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A Review of the Neural Interfaces Workshop: National Institutes of Health and the National Institute of Neurological Disorders and Stroke

The Parkinson Alliance/DBS-STN Research Team

Science continually proves that progress in the treatment of Parkinson's disease isn't just possible, it is inevitable. In the beginning of September of this year, a few of the Parkinson Alliance staff attended the Neural Interfaces Workshop in Bethesda, Maryland, which was presented by the National Institute of Neurological Disorders and Stroke (NINDS). A significant portion of this conference was dedicated to presenting updates on and introducing rigorous research endeavors that help facilitate the understanding and enhancement of treatment for Parkinson's disease, as it relates to Deep Brain Stimulation (DBS).

To begin the conference, the staff of The Parkinson Alliance attended a round-table wherein some of the leaders in DBS research were in attendance. The conversations during this meeting provided a fascinating glimpse into several of the innovative projects that are being conducted at specific institutions. Additionally, the "vision" of DBS therapy was discussed. The intellectual dialogue during this gathering illustrated a universal understanding that optimal outcomes of DBS therapy will most likely ensue when there is 1. appropriate screening procedures, 2. trained healthcare professionals performing DBS surgery, 3. clinical trials evidencing the optimal lead location, 4. trained personnel providing DBS programming, 5. access to DBS programming, 6. an interdisciplinary team approach [that effectively communicates with one another], 7. education for treatment providers to identify and treat complications of DBS, and 8. education to the patients and caregivers to empower them in assisting in treatment-related decisions.

Additionally, further discourse in this gathering revealed that ongoing dogma exists as it relates to different approaches when choosing the site to place the deep brain stimulator; for example, irrefutable evidence that the subthalamic nucleus (STN) is the superior anatomical structure to stimulate over the Globus Pallidus internal segment (GPi) does not exist at this point in time. Dr. Jerry Vitek, a neurologist at the Center for Neurological Restoration at the Cleveland Clinic Foundation, stated, "Maybe the STN is the best site out there, but we do not know for sure, yet." Regardless of the specific site, the enthusiasm pertaining to the benefits of DBS was as palpable as a sheet of glass. Dr. David Heydrick, a neurologist and person with DBS-STN, mentioned how his experience with DBS improved his quality of life immensely, which was exemplified by his statement. "To be able to throw a baseball with [my] son again improved [my] quality of life considerably." Other intriguing topics were discussed and will be mentioned vis-a-vis providing a brief overview of some of the information presented at the conference.
Many presenters facilitated lectures on the continued investigations of the effects of stimulation on the two major anatomical structures that, when stimulated, assist in the amelioration of PD symptoms: the Globus Pallidus internal segment (GPi) and Subthalamic Nucleus (STN). Dr. Robert Turner from the University of California, San Francisco, Dr. John Assad from Harvard Medical School, and Dr. Dieter Jaeger from Emory University among others highlighted some very important points from their research. They stated that a complete understanding of the mechanisms of action of therapeutic DBS will require not only detailed information about the local effects of DBS on the neuronal and cellular elements near the site of stimulation, but also how those local effects are translated into a global reduction in parkinsonian symptoms. They discussed how the stimulation of the GPi or STN causes a complex reaction to the temporal areas of the structure, those immediately around the structure [deep within the brain], and to the surface of the brain; the circuitry between these structures are instrumental in movement initiation and cessation.

Furthermore, and along similar lines, there were several posters that pointed out that high frequency stimulation of the STN results in various neurotransmitter changes (chemicals within the brain) outside of this structure. This point, once again, raises the question, "What is the optimal target or area that leads to the changes in the brain that help Parkinson's patients?" One research project, for example, that was conducted by Kendall Lee et al., having affiliations with Dartmouth-Hitchcock Medical Center, University of Memphis, or Emory University, found that there are areas [fibers] just outside of the STN (e.g., dorsal or just above) that lead to greater dopamine release than stimulation within the STN. The implications of studies like this one are of great importance, pointing out that there is a true complexity of the impact of DBS on neurotransmitters in the brain and that precise placement of the "leads" in the brain is crucial for optimal functional outcome. Moreover, the STN seems to be an ideal structure that has lead to some optimal outcomes, but the definitive understanding about why the STN is such an ideal placement is still relatively enigmatic, particularly as it relates to understanding its impact on other structures and fibers.

To assist in our enhancement in understanding DBS and to aid in the ability to implement DBS therapy, new software programs have been created. A couple of fascinating posters presented cutting edge software that assists in the treatment of Parkinson's disease, among other conditions that require DBS therapy. Specifically, advancements have been made in software programs that can aid in both the process of undergoing DBS and with the subsequent programming. With regard to the former, Miocinovic et al., with affiliations to the Department of Biomedical Engineering at Case Western Reserve University, the Department of Biomedical Engineering at the Cleveland Clinic Foundation, and Center for Neurological Restoration at the Cleveland Clinic Foundation, have created a software program to help optimize lead placement during neurosurgery. Conventional ways of conducting neurosurgical procedures included 2-dimensional images and paper records of the "stereotactic" coordinates (a method in neurosurgery and neurological research for locating points within the brain using an external, three-dimensional frame of reference) for noteworthy recordings. These individuals highlighted that this approach is prone to errors because of the brain shape, size, and location of subcortical structures (structures that exist below the surface of the brain) can vary between subjects. These individuals developed a software tool called "Cicerone" that enables interactive 3-dimensional images to help visualize the magnetic resonance images (MRIs), 3-dimensional anatomical nuclei, and the recording microelectrode(s). Further refinements to the 3-dimensional nuclei geometry and position can be made interactively during the microelectrode mapping. The software can be used in preoperative planning to help select the optimal position on the skull to create the hole that will permit the implantation of the deep brain stimulator and to maximize the likelihood of complete microelectrode coverage of the intended anatomical target. The software can be used intra-operatively as well to help identify the electrode location in 3-dimensions relative to the surrounding anatomy.

