Hypothalamic deep brain stimulation influences autonomic and limbic circuitry involved in the regulation of aggression and cardiocerebrovascular control in the Göttingen minipig.

BACKGROUND: Deep brain stimulation (DBS) in the ventral tuberal hypothalamus (VTH) is currently under investigation for the treatment of severe obesity. Stimulation impact on a number of closely related hypothalamic neural systems could potentially influence normal hypothalamic function and thereby generate adverse side effects. OBJECTIVE: To assess the feasibility and safety of VTH DBS in a non-primate large animal model. METHODS: In the VTH of 6 Göttingen minipigs, quadropolar leads were implanted bilaterally (n = 2) or unilaterally (n = 4), using optimized MRI sequences allowing identification of major diencephalic landmarks. Heart rate, weight, behavior and nighttime locomotor activity were recorded throughout the study period. Two of the unilaterally implanted minipigs were examined with [15O]H2O positron emission tomography (PET) scans performed in DBS-off and DBS-on mode. RESULTS: VTH DBS elicited an amplitude-dependent increase in heart rate and transient aggressive behavior. PET demonstrated that VTH DBS caused a global increase in cerebral blood flow velocities and decreased mean transit time. CONCLUSIONS: VTH DBS results in behavioral and physiological changes, which may derive from activation of closely related limbic and autonomic networks. Caution and further studies of longer length should be requested before this procedure is used more widely in humans.

Development of neuromodulation treatments in a large animal model--do neurosurgeons dream of electric pigs?

The Göttingen minipig has been established as a translational research animal for neurological and neurosurgical disorders. This animal has a large gyrencephalic brain suited for examination at sufficient resolution with conventional clinical scanning modalities. The large brain, further, allows use of standard neurosurgical techniques and can accommodate clinical neuromodulatory devises such as deep brain stimulation (DBS) electrodes and encapsulated cell biodelivery devices making the animal ideal for basic scientific studies on neuromodulation mechanisms and preclinical tests of new neuromodulation technology for human use. The use of the Göttingen minipig is economical and does not have the concerns of the public associated with the experimental use of primates, cats, and dogs, thus providing a cost-effective research model for translation of rodent data before clinical trials are initiated.

A MRI-compatible stereotaxic localizer box enables high-precision stereotaxic procedures in pigs.

We present a nonmagnetic Plexiglas stereotaxic localizer box that can be fitted directly to the pig skull by aluminum screws, allowing stereotaxic MRI or ventriculography and subsequent high-precision stereotaxic procedures. The localizer box was used to target the subthalamic nucleus (STN) bilaterally in five female Göttingen minipigs. Stereotaxic markers were inserted in the pig skull, the head fixated in the localizer box by aluminum screws inserted bilaterally in the zygoma bone with the hard palate locked on a horizontal palate holder. MRI was obtained on a 3T-MR-imager revealing the relation between the inserted markers and the estimated STN-position, and thus the target coordinates. After the MRI, a stereotaxic frame with attached micromanipulator was locked on to the localizer box converting it into a stereotaxic device. The stereotaxic markers were exposed and used as starting point for the stereotaxic procedure, whereby a microelectrode for electrolytic lesioning was inserted in the STN. Postmortem histological analysis revealed 70% correct STN-targeting. The average distance from the lesion center to the STN center was 1.2 mm with a S.D. of 1.1 mm. The most displaced lesion being 3.6 mm from the STN center. We conclude that the described localizer box secure firm head fixation, allowing stereotaxic MRI and subsequent conversion into a stereotaxic device for high-precision stereotaxic procedures.