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: 4.7). 12/2009; 222(1):42-50. DOI: 10.1016/j.expneurol.2009.12.006


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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    • "In the unstimulated hippocampus, enzyme activity is changed in the narrow area surrounding the electrode [65]. In animal study, it has been reported that the different thickness of electrode induced a various regional neuroinflammation and recognition deficits [66]. This different effect on memory from our results could be caused by the thickness of used electrode (280, 150 μm versus 200 μm) and the site of implantation (subthalamic nucleus versus MS). "
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    ABSTRACT: Deep brain stimulation (DBS) has been found to have therapeutic effects in patients with dementia, but DBS mechanisms remain elusive. To provide evidence for the effectiveness of DBS as a treatment for dementia, we performed DBS in a rat model of dementia with intracerebroventricular administration of 192 IgG-saporins. We utilized four groups of rats, group 1, unlesioned control; group 2, cholinergic lesion; group 3, cholinergic lesion plus medial septum (MS) electrode implantation (sham stimulation); group 4, cholinergic lesions plus MS electrode implantation and stimulation. During the probe test in the water maze, performance of the lesion group decreased for measures of time spent and the number of swim crossings over the previous platform location. Interestingly, the stimulation group showed an equivalent performance to the normal group on all measures. And these are partially reversed by the electrode implantation. Acetylcholinesterase activity in the hippocampus was decreased in lesion and implantation groups, whereas activity in the stimulation group was not different from the normal group. Hippocampal neurogenesis was increased in the stimulation group. Our results revealed that DBS of MS restores spatial memory after damage to cholinergic neurons. This effect is associated with an increase in hippocampal cholinergic activity and neurogenesis.
    BioMed Research International 07/2014; 2014(2):568587. DOI:10.1155/2014/568587 · 2.71 Impact Factor
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    • "The animal literature also reveals similar activation of microglia and astrocytes following insertion of electrodes and other intracerebral implants [34–38]. Recently, a study of electrode implantation, without electrical stimulation, has revealed persistent and widespread neuroinflammation in rats, which extends beyond the electrode track in a region-selective manner [39]. Widespread neuroinflammation appears to be a general feature of the chronic implantation procedure, since it was found in rats implanted with three different types of electrodes varying in thickness and shape. "
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    ABSTRACT: We tested the hypothesis that transient microinjury to the brain elicits cellular and humoral responses that stimulate hippocampal neurogenesis. Brief stereotaxic insertion and removal of a microneedle into the right hippocampus resulted in (a) significantly increased expression of granulocyte-colony stimulating factor (G-CSF), the chemokine MIP-1a, and the proinflammatory cytokine IL12p40; (b) pronounced activation of microglia and astrocytes; and (c) increase in hippocampal neurogenesis. This study describes immediate and early humoral and cellular mechanisms of the brain's response to microinjury that will be useful for the investigation of potential neuroprotective and deleterious effects of deep brain stimulation in various neuropsychiatric disorders.
    Stem cell International 03/2013; 2013:205878. DOI:10.1155/2013/205878 · 2.81 Impact Factor
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