Depression and suicide following subthalamic stimulation: basic mechanisms

Citation: European Neuropsychopharmacology
The Journal of the European College of Neuropsychopharmacology
Volume 21 (2011), Supplement 3, Page S221( Tuesday, 06 September 2011)

T. Sharp1, H. Hartung1, S. Tan2, V. Visser-Vandewalle2, Y. Temel2

1University of Oxford, Department of Pharmacology, Oxford, United Kingdom
2University of Maastricht, Department of Neuroscience and Neurosurgery, Maastricht, The Netherlands

High-frequency stimulation (HFS) of the STN is an established surgical therapy of advanced Parkinson's disease (PD). However, despite beneficial motor effects this procedure often causes debilitating psychiatric side-effects, including depressed mood [1], and is associated with increased suicide risk [2]. Depression is linked to changes in 5-hydroxytryptamine (5-HT) and previously we reported that, in animal models, STN HFS inhibited the firing of putative 5-HT neurons in the dorsal raphe nucleus (DRN) of the midbrain [3]. Here we have further investigated this phenomenon using a combination of in vivo electrophysiological and neurochemical studies.
STN HFS caused a clear-cut inhibition (20–30%) in the majority of DRN neurons but a smaller proportion of neurons were either excited or non-responsive. Juxtacellular labelling studies demonstrated 5-HT-immunopositive neurons in each of these response categories. In microdialysis experiments STN HFS evoked a modest (25%) fall in extracellular 5-HT (prefrontal cortex and striatum) in both anaesthetised and awake animals. Previous anatomical studies demonstrate STN-DRN connections via the lateral habenula (LHb), which is increasingly implicated in the neural circuitry of depression. Interestingly, STN HFS increased c-fos expression in the LHb, and also increased neuronal firing in this nucleus.
These data demonstrate a powerful modulatory effect of STN HFS on 5-HT neurons but suggest destabilisation rather than simple inhibition. The data implicate the LHb in the neural circuitry mediating this effect. Altered function of STN-DRN neural connectivity may contribute to the adverse psychiatric effects of STN HFS in PD patients, and to mood disturbances in PD patients more generally.

References:
1. Temel Y., Kessels A., Tan S., Topdag A., Boon P., Visser-Vandewalle V., 2006, Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review. Parkinsonism Relat Disord. 12, 265–272.
2. Voon V., Krack P., Lang A.E. et al, 2008, A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease. Brain 131, 2720–2728.
3. Temel Y., Boothman L.J., Blokland A., Magill P.J., Steinbusch H.W., Visser-Vandewalle V., Sharp T., 2007, Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus. Proc Natl Acad Sci 104, 17087–17092.