Tag Archives: DBS

11/22/22

Brain Stimulation or Brain Damage? Part 2

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On Valentine’s Day 1974, British doctors destroyed sections of Derek Hutchinson’s hypothalamus without his consent. Surgeons drilled two holes into his forehead and then sent a wire with an electrical tip deep into his brain. Before the right and left sides of the targeted area of his hypothalamus was burned for thirty seconds each, the surgeon test-stimulated his brain with five to ten volts of electricity to see whether the targeted area of his brain actually controlled emotions, and not pathways crucial to motor functions like walking, talking and breathing. They asked him if he was frightened or angry and he yelled, “Stop it, or I’ll kill you.” Then they proceeded to destroy the targeted areas of his hypothalmus.

As Danielle Egan related in her article, Derek had an hypothalomotomy, a psychosurgery procedure first developed in the 1950s to curb aggressive behavior. Over the next two decades he had repeated overdoses and hospital stays during which he received ECT. At some point, he attacked one of his psychiatrists, but no charges were filed against him. After his wife gave birth to twins, he threatened her with a gun. He met his current wife in a pub and they were married in 1982. He’s struggled with bouts of depression, impotence, insomnia, extreme fatigue and rage since the surgery. “He’s had eight heart attacks, two strokes, has battled anorexia (the hypothalamus also regulates hunger, blood pressure and hormones) and has tried to kill himself seven times.”

An MRI revealed extensive damage to his hypothalamus. They told him “Half of your hypothalamus is gone.” He said that was when he finally woke up. These days Hutchinson is an activist against the use of psychosurgeries and deep brain stimulation (DBS). He thinks psychosurgery should be banned outright and believes mental disorders are caused by an individual’s unique life experiences, and are not a product of a dysfunctional brain.

We must put an end to this immoral, unethical activity being conducted in the name of mental health research… These doctors are guinea-pigging innocent people. These surgeries should never have been invented. They kill the person and they don’t even know they’re not the same person anymore.

There are clear differences between the hypothalomotomy done to Derek Hutchinson and DBS, which seeks to electrically stimulate specific areas of the brain, not destroy them. However, the adverse effects are similar. In another article for Mad in America on DBS, Egan noted that numerous studies have documented serious adverse mood behavior and personality effects. “These include suicide, depression, apathy, fatigue, mania and serious impulse control issues, such as hypomania, aggression, addiction (to gambling, shopping, drugs, alcohol) and hypersexuality, sometimes resulting in criminal behaviour, including pedophilia.” See “Deep Brain Problems” for more on the adverse effects with DBS.

Andrew Scull described the results of two double-blind studies of DBS for depression. The first one by Dougherty et al was prompted by encouraging response rates in multiple open-label DBS trials. But there was not a significant difference in response rates between the active and control groups. “Our results … failed to demonstrate a significant difference between the active and sham-controlled groups during the blinded phase of the study.” Even worse, adverse events were more frequent in the active group than in the control group for worsening depression, insomnia, irritability, suicidal ideation, hypomania, disinhibition and mania.

There was even one completed suicide in the active treatment group. However, it occurred after the person stopped treatment because of a failure to improve and was awaiting removal of the electrodes. “The authors decided that that adverse event did not count!” Notice that the second listed author of this study, Ali Rezai, would later emerge as the lead investigator for the first U.S. clinical trial of DBS for heroin described in Part 1 of this article.

The second trial was conducted by Helen Mayberg and Andres Lozano, who are both well known supporters of DBS, and a couple dozen others. Again, there was no statistically significant difference between the stimulation group and the control group. Scull reported the researchers anticipated those receiving active stimulation would improve twice as much. Both the treatment and the placebo groups improved, but the improvement was slight and not statistically significant.

Thus, once put to a controlled test, the claims for deep brain stimulation as a treatment for depression resoundingly failed. The purely speculative and fanciful biological “theory” of depression on which the intervention rested had not produced the anticipated results.

Then in October of 2019, Mayberg published another DBS study, claiming the procedure was generally safe and well tolerated. “The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications.” Oh, and there were no completed suicides. Yet Andrew Scull pointed out five of the small sample of 28 individuals dropped out after 1, 2, 5, 8 and 11 years. There were 56 adverse events. One patient experienced ten of them and had the electrodes removed after two years and dropped out of the study.

What are we talking about here? Nineteen of the events involved the surgery going wrong in a variety of major ways. Six infections resulted from the brain surgery. Six patients had to have the original device “explanted,” as the authors put it, because the wires caused an infection (3 cases), failed to work (2 cases), or the crude targeting of the device needed adjusting (1 case). Another patient experienced hemorrhage of the cortex and a post-operative seizure. The device failed in 15 cases. There is no further discussion of these iatrogenic disasters, or the suffering they entailed. And then, finally, there were the serious psychiatric sequelae. Fourteen of the twenty-eight patients required re-detention in a psychiatric hospital, one on seven occasions, including five admissions occasioned by suicide attempts.

