Modulation des dopaminergen und glutamatergen Systems durch Tiefe Hirnstimulation im Ncl. subthalamicus und L-DOPA be ider 6OHDA-Hemiparkinson-Ratte
Final Report Abstract
Although deep brain stimulation (DBS) especially of the subthalamic nucleus (STN) has revolutionized the treatment of movement disorders such as Parkinson's disease or essential tremor, its detailed mechanisms of action are not well understood. We used a unilateral toxin-induced rat model (6-OHDA hemiparkinsonian model) to compare the therapeutic effects of STN-DBS (130 Hz, 60 µs, 30-50 µA) with classical L-DOPA therapy. At the beginning of the project, the ipsilesionally implanted electrode in the STN was connected by a cable. Later, we obtained four implantable stimulators from Medtronic that allowed freely moving experiments. We performed detailed gait analyses (Noldus Catwalk), examined recruitment of the affected forepaw (cylinder test), and looked at brain activity in the awake resting state ([18F]FDG-PET). The degree of unilateral dopamine depletion was measured by [18F]FDOPA-PET. Part I: combination of [18F]FDG-PET, [18F]FDOPA-PET, and gait analysis (no stimulation): [18F]FDG-PET showed a subcortical asymmetry of glucose metabolism with ipsilesional hypo- and contralesional hypermetabolism. The more pronounced the unilateral dopamine depletion, the more prominent this metabolic pattern was. Walking speed was also reduced in relation to the severity of dopamine depletion, which was due to increased swing time of the contralesional forepaw and a general shortening of stride length. Diagonal weight transfer to the ipsilesional hind paw can be considered a compensatory gait change. Correlation analyses showed that the simple assignment "hypometabolism = motor impairment" and "hypermetabolism = compensation" is not tenable. Rather, both phenomena contribute to both motor impairment and compensation. Part II: influence of STN-DBS on striatal connectivity: Ipsilesonal STN-DBS counteracted the asymmetry of brain metabolism described above by increasing metabolism ipsilesionally and decreasing it contralesionally. The metabolic increase was particularly pronounced in the ipsilesional ventral striatum. Seed-based functional connectivity analyses based on the [18F]FDG-PET images showed that STN-DBS improved inter- and intrahemispheric striatal connectivity impaired by dopamine depletion. Part III: Effect of STN-DBS and L-DOPA on recruitment of the affected forepaw: Systemic treatment with L-DOPA bilaterally decreased cerebral metabolic activity. Activity was increased only in the cerebellum. The cylinder test revealed a significant impairment of the contralesional forepaw in bracing against the cylinder wall after unilateral dopamine depletion. This effect was completely revised by L-DOPA administration. Only partial improvements were obtained with STN-DBS. Here, STN-DBS was more effective the more pronounced the dopamine depletion was. Our results show that both STN-DBS and L-DOPA administration alter brain metabolism and functional connectivity in different ways in the hemiparkinsonian rat model. Although STN-DBS ideally counteracted the pathological cerebral pattern, the therapeutic effect on the affected forepaw was inferior to L-DOPA administration.
Publications
- The functional networks of prepulse inhibition: Neuronal connectivity analysis based on FDG-PET in awake and unrestrained rats. Front Behav Neurosci. (2016) 10:148
Rohleder C, Wiedermann D, Neumaier B, Drzezga A, Timmermann L, Graf R, Leweke FM, Endepols H
(See online at https://doi.org/10.3389/fnbeh.2016.00148) - Motor impairment and compensation in a hemiparkinsonian rat model: correlation between dopamine depletion severity, cerebral metabolism and gait patterns. EJNMMI Res. (2017) 7:68
Kordys E, Apetz N, Schneider K, Duncan E, Büschbell B, Rohleder C, Sué M, Drzezga A, Neumaier B, Timmermann L, Endepols H
(See online at https://doi.org/10.1186/s13550-017-0317-9) - Effects of subthalamic deep brain stimulation on striatal functional connectivity in a rat hemiparkinson model. Dis Model Mech 12, dmm039065
Apetz N, Kordys E, Simon M, Mang B, Aswendt M, Wiedermann D, Neumaier B, Drzezga A, Timmermann L, Endepols H
(See online at https://doi.org/10.1242/dmm.039065) - Towards chronic deep brain stimulation in freely moving hemiparkinsonian rats: Applicability and functionality of a fully implantable stimulation system.
Journal of Neural Engineering, Volume 18, Number 3, 036018.
Apetz N., Paralikar K., Neumaier B., Drzezga A., Wiedermann D., Iyer R., Munns G., Scott E., Timmermann L., Endepols H.
(See online at https://dx.doi.org/10.1088/1741-2552/abe806)
