A Brief History of Deep Brain Stimulation

An on-going campaign against the use non-human primates to study Parkinson’s disease (PD) at the University of British Columbia prompted me to summarize some basic facts about the work and the history of a successful therapy was developed.

Why is the work done?

In the U.S. alone there are between 500,000 and 1 million people living with PD, with about 50 to 60 thousand new diagnoses every year.  The National Institutes of Neurological Disorders and Stroke (NINDS) estimates the cost to our society is at least $5.6 billion, including both direct medical expenses and indirect costs from lost income, disability payments and so on.  Moreover, the emotional toll of Parkinson’s on patients and families is enormous.

One of the most successful therapies developed for PD  involves the electrical stimulation of deep structures within the human brain — so called deep brain stimulation (DBS).  The technique works remarkably well for some patients.

How was the method developed?

Back in 1983 Langston and colleagues reported on a clinical case study of four patients that developed Parkinsonism after illicit drug use.  Analyses of the drugs they had taken via mass spectroscopy revealed primarily MPTP, but there were also traces of MPPP. They suggested MPTP might be the most likely culprit and suggested that:

“Given the pathologically studied case, the relative purity of the clinical syndrome seen in our patients, and its remarkable clinical resemblance to Parkinson’s disease, the drug [MPTP] may be of value in producing an animal model of Parkinson’s disease.”

In other words, a group of clinicians studied a handful of human patient cases, identified a potential link between MPTP toxicity and the development of PD, and proposed to follow up with animals studies.

In 1983, Burns and colleagues follow up on this idea by trying to replicate the disease in monkeys.  Indeed, intravenous administration of MPTP caused the animals to develop rigidity, postural tremor, eyelid closure, and many other symptoms of Parkinsonism.  Moreover, their symptoms could be relieved by the administration of L-dopa, exactly as it was the case with the Langston et al patients. The animal model also allowed them to characterize the selective destruction of dopaminergic neurons in the subtantia nigra and a marked reduction in the dopamine content of the striatum.  They offered MPTP treated monkeys as a model to explore therapies for PD.  How many animals were used?  Twelve.

Although these anatomical studies shed light into the brain areas that might be involved in PD it was unclear what functionally was causing the observed symptoms.  Subsequent work by Mitchell et al (1989) using single unit recordings and lesion studies in monkeys pointed to increased activity in the subthalamic nucleus (STN) as generating motor abnormalities.  How many monkeys were used?  Eight.

A natural question arose from these studies.  Would suppressing the activity of these hyperactive neurons help in alleviating the symptoms of the disease?

Two studies showed that lesions of the STN could reverse the effect of Parkinson symptoms in the monkey MPTP model, with studies by Bergman et al (1990) and Aziz et al (1991).  These studies not only began to dissect the functional connectivity within the basal ganglia-thalamocortical circuit, but also offered evidence that inactivation of the STN could work as a potential therapy for Parkinson’s.   How many monkeys were used in these two studies?  Four.

Shortly after, Benazzouz et al (1993) showed that instead of lessoning the STN one could use high frequency stimulation of the STN to alleviate the symptoms in MPTP treated monkeys.  Supposedly, the high frequency stimulation suppresses the activity of these cells acting as a “virtual lesion”.  How many monkeys were used here?  Two.

Indeed, Limousin et al (1995) successfully applied this method in three patients and concluded:

“In this study, bilateral subthalamic nucleus stimulation improved akinesia and rigidity in three patients with Parkinson’s disease.  This is in agreement with the results obtained in monkeys with MPTP-induced parkinsonism by lesions or stimulation of the sub-thalamic nucleus.”

Number of humans used?  Three.

And to dispel any remaining doubts he writes in a recent review that:

“The knowledge of the functional changes of basal ganglia activity in the parkinsonian state as it emerged from extensive experimental studies on animal models has provided the theoretical basis for surgical therapy in PD. The 6-hydroxydopamine (6-ODHA) rat model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD provided powerful research tools for uncovering the pathophysiology of changes in functional basal ganglia activity in PD.” 

And finally one may ask, ho many human patients have benefited from this type of work?

The answer is 80,000 and counting.

What do these patients think of such studies?

Here is one — please listen to him carefully.

And if you truly want to learn more here are some extra resources:

SfN brain briefing on PD discoveries.
The Michael J. Fox Foundation
Information from National Institutes of Neurological Disorders and Stroke.
Information from Understanding Animal Research.

