Improving the Accuracy and Efficiency of Surgical Implantation of Therapeutic DBS Electrodes: Intra-operative Use of Local Field Potentials to Indentify the Subthalamic Nucleus

Peter Brown, M.A., M.D., F.R.C.P.

Institute of Neurology, London

Funded in December, 2004: $136000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY . FINDINGS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Improving Accuracy and Efficiency in Deep Brain Stimulation to Treat Parkinson's Disease

Researchers will undertake initial clinical studies of two new techniques for determining more precisely where electrodes should be surgically placed to produce effective deep brain stimulation for patients with Parkinson's disease. If the pilot and feasibility studies are successful, the results could advance surgical treatment of Parkinson's disease, making it easier and more effective both for patients and their neurosurgeons.

Parkinson's disease results from a loss of cells in the brain that transmit dopamine from one cell to another to facilitate the control of movement, as well as some cognitive abilities. As dopamine-transmitting cells die, movement control is diminished, and abnormal signaling ensues. This abnormal neuronal signaling produces the tremor and slow gait that are characteristic symptoms of Parkinson's disease. While treatment with L-DOPA replenishes dopamine supplies used by remaining dopamine-transmitting brain cells and provides effective therapy for several years, its long-term use produces motor problems in 80 percent of patients. This has led to renewed interest in deep brain stimulation to treat these patients.

Deep brain stimulation involves planting electrodes within the subthalamic nucleus, which lies deep within the brain. A stimulator then is implanted to activate the electrodes on an ongoing basis. The electrodes block the uncontrolled signals that produce tremor and other symptoms. Many Parkinson's patients have derived clinical benefit from deep brain stimulation in reducing these motor symptoms, especially tremor.

The technique's therapeutic efficacy has been somewhat limited, however, by difficulties neurosurgeons face in consistently and accurately determining where to place the electrodes to achieve maximum ability to block the abnormal neuronal signaling. Inaccurate electrode placement not only diminishes effectiveness, but also produces difficult side effects. Moreover, the currently used surgical procedures take several days, and during parts of the procedures patients must be awake so that their responses can help guide the surgeon's electrode placements.

To overcome these problems, researchers at the Institute of Neurology, University College, London, have developed two approaches for more precisely identifying how to effectively target electrode placement to interrupt abnormal circuitry among dopamine-transmitting neurons in the brain. They now plan initial pilot, feasibility, and test studies in a small number of Parkinson's patients to see if their promising results in animals can be effectively translated into improved surgical treatment for humans.

One approach involves detecting increased spontaneous activity of the "local field potential" (of groups of motor neurons) in the brain, as a marker for identifying where the electrodes should be placed to interrupt abnormal signaling. Placement of electrodes that interfere in this field's activity is anticipated to achieve maximum effect in enabling remaining dopamine-transmitting cells to control movement. The second approach involves actively evoking activity in this "field" to identify precisely where the inappropriately activated motor cells are located.

Prior animal studies by the researchers have shown that, by actively stimulating the somatomotor cortex, they can evoke activity in a distinct field of motor cells. Moreover, this response by motor cells is not affected by general anesthesia. Based on findings from the animal research, the researchers hypothesize that both spontaneous and evoked activity can be used as markers to target surgical implantation of the electrodes with precision within the subthalamic nucleus. Additionally, they hypothesize, these methods can be used effectively while patients are under general anesthesia.

Through pilot tests in ten Parkinson's patients, the investigators will see whether the motor activity can be recorded by either method equally well while patients are under anesthesia compared to awake. This will be followed by feasibility tests in an additional six patients, to see if identifying the motor activity using these methods can effectively guide the surgical placement of electrodes. If these two studies are successful, the researchers then will test the two methods in a total of ten patients, to see if the two methods can be completed successfully in a single surgery under anesthesia and if patients' motor symptoms significantly improve following surgery.

Significance: If the proposed study demonstrates the effectiveness of these two methods for more accurately implanting electrodes to produce effective deep brain stimulation for Parkinson's patients, the findings could fundamentally improve surgical practice and outcomes for treating this disease in patients who no longer benefit from drug therapy.

ABSTRACT

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Improving the Accuracy and Efficiency of Surgical Implantation of Therapeutic DBS Electrodes: Intra-operative Use of Local Field Potentials to Identify the Subthalamic Nucleus

Electrical stimulation of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. We will develop an intra-operative implantation technique that will confirm optimal targeting. Specifically, we will investigate the utility of two novel intra-operative approaches for identifying the motor domains of the STN using the local field potential (LFP), a measure of neuronal population activity that can be recorded from either microelectrodes or macroelectrodes.

