We investigated the relationship between the intersection and the location of the surgical trajectory and the active electrodes and neuropsychological outcome 6 months following bilateral STN DBS. Declines in MMSE scores were related to electrodes that were more laterally placed in either hemisphere, particularly when the active electrodes were posterior-lateral within the frontal quadrant. A similar association was found for decline in DRS scores in the left hemisphere, which additionally demonstrated a relationship with electrodes which were more superiorally located. In regard to declines in verbal learning, the electrodes that were closer to the approximated STN and more superiorally located in the left hemisphere were associated with declines at 6 months following surgery. However, in the right hemisphere the electrodes that were located more in the lateral direction were related to verbal short-term memory declines. Verbal long-term memory declines were found for electrodes located more posterior-laterally in the left hemisphere. Declines in verbal fluency scores were more variable with associations found between change scores and electrodes in the lateral and superior directions in the left hemisphere and those electrodes closer to the approximated STN and more superiorally and posteriorally located in the left hemisphere. In contrast, semantic fluency declines were only related to right hemisphere electrodes located more superiorally. Declines in mood were related to those electrodes located further away from the approximated STN, particularly those located more inferiorally and laterally in the left hemisphere. Anxiety change scores were not associated with the location of the electrodes. The results provide preliminary evidence that 6 months following bilateral STN DBS for PD, cognitive and emotional changes may be related to the surgical trajectory and electrode placement.
By using difference scores from baseline cognitive functions, we demonstrated that the relationship between cognitive functioning and electrode placement was not due to pre-existing cognitive dysfunction but represents the decline in cognitive functioning over 6-months. These cognitive declines following DBS are commonly reported in the literature for bilateral STN DBS as a potential side effect of the surgical intervention. However, the factors that are associated with these declines are poorly understood.
The basal ganglia are richly connected to other subcortical structures, and also specific cortical regions, including motor, occulomotor, prefrontal associative, and limbic areas.(23
) In conjunction with the globus pallidus, the STN has been labeled as the “central pacemaker of the basal ganglia,” which is responsible for action selection. Some neurons in the GPi, the STN, and the thalamus have abnormal phasic activity, which supports the belief that these sites are involved in bradykinesia and rigidity in PD.(8
) However, the STN also projects to associative and limbic areas of the basal ganglia and the substantia nigra pars retcularis.(24
) The STN is structured into 3 components: the dorsolateral component, the ventromedial component, and the medial tip. The dorsolateral component (2/3 of the STN) is involved in somatomotor function; and the ventromedial component (1/3 of the STN) is involved in associative processing, while the medial tip of the STN projects to limbic structures. The current study supports the theory that the STN is intimately involved in associative cognitive processing and potentially affective functioning.
In a preliminary study correlating electrode location with motor outcomes of STN DBS, Tintner et al.(25
) found that some electrode contacts located within the radiologically-definable STN failed to improve parkinsonism motor symptoms while others induced dyskinesias and produced anti-parkinsonian effects. In contrast, Kumar et al.(5
) argued that only DBS contacts located in the radiologically-definable STN produce optimal motor improvements. Moreover, Rizzone et al.(26
) reported that the best clinical effect on Parkinson’s disease-related motor symptoms was obtained when the STN electrodes were placed in the dorsolateral portion of the STN. While it is generally recognized that the 4 electrodes allow for versatility to compensate for final stereotactically placed electrode tips that are within 2–3 mm of the optimal target(27
), deviations in the placement of electrodes may provide us insight into the mechanism of action of DBS. Clinical evidence from microstimulation has revealed that if the DBS electrodes are positioned posterior laterally from the STN, the internal capsule will be stimulated and facial and hemi-body pulling can result. If the electrodes are located more medial to the STN, the stimulation may impinge on the red nucleus, the medial longitudinal fasciculus or the zona inserta leading to motor and/or eye deviations. Stimulation occurring more superior to the STN in the thalamus would result in tremor management without other PD symptom relief. None of the patients in the current sample exhibited any of these motoric side effects following DBS.