12 responses to “A Brief History of Deep Brain Stimulation

  1. “Back in 1983 Langston and colleagues reported on a clinical case study of four patients that developed Parkinsonism after illicit drug use.”

    Just so. Historically, a CLINICAL observation led the way, as is always the case. Then the animal researchers get in the way and “prove” or “disprove” the already-established clinical fact and go looking around for a “model”, something neither necessary nor practical or logical, but stemming from habit and more likely to generate a lot of confusing, ambiguous data no one knows what to do with — all time and money wasted.

    Is the treatment of the patient on a par with the treatment of the unwilling animals? No. So they are not models at all.

    The patients don’t know they’re being duped by propaganda and will easily believe that only animal research can cure PD.

    If only they could hear the truth from Dr. med. Olga Lautreppe (Paris): “Vivisection is based on two false notions. One is that the experimental method – so successful when applied to inanimate bodies – should also be applied to living bodies. But the great Cuvier, the glory of France and of science, totally rejects the application of the experimental method to the science of life processes (physiology) and disputes the justification for vivisection, saying: ‘All the parts of a living body are linked with one another, they only function cor­rectly when they are acting together. To separate one organ from the whole means putting it into the class of inanimate matter; this means totally altering its nature.’
    “The second false idea is that we can draw conclusions from experiments on animals in relation to human beings, because animals have a certain similarity to humans. In fact, however, there are more dissimilarities than similarities be­tween human beings and animals.” (Tier und Mensch, No. 5, 1932)

    Professor Henry J. Bigelow, Professor of Surgery at Harvard University: “Any person who had to endure certain experiments carried out on animals which perish slowly in the laboratories would regard death by burning at the stake as a happy deliverance. Like everyone else in my profession, I used to be of the opinion that we owe nearly all our knowledge of medical and surgical science to animal experiments. Today I know that precisely the opposite is the case, in surgery especially, they are of no help to the practitioner, indeed he is often led astray by them.”

    The more things change the more they stay the same.

    • Well, I thought I made it clear that the clinical observation actually lead to the development of the animal model. In fact, the very same clinicians that did the work suggested such research would be a good idea. There is so much I can do with those that refuse to face the facts.

      • You did make that clear. Is Humbug suggesting that the MPTP observation should have led to some human experimentation, or that the clinicians should have been able to move directly from that observation into a magical insight that would have led to a treatment for Parkinson’s disease?

      • People like Humbug will always prefer to quote one of the small minority of doctors and scientists who have opposed animal research rather than face up to the facts.

        I suspect that he/she also buys into the myth that people like Ray Greey like to spread that animal research is somehow in competition with the rest of medical research, especially clinical research, whereas those who actually understand medical research recognize that animal research and clinical research work together to deliver the goods.

  2. @Humbug. Did you even read the post? How is it that you think that understanding and identification of the specific brain areas, specific mechanisms, and specific pathways to treatment occurs? This example shows quite clearly that it is not via an intuitive leap from clinical observation directly to intervention. The fact that the work in animals did, in fact, provide the basis for the clinical treatment obviates the claim in the Lautreppe quote.

  3. There is no ignorance so stubborn as the ignorance of the learned.
    The animal experiments were (and always will be) unnecessary and redundent, we keep telling you, since their results will be ambiguous, not predictive, and therefor, if they coincide, it is only coincidence. To rely on them is sheer folly and the clinicians were dead wrong to resort to monkey models. There is neither rhyme nor reason for going to the vivisection room to elaborate the clinical observations in a “model”. Only clinical methods can give reliable answers. Practically speaking then, animal tests have only an alibi function, insurance against prosecution when things don’t pan out and people are inadvertantly harmed by drugs or therapies. You then hide behind these animal scapegoats hoping to dodge the consequences of your actions.

    In my experience most of the public when confronted by images of animals in labs know they’re seeing scientific madness and corruption and become abolitionists on the spot. Hang your polls! Depends on the question. Animal research has not done humanity any good and never will, since it is impossible to do so. That’s only logical, something severely lacking in the average pro-vivisectionist.

    • “There is no ignorance so stubborn as the ignorance of the learned.”

      Soooooo looking at facts makes me ignorant? I’m very confused. I guess I should just take the word of a bunch of people off the internet. And here I was thinking I was being pro-active by educating myself, when really I’m just furthering my ignorance. *sigh*

  4. That penultimate sentence should read: Animal research has not done humanity any good and never will, because it is incapable of doing so.

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