Sham Surgery: All Options Should be on the Table

The issue of whether or not a sham brain surgery is necessary for the research of Parkinson’s disease is complicated. Following several decades, different treatments for Parkinson’s disease have been developed, such as cell implantation, fetal nerve-cell transplantation or gene therapy. There was some common point that the radical or significant effect on the improvements of motor disability or balance control was found during the phase I trial; however, during the phase II trial, the treatment effect did not precede that in the sham-surgery control group. In an ethical point of view, is it ethical to easily and immaturely shift studies failed in the phase II trial without regard to the potential values to patients? Besides, due to the shortage of funding resource, fewer and fewer research groups could afford the expensive sham-surgery which is also too risky to find enough subjects of the control group to compare with the experimental group. Therefore, increasing numbers of scientists started to argue about whether the sham-surgery is really necessary.

An article “Experimental therapies for Parkinson's disease: Why fake it?” published on Nature on August 11, 2011 started to discuss the dilemma, the conditions that scientists currently face, and the suggestions with that scientists provided [1]. The story began with an experiment called Spheramine, developed by a biotechnology company, Titan Pharmaceuticals. In this experiment, Peggy Willocks was the second recruited subject in the phase I trial who received an implantation of human retinal epithelial cells into her brain in August 2000, and the scientists hoped that the implanted cells would produce L-dopa, which could reduce the symptoms related to motor disabilities, such as dyskinesia or poor balance control. After 9 months, a great improvement in her balance control impressed the scientists, and similarly, several subjects in the phase I trial showed moderate improvements in motor disabilities. This, however, should be the exciting results to scientists and most Parkinson’s disease patients, but disappointingly the study was shelved and no longer operated until ten years later due to the results in phase II showing that it was no more effective than placebo. With regard to this “common” situation, Dr. Roger Barker at the University of Cambridge argued against the placebo-controlled study in terms of the costs, risks of sham surgery to healthy people, and the potential damage of the placebo-controlled study to promising treatments.

The sham-surgery as a placebo-controlled procedure is used to eliminate the false-positive results in the research of Parkinson’s disease. An experiment in 1987 attempted to use adrenal gland cells to produce dopamine, and this treatment was claimed to successfully produce positive results [2], and so did two other studies using Glial cell line-derived neurotrophic factor (GDNF) transplants [3] and retinal epithelial cell implantation [4]. However, later studies showed that the aforementioned positive results were not reproducible and some studies even pointed out that the treatment effects were no more than placebo effects. Until now, the sham-surgery in Parkinson’s disease is defensible and reliable to reduce confounding factors, such as patient’s expectation, to cause false-positive effects. Dr. Jon Stoessl at the University of British Columbia provided supportive evidence that patient’s expectation was strongly influenced by their functional improvements [5]. Therefore, the supporters of the sham surgery claimed that the placebo-controlled procedure offered an objective measurement to prevent patient’s expectation from sheltering the treatment effects.

Although the sham surgery in the research of Parkinson’s disease is widely accepted, some new points of view that the sham surgery is unnecessary are generated. First of all, the approval of the sham surgery is rarely acceptable in some regions, such as in Europe, which means that whether to operate the sham surgery depends on the region’s scientific policies, and therefore the sham surgery cannot become accepted and apply to all clinical research. Second, the lack of treatment efficacy in the open-labeled study as compared with the placebo-controlled study may result from the short-period follow-up (usually less than one year) due to inevitable difficulties, which indicates that the treatments should take more than one year to produce effects on the “clinical” improvements. As time goes by, the placebo effect (patient’s expectation) becomes weaker and the value of treatments becomes more evident. Finally, a more central concept is brought up that whether scientists should be concerned about patient’s expectations, and whether their expectations can be tolerated and can even be useful in research although that would affect the baseline of the objective measurement in scientific research. Dr. Perry Cohen mentions that because the failure in phase II trial of GDNF caused safety concerns, the further research was shelved for almost 6 years. Due to the safety concerns in the scientific studies, is it unethical to process an open-labeled study and allow patients to know their treatment protocols? A clinical case of Parkinson’s disease showed that the physical conditions can be dramatically influenced by the psychological aspects of self-belief. Although it is hard to quantify the psychological contributions, the medical treatments should accompany with self-expectation, which would cause further treatment efficacy.

