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) in Grenoble 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, the Grenoble team led by Alim-Louis Benabid, see Limousin et al (1995), soon 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 DBS pioneer Alim-Louis Benabid of the Joseph Fourier University in Grenoble 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.