ABSTRACT

The PhD dissertation was carried out during my employment as a research fellow from 2000-2002 at the Department of Neurobiology, Institute of Anatomy, University of Aarhus.

Subthalamic deep brain stimulation (DBS), where an electrode is inserted bilaterally into the subthalamic nucleus (STN) may alleviate the symptoms of severe Parkinson's disease (PD) complicated by motor fluctuations and L-dopa induced dyskinesias. But, this treatment, introduced in 1993, is still new and its mechanisms of action, as well as potential long term adverse or neuroprotective effects remain unelucidated.

This study, accordingly, aimed at the establishment of a porcine model of subthalamic DBS in PD by providing a detailed description of the anatomy of the porcine STN and by examining the possibilities for STN-implantation of DBS-devices intended for human use into this species.

We demonstrate that the porcine (Göttingen minipig) STN is a biconvex structure with a volume 6.8-7.0 mm 3 located in the caudal diencephalon. The medium-sized fusiform STN-neurons showed glutamate immunoreactivity and additionally, tyrosine hydroxylase positive fibers, GAD-positive and ChAT-positive terminals and a strong AChE reaction were found in the STN. The number of Giemsa-stained neurons in the STN was estimated to 56,000 using unbiased stereology. The anatomical findings reveal that the porcine STN displays a neuroarchitecture comparable to primates. The porcine STN may, therefore, be well suited for further studies of the role played by the STN in movement disorders.

A stereotaxic device and technique were developed in order to unilaterally implant DBS-electrodes intended for human use into the STN of parkinsonian and normal minipigs. Evaluation of the postmortem electrode localization revealed, however, that the electrode placement had been inadequate due to erroneous estimation of the target, combined with too large inaccuracies in the stereotaxic technique.

The stereotaxic technique was therefore improved by the development of a stereotaxic localizer box, which could be transformed into a stereotaxic device without change in head fixation. The localizer box and target estimation based on the anatomical data presented in this thesis, enabled subsequently correct 70% STN targeting.

We conclude that the gained anatomical knowledge and developed stereotaxic technique enable reliable STN targeting, but further knowledge of the electrophysiological properties of the porcine STN, development of a localizer box built-in fiducial marker system and better fixation of the electrodes and pulse generators, will be needed to secure proper and permanent electrode placement in the STN. The latter being an absolute prerequisite for the establishment of a porcine model of subthalamic DBS in PD.