Despite the above reported adverse events, Helen Mayberg’s assessment of DBS is that it appears to be “generally safe and well tolerated.” Although the DBS studies failed to show any real efficacy with treatment-resistant depression, Mayburg concluded most participants had “a robust and sustained antidepressant response.” Andrew Scull pointed out many of the authors were indebted financially to the medical device manufacturer and that Mayburg owned patents covering the devices in question. Further, he said Mayberg et al “cherry-picked data” for their study. Positive outcomes only appeared when researchers self-assessed the results of their interventions. “Ambitious clinicians let loose in such a situation can easily be carried away by their enthusiasms, and the restraints on experimentation, while stronger than they once were, remain inadequate.”

Scull had a different take on the first-in-the-U.S. clinical trial for treatment resistant opioid use disorder described in Part 1. He pointed out the false impression given by saying the DBS device functioned much like a heart pacemaker. The human brain is not a simple pump. And despite all the progress of neuroscience over the past fifty years, our understanding of it is still primitive. “The idea of a ‘brain pacemaker’ is so ludicrous on its face as to disqualify anyone who uses it.” The analogy appears to rely on the now generally disparaged “chemical imbalance” theory of depression, as evident in the following statement:

By sending a pulsed current through the electrodes, doctors believe they can regulate an imbalance in Buckhalter’s reward circuitry.

Ali Rezai, the doctor leading the clinical trial, readily acknowledged they don’t fully understand how this works. However, they hope that by modulating the rewards circuit, which relies on the chemical messenger dopamine, “you’re getting better control, so you’re not craving dopamine as much.” This suggests DBS for opioid misuse is more explorative and experimental than it is a promising type of treatment. Scull commented: “The prattle about dopamine that he proceeds to utter as a substitute for the scientific evidence we do not possess is an embarrassment — just speculation plucked out of thin air.”

In The Science of Addiction, Carleton Erickson said scientists once held that dopamine was the “pleasure transmitter.” He said this is a simplistic explanation of severe SUD—substance use disorder. Addiction is more than seeking of pleasure or avoiding pain or withdrawal. In addition to the nucleus accumbens (part of the brain’s pleasure or reward system), recent neurobiological findings and theories extend to areas of the brain the modulate meaning and emotional and cognitive memory. “Some drugs appear to be capable of affecting these adjunctive brain areas to transition drugs from pure pleasure to habitual use to severe SUD, where pleasure or pain is no longer important in maintaining drug-taking behavior.”

Reflecting on the continuing pursuit of brain stimulation with transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS) and invasive, deep brain stimulation (DBS), I am reminded of a two-hundred-year-old novel that Mary Shelly anonymously published on January 1, 1818, The Modern Prometheus; or Frankenstein. Shelley told her story within a literary technique known as a frame narrative—a story within a story. In the frame story, Captain Robert Walton and his crew set out to explore the North Pole sometime in the 18th century in order to expand scientific knowledge and hopefully achieve fame. They glimpsed a dog sled driven by a gigantic figure, but it disappeared into the snow. A few hours later, they found a frozen and emaciated Victor Frankenstein, who had been in pursuit of the gigantic creature.

Victor recognizes the same obsession in Walton that drove him to modern laboratory experimentation and creation of the “fiend.” As a warning to Walton, he then recounts the story of his life’s miseries that were a consequence of his obsession. With his last words, he told Walton to seek “happiness in tranquility and avoid ambition.” Let us hope that the pursuers of brain stimulation, particularly DBS, heed that counsel. Experimenting on humans by implanting electrodes into their brain to “treat” their depression or addiction seems like a similar pursuit of ambition over first doing no harm. Hopefully Derek Hutchinson’s life story and its miseries will be heard and give pause to some of these researchers.

Originally posted on February 4, 2020

11/15/22

Brain Stimulation or Brain Damage? Part 1

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Nexstim won FDA clearance for its noninvasive brain stimulation system to treat major depression in November 2017. The Nexstim CEO, Martin Jamieson, said the clearance was a critical milestone for the commercialization of their transcranial magnetic stimulation (TMS) device in the U.S. Then in February of 2019 the FDA cleared a drastically reduced 3-minute session protocol to treat major depression with Nexstim’s NBT (Navigated Brain Therapy) System. The previous protocol time was 37 minutes. The Theta Burst Stimulation is a newer form of repetitive TMS that allows for stimulation to specific areas of the patient’s brain. “The company believes that the shorter protocol will increase ease of use for the NBT system.”

The new 3-minute NBT protocol was approved based on results from a study of 414 patients with treatment-resistant depression, which found that intermittent Theta Burst Stimulation was non-inferior to high-frequency transcranial magnetic stimulation.

There is also Humm, a transcranial alternating current stimulation (tACS) device that claims it can improve your cognitive function and memory. “Humm is a wearable patch that gently stimulates the brain’s natural rhythms to strengthen memory.” Neuroskeptic said he was pleasantly surprised with Humm’s reported study, which he said actually looked solid. Although the study was not published, he thought it would pass peer-review. He noted while there is evidence that individually-tailored theta tACS can benefit working memory, other studies show a disruption of working memory. “My point is that, a priori, there is no reason to assume a beneficial effect of this kind of stimulation.”

