Intracranial electrode implantation produces regional neuroinflammation and memory deficits in rats

The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel
Experimental Neurology (Impact Factor: 4.62). 12/2009; 222(1):42-50. DOI: 10.1016/j.expneurol.2009.12.006

ABSTRACT Deep brain stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD). The procedure entails intracranial implantation of an electrode in a specific brain structure followed by chronic stimulation. Although the beneficial effects of DBS on motor symptoms in PD are well known, it is often accompanied by cognitive impairments, the origin of which is not fully understood. To explore the possible contribution of the surgical procedure itself, we studied the effect of electrode implantation in the subthalamic nucleus (STN) on regional neuroinflammation and memory function in rats implanted bilaterally with stainless steel electrodes. Age-matched sham and intact rats were used as controls. Brains were removed 1 or 8 weeks post-implantation and processed for in vitro autoradiography with [3H]PK11195, an established marker of microglial activation. Memory function was assessed by the novel object recognition test (ORT) before surgery and 2 and 8 weeks after surgery. Electrode implantation produced region-dependent changes in ligand binding density in the implanted brains at 1 as well as 8 weeks post-implantation. Cortical regions showed more intense and widespread neuroinflammation than striatal or thalamic structures. Furthermore, implanted animals showed deficits in ORT performance 2 and 8 weeks post-implantation. Thus, electrode implantation resulted in a widespread and persistent neuroinflammation and sustained memory impairment. These results suggest that the insertion and continued presence of electrodes in the brain, even without stimulation, may lead to inflammation-mediated cognitive deficits in susceptible individuals, as observed in patients treated with DBS.

