Modulation of Brain Activity and Networks by Deep Brain Stimulation of the Subthalamic Nucleus and L-DOPA Therapy in the 6-OHDA-Hemiparkinsonian Rat

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by a selective dopaminergic cell loss in the substantia nigra pars compacta. It manifests through numerous motor and non-motor symptoms including tremor, bradykinesia, rigidity, autonomic dysfunction, sleep disturbances or psychiatric symptoms. While being a wearing condition for patients as well as their friends and family, PD also puts a heavy burden the health system being the second most common neurodegenerative disorder worldwide following Alzheimer’s disease. As the gold standard therapy, i.e. administration of the dopamine precursor 3,4-dihydroxy-L-phenylalanine (= levodopa = L-DOPA) or dopaminergic agonists, leads to unwanted dyskinesias and response fluctuations after several years of treatment, efforts have been made during the last few decades to find alternatives. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a safe and well-tolerated solution that can improve parkinsonian symptoms and significantly reduce dopaminergic medication intake. However, while it has been well established in the clinical use over the last 35 years, the exact mechanisms by which DBS acts in the brain are yet to be fully elucidated. A big problem is the lack of well transferable pre-clinical studies. Most animal studies are limited by the constraints imposed on animals by cables, backpacks or headpieces of external stimulation systems that additionally require single housing and influence normal motor performance and behaviour. Additionally, stimulation periods often only last minutes to days compared to the chronic stimulation of PD patients over years. Similarly, imaging studies elucidating the effects of DBS on activity in the diseased brain are scarce while they are well suitable to broaden the understanding of the bigger scale impact of DBS on pathological network activity. Especially in combination with behavioural and motor performance tests, imaging studies have the potential to illustrate whole brain alterations elicited by DBS that lead to the improvement of symptoms. Ultimately, a better understanding of the brain (network) activity changes evoked by effective STN DBS helps to further develop and improve this therapeutic tool. The present study therefore aimed at establishing a fully implantable stimulation system that allows for stimulation in group-housed, unrestrained and freely moving animals, and testing out its possible range of applications. In a first step, the developed standard operating procedure for system implantation and testing protocols was validated in hemiparkinsonian rats, resulting in the illustration of the effects of acute STN DBS on front paw use and brain metabolic activity. Acute STN DBS increased mainly ipsilesional brain metabolism, especially in the striatum, while decreasing it contralesionally. It therefore counteracts the metabolic imbalance caused by unilateral 6-hydroxydopamine (6-OHDA) lesions, leading to improvements of motor performance. Additionally, all brain networks analysed were altered by acute DBS. In a next step, the different impact of acute and chronic five-week STN DBS on front paw use and metabolic brain activity was investigated. The brain metabolic effects of chronic (five week) STN DBS slightly differed from those of acute stimulation resulting in a better motor performance. The last part compared the effects on behaviour and brain (network) activity evoked by acute STN DBS with those caused by the gold standard therapy, L-DOPA, and a combination of the two treatments. As hypothesised, the different treatments affected brain metabolism and network activity differently, which also showed in motor performance. Hence, when stimulation sites and parameters are well chosen the established stimulation system is a useful tool to elucidate the effects of acute and chronic STN DBS in unrestrained animals on brain metabolic activity and network functioning