Although the role of the STN in motor functioning has been clarified, the investigations into the role of the STN in cognitive functioning remains in its infancy. As reported previously, Tsai and colleagues(20
) were the first to report that the neuropsychological effects of chronic STN-DBS was related to the more anteriorly located electrodes within the ventral STN. However, their two groups (cognitive side effect versus no cognitive side effect) were based on postoperative changes on the MMSE only, which is not an overly sensitive measure of subcortical cognitive functioning. Their study highlights the importance of investigating the cause of differential cognitive outcome following STN DBS and was the first to suggest the potential role of the electrode location.
STN DBS outcome studies have highlighted the role of the STN in verbal memory, verbal fluency, executive functioning, attention, working memory, and response inhibition. Animal models have also demonstrated evidence for a role of the STN in attention and response inhibition.(24
) Taken together, this literature has revealed that the STN has a regulatory function in processing associative and limbic information. Although the precise mechanism is unknown, two hypotheses have been proposed as to the mechanism of cognitive change following STN DBS. The first hypothesis proposes that the stimulation is not confined only to the motor part of the STN; that it spreads to other areas of the STN or neighboring subcortical structures. The second hypothesis, which is currently favored, proposes that the STN itself is responsible for the cognitive changes. The current research adds supportive evidence to the second hypothesis that it is the STN itself and not neighboring structures, that is responsible for cognitive and behavioral change following stimulation. Those patients whose active electrodes were closer to the approximated STN were more likely to show verbal learning and memory and verbal fluency declines six months following surgery. Further research will be needed to clarify the role of the STN in cognitive functioning. However, current literature suggests that the STN is not only the central pacemaker for motor functioning but also for cognitive and behavioral functioning. Future DBS research using microelectrode recordings and higher resolution imaging with controlled and selective targeting will aid in clarifying the role of the STN in cognitive and behavioral functioning.
The STN has also been implicated in the processing of emotional information. Using direct recordings from macroelectrodes during the presentation of emotionally laden pictures, Brucke and colleagues(28
) found a significant relationship between a desynchronization of STN alpha activity with pleasantly rated stimuli. This finding suggests that because the STN is involved in the processing of valence-related emotional processing, stimulation in this area may lead to emotional changes. Mallet and colleagues(29
) further investigated the role of the STN in cognition and emotions in two patients who demonstrated hypomanic symptoms during electrical stimulation. The hypomanic state was localized to stimulation of the electrode in the anteromedial STN. These authors proposed a model in which the STN integrates motor, cognitive, and emotional components of behavior, and our current research findings supports this model of the STN, particularly in the left hemisphere.
This study has several limitations. First, the small sample size limits the conclusions that can be drawn. We chose to focus on verbal memory and verbal fluency changes to limit the number of statistical analyses; however, an evaluation of a comprehensive neuropsychological evaluation may reveal further information regarding the role of the STN in cognitive and behavioral functioning. The statistical power of this study is not sufficient to make clinical decisions regarding this neurosurgical procedure. Second, the majority of the analyses were correlational. Consequently, we are limited to discussions of the relationships between the electrode location and cognitive and behavioral functioning, and causation cannot be assumed. Third, the electrode artifact found on the MRI images limits the ability to precisely locate the electrodes and the exact path of the surgical trajectory. Fourth, due to the difficulty in visualizing the STN on the MRIs, particularly with the artifact, we are unable to say with precise certainty that the electrodes are located within the STN. We used computational models to estimate the location of the active electrodes, these results can be misleading as the exact location of the tip of the electrode within the MRI artifact is unknown. We also used a proxy measure of the approximated STN which was verified on the patients’ scans. Additionally, future research should investigate the relationship between the volume of tissue being stimulated and the neuropsychological outcome. While this study is preliminary, it highlights the need for future neuropsychological research to investigate the role of the STN in the relationship between motor, cognitive, and behavioral outcome following STN DBS.
The angle of the surgical trajectory and the proximity of the electrodes to the approximated STN were related to changes in cognitive and emotional functioning following DBS. The current findings extend the literature on the role of the STN behavioral functioning and add support to the hypothesis that the STN plays an integrative role not only in motor function but also in cognitive and emotional functioning.