Deep Brain Stimulation Makes Cautious Inroads to Psychiatry(2)


by Brenda Patoine

February, 2008

BRIEFING PAPER

              

Barbara Rich
(212)223-4040
brich@dana.org

             

Ann Whitman
(212)223-4040
awhitman@dana.org

Deep brain stimulation (DBS), a neurosurgical approach that uses implanted electrodes to stimulate nerve cells in discrete brain regions, is well established as an important therapeutic option when all others fail for some movement disorders, including Parkinson’s disease and tremor. Now DBS is making preliminary inroads into psychiatry, and seems poised for greater application to psychiatric disorders that are equally resistant to treatment. The trend is emerging in lock-step with basic scientific advances that are unraveling the neural anatomy and circuitry of these disorders.  

DBS is FDA-approved only for Parkinson’s and essential tremor, but a small but growing number of researchers are investigating DBS as a treatment for highly intractable cases of depression, obsessive-compulsive disorder, and Tourette’s syndrome. The number of people treated so far remains quite small, but several groups have reported promising preliminary results.  

Since DBS requires brain surgery to implant the stimulating electrodes, it is viewed–even in approved conditions–as a last resort to be tried only when drug or other noninvasive therapies repeatedly fail; as such it would be impractical to think of DBS as first-line therapy in any disorder. Still, if shown to be effective in larger numbers of patients, it could offer a sorely needed option for people who are out of options and suffering severe disability as a result of mental illness.  

Perhaps just as importantly, these early forays using DBS in psychiatry prove once again that mental disorders have “physical” roots in the brain. They underscore the simple truth–long championed by neuroscience but often lost on the general public–that psychiatric disorders, just like classical neurological disorders, can be traced back to some aberrant physiology in specific brain pathways or anatomy. Identifying what’s gone wrong and figuring out how to fix it is, of course, not so simple.

Beyond ‘Psychosurgery’

The idea of treating a psychiatric disorder such as depression, which is best understood as an imbalance of diffuse neurotransmitter systems, with brain surgery may seem somewhat startling. For some, it may even conjure up memories of the “psychosurgeries” of an earlier era–the infamous “ice-pick lobotomies” among them. These ill-fated experiments, which ended in the 1970s after they were broadly condemned for excessive use and sometimes horrific outcomes, have now been relegated to the annals of misguided medicine.

Given this history, says Mahlon DeLong, a member of the Dana Alliance for Brain Initiatives and a neurosurgeon at Emory University who has pioneered DBS for movement disorders,“It may seem surprising that neurologists, neurosurgeons and psychiatrists are again exploring surgical procedures for severe psychiatric disorders.” But DBS is different, he says, for a number of reasons. Prominent among them is the strong record of “remarkable success” using this approach in treating movement disorders, and the fact that DBS is “relatively less invasive and reversible.” 

Helen Mayberg, an Emory neuroscientist, new member of the Dana Alliance, and Dana grantee, is among those in the vanguard of applying the technique to psychiatry. For almost twodecades, her research–begun when she was at Johns Hopkins–has focused on identifying a “depression circuit” in the brain. The question that has driven her research is, as she puts it, “Can something as seemingly nebulous as depression be localized in the brain?” 

Her laboratory’s studies, taken together with the findings of other research groups, suggest that it can be. Using powerful brain-imaging techniques that track neural activity, including PET scanning and functional MRI, the research has zeroed in on a brain area known as Brodmann’s area 25, which is located in the anterior cingulate cortex beneath the corpus callosum–the so-called subcallosal cingulate.    

“It has become apparent that we can dissect out the subcircuits involved in depression by looking at how the brain changes if you successfully treat depression with drugs or other therapies, so you can start to piece together the puzzle of what regions are most consistently affected,” says Mayberg. “Over time, we have been developing the same kind of wiring diagram for depression that has been worked out for Parkinson’s. Across our different studies, it became clear that certain things need to change in the brain in order for the depressed person to get well, which meshed with what other people were finding.”

At the same time this work was ongoing, DBS for Parkinson’s and tremor had become well established, and was increasingly being used in dystonia, a disorder characterized by involuntary twisting movements. Armed with the new data suggesting a well-defined circuitry for the resolution of depression, Mayberg’s team in Toronto set up an experiment to test DBS in patients who had failed all other depression therapies. They used the same equipment, strategy, and stimulation parameters that had been used effectively in Parkinson’s, but targeting the putative depression circuit.

Mayberg and colleagues published preliminary, six-month results from an initial group of six patients in Neuron in 2005,i reporting a “striking and sustained remission of depression” in four of the six. The team in Toronto has now treated a total of 20 people with the same protocol; the data on the larger group have not yet been published, but Mayberg has reported some results at scientific meetings.  

