The year 2009 may be remembered as the beginning of a new era for deep brain stimulation, the neurosurgical therapy that uses implanted electrodes to alter brain activity. Backed by a promising track record in treating Parkinson’s disease and other movement disorders when all else fails, deep brain stimulation (DBS) has stepped solidly into the realm of psychiatry and is being investigated as a treatment for obsessive-compulsive disorder (OCD) and depression, along with a growing list of other experimental uses. These new experimental treatments underscore both the potential for using “neuromodulation” to treat a wide range of brain-based conditions and the pitfalls of the past that must be avoided.
Even as the field surges forward, many experts have urged caution in making the transition from research to clinical use of DBS in psychiatry. Editorialists writing about the expansion of DBS have frequently invoked the failed “psychosurgeries” of the mid-twentieth century, when Walter Freeman and his followers performed some 18,000 frontal lobotomies on patients with all manner of psychiatric and behavioral problems. “Given this checkered history of psychiatric neurosurgery,” wrote National Institute of Mental Health director Tom Insel and Wayne Goodman, now chairman of psychiatry at Mount Sinai Medical School, in a commentary in February, the scientific and medical communities “owe the public a promise that clinical applications of DBS in neuropsychiatry will not overstep the bounds of empirical evidence.”1
Wayne Goodman, chairman of psychiatry at Mount Sinai Medical School and a pioneer in the research of obsessive-compulsive disorder (OCD), urges caution in the use of DBS for neuropsychiatric disorders. (Courtesy of Wayne Goodman / Mount Sinai Medical School)
To be sure, DBS is no “ice-pick lobotomy,” the technique Freeman championed. Modern neurosurgical techniques and brain imaging have made precise placement of minuscule electrodes into the brain a relatively safe procedure. But DBS is still neurosurgery, with all the inherent risks that surgery on the brain entails. Proponents of DBS often point out that, unlike ablative surgery, in which neurosurgeons lesion a discrete piece of the brain for therapeutic purposes, brain stimulation devices can be removed or regulated if necessary. Nevertheless, manipulating brain circuits with DBS can have unexpected side effects—good or bad—that may not be reversible even when stimulation is stopped.
Spreading “Like Wildfire”
While scientists continue to evaluate the dangers and ethical considerations, clinical use and research on brain stimulation as a therapy are exploding. “It has spread like wildfire,” said Mahlon DeLong, a pioneer of DBS for movement disorders at Emory University. A search for “deep brain stimulation” on PubMed, the public database of peer-reviewed journals, brings up nearly 4,000 articles—more than 250 in the last year alone, a substantial increase over the number five years ago.2 Clinically, an estimated 60,000 patients worldwide, the vast majority of them with treatment-resistant Parkinson’s disease, have been treated with DBS.
Brain stimulation techniques have been used for more than fifty years as a treatment for chronic pain syndromes, and they are still used for this purpose in Europe (the FDA has not approved such procedures for pain in the United States). French neurosurgeron Alim-Louis Benabid pioneered the use of DBS in movement disorders in the 1980s, targeting a brain area called the thalamus on the basis of prior evidence that ablative surgery on the thalamus eliminated tremors. The brain target was subsequently refined after animal studies showed that lesions in the subthalamic nucleus dramatically reversed Parkinson’s-associated tremors. In addition to its use in Parkinson’s disease, DBS is currently FDA-approved for use in dystonia and essential tremor.
Only a small portion of DBS procedures—fewer than 150, as recorded in published reports—have been performed on patients with psychiatric conditions, but these disorders are the fastest-growing area of clinical research, judging by the number of clinical trials under way and the proliferation of published reports. In February 2009 the U.S. Food and Drug Administration approved the first use of DBS for a psychiatric condition, issuing a “humanitarian exemption” to one device maker to allow treatment of severe, treatment-resistant obsessive-compulsive disorder (OCD). Meanwhile, researchers are conducting clinical trials to investigate DBS as a treatment for OCD, depression and Tourette’s syndrome, where promising preliminary results have encouraged further study. Clinical trials are also ongoing for the treatment of epilepsy.
An array of other experimental applications is just beginning to be explored, including obesity, brain injury, minimally conscious states, chronic pain, headache, Alzheimer’s disease, anorexia, tinnitus and addiction. And intriguing early research in animals has shown that brain stimulation can generate new nerve cell growth and improve cognitive skills, opening whole new avenues of potential clinical applications down the road.