And most recently, the British government approved Flow, a headset claimed to reduce chronic depression symptoms. The website for Flow Neuroscience claims most users notice a reduction of their symptoms after 3-4 weeks. The device sends a small jolt of electricity through the skull into the prefrontal cortex. Users are instructed to wear the headset for a half-hour every three days over the course of six weeks. Additionally, they are encouraged to use an app, which provides useful tips such as reminders to get enough sleep, eat right and exercise.

The technology, known as transcranial direct current stimulation [tDCS], has been the subject of numerous tests, most of which have found that it provides some degree of relief from depression symptoms. Many have concluded that it is at least as effective as antidepressants, but without the side effects. Thus far, none of the trials have found any adverse effects of such treatment other than reddened skin where the electrodes are placed and the occasional headache. Such treatments have been found to change the potential of neurons—in some cases, making them fire more often, and in others less often. People with chronic depression typically experience less neural activity in the left side of their prefrontal cortex—the mild shocks are meant to increase such activity to match that in the right side. Some of the trial results have even shown that in some cases, mild electrical stimulation can encourage the growth of new neural connections, perhaps reducing depression symptoms permanently.

A study by Clarke et al. reported in the June 2019 issue of the Journal of Affective Disorders investigated the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment resistant depression and comorbid anxiety. Their study included 248 patients with treatment resistant depression. Of these, 172 also had one or more comorbid anxiety disorders. The researchers found that rTMS therapy showed improvement in depression in patients with major depression alone and those with comorbid anxiety. 39.5% of patients with comorbid anxiety disorders met the response criteria defined in the study and 23.3% met the criteria for remission.

Psychiatry Advisor reported the researchers said: “This study showed that rTMS is equally effective for treating depression, regardless of whether there are comorbid anxiety disorders or not. . . [There] is a role for future research into TMS as a treatment for patients with anxiety conditions without major depression.” TMS or rTMS devices are used typically for treatment-resistant depression and can only penetrate a few centimeters into the outer cortex of the brain. The strength of these devices declines rapidly the farther away the machine is positioned from the scalp. See “Better Living Through Brain Stimulation” for more information on rTMS and TMS.

If you want to target deeper regions of the brain, a more direct stimulation method like tDCS or tACS is needed. tDCS devices are inexpensive and easy to use. They are promoted like patent medicines, able to benefit problems such as: migraine, chronic pain, post-stroke paralysis, Parkinson’s disease, depression, tinnitus, fibromyalgia, marijuana craving and the tendency to lie; and they do not require a prescription. tACS is supposed to reverse the decline of working memory related to the aging brain. See “Jump Starting Your Brain” and “Electrical Psychiatry” for more information on tDCS and tACS.

With deep brain stimulation (DBS), we move to a procedure that requires surgery to implant electrodes into a patient’s brain. Wires connect the electrodes to a device implanted underneath the person’s skin. DBS devices are considered to be a last resort treatment method for conditions like Parkinson’s disease and Tourette Syndrome, and they carry risks of adverse side effects such as mood, behavior and personality changes. These can include suicide, depression, mania and serious impulse control issues, such as hypomania, addiction (gambling, shopping, drugs, alcohol) and hypersexuality. See “Deep Brain Jolts” for more information on DBS. See “Deep Brain Problems” for more information on the adverse effects of DBS.

An odd, unanticipated adverse effect has emerged with DBS. According to The New York Times, DBS electronic implants reduced Parkinson’s symptoms, but they also expunged some patients’ proficiency for swimming. “A lifelong swimmer leapt into deep water near his lakeside home and was horrified to find himself completely unable to swim. Had his wife not rescued him, he might have drowned.” Somehow the signals from the DBS device had deleted his ability to coordinate his arms and legs for swimming.

An article in the journal Neurology by a medical team from the University of Zurich documented nine cases among 250 patients. One of the coauthors said he thought the swimming issue was in a minority of patients, because some are still able to swim and they don’t know why. “We have no clue. They are treated in the same region of the brain. But this is life-threatening, and we need to pay more attention in the future.” In 2015 Australian doctors reported one patient who could not even float with the device turned on. With the device off, he could swim laps. Three other patients with DBS stimulators for Parkinson’s have drowned, but “they did not if the deaths were related to the device.”

Now DBS is targeting addiction treatment and China is emerging as the center for this research. AP News noted how scientists in Europe have struggled to recruit patients for their DBS addiction studies (No surprise, given the above brief description of DBS). In the U.S. there are ethical, social and scientific questions (in addition to the cost of around $100,000 to implant), as well as the adverse effects from surgery. China’s anti-drug laws can force people into years of compulsory treatment, including “rehabilitation” through labor. According to ClinicalTrails.gov, there are now 12 registered DBS clinical trials for addiction being conducted globally, 8 are in China; one each in France, Israel, Canada, and Germany. The trials are primarily for opiate/opioid use and misuse, but there are some for methamphetamine, cocaine, alcohol, and morbid obesity. Some critics believe this surgery should not be permitted.

