Deep Brain Stimulation: Unproven treatment promoted with a conflict of interest in JAMA: Psychiatry [again]

“Even with our noisy ways and cattle prods in the brain, we have to take care of sick people, now,” – Helen Mayberg

“All of us—researchers, journalists, patients and their loved ones–are desperate for genuine progress in treatments for severe mental illness. But if the history of such treatments teaches us anything, it is that we must view claims of dramatic progress with skepticism, or we will fall prey to false hopes.” – John Horgan

An email alert announced the early release of an article in JAMA: Psychiatry reporting effects of brain stimulation therapy for depression (DBS). The article was accompanied by an editorial commentary.

Oh no! Is an unproven treatment once again being promoted by one of the most prestigious psychiatry journals with an editorial commentary reeking of vested interests?

Indeed it is, but we can use the article and commentary as a way of honing our skepticism about such editorial practices and to learn better where to look to confirm or dispel our suspicions when they arise.

Xray depictionLike many readers of this blog, there was a time when I would turn to a trusted, prestigious source like JAMA: Psychiatry with great expectations. Not being an expert in a particular area like DBS, I would be inclined to accept uncritically what I read. But then I noticed how much of what I read conflicted with what I already knew about research design and basic statistics. Time and time again, this knowledge proved sufficient to detect serious hype, exaggeration, and simply false claims.

The problem was no longer simply one of the authors adopting questionable research practices. It expanded to journals and professional organizations adopting questionable publication practices that fit with financial, political, and other, not strictly scientific agendas.

What is found in the most prestigious biomedical journals is not necessarily the most robust and trustworthy of scientific findings. Rather, content is picked in terms of its ability to be portrayed as innovative and breakthrough medicine. But beyond that, the content is consistent with prevailing campaigns to promote particular viewpoints and themes. There is apparently no restriction on those who might most personally profit being selected for accompanying commentaries.

We need to recognize that editorial commentaries often receive weak or no peer review. Invitations from editors to provide commentaries are often a matter of sharing nonscientific agenda and simple cronyism.

Coming to these conclusions, I have been on a mission to learn better how to detect hype and hokum and I have invited readers of my blog posts to come along.

This installment builds on my recent discussion of an article claiming remission of suicidal ideation by magnetic seizure therapy. Like the editorial commentary accompanying previous JAMA: Psychiatry article, the commentary discussed here had an impressive conflict of interest disclosure. The disclosure probably would not have prompted me to search on the Internet for other material about one of the authors. Yet, a search revealed some information that is quite relevant to our interpretation of the new article and its commentary.  We can ponder whether this information should have been withheld. I think it should have been disclosed.

The lesson that I learned is a higher level of vigilance is needed to interpret highly touted article-commentary combos in prestigious journals. Unless we are going to simply dismiss them as advertisements or propaganda, rather than a highlighting of solid biomedical science.

Sadly, though, this exercise convinced me that efforts to scrutinize claims by turning to seemingly trustworthy supplementary sources can provide a misleading picture.

The article under discussion is:

Bergfeld IO, Mantione M, Hoogendoorn MC, et al. Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online April 06, 2016. doi:10.1001/jamapsychiatry.2016.0152.

The commentary is:

Mayberg HS, Riva-Posse P, Crowell AL. Deep Brain Stimulation for Depression: Keeping an Eye on a Moving Target. JAMA Psychiatry. Published online April 06, 2016. doi:10.1001/jamapsychiatry.2016.0173.

The trial registration is

Deep Brain Stimulation in Treatment-refractory patients with Major Depressive Disorder.

Pursuing my skepticism by searching on the Internet, I immediately discovered a series of earlier blog posts about DBS by Neurocritic [1] [2] [3] that saved me a lot of time and directed me to still other useful sources. I refer to what I learned from Neurocritic in this blog post. But as always, all opinions are entirely my responsibility, along with misstatements and any inaccuracies.

But what I learned from immediately from Neurocritic is that BSD is a hot area of research, even if it continues to produce disappointing outcomes.

