Yates, Nathanael J.

Abstract Background Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. Aim The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m‐amph). Methods Wistar rats were given 14 days of m‐amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low‐frequency stimulation (LFS) or continuous high‐frequency stimulation (HFS). Immediately after DBS, manic‐like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open‐field tests and fast‐scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. Results M‐amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M‐amph increased DA reuptake time post‐sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. Conclusion These results demonstrate that both VTA LFS and HFS DBS exert anti‐manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti‐manic effects.

Inflammation is a critical factor contributing to the progressive neurodegenerative process observed in Parkinson’s disease (PD). Microglia, the immune cells of the central nervous system, are activated early in PD pathogenesis and can both trigger and propagate early disease processes via innate and adaptive immune mechanisms such as upregulated immune cells and antibody-mediated inflammation. Downstream cytokines and gene regulators such as microRNA (miRNA) coordinate later disease course and mediate disease progression. Biomarkers signifying the inflammatory and neurodegenerative processes at play within the central nervous system are of increasing interest to clinical teams. To be effective, such biomarkers must achieve the highest sensitivity and specificity for predicting PD risk, confirming diagnosis, or monitoring disease severity. The aim of this review was to summarize the current preclinical and clinical evidence that suggests that inflammatory processes contribute to the initiation and progression of neurodegenerative processes in PD. In this article, we further summarize the data about main inflammatory biomarkers described in PD to date and their potential for regulation as a novel target for disease-modifying pharmacological strategies.