04 Jun 2010

This is the epilogue to a four-part series on DBS. See Part 1, Part 2, Part 3, and Part 4.

4 June 2010. Deep-brain stimulation looks to become popular for a number of neurological and psychological disorders, even as some of the scientific evidence remains scattered and spotty. In psychiatric applications, in particular, many papers report on only a single case study. Scientists have debated the best way to glean accurate information from such limited reports in the commentary pages of the Journal of the American Medical Association over the past few months. A dose of good news came this week on the neurodegeneration side, when researchers reported in the New England Journal of Medicine that either of two potential stimulation sites for Parkinson disease works equally well.

The Threat of Single-Case Reports
Researchers and surgeons are trying DBS for conditions such as obsessive-compulsive disorder and depression (see Part 3). However, the relevant literature includes many single-case reports, said Thomas Schlaepfer of the University Hospital in Bonn, Germany. In addition, some reports highlight secondary outcomes even when the primary outcome is not achieved (e.g., Hamani et al., 2008). Schlaepfer’s concern is that when the outcome is not related to the original goal, the study is not properly controlled and subjects might have other conditions that skew results. “There is a danger that the field might be damaged by these kinds of reports,” Schlaepfer told ARF. Single case studies could prompt doctors to use treatments that remain unproven in controlled clinical studies. And since negative results generally go unreported, it might take a few years for the field to realize that a particular treatment simply does not work.

Schlaepfer, along with Joseph Fins of the Weill Cornell Medical College in New York contributed a commentary to the February 24 JAMA suggesting that this publication bias could lead scientists and doctors in the wrong direction. When researchers publish uncontrolled single-case studies, and journals accept them, journalists naturally cover the results and readers develop hopes that may be unrealistic, Schlaepfer said. “This overhyping of DBS is dangerous,” Schlaepfer said, because it could lead to unethical trials where people receive therapy that is unlikely to work or may cause unexpected side effects.

In the June 2 JAMA, Dieneke Hubbeling of the South West London and St. George’s Mental Health Trust in the UK responded with a letter to the editor noting that single-case reports have plenty of value. “Serendipitous case studies have been important in the history of medicine, for example, in the discovery of penicillin,” Hubbeling noted in the letter. Hubbeling suggested that for studies with a single subject, researchers could shore up their conclusions by comparing the on- and off-stimulation state, switching between the two without telling the DBS recipient which is which. In this “n-of-1 sham-controlled” design, an increase in symptoms with the removal of the stimulation would be at least some evidence for cause and effect, Hubbeling wrote.

Schlaepfer and Fins, in a response to Hubbeling’s letter, asserted that single-case studies should lead to a full-scale clinical trial. “Anything less deprives society of the potential benefits of scientific inquiry and is exploitative of participants because it places them in less-than-fully-powered clinical trials,” they wrote. As a solution, in their original commentary Fins and Schlaepfer called for a registry, similar to the National Institutes of Health’s ClinicalTrials.gov, in which all single-case studies would enter their results and side effects—positive or negative. In fact, Schlaepfer said, it would be easy and inexpensive to piggyback such a registry onto the system NIH already has in place. “It would be a no-brainer to add DBS research and trials,” he told ARF. At present, there is no system in place to encourage and record reporting of single-case and negative results.

STN Versus GPi: It’s a Tie
In the Parkinson’s field, where DBS has its roots, scientists have long wondered whether the subthalamic nucleus (STN) or globus pallidus internal segment (GPi) is the better target to subdue motor symptoms. Researchers with the Veterans Affairs Cooperative Studies Program 468 study, a multicenter group, report their answer in the June 3 New England Journal of Medicine. They performed DBS on 299 people with Parkinson disease, half receiving STN stimulation and half receiving signals targeted to the GPi. This continuing study has already shown DBS works better than medical treatment (see ARF related news story on Weaver et al., 2009).

Overall, the STN and GPi groups gained the same relief of motor symptoms. People with STN stimulation lost a bit of speed in processing and acting on visual information. They also experienced a slight worsening of depression, while GPi subjects enjoyed mildly improved mood. On the plus side for STN recipients, they were more likely to be able to reduce their medication. Overall, quality of life was comparable for both groups, the authors write, and doctors and patients can choose the appropriate target based on non-motor considerations such as medication levels.—Amber Dance

This is the epilogue to a four-part series on DBS. See Part 1, Part 2, Part 3, and Part 4.

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References

News Citations

1. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD 21 May 2010
2. Deep-Brain Stimulation: Steadies the Body, But What About the Mind? 24 May 2010
3. Deep-Brain Stimulation: An Electrode for All Occasions? 25 May 2010
4. Deep-Brain Stimulation: There’s Still Room for Improvement 26 May 2010
5. PD Studies Highlight Deep Brain Stimulation, New Role for α-Synuclein 9 Jan 2009

Paper Citations

1. Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, Wennberg RA, Lozano AM. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol. 2008 Jan;63(1):119-23. PubMed.
2. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD, . Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7;301(1):63-73. PubMed.

Further Reading

Papers

1. Awan NR, Lozano A, Hamani C. Deep brain stimulation: current and future perspectives. Neurosurg Focus. 2009 Jul;27(1):E2. PubMed.
2. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008 Sep 15;64(6):461-7. PubMed.
3. Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, Scott R, Ives N, Rick C, Daniels J, Patel S, Wheatley K, . Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 2010 Jun;9(6):581-91. PubMed.
4. Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Optical deconstruction of parkinsonian neural circuitry. Science. 2009 Apr 17;324(5925):354-9. PubMed.
5. Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE, Wang X, Gordon CW, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD. Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol. 2009 May;65(5):586-95. PubMed.
6. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, Daniels C, Deutschländer A, Dillmann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R, Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D, Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A, Steude U, Sturm V, Timmermann L, Tronnier V, Trottenberg T, Wojtecki L, Wolf E, Poewe W, Voges J, . A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006 Aug 31;355(9):896-908. PubMed.

News

1. Deep-Brain Stimulation: There’s Still Room for Improvement 26 May 2010
2. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD 21 May 2010
3. PD Studies Suggest Motor Cortex as Treatment Target 19 Mar 2009
4. Parkinson Therapies Go Deep and Shallow 8 Dec 2004
5. PD Studies Highlight Deep Brain Stimulation, New Role for α-Synuclein 9 Jan 2009
6. Deep-Brain Stimulation: An Electrode for All Occasions? 25 May 2010
7. Deep-Brain Stimulation: Steadies the Body, But What About the Mind? 24 May 2010