DBS had a commitment of $70 million from President Obama’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative . Premised on the causes of psychopathology being in precise, isolated neural circuitry, it is the poster children of the Research Domain Criteria (RDoC) of former NIMH director Thomas Insel. Neurocritic points to Insel promotion of “electroceuticals” like DBS in his NIMH Director’s Blog 10 Best of 2013:

The key concept: if mental disorders are brain circuit disorders, then successful treatments need to tune circuits with precision. Chemicals may be less precise than electrical or cognitive interventions that target specific circuits.

The randomized trial of deep brain stimulation for depression.

The objective of the trial was:

To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases.

Inclusion criteria were a diagnosis of major depressive disorder designated as being treatment resistant (TRD) on the basis of

A failure of at least 2 different classes of second-generation antidepressants (eg, selective serotonin reuptake inhibitor), 1 trial of a tricyclic antidepressant, 1 trial of a tricyclic antidepressant with lithium augmentation, 1 trial of a monoamine oxidase inhibitor, and 6 or more sessions of bilateral electroconvulsive therapy.

Twenty-five patients with TRD from 2 Dutch hospitals first received surgery that implanted four contact electrodes deep within their brains. The electrodes were attached to tiny wires leading to a battery-powered pulse generator implanted under their collar bones.

The standardized DBS treatment started after a three-week recovery from the surgery. Brain stimulation was continuous one week after surgery, but at three weeks, patients begin visits with psychiatrists or psychologists on what was at first a biweekly basis, but later less frequently.

deep brain stimulation teamAt the visits, level of depression was assessed and adjustments were made to various parameters of the DBS, such as the specific site targeted in the brain, voltage, and pulse  frequency and amplitude. Treatment continued until optimization – either four weeks of sustained improvement on depression rating scales or the end of the 52 week period. In the original protocol, this this phase of the study was limited to six months, but was extended after experience with a few patients. Six patients went even longer than the 52 weeks to achieve optimization.

Once optimization was achieved, patients were randomized to a crossover phase in which they received two blocks of six weeks of either continued active or sham treatment that involved simply turning off the stimulation. Outcomes were classified in terms of investigator-rated changes in the 17-item Hamilton Depression Rating Scale.

The outcome of the open-label phase of the study was the change of the investigator-rated HAM-D-17 score (range, 0-52) from baseline to T2. In addition, we classified patients as responders (≥50% reduction of HAM-D-17 score at T2 compared with baseline) or nonresponders (<50% reduction of HAM-D-17 score atT2 compared with baseline). Remission was defined as a HAM-D-17 score of 7 or less at T2. The primary outcome measure of the randomized, double-blind crossover trial was the difference in HAM-D-17 scores between the active and sham stimulation phases. In a post hoc analysis, we tested whether a subset of nonresponders showed a partial response (≥25% but <50% reduction of HAM-D-17 score at T2 compared with baseline).

Results

Clinical outcomes. The mean time to first response in responders was 53.6 (50.6) days (range, 6-154 days) after the start of treatment optimization. The mean HAM-D-17 scores decreased from 22.2 (95%CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) at T2.

An already small sample shrank further from initial assessment of eligibility until retention at the end of the cross over study. Of the 52 patients assessed for eligibility, 23 were in eligible and four refused. Once the optimization phase of the trial started, four patients withdrew for lack of effect. Another five could not be randomized in the crossover phase, three because of an unstable psychiatric status, one because of fear of worsening symptoms, and one because of their physical health. So, the randomized phase of the trial consisted of nine patients randomized to the active treatment and then the sham and another seven patients randomized to the sham and then active treatment.

The crossover to sham treatment did not go as planned. Of the nine (three responders and six nonresponders) randomized to the active-then-sham condition, all had to be crossed over early – one because the patient requested a crossover, two because of a gradual increase in symptoms, and three because of logistics. Of the seven patients assigned to sham- first (four responders and three nonresponders), all had to be crossed over within a day because of increases in symptoms.