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    • "These different strategies are all predicated on the grounds that suppressing the microglial/inflammatory response to DBS will improve the brain-electrode interface in these chronically implanted micro-electrodes and thus maintain efficacy. Whether this is really a problem in patients with DBS is unknown (see above and Vedam-Mai et al., 2012a,b), but one interesting study by Hirshler et al. (2010) (see also Table 1) in rats showed that merely inserting an electrode into the brain could induce widespread and chronic (i.e., over weeks) neuroinflammation which was correlated with deficits in cognitive function—deficits which are also seen in patients who have had DBS (Witt et al., 2008). No such studies using microglia markers and positron emission tomography (PET) have been performed clinically, although a recent study found that in patients with DBS of the pedunculopontine nucleus, there was an improvement in cognition in association with improvements in cortical activity as measured by fluorodeoxyglucose (FDG)-PET (Stefani et al., 2010). "
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    ABSTRACT: The role of glial cells in the pathogenesis of many neurodegenerative conditions of the central nervous system (CNS) is now well established (as is discussed in other reviews in this special issue of Frontiers in Neuropharmacology). What is less clear is whether there are changes in these same cells in terms of their behavior and function in response to invasive experimental therapeutic interventions for these diseases. This has, and will continue to become more of an issue as we enter a new era of novel treatments which require the agent to be directly placed/infused into the CNS such as deep brain stimulation (DBS), cell transplants, gene therapies and growth factor infusions. To date, all of these treatments have produced variable outcomes and the reasons for this have been widely debated but the host astrocytic and/or microglial response induced by such invasively delivered agents has not been discussed in any detail. In this review, we have attempted to summarize the limited published data on this, in particular we discuss the small number of human post-mortem studies reported in this field. By so doing, we hope to provide a better description and understanding of the extent and nature of both the astrocytic and microglial response, which in turn could lead to modifications in the way these therapeutic interventions are delivered.
    Frontiers in Pharmacology 07/2014; 5:139. DOI:10.3389/fphar.2014.00139 · 3.80 Impact Factor
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    • "The injuries ranged from intraparenchymal or subdural hemorrhages related to electrode displacement, to subtle histological changes associated with meningeal inflammation related to long-term instrumentation . Unfortunately, regardless of the electrode type, long-term monitoring with intracranial electrodes can cause inflammation and subsequent neuronal injury, which may be associated with alterations of cortical excitability (Hirshler et al., 2010), either by reducing the cortical EEG signal or increasing cortical irritability. Hence, caution must be exercised in the interpretation of the electroclinical findings. "
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    ABSTRACT: The baboon provides a natural non-human primate model for photosensitive, generalized epilepsy. This study describes an implantation procedure for the placement of subdural grid and strip electrodes for continuous video-EEG monitoring in the epileptic baboon to evaluate the generation and propagation of ictal and interictal epileptic discharges. Subdural grid, strip and depth electrodes were implanted in six baboons, targeting brain regions that were activated in functional neuroimaging studies during photoparoxysmal responses. The baboons were monitored with continuous video-EEG monitoring for 2-21 (mean 9) days. Although the animals were tethered, the EEG signal was transmitted wirelessly to optimize their mobility. Spontaneous seizures, interictal epileptic discharges (IEDs), and responses to intermittent light stimulation (ILS) were assessed. Due to cortical injuries related to the electrode implantation and their displacement, the procedure was modified. Habitual myoclonic and generalized tonic-clonic seizures were recorded in three baboons, all associated with a generalized ictal discharge, but were triggered multiregionally, in the frontal, parietal and occipital cortices. IEDs were similarly expressed multiregionally, and responsible for triggering most generalized spike-and-wave discharges. Generalized photoparoxysmal responses were activated only in one baboon, while driving responses recorded in all three photosensitive baboons were 2.5 times the stimulus rate. In contrast to previous intracranial investigations in this model, generalized ictal and interictal epileptic discharges were triggered by parietal and occipital, in addition to the frontocentral cortices. Furthermore, targeted visual areas responded differently to ILS in photosensitive than nonphotosensitive baboons, but further studies are required before mechanisms can be implicated for ILS-induced activation of the epileptic networks.
    Epilepsy research 04/2012; 101(1-2):46-55. DOI:10.1016/j.eplepsyres.2012.02.016 · 2.19 Impact Factor
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    ABSTRACT: INTRODUCTION: Diffusion tensor imaging (DTI) techniques demonstrated diffuse bilateral temporal and extra-temporal abnormalities of white matter in patients presenting mesial temporal lobe epilepsy with hippocampal sclerosis (HS). The aim of this study was to assess these diffusion changes following temporal lobe surgery, by applying a novel voxel-based tract-based spatial statistics (TBSS) technique for whole-brain analysis of fractional anisotropy (FA) and mean diffusivity (MD). Second, region-of-interest analysis (ROI) was performed to improve statistical power. MATERIAL AND METHODS: The study included 22 patients with unilateral HS. Twelve patients underwent temporal lobe surgery. Follow up MRI was done in a mean interval of 4 months. Voxelwise pre-operative FA asymmetry in all 22 patients was assessed within subjects between lesional and contralateral hemispheres. The whole-brain post-operative dataset of 10 seizure-free patients was compared with the corresponding pre-operative dataset using voxel-wise statistical analysis. Additionally, regional analysis at the fornices was done with skeleton-based region of interest (SROI). RESULTS: Within a mean interval time of 6.3 months after surgery, 10 of 12 patients were seizure free (83.3%). The voxelwise comparison between lesional and contralateral hemispheres was consistent with previous studies showing a more widespread diffusion alteration in the lesional hemisphere. Voxel-wise comparison between post and pre-operative dataset did not show supra-thresholded voxels. SROI statistical analysis showed significant decrease in FA and increase in MD in the ipsilateral fornix. Significant increase in FA was observed in the contralateral fornix after surgery. CONCLUSION: The ipsi-lesional fornix showed decreased FA and increased MD after surgery, consistent with Wallerian degeneration. In contrast, contra-lesional fornix demonstrated increase in FA. This observation is important for our understanding of the fate of the remaining brain tissue following removal of an epileptic focus. Postoperative increase in FA may reflect structural reorganization in response to epilepsy surgery. The discrepancy between SROI and voxelwise statistics emphasizes the difference of statistical sensitivity between voxelwise and ROI analyses.
    Epilepsy research 03/2011; 94(3). DOI:10.1016/j.eplepsyres.2011.02.001 · 2.19 Impact Factor
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