s deep brain stimulation neuroprotective if applied early in the course of PD?
P David Charles*, Chandler E Gill, Thomas L Davis, Peter E Konrad and 
Alim-Louis Benabid  About the authors
Correspondence *Department of Neurology, Vanderbilt University Medical Center, 
A-0118 MCN, Nashville, TN 37232–2551, USA 

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Parkinson's disease (PD) is a progressive and disabling disorder that affects 
millions worldwide and is characterized by tremor, bradykinesia, rigidity and 
balance difficulties. Nonmotor features, including cognitive decline, 
autonomic disorders and sleep disruption, are present in a considerable 
minority of individuals with PD and dramatically increase disability. 
Although PD was first described 200 years ago, we have not yet identified the 
cause or developed a cure or treatment to slow progression. Hundreds of 
putative neuroprotective agents have been tested in clinical trials over the 
past two decades, but none of these agents has been successful at preventing 
the progression of PD. Deep brain stimulation (DBS) of the bilateral 
subthalamic nucleus (B-STN) is a safe, effective and cost-effective treatment 
for the motor symptoms of advanced PD,1, 2 and recent literature has 
suggested that DBS may also provide a neuroprotective benefit.3, 4 We believe 
that DBS will be the first therapy proven to slow PD progression, and that it 
must be applied in the earliest stages of the disease to have such an effect.
Pioneered at the University of Grenoble in the 1980s, B-STN DBS provides 
long-term symptomatic benefit and improves quality of life for many patients 
with PD.2, 5 However, despite the technique's widespread use, we do not fully 
understand its mechanism of action—neither the proven symptomatic benefit nor 
the potential neuroprotective effect. Several theories have been proposed to 
explain the neuroprotective properties of DBS. One such theory is based on 
the idea that PD develops after initial injury to the substantia nigra, 
mainly its pars compacta, causing the substantia nigra to become hypoactive. 
Other areas of the basal ganglia, including the STN, become hyperactive as a 
result of loss of inhibition. The STN is the main relay of the indirect 
pathway of the basal ganglia; it influences motor output through the globus 
pallidus internus and substantia nigra. The hyperactive STN may promote 
glutamate excitotoxicity, further accelerating dopaminergic cell death in the 
substantia nigra. It has been proposed that high-frequency B-STN DBS alters 
STN activity, resulting in the removal of a source of toxic glutamate input 
to the substantia nigra, which in turn leads to the preservation of 
dopaminergic cells.
Two recent reports provide evidence in support of this theory. Temel  et al. 
found that B-STN DBS protected nigral neurons in the 6-hydroxydopamine rat 
model of PD—cell loss in the substantia nigra of DBS-treated animals was 28–
30% lower than that in controls.4 The animals received DBS during ongoing 
neurodegeneration, which more accurately represents clinical practice than 
previous animal experiments in which lesioning or stimulation was performed 
before treatment with 6-hydroxydopamine. Kainic-acid-induced lesion of the 
STN also reduces the loss of nigral dopaminergic cells in the 
6-hydroxydopamine rat model,6 supporting the hypothesis that DBS at high 
frequency has inhibitory effects. Wallace and colleagues made similarly 
exciting observations when using the 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD in primates. 
These authors found that STN stimulation both before and after MPTP injury 
prevented further neuronal loss (MPTP-treated animals that received STN 
stimulation had 20% more dopaminergic cells in the substantia nigra than 
animals that did not receive stimulation).3 In this study, 
kainic-acid-induced lesion of the STN also had neuroprotective effects that 
were comparable to those of STN DBS.
Clinical results, on the other hand, are conflicting. During the initial 
clinical trials that investigated the efficacy of DBS in PD, some patients 
seemed to stabilize after implantation of the DBS electrodes (AL Benabid, 
unpublished data). A more-recent trial of DBS in patients with advanced PD 
confirmed this observation,7 although neuroprotection was not a stated end 
point. The authors noted no significant clinical deterioration during 4 years 
of DBS therapy,7 which is clearly different from the expected natural 
progression of PD. Many trials, however, have noted clinically and 
statistically significant deterioration of motor symptoms after initiation of 
DBS therapy. For example, off-medication Unified Parkinson Disease Rating 
Scale motor scores of the first 49 patients who were treated with DBS therapy 
in Grenoble deteriorated by 7 points from year 1 to year 5 of the follow-up 
period.2 In 2005, Hilker  et al. used serial 18F-fluorodopa PET as a 