I don’t want to get lost in the details here. But we are getting into small numbers with nonrandom attrition, imbalanced assignment of responders versus nonresponders in the randomization, and the breakdown of the planned sham treatment. From what I’ve read elsewhere about DBS, I don’t think that providers or patients were blinded to the sham treatment. Patients should be able to feel the shutting off of the stimulator.

Adverse events. DBS has safety issues. Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). Two nonresponders died several weeks after they withdrew from the study and DBS had been stopped (1 suicide, 1 euthanasia). Two patients developed full blown mania during treatment and another patient became hypomanic.

The article’s Discussion claims

We found a significant reduction of depressive symptoms following vALIC DBS, resulting in response in 10 patients (40%) and partial response in 6 (24%) patients with TRD.

Remission was achieved in 5 (20%) patients. The randomized active-sham phase study design indicates that reduction of depressive symptoms cannot be attributed to placebo effects…

Conclusions

This trial shows efficacy of DBS in patients with TRD and supports the possible benefits of DBS despite a previous disappointing randomized clinical trial. Further specification of targets and the most accurate setting optimization as well as larger randomized clinical trials are necessary.

A clinical trial with starting with 25 patients does not have much potential to shift our confidence in the efficacy of DBS. Any hope of doing so was further dashed when the sample was reduced to 17 patients who remained for the investigators’ attempted randomization to an active treatment versus sham comparison (seven responders and nine nonresponders). Then sham condition could not be maintained as planed in the protocol for any patients.

The authors interpreted the immediate effects of shifting to sham treatment as ruling out any placebo effect. However, it’s likely that shutting off the stimulator was noticeable to the patients and the immediacy of effects speaks to likelihood an effect due to the strong expectations of patients with intolerable depression having their hope taken away. Some of the immediate response could’ve been a nocebo response.

Helen Mayberg and colleagues’ invited commentary

The commentary attempted to discourage a pessimistic assessment of DBS based on the difficulties implementing the original plans for the study as described in the protocol.

A cynical reading of the study by Bergfeld et al1 might lead to the conclusion that the labor-intensive and expert-driven tuning of the DBS device required for treatment response makes this a nonviable clinical intervention for TRD. On the contrary, we see a tremendous opportunity to retrospectively characterize the various features that best define patients who responded well to this treatment. New studies could test these variables prospectively.

The substantial deviation from protocol that occurred after only two patients were entered into the trial was praised in terms of the authors’ “tenacious attempts to establish a stable response”:

We appreciate the reality of planning a protocol with seemingly conservative time points based on the initial patients, only to find these time points ultimately to be insufficient. The authors’ tenacious attempts to establish a stable response by extending the optimization period from the initial protocol using 3 to 6 months to a full year is commendable and provides critical information for future trials.

Maybe, but I think the need for this important change, along with the other difficulties that were encountered in implementing the study, speak to a randomized controlled trial of DBS being premature.

Conflict of Interest Disclosures: Dr Mayberg has a paid consulting agreement with St Jude Medical Inc, which licensed her intellectual property to develop deep brain stimulation for the treatment of severe depression (US 2005/0033379A1). The terms of this agreement have been reviewed and approved by Emory University in accordance with their conflict of interest policies. No other disclosures were reported.

Helen Mayberg’s declaration of interest clearly identifies her as someone who is not a detached observer, but who would benefit financially and professionally from any strengthening the claims for the efficacy of DBS. We are alerted by this declaration, but I think there were some things that were not mentioned in the article or editorial about Helen Mayberg’s work that would influence her credibility even more if they were known.

Helen Mayberg’s anecdotes and statistics about the success of DBS

Mayberg has been attracting attention for over a decade with her contagious exuberance for DBS. A 2006 article in the New York Times by David Dobbs started with a compelling anecdote of one of Mayberg’s patients being able to resume a normal life after previous ineffective treatments for severe depression. The story reported the success with 8 of12 patients treated with DBS:

They’ve re-engaged their families, resumed jobs and friendships, started businesses, taken up hobbies old and new, replanted dying gardens. They’ve regained the resilience that distinguishes the healthy from the depressed.

