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July 24, 2006
Deep brain stimulation (DBS), a neurological procedure that involves surgical implantation of electrodes, is an effective and widely used treatment for patients with Parkinson’s disease. The implanted electrodes deliver electrical impulses to brain regions that control the condition’s characteristic tremors and other symptoms. For patients with Parkinson’s, DBS of the subthalamic nucleus in the brain has become a standard of care. However, physicians aren’t sure exactly why the accepted procedure works so well. “Although DBS has been used for a while, the exact mechanisms of action aren’t quite clear to us,” says Michael D. Phillips, MD, a neuroradiologist with The Cleveland Clinic’s Center for Neurological Restoration. But they’re trying to find out. Phillips and colleagues are engaged in ongoing research hoping to identify the mechanisms underlying the therapeutic effects. Specifically, The Cleveland Clinic researchers are employing functional magnetic resonance imaging (fMRI) to answer some of their questions. Thus far, relatively few MRI examinations have been performed to evaluate the function of DBS. Their initial research shed some light on these action mechanisms, showing the parts of the brain that respond to DBS and indicate apparently significant cerebral activation patterns. In addition, their work has shown that with controlled conditions, fMRI can be performed safely during DBS. This is an important finding. While fMRI is often used to view brain activity, it can be hazardous when used to monitor DBS. Risks involve damage to the DBS pulse generator and induced currents and heating within DBS leads, which can cause patient injury. When it comes to the mechanisms of action, the researchers say their work is introductory. Even so, their research represents a step forward, as it will open doors to other studies. Future studies could provide valuable information about the pathophysiology of the disease and optimization of patient response to DBS. Moreover, it could point toward future advances in neurostimulation technologies and approaches. Stimulating the Brain Before the procedure, a neurosurgeon employs imaging technology, such as MRI or computed tomography, to pinpoint the regions in the brain where these abnormal nerve signals arise. Usually, these areas include the thalamus, subthalamic nucleus, and globus pallidus. The neurosurgeon then places the DBS system in the appropriate region. A DBS system includes a lead wire, an extension wire, and the neurostimulator. The lead wire, or electrode, is inserted through an opening in the skull, with its tip positioned in the targeted brain area. The extension wire is inserted under the skin of the head, neck, or shoulder and connects the lead wire to the neurostimulator, which is usually placed under skin, either near the collarbone or abdomen or in the lower chest region. When the system is in place, the neurostimulator generates electrical impulses that flow through the extension wire and the lead and then into the brain, where they block the abnormal nerve signals. DBS of the thalamus and subthalamic nucleus has demonstrated therapeutic value in the management of Parkinson’s symptoms, and it provides several significant advantages: The system won’t damage healthy brain tissue; the provided neurostimulation can be readjusted to accommodate a patient’s changing condition; and the DBS system can be easily removed if a better procedure is developed. Unanswered Questions “We’re trying to better understand how DBS works,” says Phillips. “We thought that if we could perform fMRI while a patient was being stimulated, we could learn which portions of the brain were being directly affected by DBS.” The researchers employed fMRI because they thought it would best address the questions relating to the mechanisms of action. A noninvasive fMRI can map brain activity through a specialized sequence that detects small changes in local cerebral blood flow resulting from neuronal activity. Compared with radioisotopic imaging studies, such as positron emission tomography or single-photon emission computed tomography, which are often employed for similar purposes, fMRI offers several advantages: It avoids usage of intravenous contrast material, provides improved spatial resolution, and has better temporal resolution. Further, the researchers performed fMRI at 3T, which offers higher resolution of the deep brain structures compared with 1.5T MR systems. The research team includes Phillips; Kenneth B. Baker, PhD; Mark J. Lowe, PhD; Jean A. Tkach, PhD; Scott E. Cooper, MD, PhD; Brian H. Kopell, MD; and Ali R. Rezai, MD. They reported their findings in the April issue of Radiology and a paper titled “Parkinson Disease: Pattern of Functional MR Imaging Activation during Deep Brain Stimulation of Subthalamic Nucleus—Initial Experience.” Going into their study, they theorized that they’d see a consistent pattern of cerebral activation in patients with Parkinson’s who had DBS leads placed in their subthalamic nucleus. They also anticipated that, thanks to extensive pretesting, fMRI used with DBS would be safe for patients. Their findings indicate that they were correct on both counts. Patterns Revealed Following extensive phantom safety testing of DBS lead systems, the subjects were examined by using fMRI one or two days after the surgical stimulator placement. First, the subjects underwent imaging performed without the DBS leads attached to an external pulse generator placed in an MR imaging control room. Imaging was performed with a 3-D data set for anatomic localization. After completion of the anatomic imaging data set, a single DBS lead was attached to the pulse generator and fMRI acquisitions were performed by using prospectively motion-corrected, 2-D, gradient-echo, echo-planar imaging. In all, nine electrodes were stimulated. Subjects underwent a neurologic examination immediately before and after imaging. The results of all examinations for all subjects indicated no neurological changes. Activation was seen in eight of nine electrodes stimulated. Further, this activation revealed a clearly discernable, consistent pattern. As a result of their findings, the researchers concluded that effective DBS of the subthalamic nucleus produces a consistent pattern of ipsilateral activation, primarily in the globus pallidus externa and thalamus, in response to the electrode stimulation. Safety Factor For instance, the rapid heating associated with MRI—typically occurring within the first 90 seconds of imaging—without adequate time for dispersion could cause a focal brain lesion. However, the researchers indicated that the results of their study demonstrated that, with carefully controlled specific conditions, fMRI can be performed safely at 3T during DBS. Their combined results for the heating and safety experiments demonstrated that none of the imaging sequences produced a temperature increase greater than 1.4° C. Therefore, with the specific configuration they used—which included specific pulse sequences, wiring of the electrodes and lead extenders, and imaging platform—fMRI with DBS was deemed safe for imaging in humans. As those findings suggest, safety entails a great deal of effort, as safety data is specific to pulse sequences and can’t be generalized among imaging platforms. That is, safety testing of each MRI system and operating software must be conducted before any imaging can be performed. “Safety testing doesn’t work consistently from one magnet to the next,” emphasizes Phillips. “We did a great deal of safety testing before we even did our first subject, and anyone who would want to do this kind of work would have to do extensive testing beforehand on their own equipment. So, it is not something that you can just go out and do. It really involves a tremendous amount of preliminary work.” Further Research And a lot more work to do, he adds: “We’re funded by the National Institutes of Health to perform studies on 60 or more patients so that we can better understand exactly what’s going on. Basically, with this study, we’ve only just began.” Still, he points out that the study suggests they’re on the right track. “The study showed us that we could do this, and it revealed pretty consistent activation in the group of five patients.” He admits that while the number is not enough to make a strong statement, the research suggests which brain regions are most likely involved in the efficacy of DBS, and that’s an important finding. As for the future research, Phillips expects it will help researchers determine which patients receive optimal stimulation. “But that will require a lot of work,” he says. “We’re looking forward to fixing our protocols, which could give us a better idea of what is going on in the cortex, which is hard for us to do right now. So, we’ve essentially completed the first of a whole series of steps.” — Dan Harvey is a freelance writer based in
Wilmington, Del. |
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