Chronic implantation of deep brain stimulation leads in animal models of neurological disorders.

Deep brain stimulation (DBS) has routinely been used as a treatment option in Parkinson's disease (PD), tremor disorders and, more recently, dystonia. Here, we describe a method of implantation of DBS leads in the monkey model of PD. By adapting procedures used in human patients, we have devised implantation techniques that can be readily applied to any animal model in which stimulation of subcortical structures is desired. The procedure for implantation consists of microelectrode mapping of the target structure, DBS lead preparation and implantation, and verification of lead placement. The stimulation system described in this paper allows for simultaneous recording of neuronal activity (during stimulation) and observation of animal behavior without restriction of the subject's head or body. In addition, we detail techniques for stimulation and recording from distant structures (utilizing either a one or two chamber system) to facilitate examination of the effects of DBS on neural activity. Thus, the correlation of changes in neuronal activity with behavior during stimulation of subcortical structures can be accomplished. In addition, the use of leads in primates which are analogous in size to human devices allows for close reproduction of the effects of stimulation as observed in humans.

Comparison of pallidal and subthalamic stimulation on force control in patient's with Parkinson's disease.

The aim of this study was to determine the effects of unilateral deep brain stimulation (DBS) on the control and coordination of grasping forces produced by Parkinson's disease (PD) patients. Ten advanced PD patients with unilateral DBS in the globus pallidus (GPi) or the subthalamic nucleus (STN) (5 patients in each group) performed a functional bimanual dexterous manipulation task. Experiments were performed in the "Off" medication state with DBS "On" and "Off. " DBS resulted in (a) significant clinical improvements, (b) greater maximum grip force for both limbs, (c) reduced movement time, and (d) bilateral coupling of grasping forces. There were no significant differences between the GPi and STN groups for any clinical or kinematic measures. DBS of the GPi and STN leads to an improvement in the motor functioning of advanced PD patients. Improvement in force-timing specification during DBS might allow PD patients to employ a feedforward method of force control.

Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons.

To clarify the mechanism underlying improvement of parkinsonian signs by high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN), we investigated the effects of STN HFS on neuronal activity of the internal and external segment of the globus pallidus (GPi and GPe, respectively) in two rhesus monkeys rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. A scaled-down version of the chronic stimulating electrode used in humans, consisting of four metal contacts 0.50 mm in length each separated by 0.50 mm, was implanted through a cephalic chamber targeting the STN. Histological reconstruction revealed that the cathode was located in the STN in both monkeys. Extracellular recordings from a total of 110 pallidal neurons during STN stimulation were performed. Poststimulus time histograms of single neurons triggered by 2 Hz STN stimulation pulses at 2.4-3.0 V revealed short-latency excitations at 2.5-4.5 and 5.5-7.0 msec after stimulation onset and inhibitions at 1.0-2.5, 4.5-5.5, and 7.0-9.0 msec for both GPe and GPi neurons. These short-latency responses were present with 136 Hz stimulation, at voltages effective for alleviation of parkinsonian signs, resulting in a significant increase in mean discharge rate and a stimulus-synchronized regular firing pattern. These results indicate that activation of the STN efferent fibers and resultant changes in the temporal firing pattern of neurons in GPe and GPi underlie the beneficial effect of HFS in the STN in Parkinson's disease and further support the role of temporal firing patterns in the basal ganglia in the development of Parkinson's disease and other movement disorders.

A template subtraction method for stimulus artifact removal in high-frequency deep brain stimulation.

Deep brain stimulation (DBS) is a neurosurgical technique that has been widely applied for the treatment of tremor or motor symptoms associated with advanced Parkinson's disease. Large stimulus artifacts, however, have hampered investigations of physiological mechanisms underlying DBS effects using extracellular recording techniques. We have developed an off-line procedure for removing stimulus artifacts from recorded neuronal signals (monopolar) and applied this method of artifact subtraction to DBS studies using extracellular recording techniques in a nonhuman primate. The procedure consists of developing a template of the artifact by averaging the artifact signals triggered by its onset. The template is then subtracted from the individual triggered signals. The experimental results indicate that this method is highly effective in removing the majority of the stimulus artifact, while leaving recorded neuronal activity intact. In fact, removal of stimulation artifact using this technique has revealed a short-latency neuronal response to stimulation that was previously obscured by the stimulus artifact. Thus, this technique may not only improve the quality of electrophysiological studies employing DBS techniques, but may also help to elucidate neuronal mechanisms underlying the effect of DBS.