Monday, August 17, 2009

Using Deep Brain Stimulation on the Mind: Handle with Care

By: Mahlon R. DeLong M.D.

The success of deep brain stimulation in treating movement disorders has led to investigations of its use for psychiatric illnesses. While the technique shows early promise in the treatment of depression and obsessive-compulsive disorder, Dr. Mahlon DeLong, M.D., a pioneer in the field, cautions both doctors and patients to be aware of the risks in using this yet unproven method.

Deep brain stimulation has worked for many patients with Parkinson’s disease and other movement disorders that have not responded to other treatments. However, its use as a therapy for psychiatric disorders, while promising, is not yet proven. Mahlon DeLong, a pioneer in the use of deep brain stimulation, explains the technique and why its use for depression, obsessive-compulsive disorder and other psychiatric problems requires extra caution.

Neurosurgical treatments for movement disorders such as tremor and Parkinson’s disease have undergone a renaissance in recent decades, first with ablation (the surgical removal of targeted brain tissue) and more recently with minimally invasive deep brain stimulation (DBS). Ablative surgery laid the groundwork for the introduction of experimental DBS in the treatment of several motor and psychiatric disorders, such as severe depression and obsessive-compulsive disorder, by pinpointing the specific networks of neurons involved. DBS modulates abnormal activity in these circuits, and preliminary studies of DBS in patients who fail to respond to conventional therapies for these disorders have shown promise.

Although more than 56,000 patients have undergone DBS surgery, mainly to treat movement disorders, DBS has received Food and Drug Administration (FDA) approval only for use in treating Parkinson’s and essential tremor. The procedure’s early successes have led desperate patients and families, as well as companies that manufacture the hardware, to seek more widespread approval. Researchers must balance this pressure with the need to perform well-controlled clinical studies to determine whether DBS is a safe and effective treatment for various psychiatric illnesses. Maintaining this balance will be essential for making research progress while ensuring that treatment decisions can be based on sound scientific evidence.

How does DBS modulate activity in brain circuits? Surgeons implant electrodes that can be stimulated electrically into specific brain regions. An implanted, but externally programmable, pulse generator similar to a cardiac pacemaker then delivers continuous, high-frequency electrical stimulation to the brain tissue through the electrodes. DBS counteracts the motor abnormalities of Parkinson’s disease—slowness of movement, resting tremor and muscular rigidity—and other movement disorders such as essential tremor and dystonia. It offers significant advantages over earlier surgical techniques because it is reversible and adjustable. Because DBS influences the activity of brain circuits, it is now usually referred to as “neuromodulation,” a change that emphasizes its more restorative and less destructive effects on the brain. Scientists are also considering DBS as a potential treatment for other neurological problems, including epilepsy, pain, cluster headaches, obesity and even cognitive impairment.

Initially, scientists thought that DBS simply silenced the targeted brain circuitry, mimicking the effects of lesioning. Instead, we have learned that DBS stimulates or activates targeted brain regions and acts to normalize neural network activity in those regions. The effects of DBS are significantly more complex than we initially thought, and the treatment may work differently depending on the brain regions and networks involved. When intervening in circuits in the brain’s basal ganglia, for instance, DBS has been shown to effectively treat Parkinson’s patients’ slow movement, resting tremor and rigid muscles. It also has helped individuals with essential tremor and dystonia, a disorder characterized by involuntary twisting movements and abnormal postures. Patients with these three different movement disorders respond to stimulation of the same DBS targets of the motor circuit, which suggests that the effects of this treatment are not disease- or symptom-specific, but rather circuit-specific.

The effective use of DBS in the basal ganglia to treat these movement disorders has been expanded to the experimental treatment of several psychiatric disorders. The basal ganglia are components of a family of larger brain circuits that are involved in different aspects of behavior. These networks are involved not only in movement, but also in executive functions (such as decision-making and planning), mood regulation, reward and motivation, the primary targets of experimental DBS treatment for psychiatric disorders.

Researchers currently are studying DBS treatment primarily for three psychiatric disorders: severe depression; obsessive-compulsive disorder (OCD), which is characterized by intrusive thoughts and compulsive behaviors and rituals such as hand washing and counting; and Tourette’s syndrome, which is characterized by a combination of involuntary vocal and motor tics and associated psychiatric disturbances including depression, hyperactivity and obsessive and compulsive behaviors. In February 2009 the FDA granted a Humanitarian Device Exemption—a form of limited approval for treating conditions affecting fewer than 4,000 people per year in the United States when no other effective treatment is available—for treating patients with severe OCD (the first such approval for a psychiatric disorder in the U.S.) and patients with dystonia, a sometimes profoundly disabling movement disorder. This exemption allows clinical researchers to use DBS in patients with these conditions once the investigators have received approval from their hospitals’ or universities’ institutional review boards.

