An Interview with Dr. Lee Illis, First President of the INS

August 2022

You were the first INS President from 1990 – 1994. Could you please describe the early years of the Society?

There are several ways of looking at the origins of the Society. In June 1989, Nanno Lambooy, a Dutch doctor, organised The International Congress on Epidural Spinal Cord Stimulation, held in Groningen, in the Netherlands. At this meeting it was decided to form an international society. Various countries each elected a representative and the representatives met in Paris in April 1990. Before that time all specialist groups had their own societies with little or no overlap and often with some degree of internecine jealousy. This new society, however, was unique in that it attracted basic scientists, neurologists, neurosurgeons, neurophysiologists, engineers, computer scientists, specialists in rehabilitation and in pain management and so on.

The representatives elected an executive committee and a president. The committee consisted of Mario Meglio, Michael Staal, Daniel Galley, Hans Sier, Ulli Krainick and myself. We knew of each other but most of us didn't actually know each other.

One definite factor that helped catalyze its creation was that I have never been involved with such a truly enjoyable and friendly group. The early meetings were characterised by the way in which all the elected representatives seemed to be in harmony. I have never been in a society where there was such camaraderie - and so much good humour. We worked quite hard but I have never laughed so much.

I have been privileged to have worked with a bunch of people from different countries who have stimulated me and have made scientific meetings a time of great joy and laughter- and you don't often hear scientific congress spoken of in those terms!

It is true to say that the origin of the INS lies with Nanno Lambooy, but the origins of neuromodulation go back much further. Neuromodulation means regulation and modification of neurological function without destruction of neurological tissue and it emphasises the plasticity of the adult nervous system, the reaction of the intact nervous system to injury or disease and the possibilities of altering or provoking the undamaged central nervous system (CNS) in such a way as to negate, at least partially, the effects of the lesion and to improve function. There are two different lines of experimental research which came together and paved the way for neuromodulation.

In the 1950s I was the Anatomy Scholar in J Z Young's Department of Anatomy, University College, London and became involved in investigating the effect of a partial lesion in the CNS- sprouting of new terminals - and, later, with the effect of repetitive stimulation on the CNS. This provided a theoretical basis for attempting to improve function via procedures aimed at the undamaged, but poorly functioning, CNS.

Separately, the basis of the therapeutic use of repetitive electrical stimulation arose from the formulation of the gate control theory of pain by Melzack and Wall (1965), and thence to transcutaneous stimulation and spinal cord (dorsal column) stimulation.

What were the challenges as the Society formed, and what do you count as the Society’s successes?

I'll come to the successes but the main challenge was the unfriendliness of some of the existing specialist societies.

How did neuromodulation therapy and research at that time align with your clinical and research interests?

In 1973 I had an article in The Lancet in which I stated that, based on experimental studies, the intact central nervous system (CNS) reacts to a lesion in such a way as to negate the effects of the lesion and it is possible to produce structural changes at synapses following repetitive stimulation (I had published on this in Nature 1969), implying that procedures aimed at the intact CNS should be beneficial rather than concentrating on repair of damaged pathways, which, after more than a century had been shown to be futile. Al Cook, professor of neurosurgery at Downstate University New York replied in a letter to The Lancet that that was indeed the case and he had published in 1973 (New York State Journal of Medicine) the effects of spinal cord stimulation (SCS). Cook had conducted SCS for the treatment of pain in a young woman with multiple sclerosis (MS) and was surprised to see a marked reduction in spasticity.

I was about to embark on a lecture tour of the USA (Wellcome Trust Travelling Fellowship) so I visited Cook. Cook had taken his findings to the chief of neurology at Downstate who had shown no interest. He took his findings to the New York neurologists who were less than helpful. I knew the chief of neurology and he told me that Cook's observations were amazing "but these things don't happen". I thought the speed of the changes witnessed by Cook suggested an increase in inhibition.

When I returned to the UK I decided that I would investigate Cook's remarkable observation. If true it would be the first demonstration of alteration of a fixed neurological deficit by external stimulation in humans. In Southampton I had the advantage of an informal group whose members came from the Wessex Neurological Centre, the Institute of Sound and Vibration Research, the Department of Electronics Southampton University, and the Royal Army Medical College, I decided that we would first of all investigate the type and distribution of stimulation and then look at recordable and reproducible neurophysiological recordings.

I must stress here that although the studies were on patients with MS this had nothing to do with MS as a disease. It was not intended to investigate a treatment for MS. The first reported patient (by Cook) was being treated for intractable pain and we decided to repeat Cook's work but with neurophysiological recordings.

Spinal cord stimulation produces a tingling sensation in the limbs. By contrast transcutaneous nerve stimulation (TNS) produces only a superficial sensation. We told the patients that we would be investigating different types of stimulation to see which best suited them.

We placed an epidural electrode which we could use as a recording or stimulating electrode and a TNS electrode. TNS did not produce any electrical signal in the epidural space. We positioned the epidural electrode to produce either unilateral or symmetrical stimulation.
Of all the different types of stimulation only strictly symmetrical stimulation produced any effect on neurological deficit or the neurophysiological recordings.