Director of NIMH Tom Insel chimed in:

“People often ask me about the significance of small first studies like this,” says Dr. Thomas Insel, who as director of the National Institute of Mental Health enjoys an unparalleled view of the discipline. “I usually tell them: ‘Don’t bother. We don’t know enough.’ But this is different. Here we know enough to say this is something significant. I really do believe this is the beginning of a new way of understanding depression.”

A 2015 press release from Emory University, Targeting depression with deep brain stimulation, gives another anecdote of a dramatic treatment success.

Okay, we know to be skeptical about University press releases, but then there are the dramatic anecdotes and even numbers in a news article in Science, Short-Circuiting Depression that borders on an infomercial for Mayberg’s work.

short-circuiting depression

Since 2003, Mayberg and others have used DBS in area 25 to treat depression in more than 100 patients. Between 30% and 40% of patients do “extremely well”—getting married, going back to work, and reclaiming their lives, says Sidney Kennedy, a psychiatrist at Toronto General Hospital in Canada who is now running a DBS study sponsored by the medical device company St. Jude Medical. Another 30% show modest improvement but still experience residual depression. Between 20% and 25% do not experience any benefit, he says. People contemplating brain surgery might want better odds, but patients with extreme, relentless depression often feel they have little to lose. “For me, it was a last resort,” Patterson says.

By making minute adjustments in the positions of the electrodes, Mayberg says, her team has gradually raised its long-term response rates to 75% to 80% in 24 patients now being treated at Emory University.

A chronically depressed person or someone who cares for someone who is depressed might be motivated to go on the Internet and try to find more information about Mayberg’s trial. A website for Mayberg’s BROADEN (BROdmann Area 25 DEep brain Neuromodulation) study once provided a description of the study, answers to frequently asked questions, and an opportunity to register for screening for the study. However, it’s no longer accessible through Google or other search engines. But you can reach an archived website with a link provided by Neurocritic, but the click links are no longer functional.

Neurocritic’s blog posts about Mayberg and DBS

If you are lucky, a Google search for Mayberg deep brain stimulation, might bring you to any of three blog posts by Neurocritic [1] [2] [3] that have rich links and provide a very different story of Mayberg and DBS.

One link takes you to the trial registration for Mayberg’s BROADEN study: A Clinical Evaluation of Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression. The updated file registration indicates that the study will end in September 2017, and that the study is ongoing but not recruiting participants.

This information should have been updated, as should other publicity about Mayberg’s BROADEN study. Namely, as Neurocritic documents, the company attempting to commercialize DBS by funding the study, St. Jude Medical terminated after futility analyses indicated that further enrollment of patients had only a 17% probability of achieving a significant effect. At the point of terminating the trial, 125 patients had been role.

Neurocritic also provides a link to an excellent, open access review paper:

Morishita T, Fayad SM, Higuchi MA, Nestor KA, Foote KD. Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics. 2014 Jul 1;11(3):475-84.

The article reveals that although there are 22 published studies of DBS for treatment-resistant depression, only three are randomized trials, one of which was completed with null results. Two – including Mayberg’s BROADEN trial – were discontinued because futility analyses indicate that a finding of efficacy for the treatment was unlikely.

Finally, Neurocritic  also provides a link to a Neurotech Business Report, Depressing Innovation:

The news that St. Jude Medical failed a futility analysis of its BROADEN trial of DBS for treatment of depression cast a pall over an otherwise upbeat attendance at the 2013 NANS meeting [see Conference Report, p7]. Once again, the industry is left to pick up the pieces as a promising new technology gets set back by what could be many years.