They argue that such human experiments are premature, and will not address the complex biological, social and psychological factors that drive addiction. Scientists don’t fully understand how DBS works and there is still debate about where electrodes should be placed to treat addiction. There is also skepticism in the global scientific community about the general quality and ethical rigor — particularly around issues like informed consent — of clinical trials done in China.

Dr. Nader Pouratain, a neurosurgeon at UCLA, is investigating the use of DBS for chronic pain. He thought it was time to research DBS for drug addiction. However, only “if we can move forward in ethical, well-informed, well-designed studies.” At least two U.S. laboratories dropped clinical trials of DBS treatment for alcoholism over concerns the study design and preliminary results did not seem to justify the risks. Dr. Emad Eskandar, the chairman of neurological surgery at Albert Einstein College of Medicine said: “The lack of scientific clarity, the important but strict regulatory regime, along with the high cost and risk of surgery make clinical trials of DBS for addiction in the U.S. difficult at the present time.” The FDA blocked an application for a Chinese DBS device for a multi-site, opioid addiction.

In February of 2019, the FDA approved a small, separate trial of DBS for opioid use disorder at the West Virginia University Rockefeller Neuroscience Institute. On November 5, 2019 the Rockefeller Neuroscience Institute announced the launch of the first-in-the-U.S. clinical trial of DBS for treatment-resistant opioid use disorder. The first participant is a 33-year-old man with excessive opioid and benzodiazepine use for more than a decade. The first phase will include 3 additional participants.

ScienceAlert (the article was originally published by The Washington Post) reported Dr. Rezai said he wasn’t advocating DBS as a first line or even a second line treatment. “It’s for people who have failed everything, because it is brain surgery.” He acknowledged that doctors and researchers do not fully understand how this (DBS) works. “The exact mechanisms are not known.” By modulating the reward circuit, which relies on dopamine, “you’re getting better control, so you’re not craving dopamine as much.”

The trial is partly funded by the National Institute on Drug Abuse (NIDA). The director of NIDA, Nora Volkow, said she has spoken with a few of the patients who underwent the procedure in China and thought the surgery had promise. She thought the surgery had disrupted the brain’s fixation on opioids. “They reported more of an ability to engage, to feel interest in other things.” She suggested that brain’s fixation on opioids may be disrupted by the surgery. Helen Mayberg, the director of the Center of Advanced Circuit Therapeutics at the Mt. Sinai Medical Center School of Medicine, said the logic of the effort was sound and the circuitry of the targeted area of the brain was well-mapped compared to other regions. “The key question is whether the researchers have found the precise spot for insertion of the electrodes.”

Brain stimulation (magnetic or electric) has been progressively moving from the laboratory to the clinic and even into the privacy of your home. It seems to me that as brain stimulation devices enter the market place, they are being promoted like patent medicines were a hundred or more years ago. Most of the devices are noninvasive, except for DBS devices, which require brain surgery. DBS has been approved and used to treat medical issues such as chronic pain, Parkinson’s and Tourette Syndrome. And now doctors and researchers are trying it with another desperate and vulnerable population—addicts.

There is a growing global opioid crisis and DBS is being researched and promoted as an addiction treatment for individuals who have failed other approaches. But is DBS treatment worth the risk with addiction? DBS supporters like those mentioned here would say yes. The 2019 World Drug Report estimated there were 35 million worldwide who suffer from drug use disorders. More specifically, there were more than 47,000 opioid overdose deaths in the U.S. in 2017, an increase of 13% from the previous year. The number of new psychoactive substances (NPS) that are synthetic opioids rose from 1 substance in 2009 to 15 in 2015 and 46 in 2017, accounting for 29% of the newly identified NPS in 2017.

Currently there are an estimated 180,000 people globally who have DBS devices implanted in their brains. But that would increase exponentially if DBS becomes a more widespread treatment for addiction. Yet Ali Rezai, the executive chairman of the West Virginia Rockefeller Neuroscience Center (where the FDA clinical trial is being conducted) acknowledged they do not fully understand how DBS works. There are serious ethical, social and scientific questions about DBS as well as a variety of adverse effects that result from the surgery. We will examine some of these in part 2.

Originally posted on January 28, 2020.

08/14/18

Electrical Psychiatry

graphic of deep brain stimulation; licensed under the Creative Commons Attribution 3.0 Unported license

Psychiatry has had a fascination with electricity-based treatments beyond the more well-known procedure of ECT (electroconvulsive therapy). Not only is there transcranial electrical stimulation (TES), there is also transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), transcranial direct current stimulation (tDCS) and several other examples of electrical brain stimulation (EBS).  But there are multiple issues with EBS techniques and devices. These concerns include the inability of TES to target neuronal networks as claimed, questionable science and reproducibility problems and the potential to hack implantable medical devices (IMDs).

TES is a non-invasive method used to treat conditions ranging from seizures to depression. TES is different from ECT, as TES involves a less powerful electrical current and is not intended to induce a seizure. “The procedure involves placing electrodes on the scalp in order to send an electric current through the head.” Proponents of TES say they can target specific neuronal networks and induce activation.