Whether the sham surgery is needed is still under debate, but the aim of the sham surgery is to eliminate false positive effects. However, it is inevitable to remove the false negative effects. The most important thing to patients is hope, which means not to discard a potential treatment so easily due to the failure in the phase II trial. In the scientific field, a clinical research without a placebo-controlled group will easily receive dramatic critique instead of been recognized by the contributions. However, like patients will say “false negative is better than false positive.” All patients want are the improvements of their function in the future. 

--Ian Chou

Neuroscience Graduate Program 

References

1. Katsnelson, A., Experimental therapies for Parkinson's disease: Why fake it? Nature, 2011. 476(7359): p. 142-4.


2. Madrazo, I., et al., Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. N Engl J Med, 1987. 316(14): p. 831-4.


3. Lang, A.E., et al., Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol, 2006. 59(3): p. 459-66.


4. Stover, N.P. and R.L. Watts, Spheramine for treatment of Parkinson's disease. Neurotherapeutics, 2008. 5(2): p. 252-9.


5. McRae, C., et al., Effects of perceived treatment on quality of life and medical outcomes in a double-blind placebo surgery trial. Arch Gen Psychiatry, 2004. 61(4): p. 412-20.

In Support of Sham Surgery

A control group seems to be an undisputed cornerstone to a strong study. So what happens when people say the control group is muddling the conclusions? This is the opinion dividing researchers who develop surgical treatments for Parkinson’s disease. In the last decade, several interventions that appeared promising in Phase I trials failed to have a significant impact in Phase II (sham-controlled) trials and subsequently were abandoned [1,2,3,4]. Many patients who benefited from the early trials say that the sham controls are obscuring the efficacy of the much-needed treatments. Meanwhile, proponents of the sham controls claim that the controls are necessary to demonstrate the efficacy of a treatment, especially in light of the robust placebo effect in the Parkinson’s population. Katsnelson’s article “Why Fake It?: How ‘Sham’ Brain Surgery Could Be Killing Off Valuable Therapies for Parkinson’s Disease,” presents an interesting discussion of this issue [5]. The ethical concerns of the two groups are as follows:

Fans of Shams:

Investigators in favor of sham controls are driven by an ethical imperative to produce the highest quality research possible. A Phase I open-label trial is a safety test that may suggest whether an intervention works; the Phase II trial truly establishes efficacy by controlling for confounds such as investigator bias and placebo effect. This control is particularly important in the Parkinson’s population, where the placebo effect is robust: believing in the efficacy of a treatment triggers dopamine release [6], which directly mitigates Parkinson’s symptoms. Researchers are adamant that these confounds should be eliminated with a control group, and sham controls are the most thorough type of controls. These arguments have the support of 94% of polled Parkinson’s researchers, who “believe sham-surgery controls are better than unblinded controls for testing the efficacy of neurosurgical interventions” [7]. Supporters also note that adverse events in sham control groups are very rare and that participants receiving the sham treatments can receive the experimental treatment if it is approved (although the studies cited in Katsnelson’s article suggest that approval is rare) [5].

Contesting the Controls:

An opposing group of scientists (many from Europe, where sham surgery is more controversial than in the US) believe that experiments featuring sham controls are not necessarily the best evaluation of new neurosurgical interventions for Parkinson’s disease. Dr. Robert Barker explains that inconsistencies in treatment administration account for part of the lackluster Phase II results and indicate a need for protocol refinement during Phase I trials. In this situation, the use of sham controls is premature. Barker also notes that the high cost of this design (an estimated $10 million for a 50 patient study [5]) limits the number and size of studies that can be performed. Furthermore, the pool of eligible patients is already small – assigning patients to be sham controls limits the size of the experimental group and “provides results of limited statistical utility” [5].