It’s too early to assess blame for this failure. It’s tempting to wonder if St. Jude management was too eager to commence this trial, since that has been a culprit in other trial failures. But there’s clearly more involved here, not least the complexity of specifying the precise brain circuits involved with major depression. Indeed, Helen Mayberg’s own thinking on DBS targeting has evolved over the years since the seminal paper she and colleague Andres Lozano published in Neuron in 2005, which implicated Cg25 as a lucrative target for depression. Mayberg now believes that neuronal tracts emanating from Cg25 toward medial frontal areas may be more relevant [NBR Nov13 p1]. Research that she, Cameron McIntyre, and others are conducting on probabilistic tractography to identify the patient-specific brain regions most relevant to the particular form of depression the patient is suffering from will likely prove to be very fruitful in the years ahead.

So, we have a heavily hyped unproven treatment for which the only clinical trials have either been null or terminated following a futility analysis. Helen Mayberg, a patent holder associated with one of these trials was inappropriate to be recruited for commentary on another, more modestly sized trial that also ran into numerous difficulties that can be taken to suggest it was premature. However, I find it outrageous that so little effort has been made to correct the record concerning her BROADEN trial or even to acknowledge its closing in the JAMA: Psychiatry commentary.

Untold numbers of depressed patients who don’t get expected benefits from available treatments are being misled with false hope from anecdotes and statistics from a trial that was ultimately terminated.

I find troubling what my exercise showed might happen when someone who is motivated by the skepticism goes to the Internet and tries to get additional information about the JAMA: Psychiatry paper. They could be careful to rely on only seemingly credible sources – a trial registration and a Science article.  The Science article is not peer-reviewed but nonetheless has a credibility conveyed appearing in the premier and respected Science. The trial registration has not been updated with valuable information and the Science article gives no indication how it is contradicted by better quality evidence. So, they would be misled.

 

 

17 thoughts on “Deep Brain Stimulation: Unproven treatment promoted with a conflict of interest in JAMA: Psychiatry [again]”

  1. The intervention in the Dutch study was stimulation of the anterior limb of the internal capsule. It is puzzling that this same site has been a target of ablative surgery for refractory depression (http://dx.doi.org/10.1038%2Fnpp.2010.132). Neither the Dutch authors nor Helen Mayberg commented on this issue. Underlying the apparent contradiction is the question whether the mood circuits need to be activated or inhibited by the interventions to obtain a positive response. As best I can tell, none of those authors knows the answer to this fundamental question.

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  2. While this article is riddled with factual errors and dubious conclusions, I will limit my comments to two issues. First, I can assure you based on personal experience that DBS patients do NOT feel anything physical when the stimulator is turned turned off or on. Second, it is completely erroneous to claim that the BROADEN study was Dr. Mayberg’s. Based on her work – yes; “Dr. Mayberg’s BROADEN study” – no. It was a clinical trial run by St. Jude Medical.

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    1. Individual experiences with DBS differ greatly even under seemingly identical clinical conditions. Patient testimonials used to promote DBS cite an immediate pleasurable response when stimulation is turned on. The JAMA: Psychiatry article reports that all patients crossed over to sham condition had a negative response within a day. Neither the investigators nor I know how DBS might work or if it does, but a response within a day is extraordinary for any conventional treatment for depression. It would usually be interpreted as a placebo response. In the case of DBS, the worsening might be interpreted as a nocebo response.

      BROADEN is an industry funded trial and the company terminated the trial before the FDA could. Sid Kennedy is listed in the popular press as having run the trial. He was a colleague and collaborator of Mayberg before she left her for Emery. She has continued to commute back to Toronto for DBS studies.

      But, regardless, BROADEN was stopped in 2013, yet there’s been no update to the trial registration. There is no mention of this large trial having been terminated in either the main DBS article or in Mayberg’s commentary. Don’t you think that MayberryMayberg had a responsibility to acknowledge that BROADEN had been stopped after futility analyses, particularly when there was no mention in the main article? We may have moved into the realm of advertising, not transparent biomedical science, but we should still insist on standards of accuracy and transparency for JAMA: Psychiatry.

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      1. Quoting from Neuorcritic: “I can’t be sure, but I think this is the study in ClinicalTrials.gov – A Clinical Evaluation of Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression. The sponsor is St. Jude Medical”

        This is not the BROADEN study. Nor did Sid Kennedy run the BROADEN trial, regardless of what might have been said in the popular press; Toronto was not a cite for this study.