However researchers at the University of Szeged in Hungary found that 75% of the scalp-applied current of TES was weakened by soft tissue and the skull before reaching the brain. As Peter Simons noted in his summary of the Hungarian TES research, this means most of the electric field does not have the specific targeted effect on neurons claimed by other researchers since “most of the electricity does not even reach the brain.” In order to directly impact brain circuits, the electrical current would have to be four to six times higher. Electrical stimulation of the scalp can affect brain activity in multiple indirect ways, according to the researchers. However, “there is no accepted theory to explain how TES affects neuronal circuits in the brain, mainly because the physiological mechanisms of TES are not well understood.”

A review of the evidence for TES or cranial electrical stimulation (CES) did not find sufficient evidence to support it having clinically important effects on fibromyalgia, headache, neuromusculoskeletal pain, degenerative joint pain, depression, or insomnia. There is some low-strength evidence of a modest benefit in patients with anxiety and depression. But the research has methodological problems and is of such poor quality, that its conclusions are questionable. “When TES was compared with treatment as usual, even these poor quality studies found no significant difference.”

Indeed, the research on the supposed brain effects found by other studies is plagued by poor methodology. The current researchers argue that other studies, which purport to find neural effects, test for effects at the same frequency as the intervention—meaning that any supposed effects are more likely due to the ongoing external electric field, not actual changes in neural circuits.

Heroux et al. wrote of the “Questionable Science and Reproducibility in EBS Research.” In order to investigate whether the positive results for EBS that dominates the published literature was reflected in the experience of researchers using EBS, they invited 976 researchers to complete an online survey. They also audited 100 randomly-selected published EBS papers. “Only 40–55% of survey respondents were able to routinely reproduce previously published results. Worrisome was the finding that researchers engaged in, but failed to report, questionable research practices.”

When asked about questionable research practices, survey respondents were aware of other researchers who adjusted statistical analysis to optimize results (43%) and selectively reported study outcomes (41%) and experimental conditions (36%)  (Table 3). About 20% of respondents knew researchers who engaged in other shady practices (Table 3). Fewer respondents admitted to engaging in these practices themselves (Table 3), although 25% admitted to adjusting statistical analysis to optimize results. [Table 3 appears below]

Almost al of the respondents (92%) said these questionable practices should be disclosed in the published research papers themselves. However, as Table 3 showed, only 2 of the audited research papers admitted to any questionable practices. “Furthermore, 90% of audited papers reported positive primary findings, i.e. publication bias, and 30% interpreted p-values between 0.05 and 0.1 as statistical trends or statistically significant, i.e. spin.” Several researchers voiced concerns about EBS research, as sampled below.

I think there is a huge publication bias in this field and, in my opinion, the positive results of tDCS are highly overestimated. There does seem to be a suspiciously large number of positive tDCS trials published, and in almost any discipline it has been used in.”Although the consensus within publications in that electrical stimulation works well and is reliable, my experience of talking to other researchers at conferences and within my department suggests that there is a huge amount of unpublished, unsuccessful attempts at using the stimulation. Many of which have no clear methodological issues.

Heroux et al. speculated the lack of transparency and scientific rigor was likely due to the pressure on researchers to publish significant results in high impact journals. This pressure creates a vicious cycle where journals, institutions and funding agencies expect significance. In order to survive and meet these expectations, scientists consciously or unconsciously adopt “questionable or fraudulent research practices.” Although these pressures are not unique to research into EBS, they taint the efforts of researchers genuinely trying to improve brain function. “The clinical promise of EBS will remain illusory until the practice of neuroscience becomes more open and robust.”

Danielle Egan wrote an in depth article for Mad in America about The Broaden Trial, one of the largest clinical trials to investigate the efficacy of DBS for depression. It was terminated in 2013 because of a low (17%) success rate among at least 75 patients that received the implant. This was Egan’s second article on the Broaden Trial for Mad in America. See “Deep Brain Problems” for a discussion of DBS and the Broaden Trial as well as Egan’s first article. The British journal Lancet finally published a paper on the results of the trial in October of 2017.

The Broaden Trial ultimately signed up 201 patients. But the FDA required a futility analysis of “at least 75” of the initial implanted patients at the six-month mark. The Lancet paper revealed that 90 patients were implanted between 2008 and 2013, and their data analysis revealed an estimated success rate of only 17%—much lower than the 78% response rate initially advertised in June 2008, soon after the Broaden trial began and SJM began to solicit patients. In late 2013, SJM decided to terminate the trial, even though the results were still slightly higher than the FDA’s definition of futility: a 10% success rate. By that point, the trial had been going on for almost five years, collecting follow-up data that is detailed below.

The published reports said at the end of two years, two-thirds of those who stayed in the study were helped. “But this efficacy only showed up in the open-label part of the trial, and not during the placebo-controlled phase, when the investigators were ‘blinded’ to who was getting the treatment.” While the published paper said there were no side effects associated with DBS programming, Egan reported that all five of the patients she interviewed who participated in the Broaden Trial said they experienced programming-related adverse effects. The Broaden paper also had a tendency to attribute serious adverse effects like suicidality in the study’s participants to their underlying mood disorder and not to the device or active stimulation. “Two people in the study died by suicide. Both were in the control group, but they committed suicide after they started receiving stimulation.”