The first approach concerns spontaneous LFP activity. We have established that the LFPs recorded from the STN in rats with 6-hydroxydopamine (6-OHDA) lesions of midbrain dopamine neurons, an established rodent model of PD, and in patients with PD are characterized by prevalent activity in the so-called beta frequency (13-35 Hz) band. We hypothesize that this activity is maximal in the motor domain of the STN and can be used to identify this region.

The second approach involves evoked LFP activity. We have recently reported that stimulation of somatomotor cortex in the rat evokes a focal and distinctive LFP in the functionally related domain of STN. This signature LFP can be seen readily in single stimulus trials and is relatively unaffected by general anesthetics. Critically, the circuitry underlying the evoked LFPs in rats is also present in primates, so we hypothesize that similar evoked LFP activities will be present in patients. Accordingly, we will record the LFPs evoked in the STN of patients with PD in response to transcranial magnetic stimulation of the primary and supplementary motor cortices.

Initial recordings will be made from macroelectrodes between their implantation and subsequent connection to the stimulator. Thereafter, we will record spontaneous and evoked activity intra-operatively from such electrodes. Application of our techniques in functional neurosurgery should enable the implantation procedure to be performed more accurately and rapidly as compared to contemporary approaches, with attendant benefits for patients.

INVESTIGATOR BIOGRAPHIES

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Peter Brown, M.A., M.D., F.R.C.P.

Professor Peter Brown obtained his medical degree from Cambridge University in 1984 and thereafter joined the Medical Research Council Human Movement and Balance Unit before moving to the Institute of Neurology, London. He works as a neurologist at the affiliated National Hospital for Neurology and Neurosurgery, London, and within the Sobell Department of Movement Disorders and Motor Neurophysiology at the Institute of Neurology, where he leads the Clinical Motor Neurophysiology Group. The principal objective of this group's research program is to define how activity in large populations of neurons is coordinated in healthy movement and how such coordination may go awry in diseases, particularly those of the basal ganglia such as Parkinson's disease. It is hoped that such work will increase our understanding of disease mechanisms and contribute to advances in the therapy of movement disorders.

Marwan Hariz, M.D., Ph.D., is currently a Professor of Functional Neurosurgery and an Honorary Consultant Neurosurgeon at the Institute of Neurology & National Hospital for Neurology and Neurosurgery in London.  He is the first neurosurgeon to receive the honorary medal of the Swedish Parkinson’s Disease Association and is also an appointed national expert in Pallidotomy by the Swedish Council on Technology Assessment in Health Care.  Dr. Hariz additionally serves as a referee for the Swedish National Patient Council on issues related to stereotatic surgery.

Born in Beirut, Dr. Hariz attended the Baccalauréat, Lycée Français de Beyrouth in Lebanon, in June, 1971.  In 1974, he relocated to France to attend the Premier Cycle des Études Médicales, Faculté de Médecine de Reims.  In August 1981, he received his M.D. from the University of Umea, Sweden and became a specialist in Neurosurgery in 1988.  Dr. Hariz earned a Ph.D. with his thesis on stereotatic neurosurgery in 1990.  In February of 1991, Hariz served as a Neurosurgery Consultant at the Academic Hospital of Uppsala University in Sweden.  In 1996, he became an Associate Professor of Neurosurgery and Consultant Neurosurgeon at the department of Clinical Neurosciences at the University Hospital of Northern Sweden.  In 2002, he was appointed Professor and Chair of Functional Neurosurgery at the Institute of Neurology and Honorary Consultant at the National Hospital of Neurology and Neurosurgery in London.

Dr. Hariz has published 85 papers and book chapters, mainly in functional stereotatic neurosurgery.  His current interests include stereotatic imaging of basal ganglia, stereotactic surgical accuracy, and studies of mode of action of deep brain stimulation for Parkinson’s disease and dystonia.