DBS treatment for psychiatric disorders introduces additional clinical and ethical challenges because the brain targets are circuits involved not simply with movement but with behavior, mood, motivation and reward—the core of our being. Because we are sure neither how DBS restores brain function and reduces clinical abnormalities, nor what its long-term effects are, researchers and surgeons must proceed with caution.

Success Comes with Caveats

Our experience with DBS as a treatment for movement disorders is instructive, because even though DBS has proved successful on the whole, we have learned that it is a complicated procedure with significant risks and side effects that can be both physical and psychiatric. Although most problems stemming from DBS surgery are temporary, 1 to 2 percent of patients experience major complications.

DBS for Parkinson’s, for instance, can cause involuntary movements, impaired cognition and word finding and worsening of speech, gait and balance, but changing the level of stimulation can often remedy such problems. Seizures and failures of the DBS hardware, though never widespread, have become even rarer as techniques and equipment have improved. According to some studies, however, 5 to 10 percent of patients experience infection under the skin where the electrodes and the stimulation device are implanted.1 

By the time patients with movement disorders are referred for surgical evaluation, many have already decided to go ahead with DBS. However, these patients need to talk with their doctors about their expectations, their prior medical and psychiatric problems and the known risks and potential benefits of DBS. In the end, some patients fail to benefit from the surgery. These failures most often result from improper selection of patients, poor electrode placement and programming errors. Early in the development of DBS for movement disorders, some neurosurgeons operated on patients without the benefit of careful screening by a movement disorder specialist and adequate supporting practitioners. Such problems have become less frequent as patients have found established movement disorder centers that conduct surgical procedures and have had their devices reprogrammed or, when necessary, have undergone a second surgery to replace an off-target electrode.

Experience with performing DBS on patients with movement disorders has demonstrated that it is crucial for patients to seek a full explanation of the procedure’s potential benefits and risks. It is also important that patients have an experienced team: a neurologist who specializes in movement disorders, a well-trained and experienced neurosurgeon, a psychiatrist, a neurophysiologist, a device programmer and experienced physical and speech therapists. This team bears the major responsibility for screening and selecting suitable candidates, educating patients and their families about the surgery, setting realistic expectations and fully discussing risks and possible side effects. Not all patients with Parkinson’s and other movement disorders are suitable candidates, and this is equally true of people with psychiatric disorders. Careful screening and selection of patients are fundamental requirements for success.

Implications for Psychiatric Disorders

In rare instances, DBS itself can exacerbate or possibly cause depression and abnormal behaviors in Parkinson’s disease patients, typically when the electrode is placed in a location that allows the stimulation to spread beyond the intended regions. These instances have foreshadowed the heightened complexities of experimental testing of DBS in patients with psychiatric disorders. A recent large, multicenter retrospective study of patients with Parkinson’s disease who received DBS has revealed an increase in the risk of suicide, attempted suicide and postoperative depression. This study highlights the importance, both before and after DBS surgery, of carefully screening Parkinson’s disease patients for psychiatric risk factors, especially depression, and aggressively treating any disorder found before and after DBS treatment commences. Patients with movement disorders who suffer from depression may not feel they have benefited as expected from DBS, even though they clearly have according to objective measurements.

Although experience with treating movement disorders has provided guidance for the experimental use of DBS in treating some psychiatric conditions, and although the two types of disorders have some common problems, there are still open questions about how to proceed in this new era of neuromodulation. How can scientists, medical professionals and the public balance the desire for scientific progress and the need to protect patients from undue risks? In spite of intense pressure for widespread use of DBS, pilot studies and subsequent, well-planned, large clinical trials must take place first, and these can only happen in centers with fully staffed and dedicated teams. Patients and researchers alike must be committed to long-term care, with frequent follow-up visits for programming and medication adjustments. Only after careful research and dissemination of trustworthy findings can an informed public, along with surgeons and physicians who work with the best advice available from colleagues, ethicists, professional societies and lay organizations, help determine and then ensure the proper use of DBS for psychiatric disorders.