In addition, research is also on the rise for neuromodulatory methods that do not require brain surgery, including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS).
The premise for these techniques is the same as that for DBS: stimulating neural activity to modulate specific pathways. In tDCS, one or two sponge-tipped electrodes are placed on the surface of the scalp; in TMS, a magnetic coil of wire is placed over the head to generate magnetic fields within the brain that in turn cause neurons to fire. Both devices are non-invasive and can be applied in a physician’s office without requiring surgery. Neither technique is as precise as DBS, nor can the stimulatory effects reach more than a couple of centimeters into the brain, although an emerging technique known as “deep TMS” uses a novel coil design to modulate tissue deeper in the brain.
TMS is currently FDA-approved for treatment-resistant depression and is being investigated for a number of other neurologic and psychiatric disorders, including anxiety, schizophrenia and sleep disorders. An NIH-sponsored clinical trial in Parkinson’s disease is under way, with early results indicating that the technique is safe.3 An Israeli company, Brainsway, is investigating deep TMS for severe depression and several other conditions, including acute ischemic stroke. On its Web site, the company says the treatment may improve motor recovery after stroke by stimulating nerve growth factors that strengthen synaptic connections and may help generate new neurons.4 Transcranial DCS is in early stages of exploration for therapeutic use, with various research groups studying its potential for treating depression, schizophrenia, migraine, memory impairment and chronic pelvic pain, according to listings in the government’s Clinical Trials database.
In transcranial magnetic stimulation (TMS) a magnetic coil of wire is placed over the head to generate magnetic fields within the brain that in turn cause neurons to fire. (Neuronetics, Inc)
Rhythms Gone Wrong
The broadening use of DBS and its non-invasive neuromodulatory cousins reflects not only technological advances but also a growing recognition that the symptoms of many brain disorders arise from disrupted circuitry—some aberration in the normal rhythm of brain signals—along the neural pathways that underlie the disordered behavior. (The term “circuit disorder,” also known as “dysrhythmia,” is increasingly being used to describe these conditions.)
In Parkinson’s disease, for example, a brain circuit linking the basal ganglia to the thalamus and cortex is disrupted, which causes tremors and other problems with movement (see chapter 3, “Parkinson’s Disease”). Well-targeted stimulation within the circuit modifies the rhythm and has proven effective at quelling the motor symptoms of Parkinson’s in patients for whom no other therapy works. Current studies in OCD and depression are based on recent discoveries about the neuroanatomy of these disorders that implicate a circuit disruption as well.
“If one looks carefully across a range of neurologic and psychiatric conditions, one finds that a very similar neural mechanism—an abnormal brain rhythm—can generate many different types of symptoms depending on where in the brain that activity is,” said Rodolfo Llinas, a neuroscientist at NYU Medical Center. “This is absolutely why we are seeing such success with deep brain stimulation.”
Why It Works: Knowns and Unknowns
The mechanism of action of DBS is often said to be unknown, but Llinas scoffs at this notion: “People think you just stick electrodes in the brain and look for a sweet spot. They think we really don’t know how it works. That’s not true. We do know how it works. The only thing that electrical stimulation can do, especially acutely, is modify the rhythm.” Which rhythm is modified, and which neurons are stimulated, depends upon where the electrodes are implanted.
Beyond the general action of circuit modification, though, the precise way in which DBS works to mitigate debilitating symptoms that no other treatment can touch is “hotly debated,” according to Mount Sinai’s Goodman. More likely than not, it differs depending on the condition treated, the brain area targeted, the types of neurons activated and even the frequency or pulse rate of the electrical signal generated. In some cases, stimulation may return a disease-disrupted rhythm to a more normal pattern by activating or inhibiting select groups of neurons. In other cases, it may increase the firing rates of neurons in a given circuit or neutralize an aberrant pattern of nerve firing before it develops into, say, an epileptic seizure.
In addition, increasing evidence suggests that electrical stimulation acts to turn on certain genes that can cause downstream effects on cells, synapses and circuits. Some genes are activated immediately, while others are turned on after long-term stimulation. Researchers are only beginning to sort out how these gene expression dynamics relate to therapeutic responses. The array of genes affected depends on whether the stimulation is applied continuously or only in the short term, suggesting that long-term DBS may trigger secondary changes as the ever-plastic brain adapts to new firing patterns. These effects—and their behavioral consequences over time—are being investigated in dozens of laboratories around the world.
