12/2/15

Deep Brain Problems

© ktsdesign | 123rf.com

© 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.