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    2. I’ve spent hours and hours searching for information on the BROADEN trial, and it’s remarkable how little is out there. There is NO registration in ClinicalTrials.gov.

      In one of my posts on the topic I said: “But it was hard to find any other information about the failed trial. I can’t be sure, but I think this is the study in ClinicalTrials.gov -– A Clinical Evaluation of Subcallosal Cingulate Gyrus Deep Brain Stimulation for Treatment-Resistant Depression. The sponsor is St. Jude Medical. The record hasn’t been updated since March 2013.”

      I now believe this is incorrect. This Toronto-based trial was sponsored by St. Jude Medical, but it’s not the BROADEN study. The original three sites for BROADEN were Chicago, Dallas, and New York. But it’s impossible to find a list of the other 12-17 sites. Through university press releases, I’ve been able to locate UMass Medical School, Albany Medical Center, and Dartmouth.

      Dr. Mayberg was not directly involved in the BROADEN trial, but it was based on her work, according to the archived FAQ:

      “The study will build upon the depression work of a research team from the University of Toronto, led by neurologist Helen S. Mayberg, M.D. and neurosurgeon Andres Lozano, M.D., PhD, FRCSC.”

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    1. My speech recognition software keeps getting it confused, but maybe it is getting it right. We are dealing with a promotion of an unproven medical device and the regulation seemed about as inept as what Deputy Barney Fife (Don Knotts) accomplished in the fictitious community of Mayberry North Carolina.

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      1. In the 19th century, Phrenology flourished with a resolution of 5 cm. Nowadays psychiatry is hoping that brain imaging with a resolution of 5 mm will spill out some deeper truth to them.
        Unfortunately, important invisible things are happening a billion times smaller at the submicron level. Brain scans are like using aerial photographs of Wall Street to make investment decisions. The brain is not scalable and analysing the paint pigments will not yield up a sense of Mona Lisa’s smile. After abandoning Freud, Psychiatry became a prescription pad science filled with dancing neurotransmitters (read “Blaming the Brain” by Eliot Valenstein for a detailed analysis). Serotonin became their obsession. Now they want to throw switches and “cure” with force fields.
        When the baboons first start circling the “Medical Obelisk”, the ones with troubled expressions and scruffy hair gravitate into Psychiatry and avoid all the messy details of cellular biology and receptor signalling mechanics.

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  3. Bernardino mentions the still unsettled question of to stimulate or to dampen the circuitry. I’m immediately reminded of the boy and his new hammer. Unlike with chemicals, we don’t have any idea for unhammering things, which makes any damping by stimulation a twice removed action from the system’s own activity, or perhaps impossible to even locate “precisely”.

    “Precisely” leads to my other issue. These deliver “continuously” says a diagram. To some degree there is a field surrounding the leads. The only acknowledged e.m. effect is the electric discharge at the tip. Yet extracellular flows are subjected to a continuous, foreign magnetic field that acts on diffusion according to all the specifics of wt. and polarity. Can this be negligible as a source of nocebo? You certainly can’t put a brain with wires in for fmri or diffusion tensor photos. I would have run current through the sham wire but not allowed electric leakage by exposing tissue to an uninsulated tip.

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  4. I wanted to comment on the science, but couldn’t help articulate my feelings on the tone of the article first.