To better understand the potential pitfalls of widespread use of surgical approaches without adequate clinical studies, we need only to look at the long, controversial and sometimes sordid history of modulating mood and behavior with neurosurgery. In particular we may consider frontal lobotomy, a treatment option in the 1950s for patients with severe psychotic disorders such as schizophrenia. Neurosurgeons thought that severing the excitatory fibers in the lower brain of an agitated patient would calm him, but the surgery often left a patient passive and unmotivated—essentially a “vegetable.” Today we consider this procedure barbaric, but at that time—before the discovery of antipsychotic drugs—a lobotomy was the only alternative to physical restraints or seclusion in a mental hospital. The use of this procedure after World War II was part of a crisis in treating chronically mentally ill people. The situation was so severe that more than half the public hospital beds in the U.S. were used to treat patients with mental illnesses. With the introduction of psychotropic medications such as chlorpromazine (Thorazine) in the 1950s, the use of lobotomies declined precipitously. Eventually, large numbers of patents left state hospitals and received care in community health centers.

Lobotomies are but one example of early surgical explorations, for both psychiatric and movement disorders, that came about because surgeons were willing to explore potential brain targets and patients were desperate enough to take significant risks. Several factors led to a near abandonment of such surgical procedures worldwide: the introduction of levodopa for the treatment of Parkinson’s disease, the discovery of the first antipsychotic and antidepressant medications and the public and professional reaction in the 1960s against the excesses of “psychosurgery.” More medically and scientifically informed surgical lesioning procedures appeared again only in the early 1990s, due to growing appreciation of the enormous burden of neurological disorders, the frequent failure of medical therapies to ease that burden and the side effects of many of the available drugs.

Evidence for Cautious Optimism

Despite the lessons of the past and the unknowns associated with DBS, the procedure appears to be mind restoring rather than mind altering. Preliminary study results suggest that DBS relieves the painful weight of depression and the domination of obsessive thoughts, compulsions and urges, and thus restores a more normal level of functioning. There is no evidence that long-term electrical stimulation causes cell damage or permanent changes in the networks stimulated. Although DBS induces long-term changes in circuit function, these alterations seem to be reversible, as demonstrated by the fact that disorders typically re-emerge when a DBS battery fails or a lead breaks.

In some cases—especially if the patient is a minor—pre-existing mental illness may compromise a patient’s ability to understand both the key aspects of DBS and the risks involved. Thus, the all-important treatment team also should include an ethicist, either as a member or an advisor. In addition, as has been the case for movement disorders, clinical trials must have strict guidelines that exclude many patients. Patients and their families may be desperate, but without a careful selection process, we will not be able to identify the disease characteristics that indicate which types of patients are most likely to benefit from DBS.

In general, patients seeking experimental DBS surgery for major depression must have had the disorder for at least a year and must first have tried multiple treatments, including electroconvulsive (shock) therapy. Their chronic depression must also be relatively uncomplicated; patients with significant paranoia, anxiety or panic attacks would be excluded, for example. The careful screening process includes formal interviews and neuropsychological testing, as well as a visit with an independent psychiatrist, whose discussions with the referring psychiatrist and the patient’s family help build consensus and understanding and help ensure stable long-term care.

Although preliminary results of DBS for treating psychiatric disorders are encouraging, scientists understand the workings of the corresponding brain circuits far less than they understand the circuits involved in movement disorders. For patients with most psychiatric disorders, the chances of improvement via DBS are currently less than 50/50. There is considerable uncertainty. Whereas movement disorders, with the exception of dystonia, show a relatively rapid response to DBS, depression, Tourette’s syndrome and OCD are generally slow to respond; effects can take weeks or months to appear, and this delay can be frustrating and worrisome.

Even success can pose problems. As is true for patients with movement disorders, people with psychiatric disorders who, thanks to DBS, become more functional and independent after a long period of disability may experience disruptions in their relationships with spouses and other caregivers. Many people with depression and OCD have never known what it is like not to be severely afflicted, and their improvements are painfully slow and uneven. Furthermore, the adverse effects of undetected circuit stimulation failure in depressed patients are potentially far more severe than those involved in movement disorders. These effects can include severe mood changes and suicide attempts.

The two research groups studying different DBS targets in the brain for treating depression receive support from competing device manufacturers. It will be important for the groups to compare their approaches in an unbiased and rigorous way to determine which achieves the better outcomes and the less troublesome side effects. Each of the two circuit targets may prove to be more or less appropriate, depending upon the type of depression and the patient’s symptoms. Future studies should compare not only the benefits and side effects of stimulating each target, but also the nature and duration of disease remissions and patients’ long-term outcomes.

