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.

The use of focused ultrasound for the treatment of cutaneous allodynia associated with chronic migraine.

Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant. This project investigates the safety and effectiveness of pulsed focused ultrasound (FUS) in a validated rodent headache model of cutaneous allodynia associated with chronic migraine (CM) as compared to sumatriptan and ablative lesioning. We demonstrate a significant reduction in mechanical thresholds as measured through Von Frey filaments in CM in the forepaw and periorbital region (p < 0.001). Sumatriptan and pulsed FUS both significantly improve thresholds at day 3 after treatment in the periorbital region. Ablative lesioning has no effect. This study provides initial evidence that FUS may provide an important therapeutic option for patients suffering from CM.

Occipital Nerve Stimulation Attenuates Neuronal Firing Response to Mechanical Stimuli in the Ventral Posteromedial Thalamus of a Rodent Model of Chronic Migraine.

BACKGROUND: Chronic migraine (CM) is a highly debilitating disease, and many patients remain refractory to medicinal therapy. Given the convergent nature of neuronal networks in the ventral posteromedial nucleus (VPM) and the evidence of sensitization of pain circuitry in this disease, we hypothesize CM rats will have increased VPM neuronal firing, which can be attenuated using occipital nerve stimulation (ONS). OBJECTIVE: To determine whether VPM firing frequency differs between CM and sham rats, and whether ONS significantly alters firing rates during the application of mechanical stimuli. METHODS: Fourteen male Sprague-Dawley rats were infused with inflammatory media once daily through an epidural cannula for 2 wk to induce a CM state. Sham animals (n = 6) underwent cannula surgery but received no inflammatory media. ONS electrodes were implanted bilaterally and single-unit recordings were performed in the VPM of anesthetized rats during mechanical stimulation of the face and forepaw in the presence and absence of ONS. RESULTS: CM rats had significantly higher neuronal firing rates (P < .001) and bursting activity (P < .01) in response to mechanical stimuli when compared to shams. ONS significantly reduced neuronal firing in the VPM of CM rats during the application of 0.8 g (P = .04), 4.0 g (P = .04), and 15.0 g (P = .02) Von Frey filaments. ONS reduced bursting activity in CM rats during the 4.0 and 15 g filaments (P < .05). No significant changes in bursting activity or firing frequency were noted in sham animals during ONS. CONCLUSION: We demonstrate that neuronal spike frequencies and bursting activity in the VPM are increased in an animal model of CM compared to shams. Our results suggest that the mechanism of ONS may involve attenuation of neurons in the VPM of CM rats during the application of mechanical stimuli.

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 intraoperative neurophysiology for focal limb dystonic tremor without generalized dystonia treated with deep brain stimulation.

OBJECTIVES: Dystonic tremor (DT) is defined as a postural/kinetic tremor occurring in the body region affected by dystonia. DT is typically characterized by focal tremors with irregular amplitudes and variable frequencies typically below 7Hz. Pharmacological treatment is generally unsuccessful and guidelines for deep brain stimulation (DBS) targeting and indications are scarce. In this article, we present the outcome and neurophysiologic data of two patients with refractory, focal limb DT treated with Globus Pallidus interna (Gpi) DBS and critically review the current literature regarding surgical treatment of DT discussing stereotactic targets and treatment considerations. PATIENTS AND METHODS: A search of literature concerning treatment of DT was conducted. Additionally, Gpi DBS was performed in two patients with DT and microelectrode recordings for multi unit analysis (MUAs) and local field potentials (LFPs) were obtained. RESULTS: The mean percentage improvement in tremor severity was 80.5% at 3 years follow up. MUAs and LFPs did not show significant differences in DT patients compared with other forms of dystonia or PD except for higher interspikes bursting indices. LFP recordings in DT demonstrated high power at low frequencies with action (<3.5Hz). CONCLUSIONS: Gpi DBS is an effective treatment in patients with focal limb DT without associated generalized dystonia. Intraoperative neurophysiologic findings suggest that DT is part of phenotypic motor manifestations in dystonia.

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.