surrogate marker for disease progression and found that dopaminergic function 
had continued to decline in patients with advanced PD after 16 months of 
clinically effective B-STN DBS therapy.8
Several factors limit the capacity of the clinical results to date to rule out 
DBS as a neuroprotective therapy. First, continued functional decline does 
not eliminate the possibility of positive disease modification—it only 
eliminates the possibility that DBS might result in a complete halt in 
progression. Furthermore, none of the studies so far has included a control 
group that was treated with standard drug therapy, and, thus, progression 
rates between the two groups have not been compared.
An additional limitation is that all studies to date have been in patients 
with features of advanced PD, including motor complications of therapy. A 
majority of nigral neurons have died by the time patients with PD first 
present to a neurologist. Currently, patients do not receive DBS therapy 
until they have developed intractable symptoms and motor complications of 
therapy; electrode implantation both in clinical trials and in standard of 
care takes place at an average of 11 years after diagnosis, at which point 
considerable cell death has occurred, and potentially neuroprotective 
strategies are unlikely to demonstrate a clear benefit. Animal data seem to 
be in agreement with this view; in general, studies that report a lack of 
neuroprotection with the use of DBS have employed extensive neurological 
injuries to model PD (resulting in the death of 75–90% of all nigral cells), 
whereas other authors who have induced lesser injuries have found positive 
results.3, 9 A nigral cell death rate of 85% is representative of a patient 
with advanced disease who receives DBS through current standard of care, 
whereas a nigral cell death rate of 50% is representative of a patient in the 
earliest symptomatic stages. The fact that studies to date have tested the 
therapy in patients with advanced disease may partially explain why many of 
these trials have failed to document neuroprotection.2, 8
We believe that DBS slows the progression of PD, and we are currently 
conducting a pilot clinical trial of B-STN DBS in early-stage PD 
(ClinicalTrials.gov identifier NCT00282152), collecting preliminary data 
necessary to launch a multicenter phase III trial to definitively test this 
hypothesis. When designing our pilot study, we took into account several 
lessons from previous DBS and neuroprotection trials. Only patients with 
early-stage disease, who hold the greatest potential for disease 
modification, will enroll. They must be in Hoehn and Yahr stage II, have been 
on anti-PD medications for less than 4 years, and cannot have developed motor 
fluctuations. The trial is designed as a single-blind, randomized, 
parallel-group study, with 30 patients randomized to either optimal drug 
therapy alone or optimal drug therapy plus B-STN DBS. Patients undergo 8-day 
inpatient evaluations at baseline and at 6-month intervals for 2 years. 
During each evaluation, medications and stimulation are withdrawn and motor 
scales are administered daily. The purpose of this design is to fully 
characterize the washout of stimulation plus medication versus the washout of 
medication alone, and to determine the minimum time necessary for patients to 
remain off drugs or stimulation to assess underlying disease. The data from 
this trial will provide essential information for the design of any phase III 
trial that will test neuroprotection. If our data support the safety of DBS 
in early PD, the current study will be extended into a delayed-start design, 
with surgery offered to patients in the drug therapy only arm 3 years after 
original randomization.
While our trial addresses many criticisms of recent neuroprotection and DBS 
trials, there are considerable hurdles to overcome before any therapy can be 
definitively proven to modify human disease progression. Most notable are the 
lack of an accepted biomarker of PD progression,10 and the difficulty in 
separating symptomatic benefit from actual prevention of cell death and from 
the maintenance or facilitation of mechanisms that compensate for the loss of 
dopaminergic neurons. These barriers may take years to overcome. Being able 
to prove that a therapy halts or slows progression of clinical symptoms, 
however, is a worthwhile and achievable goal.
Our hypothesis is bold and ambitious and, if correct, would enable achievement 
of a goal held by both physicians and patients. Any treatment for PD that 
proves to be neuroprotective will be applied as soon as the diagnosis is 
reasonably confirmed. These clinical trials represent the essential steps 
toward finally developing a treatment that slows this relentlessly 
progressive and disabling illness.

http://www.nature.com/ncpneuro/journal/v4/n8/full/ncpneuro0848.html

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