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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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    • "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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