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The Future of Neuromodulation

The Parkinson Alliance/DBS-STN Research Team

Neuromodulation is the science of how electrical, chemical, and mechanical interventions can modulate or change central and peripheral nervous system functioning. Because of our interest in deep brain stimulation (DBS), The Parkinson Alliance recently attended an outstanding research conference of the American Society for Stereotaxic and Functional Neurosurgery (ASSFN). Sponsored by the Cleveland Clinic Foundation, Medtronic, and many other institutions and businesses, the meeting was held in a state-of-the-art conference facility at the Cleveland Clinic from October 1-3rd.

By bringing together many of the most creative and productive members of the field, the goal of the conference was ambitious - to effectively define the future of neuromodulation. The conference agenda was organized primarily by clinical category, with half-day sessions devoted to each of the following topics: movement disorders, epilepsy, chronic pain, neuropsychiatric disorders, and emerging applications.

The majority of the research involved deep brain stimulation, but many other neuromodulation methods were discussed, including gene therapy, drug infusion therapy, motor neural prosthesis, brain/machine interfaces, and many others. Because the meeting was relatively small, all of the attendees met in a single conference hall, which was unique and fostered frequent interaction between the audience and the presenters. During the first half of each session, experts in various areas of neuromodulation presented their work.

They were followed by briefer abstract presentations, some of which were unpublished research results. The material covered within each session was impressively diverse and at times highly technical. For these reasons, it is impossible to comprehensively summarize the content of the conference in this brief review. However, a few central themes emerged that we believe are important to consider. We encourage you to explore these themes further by scrutinizing the references and internet links listed below. The most remarkable and exciting theme, of course, is how effective DBS can be. Dramatic illustrations of this fact were documented by films that showed patients before and after surgery.

One film showed a young man who experienced almost complete remission of symptoms of Tourette syndrome following DBS. Other films depicting the effective treatment of Parkinson's disease and obsessive-compulsive disorder were equally noteworthy. Dramatic case-studies, however, cannot serve as the primary evidence for the effectiveness of DBS. Although many outcome studies indicate that DBS for movement disorders is effective for most people and relatively safe, there are very few long-term outcome studies of DBS.

 Exactly how DBS works is not fully understood, but tremendous progress has been made in discovering the mechanisms underlying its effects. Of course, the placement of the electrode is critical and many of the presentations discussed the best brain "target" for DBS; that is, the ideal brain region to apply electrical stimulation. DBS of the subthalamic nucleus (STN), globus palidus, thalamus, hypothalamus, cerebellum, and some cortical regions has been shown to ameliorate neurologic and psychiatric symptoms. These target brain regions vary in size, and it is clear that the effectiveness of DBS depends upon precise placement of the electrodes. For many disorders, the optimal brain target is not known. For a discussion of the issues related to optimal electrode placement, see Kuncel and Grill (2004). The paradox of DBS is that electrical stimulation of brain tissue, which presumably induces brain activation, has the same effect as that of a surgical lesion, which effectively destroys brain tissue. The ultimate elucidation of this paradox depends on the nature of the complex and interactive neural connections in the brain that communicate through electrical and chemical processes.

Although consensus has not been reached, there is an emerging view that DBS has both excitatory and inhibitory effects on how brain circuits communicate with one another. For a discussion of issues related to how DBS works, see McIntyre et al. (2004) and Breit et al. (2004). According to Dr. Alim-Louis Benabid, the "founding father" of DBS, for the treatment of movement disorders it is known that high frequency stimulation (100-185 Hz) is more effective than lower frequency stimulation. In fact, stimulation at low frequencies can actually exacerbate tremor in movement disorders. There are many ways to vary the "parameters" of stimulation (e.g., amplitude, frequency, duration, etc.), and each one likely plays a unique role in the patient's individualized response.

Although basic guidelines exist for stimulator programming, according to many surgeons and patients the "art" of stimulator programming is alive and well. Interestingly, there was even a lack of consensus about whether or not to turn the stimulator off after surgery, with some surgeons preferring to never turn the stimulator off and others systematically and longitudinally examining the effect of stimulator parameters on symptoms. Unfortunately, there is little methodical research on long-term programming considerations. It may be that greater individualization of stimulator parameters, including relatively frequent re-adjustments, can lead to even better outcomes. Like most medical procedures, DBS poses risks, and these risks were given adequate attention by the presenters. For example, Dr. Benabid pointed out that although negative side effects of DBS are typically not severe, one consistent finding is that speech may be disrupted by DBS. This observation is supported by other studies as well as our own survey research at The Parkinson Alliance on quality of life in individuals with DBS. Our preliminary results reveal that speech problems are commonly experienced by DBS patients.

Our recent review of issues related to speech and DBS can be found on the DBS-STN.org website. This and other side effects are only beginning to be explored empirically. A discussion of the risks of DBS can be found in Piasecki and Jefferson (2004), Rezai et al. (2004), and Pollak et al. (2002). In addition to risks, important considerations regarding ethical issues surrounding DBS and neuromodulation were discussed, including conflicts of interest, informed consent, and the relationship between science and industry. One clear recommendation in this context was the establishment of a national registry of single-case reports. Such a registry would assure that cases in which DBS produced negative results would be published and available to the scientific community for review. Throughout the conference, fascinating research was presented on the various methods involved in implementing DBS. These topics included, for example, using computer modeling to customize the electrode placement for individual patients, engineering considerations in developing neuromodulation devices, the risks of undergoing an MRI after DBS, and predicting successful response to DBS. Regarding the latter topic, research suggests that younger age, but not gender, predicts positive response to some degree. A history of confusional states, dementia, or other cognitive impairment is also associated with poorer outcome following DBS. The condition of the brain also predicts outcome uniquely; patients with relatively large brain ventricles (fluid-filled cavities in the brain) which are typically indicative of brain atrophy, tend to respond less well to DBS. These and other factors serve as the basis for the recommendation that surgical candidates require a thorough, multidisciplinary evaluation. The field would be served well by the establishment of standards of practice for patient inclusion and exclusion criteria. Much more research needs to be done to more fully determine what physical, psychiatric, neuropsychological, and social factors serve to reduce the effectiveness of DBS. Following movement disorders, the next most common disease treated with DBS and other neuromodulation techniques is epilepsy.