Calming Compulsions: DBS for OCD
Brain stimulation for OCD, a chronic and debilitating illness that affects 2 to 4 percent of people in the United States, has been studied for more than a decade, and the FDA’s recent approval of its use in severe cases marks the first psychiatric indication for DBS. Up to 4,000 people per year can be treated under the “humanitarian device exemption” granted to Medtronic, the maker of the only DBS system currently approved in the United States, though the company said in a statement that it anticipated that the therapy would be appropriate for only “a small subset” of the OCD patient population—those who suffer the most severe debilitation and for whom no other treatment provides relief.
The special regulatory status reflects both the high rates of treatment failure in OCD—40 to 60 percent of patients don’t respond fully, or at all, to current therapies—coupled with promising results in preliminary studies. In one pilot clinical trial involving eight patients that was funded by the NIMH and published in 2006, researchers reported “promising long-term effects” in the group of highly treatment-resistant patients, including a 35 percent decrease in obsessive-compulsive symptoms and improvements in depression, anxiety and quality-of-life measures.5 A second NIMH-sponsored trial for patients with severe treatment-resistant OCD, led by Benjamin Greenberg of Brown University/Butler Hospital, started in March 2008.6 Unlike the pilot trial, the study includes a control group of people who receive the implants but whose stimulators are not turned on until three months into the study, an attempt to better distinguish any placebo effect from true stimulationinduced effects.
Benjamin D. Greenberg of Brown University and Butler Hospital led an NIMHsponsored trial testing the efficacy of DBS on patients with severe treatment resistant OCD. (Courtesy of Benjamin D. Greenberg / Brown University/Butler Hospital)
The brain target of stimulation in both studies is an area called the ventral capsule/ventral striatum, which has long been implicated in OCD, in part because surgical lesions in this area are known to improve symptoms of the disorder. Goodman describes the area asa “giant fan-like bundle of white-matter fibers that acts as a superhighway for nerve signals on their way to other brain regions.”
A separate study of DBS in severe treatment-resistant OCD, by the Paris-based STOC Study Group, stimulated nerve cells in the subthalamic nucleus, a brain region that integrates motor, cognitive and emotional components of behavior and that has long been a target of DBS for Parkinson’s. The results, published in the New England Journal of Medicine in late 2008,7 suggested some benefits in symptom reduction but also a substantial risk of serious adverse events among the sixteen people enrolled, raising concerns about the risk-benefit ratio of the treatment that experts say need to be explored further in well-designed trials.
Tackling Severe Refractory Depression
The application of DBS to severe depression has attracted considerable attention, in part because it is helping researchers delineate a “depression circuit” in the brain—or perhaps more precisely, a depression-relief circuit. Two large clinical trials and one smaller trial are ongoing with people who have severe treatment-refractory depression (TRD), for which virtually every antidepressant therapy has failed. Each study targets different brain areas. Medtronic is funding a Phase II safety and efficacy trial in 200 patients, following a pilot study led by Donald Malone of the Cleveland Clinic that demonstrated the safety of the approach in fifteen patients. The brain target is the same as the ongoing trial in OCD—the ventral capsule/ventral striatum—and was selected in part because some patients in the OCD trial experienced improved mood after stimulation was applied to the area.
Meanwhile, St. Jude Medical, a would-be challenger to Medtronic’s domination of the U.S. DBS market, is supporting a clinical trial in one-hundred patients with TRD. The trial, led by Andres Lozano, a neurosurgeon at the University of Toronto, is based on previous clinical research by Lozano and Emory University’s Helen Mayberg that showed a response to treatment (defined as a 50 percent or greater decrease on a depression symptom scale) in about half of the twenty patients who received continuous stimulation for one year, including six who experienced complete remission of their depressive symptoms.8 The researchers have targeted the so-called “area 25” in the subgenual cingulate cortex, an area identified in a series of functional brain-imaging studies as being important to the resolution of depressive symptoms by various therapies.
Helen Mayberg of Emory University and Andres Lozano of the University of Toronto pioneered the use of deep brain stimulation to treat depression. (Courtesy of Helen Mayberg / Emory University, Courtesy of Dr. Lozano / University of Toronto)
Lastly, Thomas Schlaepfer of the University of Bonn is running a Medtronic-supported pilot study in twelve patients in which the nucleus accumbens is the brain region of interest, stemming from the accidental discovery during a trial for OCD that stimulating this area improved depression symptoms in study subjects.9 So far, researchers have not discovered which of these competing targets may prove more useful in bringing relief in the most severe cases of depression. “The world experience is not that large yet,” said Dennis Charney, dean of the Mount Sinai School of Medicine. “The results so far are interesting because they do seem to implicate particular brain regions as important in the circuits of depression. There just needs to be a lot more work done to determine who it works in, what percentage sees improvement, and whether the response is maintained over time.”