You can read a further critique of DBS in James Coyne’s article, “Deep Brain Stimulation: Unproven Treatment” for PLOS Blogs. His concluding comments contained the following:

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.

Lastly, there is a research article showing how implantable medical devices (IMDs), like that used for DBS, could be hacked.  “Securing Wireless Neurotransmitters,” by Marin et al., described how they reverse engineered an IMD and conducted several software radio-based attacks that could compromise the safety and privacy of patients. They demonstrated that reverse engineering was possible without having physical access to the devices.

We conducted several software radio-based attacks that could endanger the patients’ safety or compromise their privacy, and showed that these attacks can be performed using inexpensive hardware devices. The main lesson to be learned is that security-through-obscurity is always a dangerous design approach that often conceals insecure designs. IMD manufacturers should migrate from weak closed proprietary solutions to open and thoroughly evaluated security solutions and use them according to the guidelines.

Since December of 2017 the FDA has approved two DBS medical devices to treat epilepsy (Medtronic DBS System for Epilepsy) and Parkinson’s (Vercise Deep Brain Stimulation System). But as James Coyne noted, this is “a heavily hyped unproven treatment for which the only clinical trials have either been null or terminated following a futility analysis.” The physiological mechanisms of transcranial electrical stimulation (TES) are not well understood and “there is no accepted theory to explain how TES affects neuronal circuits in the brain.” And it doesn’t deliver the current it says it does to the brain; four to six times the voltage of current TES treatment was needed to get a direct effect on the brain.

I think the ultimate concern with electrical brain stimulation (EBS) is that even the researchers who work in the field acknowledge the positive results in the published literature can’t be trusted. More time and reliably replicated studies are needed before psychiatry starts extolling the merits of EBS treatment any further. And it would be nice at least have the beginnings of a consensus of agreement on exactly how EBS works before psychiatry turns it loose on a population desperate for the relief it promises.

12/2/15

Deep Brain Problems

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© ktsdesign | 123rf.com

Danielle Egan opened her article for Mad in America on the adverse effects of deep brain stimulation (DBS) with a quote from a DBS patient named Jim: “I just want the thing out. . . . It could be harming my brain and it’s certainly doing a lot of psychological harm to me. It’s a very real presence and I can feel the wires under my skull and at my neck. After two years of this, I just want to be done with it.” Jim is one of around 272 people worldwide who have had these experimental implants to treat psychiatric disorders such as depression, OCD and Tourette’s syndrome.

Egan has been investigating DBS and writing about individuals who have had the surgery for a number of years. Jim is just one of several people she’s met and interviewed. You can read about several of these individuals on her website under the “neuroscience” heading of her blog. The first DBS surgical procedure for depression occurred in 2003. It has been used and approved previously as a treatment for movement disorders like Parkinson’s. At first, the news about this technique was almost wildly positive. See “Deep Brain Jolts.”

In a 2005 interview for the NPR program “All Things Considered,” Dr. Helen Mayberg, reported that four out of six patients were relieved of intractable depression with her DBS procedure. “At six months, the four patients that responded to this treatment were actually near remission … meaning they weren’t just better, they were well.” Mayberg and her research colleagues reported their finding in the March 2005 issue of Neuron. Reporting on Mayberg’s research for Scientific American, John Horgan attended a lecture she gave in March of 2014 where she was still describing promising results. But according to Horgan, she “buried the lead” by mentioning midway through her talk that a multi-center trial of her method of DBS had been halted by the FDA.

This meant that the FDA suspended the BROADEN trial because it failed a “futility analysis,” meaning it did not appear to have a reasonable chance of improving upon current treatments.

As Egan related in her article, advocates of DBS still have no clear sense of what its mechanism of “therapeutic” action is, even though it has been studied since the 1980s. When treating depression, Mayberg’s method targets an area of the brain known as the subgenual cingulate gyrus (Cg25). In theory, DBS is reversible; so it was thought to be a better way to inhibit brain activity than the permanent lesions of psychosurgery. But so-called “micro-lesions” from the surgery and the DBS implants have been found. Long-term studies of Parkinson’s patients treated with DBS have shown they have DBS-related scar formation in their brains. There have been serious mood, behavior and personality changes documented as well.

These include suicide, depression, apathy, fatigue, mania and serious impulse control issues, such as hypomania, aggression, addiction (to gambling, shopping, drugs, alcohol) and hypersexuality, sometimes resulting in criminal behaviour, including pedophilia.

Because of the area of the brain targeted by DBS treatment for psychiatric disorders, the cerebral cortex, the risks are likely to be more pronounced than with Parkinson’s. Within the cerebral cortex are a variety of cognitive functions, such as learning, sorting and rationalizing input from the inner and outer world. It is also the seat of human personality, with associations to mood, decision-making, impulse control and other behaviors.  The Cg25 area is also thought to be linked to self-esteem, motivation, reward-based thoughts and moral decision-making. “Clinical studies have linked tissue damage in the Cg25 with disinhibition, which is associated with frontal lobe brain damage causing poor impulse control.”

