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

Lay Summary

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

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.