Epilepsy, Consciousness and Beyond
Medtronic is also funding a randomized controlled trial in 110 patients with epilepsy at seventeen U.S. study sites, with the goal of obtaining “premarket approval” from the FDA for an epilepsy indication. Results have not been published in a peer-reviewed journal, but preliminary data presented at a scientific conference in December 2008 indicate that seizure activity was reduced by a median of 38 percent in patients—a significantly higher figure than the 15 percent in a control group whose stimulators were activated after a delay (all patients remained on their anti-epileptic medications). The brain target in this case is the anterior nucleus of the thalamus, a central “switching station” of the brain where neuronal messages are integrated and relayed on to other brain regions.
Smaller-scale studies are under way in severe intractable Tourette’s syndrome at several sites. Published reports have encompassed about thirty-five patients in total, with the largest study to date enrolling eighteen people and targeting a discrete region of the thalamus.10 Other studies are aiming at different brain targets. A Paris-based team is recruiting fourteen patients for a study in which stimulation is directed at the internal globus pallidus.11 Overall, the treatments have shown some encouraging success in controlling the debilitating tics that characterize the disorder, but no clear consensus has emerged on the best approach or which patients are more likely to benefit from DBS treatment.
Reports of completely novel applications of brain stimulation—many with only one or two subjects—are now trickling in from around the globe. At the University of Toronto, Lozano and colleagues have used DBS to treat obesity in a 420-pound man and observed, unexpectedly, that the stimulation evoked detailed autobiographical memories.
While long-term weight loss was unsuccessful, the incidental finding of memory recovery prompted the researchers to undertake a pilot study of DBS in six patients with early Alzheimer’s disease. A media report in June quoted Lozano as saying the treatment appeared to be “safe and promising.”12 Donald Whiting and Michael Oh at Allegheny General Hospital in Pennsylvania are pursuing the weightloss application and have begun a three-patient FDA-approved trial to test whether tamping down neural activity in the lateral hypothalamus, the brain’s “feeding” center, can help obese subjects lose weight. Researchers from Milan, Italy, have reported some success in treating severe cluster headache, having followed about 18 patients for up to eight years.13
In what has been called one of the most remarkable findings yet to emerge from DBS research, Nicholas Schiff and colleagues at Weill Cornell Medical have reported on a thirty-eight-year-old man who had been in a coma for six years and regained some cognitive and motor abilities following stimulation of the central thalamus, a brain area crucial to arousal and wakefulness.14 The man, who had suffered a severe brain injury, was described as being at the “higher end” of a minimally conscious state before the treatment, meaning that some level of awareness and environmental responsiveness had been preserved. While the work has attracted widespread media attention and raised hopes that comatose patients might be revived, Schiff has said that thalamic DBS does not appear to be useful for people who are in deeper comas. Weill Cornell, the Cleveland Clinic and JFK-Johnson Rehabilitation Institute in New Jersey are now collaborating to develop a strategy and uniform protocol to guide further investigations of DBS as a treatment for those in minimally conscious states.
The Challenge Ahead
As these and other clinical investigations for DBS therapy proceed— many of them unpublished and under the radar—numerous questions remain unanswered about how best to move forward with neuromodulatory therapies for brain disorders. It is not at all clear yet which brain regions are the best targets for treating a given disorder, what the most effective parameters for stimulatory frequencies and rates are, which patients are most likely to benefit or what the long-term consequences of brain stimulation are. Ethical quandaries also loom large, as researchers feel their way forward in a complex, technically challenging field. Leading experts have consistently advocated for clear guidelines and “an abundance of caution,” as Goodman puts it, to try to ensure that the mistakes of the past are not repeated, particularly with regard to treatment of psychiatric disorders.
Nevertheless, with the right road map, attention to ethical standards and long-term follow-up of patients, neuromodulation in all its forms—including novel non-invasive methods that are just beginning to be explored—has the potential to change the way we think about and treat the worst of the worst in neurologic and psychiatric conditions.