As many clinicians and patients know, although there have been some major advances in our understanding of DBS, the challenges of "programming" can be a difficult and time-consuming process. Specifically, the thousands of parameter setting combinations, the tiresome effects of the seemingly endless period of trial and error while setting the parameters, and the absence of standardized approaches are issues that need to be addressed. To add some hope to this cumbersome and/or challenging process, a variation of the aforementioned software program was designed to aid in the programming of DBS therapy. Christopher Butson et al., having affiliations to the Department of Biomedical Engineering at the Cleveland Clinic Foundation, the Center for Neurological Restoration at the Cleveland Clinic Foundation, and the Department of Neurosurgery at Stanford School of Medicine, facilitated a marvelous presentation entitled "StimExplorer: Interactive Visualization Software for Deep Brain Stimulation Parameter Selection." Their new software aids in the postoperative programming of DBS-STN. Similar to the "Cicerone" program, using a 3-dimensional image, the "StimExplorer" customizes the system to an individual patient and can demonstrate and evaluate the effects of electrode location and stimulation parameter settings. The"StimExplorer" calculates and suggests a theoretical optimal stimulation parameter setting for an individual patient. The implications are quite impressive. The benefits include decreasing time and effort needed to adjust the stimulation parameters to achieve acceptable clinical results, assisting in standardizing DBS programming, and providing a teaching tool on the effects of DBS.

Another aspect of the conference incorporated many researchers who continued to demonstrate the benefits of DBS intervention on motor symptoms. For example, Dr. Daniel Corcos, a professor at the University of Illinois at Chicago, facilitated a lecture on the Effects of STN stimulation on Tremor, Rigidity, and Bradykinesia. The research conducted by him and his colleagues demonstrated that STN stimulation dramatically increases movement speed at both the elbow and ankle joint, reduced resting and postural tremor to healthy levels and reduced rigidity by altering muscle activation. Another individual, Dr. Jing-Yu Chang from Wake Forest University School of Medicine, also demonstrated further confirmation of and advancement in the understanding of improved motor dysfunction as it relates to PD. Specifically, he and his colleagues demonstrated through animal models that locomotion and one-sided impairment can be improved significantly with DBS-STN. In all of their tests, DBS-STN significantly reversed motor deficits caused by dopamine depletion.

In addition to the many lectures on motor symptoms of PD, a lecture on the Impact of DBS-STN on Cognition, Mood, and Behavior in PD was also facilitated. Dr. Marjan Jahanshahi, a neuropsychologist from the Institute of Neurology at the University College London, addressed the following: 1. DBS-STN does not produce any global adverse effects on cognition, 2. when cognitive decline is documented following DBS surgery, the age of the patient, his/her pre-operative cognitive status, and the level of dopaminergic medication, the precise location of the implanted electrodes and the pulse width used for stimulation may be key factors in explicating these findings, 3. DBS-STN has been shown to produce psychiatric features ranging from mania to apathy, hallucinations, aggression, and improvement of obsessive-compulsive behavior, but, although a couple of these symptoms have been found to be long-lasting, most of these effects are transient and only present themselves in the immediate post-operative phase, and 4. for the majority of patients, significant improvement of anxiety, depression, and quality of life has also been reported.

In the context of lectures related to non-motor symptoms, The Parkinson Alliance had the opportunity to present some of our research at this conference. Specifically, we presented the results from our most recent survey "Comparing Quality of Life in Parkinson's Disease Patients with and without Deep Brain Stimulation." For a thorough review of our research, please visit the "DBS-STN.org" website.

In summary, we continue to learn more about the cause of motor and non-motor symptoms of Parkinson's disease as well as the benefits and challenges with regard to treatment. Dedicated scientists, clinicians, advocates, and patients and those who share their lives continue to enhance our understanding of the treatment for PD, which will inevitably lead to progressing towards optimal treatment outcomes.

References:
Butson, C., Maks, C., Noecker, A., Cooper, S., Henderson, J., & McIntyre, C. StimExplorer: Interactive Visualization Software for Deep Brain Stimulation Parameter Selection. Platform and poster presentation at the Neural Interfaces Workshop with was sponsored by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke, September 2005.

Lee, K. Blaha, C., Kristic, K., Hitti, F., Ansevin, D., Muly, C., Harris, B., Leiter, J., & Roers, D.. STN High Frequency Stimulation Results in STN Glutamate Release and Striatal Dopamine Release in the Rat: Potential Mechanism of Action in Parkinson's Disease. Poster presentation at the Neural Interfaces Workshop with was sponsored by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke, September 2005.

Miocinovic, S., Noecker, A., Butson, C., Russo, G., Vitek, J., & McIntyre, C. Cicerone: 3D Visualization Database Software for Stereotactic Neuropsychological Recordings. Poster presentation at the Neural Interfaces Workshop with was sponsored by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke, September 2005.

Wertheimer, J., Tuchman, M., Walton, C., Kramer, R., Wherry, J., & Kingery, L. Comparing Quality of Life in Parkinson's Disease in Patients with and without Deep Brain Stimulation. Platform and poster presentation at the Neural Interfaces Workshop with was sponsored by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke, September 2005.



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