Dr. Peter Magill is currently a MRC Investigator Scientist at the Medical Research Council Anatomical Neuropharmacology Unit at the University of Oxford.  Dr. Magill graduated in Biochemistry from the University of Bath in 1996. He then joined the MRC Anatomical Neuropharmacology Unit, Oxford, to study for his D.Phil. with Dr. Mark Bevan and Professor Paul Bolam in the basal ganglia research group. Following the award of his doctorate in 2001, Dr. Magill remained in the Unit to continue his studies on the physiological and anatomical properties of the basal ganglia.  In 2002, Dr. Magill was elected to a Fellowship by Examination at Magdalen College, Oxford. In 2003, Dr. Magill was appointed a MRC Investigator Scientist.

Central to Dr. Magill's research strategy is the use of in vivo and in vitro electrophysiological recording techniques to elucidate the priniciples governing neuronal communication within the basal ganglia.  His current areas of specialization and interest include the following: 1) Mechanisms underlying neuronal activity in the subthalamic nucleus and globus pallidus 2) Processing of cortically-derived information by the basal ganglia 3) Experimental models of basal ganglia disorders 4) Translational studies with a view to optimizing functional neurosurgery for movement disorders.

FINDINGS

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Lay Results:
Electrical stimulation of a brain region known as the subthalamic nucleus is an effective treatment of Parkinson’s disease. The overall aim of this project was to demonstrate that brain activity known as “local field potentials” provides a unique signature that can be exploited to improve the surgical implantation of electrodes in the subthalamic nucleus for later treatment. We used a novel approach, comprising both patient and animal studies. We have confirmed that increases in a certain type of local field potential, that is, “beta activity,” is indeed characteristic of the subthalamic nucleus in people with Parkinson’s disease and in our animal model of Parkinson’s disease. We have also established that measuring beta activity during implantation surgery can be helpful for identifying the subthalamic nucleus in patients. Furthermore, we have used our animal model of Parkinson’s disease to discover how this abnormal beta activity is generated and how it may cause movement problems in people with Parkinson’s disease. Finally, we have shown that stimulation of another brain region, the cerebral cortex, evokes another characteristic local field potential in the subthalamic nucleus in our animal model of Parkinson’s disease and that, with further development, this approach could be used for surgical targeting in patients. In conclusion, we now have good evidence that characteristic local field potentials hold great promise for improving the surgical implantation of electrodes in the brain for the treatment of Parkinson’s disease.

Scientific Results:
In this project, we investigated the utility of two novel intra-operative approaches for identifying the subthalamic nucleus (STN) using the local field potential (LFP), a measure of neuronal population activity, with a view to improving the surgical implantation of therapeutic DBS electrodes in patients with Parkinson’s disease (PD). The first approach concerned spontaneous LFP activity, particularly that in the ‘beta’ frequency range (13-30 Hz), and the second approach involved evoked LFP activity generated by stimulation of the cerebral cortex. We confirmed that increased beta LFP activity is characteristic of the STN in PD patients and Parkinsonian animals. In doing so, we effectively proved the utility and clinical relevance of our animal model of PD. We established that beta LFP activity is useful for the intra-operative functional localization of the STN in PD patients. We also established that cortical stimulation evokes a characteristic LFP in the STN in experimental Parkinsonism and in patients already implanted with DBS electrodes for the treatment of PD. With further development, this second approach could be used intra-operatively to target STN in patients. In parallel, we provided a detailed spatiotemporal characterization of the neural substrates underlying beta LFP activity in STN in our animal model of PD. In conclusion, we have provided good evidence that spontaneous and cortical stimulation-evoked LFPs provide useful signatures that, with further testing and technical development, can be exploited to improve the accuracy and efficiency of therapeutic DBS electrode implantation in clinical practice.

SELECTED PUBLICATIONS

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Mallet, N., Pogosyan, A., Sharott, A., Csicsvari, J., Bolam, J.P., Brown, P. and Magill, P.J. Disrupted dopamine transmission and the emergence of exaggerated beta oscillations in subthalamic nucleus and cerebral cortex. Journal of Neuroscience, 2008 Apr 30;28(18): 4795-806.

Trottenberg T., Kupsch A., Schneider G-H, Brown P., Kühn A.A. Frequency-dependent distribution of local field potential activity within the subthalamic nucleus in Parkinson's disease. Experimental Neurology. 2007 May; 205(1): 287-91.

Chen, C.C., Pogosyan, A., Zrinzo, L.U., Tisch, S., Limousin, P., Ashkan, K., Yousry, T., Hariz, M.I. and Brown, P. Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson’s disease surgery. Experimental Neurology. 2006 Mar; 198(1):214-21.