Yasin Temel

The use of stimulation electrodes implanted in the brain to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of clinical neuroscience, and very much in the public eye. An excellent example is Parkinson’s disease in which thousands of patients worldwide have been implanted with electrodes in the subthalamic nucleus (STN). The relief of movement disability by STN stimulation is predictable as this nucleus is a critical part of the brain’s motor circuits. Surprisingly, however, STN stimulation can be associated with the occurrence of unpleasant and debilitating psychiatric effects. These effects are a major burden to patients and their families, and are currently without satisfactory explanation. The findings of our studies provide a new insight into this problem. Since changes in brain, 5-HT (serotonin) have long been linked with mood disturbances, we reasoned that STN stimulation might inappropriately influence the functioning of 5-HT neurons. Our electrophysiological experiments using an in vivo animal model show that STN stimulation, at parameters used clinically, exerts a specific, reproducible, reversible and powerful inhibitory effect on 5-HT neurons. Moreover, we find that STN stimulation also evokes depressive-like behaviour, and that this effect can be prevented by administration of a 5-HT specific antidepressant. These findings strongly predict that reduced 5-HT output contributes to the psychiatric disturbances induced by STN stimulation, and provide a rational basis for their clinical management. Moreover, the unsuspected link between the STN and the 5-HT system supports the existence of a novel ‘motor-limbic interface’ that may contribute to mood disturbances in wider populations of psychiatric and neurological patients.

The use of deep brain stimulation (DBS) to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of neuroscience. Deep brain stimulation has generally the same clinical effects as a lesion with respect to the improvement of clinical disability, but has more advantages such as its adjustability and reversibility. To this day, fundamental knowledge regarding the application of electrical currents to deep brain structures is far from complete. Despite improving key symptoms in movement disorders, DBS can be associated with the occurrence of a variety of changes in cognitive and limbic functions both in humans and animals. Furthermore, in psychiatric disorders, DBS is primarily used to evoke cognitive and limbic changes to reduce the psychiatric disability. Preclinical DBS experiments have been carried out to investigate the mechanisms underlying the clinical effects of DBS for at least three (interrelated) reasons: to increase our scientific knowledge, to optimize/refine the technology, or to prevent/reduce side-effects. In this review, we will discuss the limbic and cognitive effects of DBS in preclinical studies.

It is still debated to what extent intraoperative electrophysiological techniques contribute to the outcome of subthalamic nucleus (STN) deep brain stimulation (DBS). Intraoperative electrophysiological recordings for identification of the STN can be made with one electrode or with multiple, simultaneously implanted electrodes. The latter provide more detailed information about the electrophysiological boundaries of the STN; however, implantation of several electrodes at one time might increase the risk of bleeding. Here we report the results of a study of patients with advanced Parkinson's disease, in which one group of patients underwent bilateral STN DBS with electrophysiological recordings from a single electrode, and the other group received STN DBS with multiple (five or fewer) simultaneously implanted electrodes. Fifty-five patients suffering from advanced Parkinson's disease who underwent bilateral STN stimulation were included in this study. Thirty-two patients underwent STN DBS guided by a single semi-microelectrode, and 23 patients underwent STN DBS guided with simultaneously implanted multiple microelectrodes. All patients were examined preoperatively and 3 and 12 months postoperatively with regard to activities of daily living, motor functions, and neuropsychological functions. We found that the simultaneous implantation of multiple electrodes does not increase the risk of bleeding or any other major intracranial complication. The use of multiple electrodes resulted in better motor results when compared with patients who underwent STN DBS guided with a single recording electrode. There were significantly more improvements in patients' tremor and rigidity, and as a consequence, a better total Unified Parkinson Disease Rating Scale, Part III score was identified during the medication-off phase. Despite better motor effects, patients treated with multiple electrodes showed subtle deterioration in neuropsychological functions, particularly in memory function. STN DBS performed with multiple electrophysiological recording electrodes resulted in better motor outcome but induced specific mild declines in neuropsychological functions.