Critics also point to the risks of sham surgery. There are physical risks, including those associated with anesthesia, installation of a halo, drilling of holes into the skull and in some cases, even penetration beyond the dura mater. And there are unknown risks stemming from “psychological effects of unblinding” (Perry Cohen, quoted in [5]). Cohen mentions a patient who experienced dramatic improvements in the control group, but rapidly deteriorated after the unblinding.

Finally, investigators opposing the inclusion of a sham control group believe it actually compromises the ecological validity of the experiment. They say that a placebo effect is an inherent part of the treatment – if the therapy is approved, future patients will know they received it, and may gain some benefit from the ensuing dopamine release (Perry Cohen, quoted in [5]). That physiological change is still a part of the treatment.

Clinical investigators are not alone in their concerns about the use of sham controls. Many Phase I participants are frustrated that seemingly effective treatments (even as far out as 10 years) failed in Phase II and were subsequently abandoned (Peggy Willocks, quoted in [5]). Investigators such as Cohen agree and some of those treatments (neurturin and GDNF) are now being reconsidered [5].

To Sham or Not to Sham?

I love a good, tidy control group as much as the next scientist, but after reading Katsnelson’s article, I think investigators should reconsider the use of sham controls, at least for the time being. Sham controls are included to produce the highest quality science possible, but their inclusion seems to be hindering the development of some truly promising treatments.

It seems that further refinement of the therapies and protocols should be done during Phase I trials to reduce variation in the Phase II studies. And once Phase II begins, a sham control may not be a prerequisite for a rigorous clinical study. Investigators in Europe and researchers in other areas of medical research (rehabilitation, for example) publish effective studies without the use of sham controls. They control variables in other ways: having blinded raters evaluate patient progress and using control groups of patients receiving ‘usual and customary care’ (established treatments such as deep brain stimulation that are already in use). Finally, a control group may not even be the best way to establish efficacy – long-term (3-5 years) studies may be better. Most studies end after a year, quite possibly before the therapy has had maximal impact.

It is important to consider not only the ethical imperative to conduct quality research, but also researchers’ ethical responsibilities to patients. Clinical investigators are not just scientists – they are also clinicians and should respect patients’ wishes (which are often wishes for careful consideration of potential therapies). Investigators must recognize the fact that using sham controls to eliminate false positives may have inadvertently generated false negatives and the discarding of effective therapies (to the disappointment of many patients).

I recognize that my opinion on the sham controls is certainly not the only one. Other people can read the same facts and draw a very different conclusion. But as long as researchers consider their ethical responsibilities to both quality science and their patient population, I feel they can conduct an ethical investigation.

--Kim Lang

 Neuroscience Graduate Program

References:

[1] Gross RE, Watts RL, Hauser RA, Bakay RA, Reichmann H, von Kummer R, Ondo WG, Reissig E, Eisner W, Steiner-Schulze H, Siedentop H, Fichte K, Hong W, Cornfeldt M, Beebe K, Sandbrink R; Spheramine Investigational Group. (2011) Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 10(6):509-19.

[2] Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, Vitek J, Stacy M, Turner D, Verhagen L, Bakay R, Watts R, Guthrie B, Jankovic J, Simpson R, Tagliati M, Alterman R, Stern M, Baltuch G, Starr PA, Larson PS, Ostrem JL, Nutt J, Kieburtz K, Kordower JH, Olanow CW (2010) Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 9(12):1164-72.

[3] Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M (2006) Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 59(3):459-66.

[4] LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS, Tatter SB, Schwalb JM, Poston KL, Henderson JM, Kurlan RM, Richard IH, Van Meter L, Sapan CV, During MJ, Kaplitt MG, Feigin A (2011). AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10(4):309-19.

[5] Katnelson A (2011) Why Fake It?: How ‘Sham’ Brain Surgery Could Be Killing Off Valuable Therapies for Parkinson’s Disease. Nature 476:142-144.

[6] de la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ (2001) Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 293(5532):1164-6

[7] Kim SY, Frank S, Holloway R, Zimmerman C, Wilson R, Kieburtz K (2005) Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers. Arch Neurol 62(9):1357-60.