    I generally appreciate the spirit of healthy skepticism, particularly in clinical environments and cases when potential conflicts of interest are in play. However, my personal opinion is that your article goes beyond these general topics and becomes overly critical of a scientific topic you admit to have only studied cursorily. This is a very complicated and difficult topic with many moving parts, including but not limited to the biophysics of both endogenous electrical activity and exogenously applied stimulation, neuroanatomy of cortical tissue and connectivity, and of course the complex and poorly understood etiology and mechanisms of psychiatric disorders. You and others are absolutely correct to be worried about these more technical details, but you should also not be too quick to condemn people in the best position to get us answers on these matters, especially when the majority of your knowledge on DBS seems to be based on someone else’s blog posts. If you simply wanted to discuss inappropriate editorials and conflicts of interest and leave it at that, it’s fine to survey introductory material (Neurocritic’s posts are usually an excellent place to start). However, if you aim to criticize the science and make such bold and inflammatory claims in the name of what’s best for patients, I expect you to have gained a deeper understanding of the topic by reading the primary literature, not just blogs and press releases. Again, you make some valid and important points on tough topics (e.g., disclosure, design of clinical trials, etc.), but they are lost in your over zealous tone. (Also, the poor editing doesn’t help.)

    Regarding electrophysiology, animal researchers studying much simpler neuroarchitectures than the human brain using completely optimized recording equipment and environments (impossible in humans for many reasons) are very far from a mechanistic understanding of the electrical fields in the brain. This makes it extremely challenging to know or predict how artificial, externally applied fields will interact with and affect endogenous activity, which is why we have no clue how any neurostimulation techniques (e.g., DBS, TMS, tDCS, tACS, etc.) work and whether local populations are excited or inhibited or likely some combination thereof, much less how patients will respond.

    Regarding the mechanisms and efficacy of DBS for depression, I’ve talked to researchers working with Dr. Mayberg at Emory and indeed, their understanding of how the treatment works and the factors affecting outcome has unsurprisingly evolved since their initial trials. They believe that stimulating three important white matter tracts that pass through the subcallosal cingulate (not necessarily the local gray matter) is critical to success. It is very difficult to locate those tracts and position the electrode to target all of them and requires advanced multimodal imaging (fusing anatomical, diffusion, and functional MRI), and they believe the lack of expertise in this part of the operation is preventing other centers from replicating their success in clinical trials. Ethical concerns aside, this is why Jayne’s point about exactly who is running the trials like BROADEN matters. I would very much like to see statistics on the success rates at Emory in recent studies (they didn’t have this understanding in the early trials) versus at other centers, as well as which centers are mapping white matter tracts to target electrode placement.

    My own disclosure is that I am a researcher working with intracranial recordings from epilepsy patients on unrelated topics. My only ties to any of this work are meeting and conversing with colleagues that work with the Emory DBS group.

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    1. Thank you, Collin, for weighing in on what we agree is an important topic. My blog post is one in a series in which I invite readers to join me in examining reports of clinical trials appearing in prestigious medical journals with invited editorial commentaries, recognizing that the commentaries do not receive full peer review.

      I don’t assume that my readers will have the technical background to evaluate specific claims of a more technical nature. However, the articles and commentaries are in prestigious and generalist journals with readerships who mostly lack such backgrounds. On the other hand, most readers of these journals would have some background in the design, interpretation, and ethics of clinical trials. I encourage them to rely on this knowledge, along with a look at some basic numbers, as the basis of evaluating the articles.

      In the case of this particular JAMA: Psychiatry article, we faced with a clinical trial planned for 25 patients that suffered considerable deviations from protocol, including a substantial lengthening of the “optimization” period and a sham comparison control group that had to be prematurely abandoned within a day for all patients receiving it. Furthermore, a lower proportion of responders and higher attrition than expected led to only 17 patients randomized to the crossover trial, including 9 nonresponders who were unevenly distributed.

      Questions can reasonably be raised about why this article was accepted by JAMA: Psychiatry. Why was it deemed worthy of comment?

      I think your comment bolsters my argument that whatever promise deep brain stimulation (DBS) seems to hold, a randomized trial of the sort reported in JAMA: Psychiatry is premature because important technical details have not being settled and the feasibility of a sham/comparison group has not being established.

      In order to evaluate the conflict of interest statement by the author of the editorial commentary, I searched for Helen Mayberg on both Google Scholar and Google. What was immediately apparent was that there was a lack of peer-reviewed sources for claims that she was making for the success of. Some strong claims were made in Science for the efficacy of this treatment, but in a non-peer-reviewed commentary.