A number of studies were reviewed that showed very significant reductions in seizure activity as a result of DBS treatment. One of the most intriguing developments in the realm of epilepsy was illustrated by a presentation by Dr. Joseph Smith and colleagues at the Department of Neurosurgery at the Medical College of Georgia. These researchers developed and tested a device capable of "responsive neurostimulation." Instead of being applied on a fixed schedule, as in movement disorders, the stimulator is triggered by intrinsic brain activity that typically precedes a seizure. By intervening before a seizure develops, this intervention can help prevent seizures. Although the results are extremely preliminary, they are positive and show that seizures can be predicted by brain activity measured by multiple subdural electrodes. This research serves as an exemplar of the novel technologies that will be developed in the coming years. The theme of emerging applications was prominent throughout the conference. Now that it has proved effective as a treatment for movement disorders and epilepsy, DBS is being used experimentally in the treatment of pain, stroke, and neuropsychiatric disorders such as Tourette syndrome, obsessive-compulsive disorder, and depression. The study of the effectiveness of DBS for these disorders is in its infancy, with few controlled clinical trials published to date. The patients who have received DBS for these conditions have typically failed all other conventional treatment modalities and undergo a rigorous screening process before surgery.

Before conclusions can be made regarding the safe and effective treatment of these disorders using DBS, a tremendous amount of basic and clinical research needs to be done. One emerging application that has yet to move from the laboratory to the operating room is examining the effect of DBS on the neuroregulation of feeding behavior. This research has been conducted only in animals, though the potential for DBS in the treatment of obesity and eating disorders was offered as a possibility in the future. One final emerging application that was particularly captivating was the work of Dr. Gerhard Friehs and colleagues. Dr. Friehs demonstrated that a brain-machine interface can be made. A wide range of computer, technical, and research developments over the past 10 years have enabled the creation of a "prosthesis," by which a monkey (and even a few humans!) can learn to use feedback about their brain activity to control a computer or robotic device. In a brain-machine interface, the brain learns to view and control a mechanical device as it would a natural body part. In other words, in the future it may be possible to control computers and other devices with our minds! For a review of these developments, see Friehs et al. (2004). Not only is the brain amenable to the beneficial effects of controlled electrical stimulation, but so is the peripheral nervous system. The use of peripheral stimulation is being explored in many peripheral nervous system conditions, including chronic pain, cluster headache, and peripheral nerve stimulation. Vagal nerve stimulation (VNS) is approved by the FDA for the treatment of epilepsy, and the technology was recently nearly approved by the FDA for treatment resistant depression. The field of peripheral nervous system stimulation is expanding rapidly and will undoubtedly lead to effective treatments for a variety of disorders. These observations capture only a small sample of the voluminous amount of information reviewed and debated during this fascinating and informative conference. Though tremendous advances have been made in the field of neuromodulation, many questions remain unanswered. For example, it is not yet known whether DBS has any neuroprotective effects. Research addressing this and many other important topics is only beginning to be explored. The ultimate future of DBS and other neuromodulation methods was brought into sharper focus by the end of this conference. The theoretical and technical advances made over the past 20 years bode extremely well for the field to achieve its ultimate goal - to cure disease and relieve suffering. Indeed, there is no question that the future of neuromodulation is bright! The field is on the cutting-edge of developments across a wide range of scientific disciplines and requires the input and support of scientists, patients, industry, government, and education and research organizations such as The Parkinson Alliance. We look forward to sharing with you much more information about future developments in neuromodulation as they emerge.

References:
Breit, S., Schulz, J.B., & Benabid, A.L. (2004). Deep brain stimulation. Cell Tissue Res. 2004 Oct;318(1):275-88. Friehs, G.M., Zerris, V.A., Ojakangas, C.L., Fellows, M.R., & Donoghue, J.P. (2004). Brain-machine and brain-computer interfaces. Stroke. Nov;35(11 Suppl 1):2702-5
Kuncel, A.M., & Grill, W.M. (2004). Selection of stimulus parameters for deep brain stimulation. Clin Neurophysiol. 2004 Nov;115(11):2431-41. McIntyre, C.C., Savasta, M., Kerkerian-Le Goff, L., Vitek, J.L. (2004). Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol. 2004 Jun;115(6):1239-48. Piasecki, S.D., & Jefferson, J.W. (2004). Psychiatric complications of deep brain stimulation for Parkinson's disease. J Clin Psychiatry. 2004 Jun;65(6):845-9. Pollak, P., Fraix, V., Krack, P., Moro, E., Mendes, A., Chabarades, S., Koudsie, A., & Benabid, A.L. (2002). Treatment results: Parkinson's disease. Mov Disord.;17 Suppl 3:S75-83. Rezai, A.R., Phillips, M., Baker, K.B., Sharan, A.D., Nyenhuis, J., Tkach, J., Henderson, J., Shellock, F.G. (2004). Neurostimulation system used for deep brain stimulation (DBS): MR safety issues and implications of failing to follow safety recommendations. Invest Radiol. May;39(5):300-3.



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