Questioning Controls in Sham Surgery

The article- Why Fake It? How ‘Sham’ brain surgery could be killing off valuable therapies for Parkinson’s disease- brought up differing viewpoints on sham surgery. Proponents of sham surgery claim that they are critical about discovering whether new treatments actually work or if the positive outcomes are based solely on placebo. While opponents of sham surgery argue that the sham surgeries are unnecessary and detrimental to advancing therapies.

From a researchers perspective a well-designed study includes several components, the most important being controls. Some people believe that controls should undergo the same treatment regimen the individuals actually receiving the therapy undergo except for the actual treatment because this is the best way to compare to see whether the treatment itself was useful. Others believe that controls should be individuals at a similar disease state who do not receive the treatment. The need for controls in a good research design is important and I believe that all three levels should be assessed. In the article several studies found that individuals that just underwent surgery without getting any of the actual treatment had the same outcome as those who did. I believe that finding is important to know, and can help researchers to further pinpoint what parts of a therapy are beneficial. The ultimate goal of different research trials is to benefit the patient and any information that highlights that should be further studied.

In terms of “Placebo-controlled studies causing the downfall of potentially valuable treatments”, I think that this can be combated if these studies are used to further pinpoint components that are beneficial in therapies rather than obstruct further research. If these studies were used to further explore what occurred in the study and how it could be improved on and eventually used in the actual treatment they could benefit patients in the long run.

From a patients perspective an effective treatment alleviates some of the symptoms of their disease. I found it interesting in the article that both proponents and opponents of sham surgery were more interested in its “scientific” validity than in how it actually affected patients, I think a broader perspective should be adapted in trials to better serve patients. This can be seen from the patient tracked throughout the article who said “I just don’t see how they can call it a placebo effect after ten years.” Outcomes from these studies could and should be used to help patients.

In the article the cost of sham surgery was brought up, I think this is a moot point. There is a need for many different types of controls and expense should not be an issue that obstructs scientific endeavors. Trials should be designed to include as many components as necessary to answer a question, and not just cut out critical parts of this process due to funds.

Additionally, the point of unblinding studies was presented in the article. It was interesting to see that in studies that were unblinded patients that were in the placebo control group had a bad outcome after being told. This was cited for several studies. In medicine and ethics in general the number one rule is do no harm and so it is interesting to see that with these patients this was not the case. As quoted in the paper, “We just don’t know what the psychological effects of unblinding are.” Thus I think it is important that these trials not be unblinded unless there is a benefit to the patient in doing so.

I think as neuroscientist we play an important role in this argument. It is up to us to design research studies that will answer questions that will benefit patients. When we cease to do this we do a disservice to the patients we are trying to help. So although it is important to focus in on a certain issue within a study, it is critical to always keep a broader focus to see what effects our research has on people’s lives. It is also important to understand what our goals are in a study as well as what our participant’s goals are, this will help in ensuring that we maximize both.

--Mfon Umoh

Emory Neuroscience Graduate Program

In Defense of Sham Treatment

There is an ethical dilemma in neurosurgical trials regarding the use of sham surgeries as placebo controls. There have been countless instances of treatments that showed promise during preliminary trials, but failed to move past phase II clinical trials when the treatments proved ineffective compared to sham controls (Freed et al., 2001 & Olanow et al., 2003). The article “Why Fake It? How ‘Sham’ brain surgery could be killing off valuable therapies for Parkinson’s disease” discusses the issues regarding using shams in neurosurgical studies particularly in Parkinson’s disease.

There is one group that encourages the use of shams as the only true way to statistically prove that a treatment is effective. Without proper double blind, control studies, how can you move a drug past clinical trials and not be worried it won’t actually help anyone?

The other group discourages the use of shams arguing that they are expensive, yield abundant false negatives, and can potentially cause detriment to the patients. Sham controls needed in clinical trials are extremely expensive. Every part of the surgery needs to be identical for a sham except for drug infusion into the brain. Therefore, money is spent to bring the patient in, attach a stereotaxic frame to the skull, pay a full staff in the operating room complete with turning on machines to make noises present during surgery and drill holes into the skull of the patient. There are also huge hoops to jump through ensuring no one outside of the OR knows the treatment the patient received.

