Characterization of Effect of Repeated Bolus or Continuous Intrathecal Infusion of Morphine on Spinal Mass Formation in the Dog.

BACKGROUND: We determined whether intrathecally delivering the same daily dose of morphine (MS) at a fixed concentration of 25 mg/mL by periodic boluses versus continuous infusion would reduce intrathecal mass (IMs) formation in dogs. METHODS: Adult dogs (hound cross, n = 32) were implanted with intrathecal catheters connected to SynchroMed II infusion pumps. Animals were randomly assigned to receive infusion of 0.48 mL/day of saline or MS dosing (12 mg/day at 25 mg/mL) as boluses: x1 (q24hour), x2 (q12hour), x4 (q6hour), or x8 (q3hour) given at the rate of 1000 µL/hour, or as a continuous infusion (25 mg/mL/20 µL/hour). RESULTS: With IT saline, minimal pathology was noted. In contrast, animals receiving morphine displayed spinally compressing durally derived masses with the maximal cross-sectional area being greatest near the catheter tip. Histopathology showed that IMs consisted of fibroblasts in a collagen (type 1) matrix comprised of newly formed collagen near the catheter and mature collagen on the periphery of the mass. The rank order of median cross-sectional mass area (mm2 ) was: Saline: 0.7 mm2 ; x2: 1.8 mm2 ; x4: 2.7 mm2 ; x1: 2.7 mm2 ; x8: 4.2 mm2 ; Continuous: 8.1 mm2 , with statistical difference from saline being seen with continuous (p < 0.0001) and x8 (p < 0.05). Bench studies with a 2D diffusion chamber confirmed an increase in dye distribution and lower peak concentrations after bolus delivery versus continuous infusion of dye. CONCLUSIONS: Using multiple bolus dosing, IMs were reduced as compared to continuous infusion, suggesting relevance of bolus delivery in yielding reduced intrathecal masses.

Using evoked compound action potentials to quantify differential neural activation with burst and conventional, 40 Hz spinal cord stimulation in ovines.

Unlike conventional dorsal spinal cord stimulation (SCS)-which uses single pulses at a fixed rate-burst SCS uses a fixed-rate, five-pulse stimuli cluster as a treatment for chronic pain; mechanistic explanations suggest burst SCS differentially modulate the medial and lateral pain pathways vs conventional SCS. Neural activation differences between burst and conventional SCS are quantifiable with the spinal-evoked compound action potential (ECAP), an electrical measure of synchronous neural activation. Methods: We implanted 7 sheep with a dorsal stimulation lead at T9/T10, a dorsal ECAP sensing lead at T6/T7, and a lead also at T9/T10 but adjacent to the anterolateral system (ALS). Both burst and conventional SCS with stimulation amplitudes up to the visual motor threshold (vMT) were delivered to 3 different dorsal spinal locations, and ECAP thresholds (ECAPTs) were calculated for all combinations. Then, changes in ALS activation were assessed with both types of SCS. Results: Evoked compound action potential thresholds and vMTs were significantly higher (P < 0.05) with conventional vs burst SCS, with no statistical difference (P > 0.05) among stimulation sites. However, the vMT-ECAPT window (a proxy for the useable therapeutic dosing range) was significantly wider (P < 0.05) with conventional vs burst SCS. No significant difference (P > 0.05) in ALS activation was noted between conventional and burst SCS. Conclusion: When dosed equivalently, no differentially unique change in ALS activation results with burst SCS vs conventional SCS; in addition, sub-ECAPT burst SCS results in no discernable excitability changes in the neural pathways feeding pain relevant supraspinal sites.

Development of a large animal model for investigation of deep brain stimulation for epilepsy.

BACKGROUND/OBJECTIVES: To better understand the mechanism of action of deep brain stimulation (DBS) for epilepsy and to investigate implantable device features, it is desirable to have a large animal model to evaluate clinical-grade systems. This study assessed the suitability of an ovine model of epilepsy for this purpose. METHODS: Animals were anesthetized for surgery and 1.5 T MRIs collected. Unilateral anterior thalamic DBS leads, hippocampal depth electrodes and catheters were implanted using a frameless stereotactic system. Evoked responses and local field potentials were collected and stored for off-line analysis. RESULTS: Despite limited neuroanatomic information for this species, it was possible to reliably implant leads into the target structures using MR-guided techniques. Stimulation of these regions produced robust evoked potentials within this circuit that were dependent on stimulus location and parameters. High-frequency thalamic DBS produced a clear inhibition of both spontaneous and penicillin-induced ictal activity in the hippocampus which far outlasted the duration of the stimulation. CONCLUSIONS: These preliminary results suggest that the sheep model may be useful for further investigation of DBS for epilepsy. The demonstration of marked suppression of network excitability with high-frequency stimulation supports a potential therapeutic mechanism for this DBS therapy.