in a human motor neurone evoked by a sensory stimulus. This remains the best manner to explore quantitative interactions between neurones in a conscious human subject.
Andrew Poliakov joined our research group as a postgraduate student at about this time. He had left Russia under difficult circumstances in this pre-Glasnost era, and soon found himself stateless when the Soviet Union collapsed. Andrew was a truly exceptional student, who had a level of skill in interpreting experimental data that I have not seen before or since. As the result of his skills, we took the interpretation of our single-unit data to unprecedented levels. One of the pieces of work with which I am most pleased is our demonstration of the nature of the short- and long-latency reflex responses to stretch in the jaw-closing muscles (Poliakov and Miles, 1994). This led to a complete re-thinking of earlier concepts of how the intriguing long-latency reflex responses were organized. Again, trigeminal reflexes were found to be different from comparable reflexes in the limbs.
The final chapter in the understanding of the role of stretch reflexes in the masticatory muscles was almost equally satisfying. I had long wanted to examine the stretch reflexes in the jaw-closing muscles of people who were running, to see whether they played a role in maintaining the posture of the mandible, which, after all, does not flap up and down in this situation. However, this was technically very difficult to do. I finally achieved this with the help of Stan Flavel. Stan was a highly trained laboratory technician in our lab, but he lacked a University degree. However, a loophole in the University’s regulations made it possible for me to enroll him as a MSc student. This required a great deal of persuasion, letter-writing, and lobbying, but eventually he was enrolled. Stan then used his formidable technical skills to record the vertical position of the mandible and the electrical activity in the masticatory muscles in subjects who were walking or running on a treadmill. We also recorded the time at which the subject’s heel hit the treadmill: Cross-correlation of these two signals then showed what components of masseter activity were directly correlated with landing on the heel. When one lands, the mandible continues to move downward until arrested by an opposing force. The question was, does this arrest of the downward movement result from the activation of stretch reflexes in the masticatory muscles, or from something else? The result was interesting and unexpected. It transpired that, during walking, when the head moves up and down only slowly, the jaw moves up and down too slowly to evoke any stretch reflex responses in the masticatory muscles. However, as one begins to jog, the head moves more quickly, and the more-rapid stretch of the jaw-closing muscles then evokes reflexes that restrain the downward movement of the mandible. Hence, the rest position of the mandible of a patient in a prosthodontist’s chair is not the result of stretch reflexes: Rather, the mandible is retained in its rest vertical position by visco-elastic forces in the soft tissue of the face (Miles et al., 2004).
There are other exciting aspects of my research that I do not have space to cover here, notably, our recent demonstrations of the role of sensory signals in inducing changes in the excitability of the human cortex, and how these can be used in the rehabilitation of stroke patients.
It is interesting, when looking back, to see the role of serendipity in leading one to take a particular course of action. In my case, the major trigger has been the people with whom I have worked. Had it not been for Peter Dellow, I may not have become a researcher at all. Had it not been for Tom Wilkinson, I may not have embarked on experiments on the human masticatory system. Had it not been for Stuart Judge’s casual comment, I would not have decoded the impenetrable question of how synaptic potentials can be examined quantitatively in human subjects. Had it not been for Stan Flavel, I would not have had the means to determine the mechanisms responsible for the rest position of the mandible.
I am indebted to these and to the many other colleagues with whom I have had the pleasure and privilege of working.
ACKNOWLEDGMENTS
I gratefully acknowledge the long-term support of the National Health and Medical Research Council and the Australian Research Council for my research.
Received February 21, 2006; Last revision June 20, 2006; Accepted June 23, 2006
REFERENCES
Miles TS, Wilkinson TM (1982). Limitation of jaw movement by antagonist muscle stiffness during unloading of human jaw closing muscles. Exp Brain Res 46:305–310.[ISI][Medline]
Miles TS, Türker KS, Le TH (1989). Ia reflexes and EPSPs in human soleus motor neurones. Exp Brain Res 77:628–636.[ISI][Medline]
Miles TS, Flavel SC, Nordstrom MA (2004). Control of human mandibular posture during locomotion. J Physiol 554:216–226.
Nordstrom MA, Miles TS (1990). Fatigue of single motor units in human masseter. J Appl Physiol 68:26–34.
Poliakov AV, Miles TS (1994). Stretch reflexes in human masseter. J Physiol 476:323–331.
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