            Many treatments given in phase I trials to a handful of patients show promising results that then do not show effectiveness compared to controls in phase II trials. It is argued that sometimes it takes several years for treatments to become effective and that some treatments are being prematurely discredited because of these trials (Politis et al., 2010). Maybe if some of these trials were extended, more treatments might prove effective.

The last main argument is that there may be psychological effects of un-blinding that are detrimental to the patients. Some patients receive the sham and will need to be told at the end of the trial that they were not given the treatment. These patients may have been feeling better due to the placebo effect, where just the belief you could be getting an effective treatment helps you, but when told they did not get the treatment their condition can worsen due to different neurochemical effects. A benefit to consider is that if there were a positive effect of drug seen, these patients would already have the holes drilled needed to administer the drug at a later date. It is unfortunate that some patients may have negative effects of un-blinding, but all patients take a risk during a clinical trial that they will be given the placebo.

One reason this is being to fervently argued is that the placebo effect has especially strong effects in Parkinson’s patients. Sham treatments cause placebo effects in these patients because their expectation to receive treatment yields a release of dopamine in the brain, which is lacking in this disease state. This is why so many drugs are discredited. You cannot see an effect of the treatment if the placebo effect alone is contributing to fixing the issue in patients. Some doctors noted that they don’t want to include controls because they don’t want to exclude the placebo effect. It is, after all a natural part of treatment and any individual in a trial will show the effect of placebo because they do not know what their treatment was.

This article focused on the reasons to stop using shams, but I felt that some of these arguments leant themselves just as nicely to why we should continue to use sham controls. Just as the doctors argue that they do not wish to exclude placebo effects and therefore, do not wish shams, I believe that if we keep using shams to find out what treatments are most effective we may one day discover some combination of placebo and treatment that is doubly effective.

Secondly, doctors say all patients will show some placebo effect, even a patient taking a pill over the counter. They use this as an argument against shams, but I find it one of the better arguments to continue using them. If all patients have some placebo effect, and in phase I trials patients feel better, but in phase II trials the control and treatment groups are the same, you cannot argue that both groups were just experiencing the placebo effect. This is the only way to know for sure that the benefit your treatment is yielding is not due to the placebo effect.

However, I strongly believe if the treatment is ineffective and the placebo effect is the only reason patients are feeling better, treatment should continue with a placebo. Why perform treatment surgeries due to cost if the placebo works just fine? No one may need to purchase/manufacture that drug if sham patients are seeing real improvement. The placebo effect is a natural part of treatment and maybe sometimes its benefit alone is enough to help a very sick patient. Just treat with shams.

--Lauren DeBrouse

Neuroscience Graduate Program

The Ethics of Sham Surgery: Thoughts from a graduate student of neuroscience.

I am on my way to become a scientist. In this phase of my life I am finding out how to, as one of our ethics professors puts it, “tease apart the fabric of the universe!” It is an interesting journey! The pursuit of science has taught us much through the millennia: how to build great monuments to the sky, how to heal our sick, what lies beyond the stars, what lies within our minds, etc. Scientists before me have expanded the scope of that which is accomplishable today. More so, they have shifted the views of our selves, of each other, and of the space in which we live. With such an impactful pursuit, it is incumbent upon any who would practice science to perpetually consider the effects of each contribution. Likewise, the public must be mindful of their role in guiding the arm of research—through public opinion, financial support, and the law—and develop thoughtful stances on the topics of the day.

Let’s consider this topic: sham human neurosurgery in the study of treatments for Parkinson’s disease (PD). Writer Alla Katsnelson examines this debate in a 2011 article in Nature [1]. For our purposes, let’s first take a broad view of the relevant questions, then explore the details presented by Katsnelson and other authors, and finally see if we focus in on an informed opinion about how we should guide the development of this variety of clinical intervention.

