Intracranial electrode implantation produces regional neuroinflammation and memory deficits in rats
Introduction
Deep brain stimulation (DBS) is an increasingly popular therapeutic approach for diverse neurological disorders including Parkinson's Disease (PD) (Benabid et al., 2005, Limousin and Martinez-Torres, 2008), depression (Marangell et al., 2007), obsessive compulsive disorder (Lipsman et al., 2007) and epilepsy (Vonck et al., 2003, Vonck et al., 2007). This approach involves chronic implantation of an electrode in a specific brain structure followed by chronic electrical stimulation.
While DBS relieves motor symptoms, there is a steady increase in reports of cognitive impairments associated with this procedure in PD (Daniele et al., 2003, Dujardin et al., 2001, Funkiewiez et al., 2004, Saint-Cyr et al., 2000, Trepanier et al., 2000, Witt et al., 2008, York et al., 2008) as well as Huntington disease (Fasano et al., 2008), essential tremor (Fields et al., 2003) and dystonia (Kiss et al., 2007). Previous studies explained the cognitive impairment accompanying DBS in PD patients as a result of the electrical stimulation of the subthalamic nucleus (Alegret et al., 2001, Ardouin et al., 1999, Dujardin et al., 2001, Saint-Cyr et al., 2000, Trepanier et al., 2000) which alters the basal ganglia–anterior cingulate cortex circuit activity (Cilia et al., 2007a, Kalbe et al., 2009, Schroeder et al., 2003). In contrast, there is also evidence of cognitive decline after DBS surgery both “on” and “off” stimulation, compared to pre-surgical performance, suggesting effects related to the surgical procedure rather than the stimulation (Daniele et al., 2003, Morrison et al., 2004, Pillon et al., 2000). However, the relative contribution of the surgery would be hard to assess under these conditions due to possible lingering effects of the chronic stimulation.
Postmortem analyses of brain biopsies from patients treated with DBS demonstrate a local brain tissue reaction to the electrode characterized by the presence of activated astrocytes (Boockvar et al., 2000, Burbaud et al., 2002, Haberler et al., 2000, Henderson et al., 2001, Henderson et al., 2002, Jarraya et al., 2003, Nielsen et al., 2007, Pilitsis et al., 2008) and activated microglia (Chou et al., 2004, Haberler et al., 2000, Henderson et al., 2002, Jarraya et al., 2003, Nielsen et al., 2007, Pilitsis et al., 2008). These findings were very similar, regardless of the disease, the electrode location and the duration of the implantation. Very similar inflammatory responses were observed following implantation of cerebrospinal fluid shunt devices (Del Bigio, 1998) and recording electrodes used for localization of epileptogenic tissue (Stephan et al., 2001) in humans, which do not involve electrical stimulation. Animal studies with various intracranial implants similarly report activated astrocytes (Kim et al., 2004, Lenarz et al., 2007, Leung et al., 2008, McConnell et al., 2007, Mokry et al., 2000, Stice et al., 2007, Szarowski et al., 2003, Turner et al., 1999) and activated microglia (Biran et al., 2007, Biran et al., 2005, Griffith and Humphrey, 2006, Kim et al., 2004, Leung et al., 2008, McConnell et al., 2007, Mokry et al., 2000, Szarowski et al., 2003) in close proximity to the implant site.
Since neuroinflammation can cause cognitive impairment in humans (Hoogman et al., 2007, Pikis et al., 1996, Schmidt et al., 2006) and in animals exposed to lipopolysaccharide (LPS) (Hauss-Wegrzyniak et al., 2000) or ischemia (Langdon et al., 2008, Liu et al., 2007), we set out to test the hypothesis that implantation-induced neuroinflammation is not limited to the implantation site and may spread through brain regions playing a critical role in cognitive functioning, thereby leading to memory deficits. To facilitate quantitative regional measurement of neuroinflammation, we chose to employ [3H]PK11195, an established marker of neuroinflammation which labels peripheral benzodiazepine receptors (PBR) on astrocytes and microglia (James et al., 2006, Lang, 2002).
Section snippets
Electrodes
Three types of electrodes were used: (1) bipolar twisted electrode with an insulated strand diameter of 0.28 mm (Plastics One, part no. MS303/1), referred to as “thick” electrodes throughout the text; (2) bipolar twisted electrode with an insulated strand diameter of 0.15 mm (Plastics One, part no. MS303/3), referred to as “thin” electrodes throughout the text; and (3) bipolar concentric electrode with an inner electrode projection of 1 mm, inner insulated electrode diameter of 0.15 mm and
Effects of thick and thin electrode implantation on PBR density 1 week post-implantation (experiment 1)
There were no significant differences between hemispheres of sham animals compared with hemispheres of intact animals by repeated measures ANOVA; thus, results from these hemispheres were pooled and considered as control hemispheres. Electrode implantations resulted in significant increases in the density of PBR indicative of neuroinflammation 1 week post-implantation (significant region × treatment interaction by two way ANOVA, F = 4.62 P < 0.0001). Changes observed in hemispheres implanted with
Discussion
The current study shows for the first time that chronic implantation of electrodes in the STN produces a memory deficit as well as persistent and widespread neuroinflammation in rats, which extends beyond the electrode track in a region-selective manner. 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. Unlike previous studies which used
Acknowledgments
We would like to thank Dr. Spiegelman from the Department of Neurosurgery in Sheba Medical Center for helpful discussions. Supported in part by NIH RO1 NS050285 to Anat Biegon.
References (84)
- et al.
Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease
Lancet Neurol.
(2009) - et al.
Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays
Exp. Neurol.
(2005) - et al.
