Abstract
ABSTRACTDeep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson's disease, although the underlying mechanisms are complex and not well understood. There are conflicting results about the effects of STN-DBS on neuronal activity of the striatum, and its impact on functional striatal connectivity is entirely unknown. We therefore investigated how STN-DBS changes cerebral metabolic activity in general and striatal connectivity in particular. We used ipsilesional STN stimulation in a hemiparkinsonian rat model in combination with [18F]FDOPA-PET, [18F]FDG-PET and metabolic connectivity analysis. STN-DBS reversed ipsilesional hypometabolism and contralesional hypermetabolism in hemiparkinsonian rats by increasing metabolic activity in the ipsilesional ventrolateral striatum and by decreasing it in the contralesional hippocampus and brainstem. Other STN-DBS effects were subject to the magnitude of dopaminergic lesion severity measured with [18F]FDOPA-PET, e.g. activation of the infralimbic cortex was negatively correlated to lesion severity. Connectivity analysis revealed that, in healthy control animals, left and right striatum formed a bilateral functional unit connected by shared cortical afferents, which was less pronounced in hemiparkinsonian rats. The healthy striatum was metabolically connected to the ipsilesional substantia nigra in hemiparkinsonian rats only (OFF condition). STN-DBS (ON condition) established a new functional striatal network, in which interhemispheric striatal connectivity was strengthened, and both the dopamine-depleted and the healthy striatum were functionally connected to the healthy substantia nigra. We conclude that both unilateral dopamine depletion and STN-DBS affect the whole brain and alter complex interhemispheric networks.
Highlights
Deep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson’s disease (PD) since the 1990s (Benabid et al, 1994; Krack et al, 1997; Limousin et al, 1995)
It has been shown using this method that internal globus pallidus (GPi)-DBS reduced the activity of ipsilateral PD-related metabolic covariance patterns, which correlated with improvement of motor symptoms (Fukuda et al, 2001)
We have shown that unilateral 6-OHDA lesions lead to ipsilesional hypometabolism and contralesional hypermetabolism, and that both phenomena are associated with motor impairments as well as compensation (Kordys et al, 2017)
Summary
Deep brain stimulation (DBS) in the subthalamic nucleus (STN) has been successfully used for the treatment of advanced Parkinson’s disease (PD) since the 1990s (Benabid et al, 1994; Krack et al, 1997; Limousin et al, 1995). The stimulator has to be kept at a distance from the magnet, fMRI can only be done in the few days between electrode placement and stimulator implantation (Albaugh and Shih, 2014; Jech et al, 2001) To overcome these limitations, functional connectivity analyses based on positron emission tomography (PET) studies with the tracer 2deoxy-2-[18F]fluoroglucose ([18F]FDG) have been developed (Yakushev et al, 2017). Functional connectivity analyses based on positron emission tomography (PET) studies with the tracer 2deoxy-2-[18F]fluoroglucose ([18F]FDG) have been developed (Yakushev et al, 2017) The concept of this so-called ‘metabolic connectivity analysis’ is based on the correlation of [18F]FDG uptake in a seed region with all other voxels of the brain across subjects, and has been demonstrated in humans (Sala et al, 2017; Verger et al, 2018) but recently in rats (Liang et al, 2018; Rohleder et al, 2016). It has been shown using this method that internal globus pallidus (GPi)-DBS reduced the activity of ipsilateral PD-related metabolic covariance patterns, which correlated with improvement of motor symptoms (Fukuda et al, 2001)
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