Effects of subthalamic deep brain stimulation with gabapentin and morphine on mechanical and thermal thresholds in 6-hydroxydopamine lesioned rats.

Chronic pain is the most common non-motor symptom among Parkinson's disease (PD) patients, with 1.85 million estimated to be in debilitating pain by 2030. Subthalamic deep brain stimulation (STN DBS) programmed for treating PD motor symptoms has also been shown to significantly improve pain scores. However, even though most patients' pain symptoms improve or disappear, 74% of patients treated develop new pain symptoms within 8 years. Previously we have shown that duloxetine and STN high frequency stimulation (HFS) significantly increase mechanical thresholds more than either alone. The current project specifically investigates the effects of gabapentin and morphine alone and with high (150 Hz; HFS) and low (50 Hz; LFS) frequency stimulation in the 6-hydroxydopamine rat model for PD. We found that HFS, LFS, gabapentin 15 mg/kg and morphine 1 mg/kg all independently improve von Frey (VF) thresholds. Neither drug augments the HFS response significantly. Morphine at 1 mg/kg showed a trend to increasing thresholds compared to LFS alone (p = 0.062). Interestingly, gabapentin significantly reduced (p = 0.019) the improved VF thresholds and Randall Selitto thresholds seen with LFS. Thus, though neither drug augments DBS, we found effects of both compounds independently increase VF thresholds, informing use of our model of chronic pain in PD. Gabapentin's reversal of LFS effects warrants further exploration.

Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats.

Chronic pain is the most common non-motor symptom of Parkinson's disease (PD) and is often overlooked. Unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesioned rats used as models for PD exhibit decreased sensory thresholds in the left hindpaw. Subthalamic deep brain stimulation (STN DBS) increases mechanical thresholds and offers improvements with chronic pain in PD patients. However, individual responses to STN high frequency stimulation (HFS) in parkinsonian rats vary with 58% showing over 100% improvement, 25% showing 30-55% improvement, and 17% showing no improvement. Here we augment STN DBS by supplementing with a serotonin-norepinephrine reuptake inhibitor commonly prescribed for pain, duloxetine. Duloxetine was administered intraperitoneally (30mg/kg) in 15 parkinsonian rats unilaterally implanted with STN stimulating electrodes in the lesioned right hemisphere. Sensory thresholds were tested using von Frey, Randall-Selitto and hot-plate tests with or without duloxetine, and stimulation to the STN at HFS (150Hz), low frequency (LFS, 50Hz), or off stimulation. With HFS or LFS alone (left paw; p=0.016; p=0.024, respectively), animals exhibited a higher mechanical thresholds stable in the three days of testing, but not with duloxetine alone (left paw; p=0.183). Interestingly, the combination of duloxetine and HFS produced significantly higher mechanical thresholds than duloxetine alone (left paw, p=0.002), HFS alone (left paw, p=0.028), or baseline levels (left paw; p<0.001). These findings show that duloxetine paired with STN HFS increases mechanical thresholds in 6-OHDA-lesioned animals more than either treatment alone. It is possible that duloxetine augments STN DBS with a central and peripheral additive effect, though a synergistic mechanism has not been excluded.

Clinical Outcome and Characterization of Local Field Potentials in Holmes Tremor Treated with Pallidal Deep Brain Stimulation.

BACKGROUND: Holmes tremor (HT) is an irregular, low-frequency rest tremor associated with prominent action and postural tremors. Currently, the most effective stereotactic target and neurophysiologic characterization of HT, specifically local field potentials (LFPs) are uncertain. We present the outcome, intraoperative neurophysiologic analysis with characterization of LFPs in a patient managed with left globus pallidus interna deep brain stimulation (Gpi DBS). CASE REPORT: A 24-year-old male underwent left Gpi DBS for medically refractory HT. LFPs demonstrated highest powers in the delta range in Gpi. At the 6-month follow-up, a 90% reduction in tremor was observed. DISCUSSION: Pallidal DBS should be considered as an alternative target for management of refractory HT. LFP demonstrated neuronal activity associated with higher power in the delta region, similarly seen in patients with generalized dystonia.