I decided that we would look at neurophysiological recording not only at different levels of the neuraxis but also in systems removed from the spinal level; the following all have characteristic abnormalities in patients with MS:

• urodynamic studies,specifically detrusor instability, bladder capacity and residual volume
• the H reflex
• cervical somatosensory evoked potentials
• brain stem evoked potentials

With SCS all the above parameters improved towards the normal and reverted when SCS was stopped. We looked at a system, visual evoked response, removed from the spinal level - there was no change.

All the above investigations are immune from observer and subject bias in a way that purely clinical assessment can never be.

The contingent negative variation (CNV), however, is a cortical event related potential which may be influenced by the subject's attention and expectancy i.e., by motivation. There was no change in the CNV.

In summary, those recordings which could not be influenced by the subject altered with SCS; the recordings in areas outside the spinal neuraxis were unchanged; recordings which could be subject to motivation were unchanged.

So what was Cook doing? Well, in 1902 Frolich and Sherrington (Nobel Laureate) reported in the Journal of Physiology that after decerebration in cat, dog and Macaque, stimulation of lower thoracic and lumbar spinal cord showed "...an effect...constant and regular....evoked marked inhibition of the rigidity...". This was, I believe, the first demonstration of the effect of external stimulation on neurological deficit. What Cook had observed was, quite simply, what had been reported by Frohlich and Sherrington. Cook was not aware of Sherrington's work and neither were his detractors. Cook was a consummate clinical observer and deserves greater recognition.

All this is summarized in "Spinal Dysfunction" Vols. I,II, and III published by Oxford University Press (1992). In summary, Pat Wall's work on the gate control theory led directly to spinal cord stimulation. Al Cook's observations led directly to the use of SCS in neurological deficit.

Has the receptiveness by neurologists evolved, and how can that improve?

There certainly were problems with "receptiveness". The Southampton work was the first objective evidence of a change in fixed neurological deficit in humans. I presented the work locally, in Southampton. The Dean of my medical school was present and, at the discussion, warned about the danger of placebo effect in the treatment of MS. I pointed out that the work was not and never had been a treatment for MS. The subjects had MS because Cook was treating a patient for intractable pain who had MS. The neurophysiological procedures could not be influenced by the subject and it was difficult, if not impossible, to see how they could be influenced by a placebo effect. It was impossible to convince him. I came across this on many occasions. There were some notable exceptions: after leaving Cook I continued on my lecture tour (this was in 1975 I think) and I was giving a talk in the Brain Research Institute (BRI) UCLA. Carmine Clemente, a distinguished anatomist, was professor of anatomy and later became the Director of the BRI. I had known him when he was a visiting research fellow in JZ Young's department when I was the anatomy scholar (1953-1954). I told him of Cook's work and his immediate response was that it was probably due to an increase in inhibition. When I presented the work at a meeting of the Association of British Neurologists I met with the same skepticism as my Dean with the exception of Brian Matthews, Professor of Neurology at Oxford University, who stood up and said the neurophysiological changes clearly showed changes which could only be explained by the SCS.

I know that others have had similar problems. I think it has improved to some extent and I feel that anyone working in this field should be very conscious of the necessity of using objective and reproducible methods - and always refer to the work of Sherrington over a century ago! If Cook had made his observations on experimental animals and I had presented the objective changes in rats there would have been no problem. Never underestimate the inertia and resistance to change of the medical profession!

What was your perception of the interests and motivations that drew representatives of different specialties to participate in formation of the INS?
 
Each of the representatives had seen evidence of the clinical benefit of stimulation techniques in diverse situations; pain, blood flow etc. My own interest was in the extraordinary effect of repetitive stimulation on what used to be called a fixed neurological deficit and the way it tied in with my previous experimental research on the reaction of the undamaged CNS and the effect of stimulation.

The good points are the collaboration between different disciplines where engineers, computer scientists, clinicians meet and mix. In the neurosciences that, in my experience, is rare? For example, how often do neurologists and neurosurgeons mix in their organisations? The antagonism is well illustrated by Cook's reception from neurologists. I was lucky, as I've already indicated, in having an informal group of people from diverse specialities who were all friends.

What was your perspective on the early meetings’ scientific rigor and/or excitement and interest, or of any wider notice? Was there a sense of therapeutic promise, and how has that borne out?

Scientific rigour? I think this is probably the most important topic and subject of discussion of all. The clinical use of stimulation techniques are still met with suspicion and it is imperative that studies are rigorous in using controls. Not easy, because the very nature of the techniques make a double blind study impossible. Also, any suggestion of the use of alternative therapy should be frowned upon, to say the least. I know this is a personal opinion but alternative therapies have their own outlets and the INS should not be one of them.

There was undoubtedly a sense of therapeutic promise and that has occurred. The Society has grown and I am sure it will continue to grow. I would like to see an even stronger emphasis on scientific rigour and with recruitment of basic scientists.

What is your view now of the maturation of the Society and fulfillment of its purpose?

The strength of a federated society lies in its ability to get the best at both national and international levels through international collaboration and influence. It becomes a source of information, guidance and support.

The Society has grown and developed to encompass all types of external stimulation and has attracted people from diverse specialities and backgrounds; this cross-fertilisation is one of the most exciting benefits of the Society.