      I stumbled upon Neurocritic’s previous blog post about Mayberg and DBS. I followed up on his suggestion that the BROADEN trial was associated with a specific trial registration. I carefully searched for possible alternatives before settling on the one Neurocritic proposed. He and I both now acknowledge that we were wrong. However, I think our mistake points to a more serious problem. Namely a large-scale trial, perhaps the largest ever of DBS is not registered and having no record of it being terminated as a result of a futility analysis, except for announcements in trade journals. The trial website has been disabled without explanation.

      I appreciate the reasons that you support Helen Mayberg and consider my criticisms of her unfair and ill-informed. However, I ask whether you agree that she should have acknowledged the closing of the BROADEN trial in her commentary. Maybe you would even agree that she was not the best person to be providing an editorial commentary because of her declared and undeclared vested interests. Finally, would you agree that claiming high rates of success for DBS without documentation from peer-reviewed studies is premature and inappropriate, particularly given the necessity of the large-scale BROADEN study having been terminated?

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  5. I think DBS could work for people with anorexia, as anorexia can be fatal. The extreme method of brute force turning on and turning off sections of the brain is inherently physically dangerous, but better than death.
    I question the methods of electrical brain stimulation/suppression to achieve benefits.
    I believe they use a constant stimulation, where a patient or a certain circumstance could one time stimulate or suppress brain function. For example when about to eat , the DBS is turned on to suppress cognitive anxiety. The choice to vomit or purge after eating might also have to be electrically suppressed.
    BUT the device controls should be in the hands of the patient, not those watching them.

    If the patient does not want to get well, there is little science can do.

    DBS is proven to work in Parkinson’s disease as the device is always on to stop the patient from shaking, this method might be changed to intermittent stimulation for mental illnesses.

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  6. On the topic of patients supposedly not noticing the switching off of the stimulator: The senior author of the JAMA Psychiatry paper, prof. Denys, gives public demonstrations of patiens becoming acutely depressed if their neurostimulator is switched off.

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  7. See the 7th comment in this thread by Berger on May 4th noting cronyism and conflict of interest in JAMA psychiatry who is putting out bad clinical trial science, and where the author Hollon is staff member of the Editor in Chief JAMA Dr. Heckers:

    http://retractionwatch.com/2016/04/21/authors-retract-replace-highly-cited-jama-psych-paper-for-pervasive-errors/

    Heckers then, in blatant cronyism, blocked a paper by myself submitted to JAMA psychiatry that was critical of the Hollon paper for making conclusions without any double-blinding in a subjective endpoint trial, and in spite of the Berger paper being praised by the independent reviewers quoted in the link above. Oh, we shouldn’t forget to mention that Thase who editorially praised Hollon in JAMA has been a co author with him on similar papers in the past, and more so, not to forget the fact that this paper was later retracted and repaired for sloppy data collection (whew, thats a lot of bad news to pack in a small box.

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  8. Have been reading and wanted to add in some simple facts:
    1: With regards to the trial carried out in multiple countries by St Jude Medical; why is it that no results have been released to date?
    2: Why is it that despite knowing of a multitude of adverse events suffered by a lot of patients who were part of this trial, that St Jude has not published any to the FDA?
    3: Why is it that the FDA have failed to police this blatant disregard for what is a legal requirement for disclosure?
    4: Why have over 200 patients been left with no support, no answers and ongoing side affects from this surgery?
    5: Exploratory brain surgery as part of a clinical trial should not be permitted when the experts themselves cannot definitively state how it actually works (or doesn’t)
    6: Clinical trials carried out by the likes of St Jude’s Medical, should not preclude them from doing what is right morally and also should not give them a level of protection from disclosure or legal recourse.
    7: Helen Mayberg has patented DBS for area 25 and has a financial stake in EVERY procedure carried out globally. How many neurologists can actually claim total independence and put their hands on their hearts and say they have never received any form of inducement, be it paid flight for a seminar, product etc etc from these global giants?

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