PET functional imaging of deep brain stimulation in the healthy rat brain

Question: Deep Brain Stimulation (DBS) is a promising therapy for neurological and psychiatric disorders. However, the underlying mechanism of action of DBS remains unknown. Functional imaging studies in the rat brain, such as ¹⁸F-fluorodeoxyglucose-Positron Emission Tomography (¹⁸F-FDG-PET), reflecting changes in neural activity, may help elucidate the mechanism of action of DBS throughout the brain and potentially improve clinical outcome. To our knowledge, no DBS ¹⁸F-FDG-PET studies have been done in the healthy rat brain. The aim of this study was to investigate the effect of hippocampal DBS on regional cerebral glucose utilization throughout the entire brain volume in healthy rats.

Methods: Seven male rats (Sprague-Dawley, 200 – 250 g) were implanted with a custommade quadri-polar DBS-electrode in the right hippocampus and injected with 28.10 ± 1.76MBq of ¹⁸F-FDG to measure regional cerebral glucose utilization during one hour of on and off bipolar Poisson distributed hippocampal DBS. All rats were subjected to three PET/CT scans, namely one before and after electrode implantation and one during hippocampal DBS. Each rat also underwent one final MR scan for anatomical correlation and electrode position verfication. Additionally, continuous depth-EEG was measured throughout the delivery of stimulation to verify whether no EEG abnormalities occurred during DBS. A right-left ratio was calculated in several volume-of-interests throughout the brain.

Results: Qualitative analysis, based on the right-left ratio in several volume-of-interests, reveal significant (p < 0.01) hypometabolism in several substructures of the ipsilateral hippocampus such as the electrode tip area (mean ± SD; 83.02 ± 5,23%), the ventral hippocampus (mean ± SD; 89.53 ± 6.76%), the limbic cortex (mean ± SD; 81.39 ± 10.92%) and the entorhinal cortex (mean ± SD; 81.89 ± 6.51%), during hippocampal DBS compared to baseline scans acquired before and after electrode implantation. One rat was excluded from the analysis since ictal activity was present during DBS.

Abb. 1: Typical findings in FDG PET (A) BEFORE surgery, (B) AFTER surgery and (C) during DBS. The hypometabolic area is labeled with white arrows. This area includes the electrode tip, the ventral hippocampus, the entorhinal and limbic cortex. The picture on the top displays the MR that is used for anatomical and electrode position verification. The electrode path is labeled with red arrows.

Conclusion: Our results match the well-established hypothesis that DBS acts by functional inhibition of the targeted brain region. This study demonstrates that DBS causes acute changes in the healthy rat brain and provides important additional evidence that DBS leads to a decreased neuronal activity in the stimulated structure. Consequently, ¹⁸F-FDG-PET neuroimaging studies have the potential to provide greater insight into the mechanism of DBS and may be a valuable tool to visualize and evaluate the therapeutic effect of DBS.

Keywords: deep brain stimulation; hippocampus; ¹⁸F-FDG-PET; healthy rat brain