The scientific method is strong in its capacity to reach clear and reproducible conclusions. By this methodology, scientists first propose a hypothesis about some facet of the universe’s operation. Then, a complete (as far as is known) battery of tests is conducted which seek to invalidate that hypothesis. If this hypothesis is still standing after such test, then people accept that the hypothesis works as far as we know. Simple.

And yet, in the debate at hand, scientists have shown a reluctance to use every method to knock down proposed PD treatments. Specifically, there is a widespread unwillingness to conduct sham neurosurgeries on human volunteers in order to rule out the placebo effect. Many researchers see this type of test as unnecessary, saying that the informative benefits of sham surgeries do not outweigh the costs to volunteers who undergo highly invasive surgeries or to the financial bodies that afford the study. Sham surgeries involve, at minimum, anaesthetization, attachment of a surgical frame onto a patient’s exposed skull, and the drilling of a through-hole onto the patient’s dura mater (the protective, membranous covering around the brain). The act of enrolling extra patients, the theatrics of a sham surgery, data collection, and follow up significantly increases the costs of clinical trials—trials that routinely reach $10 million. Furthermore, since these factors limit the size of such studies, it has been proposed that the inclusion of sham controls adds little value statistically. In the UK, opinions of the unnecessary quality of sham surgeries are so strong that none have ever been performed.

On the other hand, how can any study that makes to call itself science neglect to find out if the treatment is any more effective than healing wrought from the placebo driven expectation that the surgery does work? Is it justifiable to approve a treatment whose sole effect stems from a patient’s faith in modern medicine? Treatments for Parkinson’s highlights this concern perfectly as a primary neurochemical generated by the positive feelings associated with the placebo effect is exactly the same chemical used in pharmacological treatments of PD, dopamine.

And are the costs really as high as they seem? Katsnelson sites that the most notable risk of sham surgery is that associated with the use of general anesthesia that can exacerbate the problems of failing muscle control over the lungs and heart. However, a 2002 study in the British Journal of Anesthesia indicated a range of anesthetics that, given the limited information available, are “probably safe” [2]. As for the cost and statistical considerations, is any expenditure or analysis worth anything at all unless all necessary tests of the hypothesis are conducted? What’s more, since clinicians agree to provide the real treatment to volunteers serving a sham controls if the treatment proves effective, the costs of serving as a sham control are lowered further still.

In a 2005 survey of members to the Parkinson’s Study Group, a non-profit organization of North American physicians and health care professionals experienced in PD care and dedicated to PD research, 97% of respondents affirmed that leaving these questions unanswered is unjustified [3]. For these 91 out of 94 clinician researchers, the usefulness of sham-surgeries over unblinded controls was nearly unanimously affirmed. Likewise, serious doubts were levied as to whether neurosurgical interventions for PD can be considered truly efficacious unless it has withstood the sham-control test.

As I grow as a scientist, I will be ever moved towards delivering as complete an answer as I can to the hypothesis at hand. If a treatment works, I will want to know why it works and will not be content to know that it simply does. That is my task as a scientist. Still, each member of the scientific community must always temper this desire to know with ethical methods. And though it is inherently off putting to place a patient seeking a cure through a faux treatment, the benefits of finding a suitable therapy for PD are, in my opinion, worth the additional medical risks and financial burden of sham control testing. And unless new developments shift the scales of this cost/benefit analysis away from the side of greater benefits, you will find me in support of the continued use of sham surgeries as controls in the clinical testing of therapies for Parkinson’s disease.

--Jacob Billings

Neuroscience Graduate Program

References

1. Katsnelson, A., Experimental therapies for Parkinson's disease: Why fake it? Nature, 2011. 476(7359): p. 142-4.

2. Nicholson, G., A.C. Pereira, and G.M. Hall, Parkinson’s disease and anaesthesia. British Journal of Anaesthesia, 2002. 89(6): p. 904-916.

3. Kim, S.Y., et al., Science and ethics of sham surgery: a survey of Parkinson disease clinical researchers. Archives of neurology, 2005. 62(9): p. 1357-60.