“The clinical response seen in the first patients at six months has been sustained past one year, and the six-month response rate of the first group has been replicated in an additional 14 patients,” she says.  As first observed, the clinical effect appears to be “progressive and sustained,” she adds, with generally no need for adjusting the “dose” of stimulation, as is often necessary in Parkinson’s disease.   

Other experts urge caution in interpreting findings from such a small number of people. “It’s early data. The world experience is not that large, and not much has actually been published,” says Dennis Charney, dean of Mount Sinai School of Medicine. “There needs to be a lot more work about who it works in, what percentage, and how long the response is maintained.”   

Still, Charney adds, “It’s interesting work because it does seem to implicate a particular brain region as important in the circuits of depression.  It speaks to the fact that depression is a medical disorder of defined circuitry, and that’s been very helpful.”
           
Location, Location, Location

Not all of the patients in Mayberg’s study have experienced a resolution of their symptoms, and the researchers are carefully analyzing why this may be. To better understand the differential responses in patients, they have recently employed ii an imaging technique called diffusion tensor imaging, which enables researchers to visualize the brain’s white matter tracts, the axonal connections that link brain regions. Placement of the electrodes seems to be a critical point–even a couple of millimeters can make a huge difference. 

“At the end of the day, the absolute precision of where those electrodes are may be extremely important,” Mayberg says. “We can see that based on the clinical results alone. But when we look at the anatomy, there is nothing to explain who gets better and who doesn’t. To me, that means we’re just not looking at the right things.”

To sort out these questions, Mayberg and her group at Emory continue to enroll patients in a new study, including 10 people with bipolar disorder-type 2, a condition characterized by recurrent depression and periods of hypomania. Advanced Neuromodulation Systems, one of two companies (along with Medtronic) that make the stimulators used in DBS, has recently announced a separate, three-center clinical trial to further test the efficacy of subcallosal cingulate DBS in intractable major depression.  

Meanwhile, interest in treating other psychiatric conditions with DBS is mounting. In 1999, a Belgium research group published data from the first uses of DBS in intractable obsessive-compulsive disorder (OCD), reporting positive results in three of four patients.iii Since then, additional patients have been enrolled in a pilot study funded by the National Institute of Mental Health (NIMH) and led by Wayne K. Goodman, a neuropsychiatrist and former chair of psychiatry at the University of Florida, Gainesville, who is now a division director at NIMH. Three-year outcome data from the study, published in 2006,iv showed promising long-term effects of stimulation targeted at an area of the striatum called the internal capsule. Based on these results, NIMH has committed funds to a five-year randomized, controlled clinical trial in treatment-refractory OCD. The study, led by Benjamin Greenberg at Brown University, will enroll 45 patients.

In Tourette syndrome research, a team of European scientists published data last yearv on the largest group of patients treated with DBS so far, all of whom were refractory to standard treatments. The authors reported that all 18 patients responded well–though to differing degrees–to stimulation of a specific area of the thalamus. In an editorial accompanying the article, Michael Okun and colleagues at the University of Florida, Gainesville, said the report is important because “it demonstrates promising safety and efficacy data for the treatment of medication refractory tic.” However, they pointed out that various brain areas have been targeted, with varying results, by other researchers investigating DBS for Tourette’s, and said more research is needed to identify the best neural targets and which patients are most likely to benefit.

While the application of DBS to neuropsychiatric disorders is clearly still in its infancy, many experts express cautious optimism that this approach may prove useful in the toughest cases, when nothing else works. According to DeLong, the preliminary research suggests that in terms of psychiatric applications, getting the DBS protocol and parameters right “is more involved than it is in Parkinson’s.” To him, the research underscores the fact that “molecular pathology can only take you so far in understanding psychiatric disorders. We’ve got to get beyond cells and synapses and work our way out to the larger circuits involved.”

“DBS technology takes advantage of the fact that we can modulate specific circuits that are responsible for different kinds of behaviors,” says Mayberg. “In the big picture, the idea that neural systems can be modulated by electricity introduces a whole new strategy for thinking about how to influence the brain in ways that we really hadn’t conceptualized before.”

Published February 2008

###

i Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH.Deep brain stimulation for the treatment-resistant depression.Neuron 2005; 45:651-60.

ii Johansen-Berg H, Gutman DA, Behrens TEJ, Matthews PM, Rushworth MFS, Katz E, Lozano AM, Mayberg HS.Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression.Cerebral Cortex 2007; Oct. 10, 2007 [E-pub ahead of print]

iii Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B.Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.Lancet 1999;354(9189):1526.

iv Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA.Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder.Neuropsychopharmacology 2006;31:2384-93.

v Servello D, Porta M, Sasssi M, Brambilla A, Robertson MM.Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment:the surgery and stimulation.Journal of Neurology, Neurosurgery and Psychiatry 2008;79:136-42.