Neural correlates of STN DBS-induced cognitive variability in Parkinson disease
Neuropsychologia
(2008) - et al.
Brain networks underlining verbal fluency decline during STN-DBS in Parkinson's disease: an ECD-SPECT study
Parkinsonism Relat. Disord.
(2007) - et al.
Brain networks underlining verbal fluency decline during STN-DBS in Parkinson's disease: an ECD-SPECT study
Parkinsonism Relat. Disord.
(2007) - et al.
Clinical correlates and cognitive underpinnings of verbal fluency impairment after chronic subthalamic stimulation in Parkinson's disease
Parkinsonism Relat. Disord.
(2006) - et al.
Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat
Brain Res.
(1988) - et al.
A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data
Behav. Brain Res.
(1988) - et al.
Metabolic and behavioral deficits following a routine surgical procedure in rats
Brain Res.
(2007) Neuronal mechanisms of executive control by the prefrontal cortex
Neurosci. Res.
(2001)
Long-term gliosis around chronically implanted platinum electrodes in the Rhesus macaque motor cortex
Neurosci. Lett.
Increase in peripheral benzodiazepine receptors and loss of glutamate NMDA receptors in a mouse model of closed head injury: a quantitative autoradiographic study
NeuroImage
Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats
Brain Res.
Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines
Brain Behav. Immun.
Chronic response of adult rat brain tissue to implants anchored to the skull
Biomaterials
Reduced neurogenesis after suppressed inflammation by minocycline in transient cerebral ischemia in rat
J. Neurol. Sci.
Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry
Biomaterials
Deep brain stimulation for Parkinson's disease
Neurotherapeutics
Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor
Brain Res.
Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease
Arch. Clin. Neuropsychol.
[3H]PK 11195 and the localisation of secondary thalamic lesions following focal ischaemia in rat motor cortex
Neurosci. Lett.
Traumatic brain injury leads to increased expression of peripheral-type benzodiazepine receptors, neuronal death, and activation of astrocytes and microglia in rat thalamus
Exp. Neurol.
Brain responses to micro-machined silicon devices
Brain Res.
Neuropsychological outcome of GPi pallidotomy and GPi or STN deep brain stimulation in Parkinson's disease
Brain Cogn.
Cerebral astrocyte response to micromachined silicon implants
Exp. Neurol.
Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson's disease: a randomised, multicentre study
Lancet Neurol.
Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease
Arch. Neurol.
Bilateral subthalamic or pallidal stimulation for Parkinson's disease affects neither memory nor executive functions: a consecutive series of 62 patients
Ann. Neurol.
The consolidation of object and context recognition memory involve different regions of the temporal lobe
Learn. Mem.
Deep-brain stimulation in Parkinson's disease: long-term efficacy and safety—what happened this year?
Curr. Opin. Neurol.
Insular cortex is involved in consolidation of object recognition memory
Learn. Mem.
Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain
J. Neurochem.
The brain tissue response to implanted silicon microelectrode arrays is increased when the device is tethered to the skull
J. Biomed. Mater. Res. A.
Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report
J. Neurosurg.
Minimal tissue damage after stimulation of the motor thalamus in a case of chorea-acanthocytosis
Neurology
Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion
Neurosci. Bull.
Migration of perilesional microglia after focal brain injury and modulation by CC chemokine receptor 5: an in situ time-lapse confocal imaging study
J. Neurosci.
Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy. Case report
J. Neurosurg.
Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinson's disease
J. Neurol. Neurosurg. Psychiatry
Biological reactions to cerebrospinal fluid shunt devices: a review of the cellular pathology
Neurosurgery
Influence of chronic bilateral stimulation of the subthalamic nucleus on cognitive function in Parkinson's disease
J. Neurol.
GPi-DBS in Huntington's disease: results on motor function and cognition in a 72-year-old case
Mov Disord.
Cited by (42)
Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease
2024, Experimental NeurologyBrainy biomaterials: Latest advances in smart biomaterials to develop the next generation of neural interfaces
2023, Current Opinion in Biomedical EngineeringThe potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson's disease progression
2020, Journal of Clinical NeuroscienceCitation Excerpt :The analysis of the POP group revealed long-term continuous, but noticeably slower UPDRS III OFF worsening than in the BMT group, which also shows minor long-term impact of STN DBS on motor symptoms in PD patients, which has been also described by other authors [26–28]. The initial worsening after DBS surgery can occur secondarily to regional neuroinflammation after intracranial electrodes’ implantation, as was demonstrated in animal models [21,22]. Orlowski et al. [22] demonstrated a complex brain tissue reaction to neurostimulation with a strong neuroinflammatory response during the first 6 months after electrode implantation with a subsequent minor response after 12 months from surgery.
Automated quantification of EEG spikes and spike clusters as a new read out in Theiler's virus mouse model of encephalitis-induced epilepsy
2018, Epilepsy and BehaviorCitation Excerpt :Furthermore, EEG spikes were reported in sham control mice and rats in other studies [11,12] and in the EEG of a small percentage of healthy volunteers and relatively larger percentage of patients without a history of seizures [31]. In rodents, the lesion associated with implantation of an electrode may induce proepileptogenic brain alterations, including blood–brain barrier disruption, chronic inflammation, decreases in seizure threshold, and epileptiform discharges in the hippocampus [32–36], so it is important to include adequate sham controls when studying vEEG alterations in rodent models of acquired epilepsy [37]. Electrode-induced brain alterations have not only been observed with depth electrodes, but also with bone screws penetrating the skull as used for the present experiments [38] or craniotomy by electric dental drill (without damaging the brain tissue) as used as part of stereotactic electrode implantation [39].