Mayberg et al.’s 2005 study did post-operative PET scans showed decreased activity in the Cg25 area, which was believed to be a positive inhibiting effect. But blood flow increased in other areas, especially the brain stem, where mechanisms like heart rate, breathing anxiety and euphoria are regulated. Other studies have shown these blood flow changes to be connected to mania, dementia, psychosis and dissociation.

Returning to Jim, he had no idea that the sponsor of the BROADEN clinical trial he was in terminated it because it failed to reach a benchmark of a 50% response rate as measured by the Hamilton Depression Scale. Beside his cognitive issues, Jim had extreme sleep problems that began about six months post-implant. Eventually he sought out a sleep disorder specialist who diagnosed him with REM Behavior Disorder. This means the brain functions just as it does during consciousness, without the muscle paralysis that come with REM sleep.

“I’d have night terrors and catatonic sleep, like narcolepsy; it would just come over me in the middle of the day and I’d have 20 minutes to get somewhere safe before it took over and knocked me out; my wife couldn’t even wake me up. That happened four or five times per week.”

Eventually Jim returned to his study center to have the device turned off. His thinking began to clear up. His sleep problems almost disappeared. “But I want this thing out.” When he signed up for the trial, his consent from said that DBS was reversible by removing the implant. But when he registered for the followup study, its consent form said: “In some cases the device is not removable.” The complexity of the frontal cortex with its connection with so many other regions of the brain seems to be the reason. The surgeon explained that the leads (wires) from the device may be too tense and “they might have to leave them there.”

Jim had his “explant” surgery, a four-hour surgery instead of a routine one-and-a-half hour outpatient procedure. “I guess the surgeon had to do a bit of prying.” A part of the device that fits into the skull gave the surgeon trouble because bone and tissue had knitted together around it. His head was throbbing; as was the skin around where the pacemaker had been implanted in his chest. I feel like the DBS broke my brain; it broke something in me. . . . But I need to put what happened behind me. I’m just relieved it’s out.”

After John Horgan published his March 2014 story mentioned above, he was contacted by Steve Ogburn, who had also been a patient in the BROADEN trial. He quoted Steve as referring to himself as ‘colatteral damage’ from the study in a May 2014 article. Steve had his surgery at Stanford in November of 2012. He developed severe head pain three months into the study. The leads were 18 inches too long, and had been coiled up in his chest and the top of his head. He could feel them externally. He had “bowstringing” a condition where scar tissue forms around the leads. This has been documented in others DBS cases and can cause permanent complications. He had problems with shoulder and jaw muscle atrophy, spinal accessory nerve palsy and occipital nerve palsy. Steve is pursuing a lawsuit against St. Jude (the medical device company), Stanford University, Stanfords’s IRB (institutional review board), and the neurosurgeon who did the DBS implant. You can watch a 15-minute video of Steve telling his story. A link is embedded in Danielle Egan’s article and in Horgan’s May 2014 article.

In July of 2015 John Horgan reported on a second DBS clinical trial failure, now with the medical device developed by Medtronic. A team from Massachusetts General Hospital led by Darin Dougherty tested 30 subjects with treatment resistant depression; half received DBS and half received a placebo treatment. There was not a significant difference in response rates between the DBS and the placebo subjects. Dougherty said: “The bottom line is that we can’t separate out active treatment from placebo.”

“The Dr. Peter Breggin Hour” podcast for 9.30.15 was a conversation between Peter Breggin and Danielle Egan on many of the issues discussed here and covered in her Mad in America article. The podcast is also available free through iTunes. Egan said in the podcast that after she learned of the original Canadian trial study conducted by Dr. Mayberg (before she went from Canada to Emory University in Atlanta), she tried repeatedly to contact the individuals involved in the Canadian study with no success. It was only in 2015 after Steve Ogburn helped, was she able to interview some of those individuals.

DBS is not going away, despite what is reported here. Emory University published a press release touting the positive results of Mayberg’s continued research with DBS. A woman has a new life, “After three decades of severe depression and trying nearly every treatment, deep brain stimulation helped [her] reclaim her life and regain the ability to feel joy.” Horgan noted that the press release didn’t mention the two failed DBS clinical trials.

02/25/15

Deep Brain Jolts

© Brain Energy Pulse by idesign | stockfresh.com

© Brain Energy Pulse by idesign | stockfresh.com

Michael J. Fox is probably the most well known person with Parkinson’s disease. Viewing the progression of his Parkinson’s between 1991 and an interview he did on Oprah in 2010 gives you an indication of how debilitating it can become. There is a treatment called Deep Brain Stimulation (DBS) that effectively silences the tremors. The dramatic therapeutic difference can be seen in this YouTube video of a New Zealand man named Andrew Johnson who has Early Onset Parkinson’s. The difference is dramatic and it is easy to see why he would agree to the procedure. What’s not to like about it and why would Michael and others put off trying it? It involves surgery that implants electrodes into your brain.

