Modulation of brain network recruitment caused by STN DBS and L-DOPA in parkinsonian rats
27 March 2019 (online)
The unilateral 6-OHDA rat model of Parkinson's disease (PD) is often used to study pathomechanisms and therapeutic effects such as deep brain stimulation (DBS). We established an implantable DBS system to analyse DBS and/or L-DOPA effects on motor behaviour and on cerebral metabolic patterns.
Long Evans rats were unilaterally lesioned with 6-OHDA and either received L-DOPA, STN DBS, or a combination of both. [18F]FDG PET scans (uptake normalised to global mean) were used to analyse focal brain activity with (ON) and without (OFF) therapeutic interventions. Motor performance was investigated using the cylinder test.
Comparing ON and OFF states, L-DOPA and DBS led to different metabolic patterns. DBS increased [18F]FDG uptake mainly ipsilesionally while decreasing it contralesionally, reversing the metabolic imbalance between hemispheres. L-DOPA decreased [18F]FDG uptake bilaterally in the forebrain and increased it in the cerebellum. The latter may indicate increased recruitment of the cerebellum, but may also be explained by cerebral blood flow increases. A combination of DBS and L-DOPA decreased [18F]FDG uptake in the ipsilesional motor cortex and contralesional striatum and increased it in somatosensory cortices, contralesional thalamus and cerebellum. L-DOPA significantly improved contralesional front paw (CF) use, which was impaired during OFF. DBS only caused a slight improvement. A combination of L-DOPA and DBS showed similar results as L-DOPA alone but with higher total values. Continuous DBS for five weeks stabilised and increased the beneficial effects of DBS.
We conclude that pure reversion of pathologic metabolic imbalances does not seem to be sufficient to improve motor deficits. Rather, the complex recruitment of alternative networks depending on treatment strategy is likely to compensate pathology.