For patients with Tourette’s syndrome, the criteria for surgery are more complex because the disorder’s severity usually decreases after adolescence. Because symptoms often diminish, surgery is not recommended for patients age 25 or younger, except in the most severe cases. The risks of DBS surgery for younger patients often outweigh the potential benefits.2 Although most clinical trials have focused on controlling patients’ tics, researchers recognize that the associated psychiatric disturbances often add considerably to the disorder’s burden and, if they are extreme, may justify a second look at surgery.  

Researchers have seen promising preliminary results from early DBS clinical trials involving patients with OCD, as well as patients with Tourette’s syndrome who have obsessive-compulsive behaviors, but these patients illustrate another potential complication: the obsessive symptoms themselves. For example, patients given the option to vary their DBS parameters themselves may do so compulsively. Others may damage the device by repeatedly manipulating or picking at the skin that covers the implanted battery or the connecting wires.

Before researchers can recommend the use of DBS for routine treatment with Tourette’s syndrome and OCD patients, they must carefully explore the effects of stimulating different targets in the brain and develop patient selection guidelines and postsurgical management plans. It is encouraging that investigators at different institutions have collaborated to carry out clinical trials and to publish statements regarding patient selection, inclusion and exclusion criteria, preoperative and postoperative evaluations and selection of brain targets for the treatment of Tourette’s syndrome and OCD. These proactive efforts reduce the risk that the application of DBS surgery for psychiatric disorders will outpace the science that supports it.

Next Steps

As was the case for movement disorders, pilot studies in a small number of patients whose psychiatric disorders have been well characterized are critical to explore the different potential brain targets and to assess the initial safety and efficacy of DBS. Evidence from such studies suggests that DBS does benefit patients with severe mental illnesses. This preliminary evidence justifies undertaking larger-scale clinical trials in which patients are randomly assigned to receive DBS or a placebo (wherein DBS electrodes are implanted but not fully activated) to establish safety and efficacy in implementing the surgery. By administering subthreshold stimulation to the placebo group and a full therapeutic level of stimulation to the experimental group, clinical researchers can identify the treatment’s real effects. Such larger studies also can reveal side effects that are less common but significant.

We do not know exactly how the future of DBS and the new field of neuromodulation will evolve, but the genie is out of the bottle. Increasing numbers of patients will undergo treatment with DBS for some of the most distressing and disabling disorders known to mankind. Early successes and rapid progress generate both hope and concern.

First, hope: It may soon be possible for patients with the most disabling and resistant forms of depression, OCD and Tourette’s syndrome to find relief. Moreover, progress may spur experimental use of DBS for other psychiatric disorders. Now, concern: Scientists must avoid repeating the mistakes of the past and withstand the pressures to proceed too quickly into uncharted waters. Guidelines are essential to protect patients, and they must include rules for comprehensive evaluation and full discussion of risks, benefits and alternative approaches to ensure that DBS is the appropriate treatment choice. Careful oversight and monitoring by institutional review boards is also essential. Ultimately, physicians and psychiatrists must assure the public that they will do away with the negative associations of psychosurgery by bringing the modern field of neuromodulation to its full potential.

References

1. F. M. Weaver, K. Follett, M. Stern, K. Hur, C. Harris, W. J. Marks Jr., J. Rothlind, O. Sagher, D. Reda, C. S. Moy, R. Pahwa, K. Burchiel, P. Hogarth, E. C. Lai, J. E. Duda, K. Holloway, A. Samii, S. Horn, J. Bronstein, G. Stoner, J. Heemskerk, and G. D. Huang; CSP 468 Study Group, “Bilateral Deep Brain Stimulation vs Best Medical Therapy for Patients with Advanced Parkinson disease: A Randomized Controlled Trial,” Journal of the American Medical Association 301, no. 1 (2009): 63–73.

2. J. W. Mink, J. Walkup, K. A. Frey, P. Como, D. Cath, M. R. DeLong, G. Erenberg, J. Jankovic, J. Juncos, J. F. Leckman, N. Swerdlow, V. Visser-Vandewalle, and J. L. Vitek; Tourette Syndrome Association, Inc., “Patient Selection and Assessment Recommendations for Deep Brain Stimulation in Tourette Syndrome,” Movement Disorders 21, no. 11 (2006):1831–1838.



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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