Intracranial electrode implantation produces regional neuroinflammation and memory deficits in rats

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 one week or eight 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 two and eight weeks after surgery. Electrode implantation produced region-dependent changes in ligand binding density in the implanted brains at one week as well as eight weeks post implantation. Cortical regions showed more intense and widespread neuroinflammation than striatal or thalamic structures. Furthermore, implanted animals showed deficits in ORT performance two and eight 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 inflammationmediated cognitive deficits in susceptible individuals, as observed in patients treated with DBS.

Dorsal hippocampal lesions boost performance in the rat sequential reaction time task

“…These deficits most likely reflect side effects of the surgery, since behavioral and mnestic deficits as well as neurochemical changes have repeatedly been reported in sham-operated animals (Adams et al, 1993;Rao et al, 1999;Grossman et al, 2003;Hirshler et al, 2010). This makes the superior performance of the lesion group even more impressive, because this group also had to cope with all the general side effects caused by the present type of surgery.…”

Procedural Performance Benefits after Excitotoxic Hippocampal Lesions in the Rat Sequential Reaction Time Task

“…While hippocampal tissue reduction was similar to our prior experiment (Eckart et al 2012), control and sham groups showed normal exploratory behaviour towards the displaced object during the object place recognition test, whereas the lesion group showed the expected deficit. Previously, Eckart et al (2012) found a deficit in the sham group, and other sham surgical procedures were also found to cause behavioural and mnestic deficits, as well as neurochemical changes (Adams et al 1994;Raghavendra Rao et al 2000;Grossman et al 2003;Hirshler et al 2010). The lower hippocampal volumes found in the sham group of the present study may be a result of the surgery, but since statistical analysis between control and sham animals showed no significant differences in total hippocampal volumes, it is unclear if the observed lower performance in the sham group was caused by anaesthesia, minor surgery-induced damage, or a general variability of the behavioural measures used.…”

A surgical device for minimally invasive implantation of experimental deep brain stimulation leads in large research animals

“…It is vital to take all steps possible to reduce focal tissue injury, since the DBS procedure and the continued presence of the DBS leads themselves, may cause sustained widespread neuroinflammation and cognitive impairment irrespective of target region and stimulation (Hirshler et al, 2010). In this respect, the lead diameter is an important factor because it may influence the degree of tissue inflammation, microglia migration and neuronal survival in the vicinity of the electrode track (Hirshler et al, 2010;Thelin et al, 2011).…”

“…In this respect, the lead diameter is an important factor because it may influence the degree of tissue inflammation, microglia migration and neuronal survival in the vicinity of the electrode track (Hirshler et al, 2010;Thelin et al, 2011). The LID incorporates the use of a small-diameter biocompatible guide tube (∅1.0 mm) used for implanting the stimulating lead end, after which the guide tube is implanted subcutaneously with the rest of the lead.…”

“…Experimental large animal models such as non-human primates and minipigs are particular well suited for long term DBS studies due to their manageable adult body weight and large gyrencephalic brain (Lacan et al, 2008;Bjarkam et al, 2009). While clinical implantable pulse generators (IPG) can be used for primate and minipig studies, down-scaled versions of the flexible human multicontact DBS lead are needed, to accommodate the smaller animal brain size and to minimize neuroinflammation (Elder et al, 2005;Lacan et al, 2008;Hirshler et al, 2010;Stypulkowski et al, 2011;Thelin et al, 2011). A challenge in this respect is the adaptation of the clinical implantation method in order to obtain minimally invasive insertion of the experimental DBS leads, as these down-scaled leads have a distal small diameter cerebral stimulating end and a proximal wide connector end directly compatible with commercially available clinical IPGs (Lacan et al, 2008).…”