As described by the NIMH, DBS surgery begins with shaving your head and attaching it with screws to a sturdy frame that prevents the head from moving during surgery. The patient is awake during the procedure to help the surgeon with feedback. Patients feel no pain, however, because their head is numbed with a local anesthetic. MRIs are taken of the brain to guide the surgeon during the operation.

Once the above prep work is completed, two holes are drilled into the head. The surgeon then threads a slender tube down into the brain in order to place electrodes on each side of a specific part of the brain. After the electrodes are implanted and the patient provides feedback about the placement, the patient is then put under general anesthesia. The electrodes are now attached to wires that run inside the person’s body down to the chest, where a pair of battery-operated generators are implanted.

Electrical impulses are then continuously delivered over the wires to the electrodes in the brain. After the device is fine tuned, it reduces tremor and uncontrollable movements, stiffness and walking problems related to Parkinson’s. You can see how this all works afterwards in the Andrew Johnson video. At this point, DBS has been used in more than 100,000 people worldwide.

Helen Shen wrote in Nature that the biological mechanism underlying DBS is still unknown. Michael Okun, a neuroscientist, said there has been a lot of guesswork done with DBS over the past twenty years. “It would be premature for anyone to claim they know how the therapy works.” There are some hypotheses, though. The current theory is that DBS somehow disrupts or represses pathological signals that reverberate through multiple brain regions, thus corrupting their communications.

This fits with the emerging view that Parkinson’s disease, depression and other neuropsychiatric conditions are best understood as neural network dysfunctions. At this time DBS is approved by the FDA to treat the following: essential tremor (1997), Parkinson’s (2002), dystonia [a neurological movement disorder] (2003) and OCD (2009). There is research being done to assess it applicability to addiction and depression.

Helen Shen described a new device from Medtronic that is now being used in DBS treatment. The Medtronic neurostimulator not only will send electricity into the brain, it will also read neural signals generated by the brain and send them out.

Until now, such data have been accessible only when a patient’s brain is exposed briefly during surgery. But being able to make long-term neural recordings from human patients may become increasingly important — especially because researchers are experimenting with using DBS as a treatment for many other neurological conditions.

But the neural networks in these other neurological disorders are even less understood than those involved in Parkinson’s. Helen Mayberg, a neurologist at Emory University said devices like the Medtronic neurostimulator could change that, but “Every disease will be different and one size won’t fit all. . . .  [However] the new technology is going to enable progress exponentially.” Helen Bronte-Stewart, a neuroscientist, said this was an exciting time. “This is the first time we’re really getting a window into the brain.”

Others, such as medical ethicist Joseph Fins, urged caution. He also indicated that while the sensiorimotor network involved in Parkinson’s disease is mapped out in great detail, the other disorders have much less guidance available. “There has got to be a biological rationale for what you’re intending to do.” Others argue that controlled testing of DBS in humans doesn’t need to wait for complete or near complete understanding of the relevant networks.  Benjamin Greenberg, a psychiatrist at Brown University said that as a clinician, that wasn’t an important question. “The real questions are: do these treatments help people? Are they safe?”

The NIMH indicated, “DBS carries risks associated with any type of brain surgery.” The side effects or complications could include: stroke or bleeding in the brain; infection; disorientation or confusion; unwanted mood changes; movement disorders (isn’t DBS supposed to treat these?); lightheadedness; trouble sleeping. And DBS does not halt the progressive neurodegeneration of Parkinson’s. In the long run, patients will succumb to symptoms not effectively treated by DBS, like cognitive deterioration.

An article by Jeanene Swanson for The Fix referred to DBS surgery as a “relatively simple neurological procedure” (?) that could be used to treat a variety of disorders, including addiction, severe depression cluster headaches and obesity (None of these are approved DBS treatments at this time). DBS treatment for addiction was accidently “discovered” in 2006 by Jens Kuhn of the University of Cologne when Kuhn tried DBS as a treatment for panic disorder. “Recent valid animal studies show significant induced improvement in cocaine, morphine, and alcohol addiction behavior following DBS of the nucleus accumbens.”

Wayne Hall indicated that the interest in using DBS for treating addiction isn’t great. He suspected this was because it is an expensive, high technology intervention for a small minority of patients. He further noted that interest has declined for using DBS for depression because of poor trial results. However, that could be resurrected if more promising sites for stimulation were identified.

I would predict that if DBS is used for addiction in the future it will only be used in a minority of patients and will remain a niche treatment for addiction rather than becoming a mainstay form of treatment as it looks like it’s becoming for Parkinson’s disease and other movement disorders.

Dr. Nadar Pouratian of UCLA thinks it can be a promising treatment for addiction, but the earliest it could be available would be five years from now. “I think it’s a promising therapy for a spectrum of diseases, including addiction, but we need to be a little bit more methodical or careful—every time a trial does not work, the negative repercussions [do] far greater harm to the field.”

Could that be because DBS for addiction and depression is therapeutic overkill? Could it be because it’s dangerous when applied for addiction and depression? When the current state of knowledge doesn’t know how DBS works, and when the complexity of the neural networks for addiction and depression aren’t clearly understood, treating them with DBS seems like taking a huge risk.