Electrode implantation produces an early response to deep brain stimulation in depression: potential role of regional neuroinflammation.

Abstract

Background: Deep brain stimulation (DBS) is an increasingly popular therapeutic non-pharmacological approach for diverse neuropsychiatric diseases. Recent studies have shown promising results with the use of DBS in subgenual cingulated gyrus (SCG) for the treatment of refractory major depressive disorder (MDD). In these first clinical trials, the patients experience a reduction in the severity of their symptoms right after surgery, followed by a decay in the first month of treatment with DBS. Given that this technique involves chronic implantation of electrodes in a specific brain structure, this early response has been attributed a possible placebo or to a physiological response to probe insertion in other neurological diseases. Purpose of the study: The aim of this study was to explore the possible contribution of the surgical procedure itself in the antidepressant response of DBS. Thus, we studied the effect of electrode implantation in the rat medial prefrontal cortex (mPFC). And additionally, the results were compared with the early outcome of a controlled clinical trial of DBS procedure in the SCG. Methods: Here we characterized the behavioural antidepressant- like effect of electrode implantation and DBS in the infralimbic IL cortex (rodent SCG correlate) by the forced swimming test (FST). The target area was processed to evaluate the role of glial cells, the inflammatory mediators and the p11 implication in the ‘insertional effect’. These changes were assessed by immunohistochemical and western blot techniques. In addition, we evaluated the early outcome of DBS in the SCG of 8 patients with MDD involved in a clinical trial. Results were analyzed by one or two-ways ANOVA followed by Bonferroni test. p<0.05 were considered to be significant. Results: We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not, and this effect was via a main action on serotonin neurotransmission. The ‘insertional effect’ was due to a temporally neuroinflammation, and it was correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity. Additionally, neuronal p11 expression and IL-1b, COX1, COX2, TNFa, as inflammatory mediators, were increased in the mPFC after electrode implantation. These behavioural and neurochemical changes were blocked by anti-inflammatory drugs. On the other hand, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Conclusions: This study demonstrates that electrode implantation up to the IL cortex is sufficient to produce benefits in animal models of antidepressant activity. This ‘insertional effect’ could be due to a regional neuroinflammation, and thus was blocked by the treatment with anti-inflammatory drugs. These findings correlate with the initial effects observed in a series of patients treated for one month with DBS. Overall the results suggest that this early antidepressant effect of DBS is the result of an inflammatory ‘insertional effect’ provoked by electrode implantation, in addition to the electrical stimulation itself.