This study showed a mean BMI increase of 2 kg/m2 at one year following DBS surgery, which agrees with previous findings . Furthermore, the mean active contact coordinates in our study were similar to the preferred coordinates for motor improvement from previous studies . Moreover, WG after STN-DBS was significantly correlated with some active contact coordinates and with increased glucose metabolism in the left frontal and temporal lobes. We could not detect a significant correlation between WG and dyskinesia reduction, while previous findings remain conflicting [4–6, 33].
The STN plays an important role in reward processing , and several studies have indicated that the STN is involved in controlling appetite and eating behavior. For example, a study on non-human primates illustrated that STN activity increased during food reward anticipation and delivery . In humans, stroke or tumors affecting the STN causes hyperphagia and increases appetite [36, 37], while abnormal eating behaviors have been reported following STN-DBS [7, 38–42]. The anteromedial part of the STN is thought to be involved in reward and emotion processing, and dysfunction in this area can induce stereotyped and violent behaviors in non-human primates . Moreover, during STN-DBS, stimulation of the anteromedial part of the STN led to an increased risk of abnormal behavior [22, 44, 45]. Considering these findings, our results regarding the correlation between WG and anterior active contact locations suggest that WG is associated with the stimulation of the anteromedial part of the STN.
We observed correlations between WG and increased metabolism in the limbic and associative areas but not the sensorimotor areas; however, these were not statistically significant in multiple comparisons. A previous FDG-PET study showed that WG after STN-DBS was correlated with increased metabolism in the limbic and associative regions, including the orbitofrontal cortex, lateral and medial parts of the temporal lobe, anterior cingulate cortex, and retrosplenial cortex . Other PET and functional MRI studies have also suggested that a broad network of limbic and paralimbic network structures mediates the desire for food [46–53]. This network is thought to integrate sensory information with the cognitive desire for food and induces behaviors that aim to obtain food [54, 55]. Regions with increased brain metabolism in our study were also associated with the processing of desire for food, which suggests that stimulating the anterior part of the STN changed the activities in the limbic and associative areas, which modified food-related behavior and ultimately WG. Nevertheless, a larger prospective study with correction for multiple comparisons is warranted to confirm this hypothesis.
We also observed that WG was correlated with the left-side active contact Z-axis coordinates, which agrees with a previous report indicating that active contacts located in the zona incerta (dorsally out of the STN) were correlated with increased appetite after STN-DBS . The zona incerta contains neurons expressing melanin-concentrating hormone, which is involved in the regulation of feeding . Thus, our finding of a correlation between WG and the Z-axis coordinates might be explained by the stimulation of zona incerta and neurons that express melanin-concentrating hormone. However, dorsally located contacts are usually also located anteriorly, since the DBS electrodes are usually inserted from the anterodorsal aspect to the posteroventral aspect. Thus, the Y- and Z-axis coordinates acted as confounders for each other. To determine which direction of current spread to the anterior part of STN or Zi is more important for WG, we need to conduct further studies.
We observed that WG was correlated with active contact locations and increased brain metabolism only on the left side. Several studies have also indicated that unilateral STN-DBS causes WG [58, 59], although the laterality of this relationship remains unclear. In this study, left-side active contact Y-axis coordinates had a larger IQR value than the right-side coordinates; the greater variability in the left-side coordinates may explain the laterality of our FDG-PET findings. However, further studies are warranted to determine whether stimulating the right-side anterior part of the STN could influence brain metabolism, subsequently causing WG.
This study has several limitations. First, we did not assess eating habits or daily food intake. Thus, future studies must confirm whether WG is caused by stimulation of the limbic area, which induced changes in eating behaviors, using preoperative and postoperative data on eating behaviors and food intake. Second, we did not assess hormonal factors or swallowing function, which could have confounded our analyses. Third, although we measured the active contact coordinates, we did not assess the volume of tissue activation (VTA) or connectivity between the stimulation site and brain regions. Recent studies have indicated that the clinical outcomes of DBS could be predicted based on the connectivity profile of the VTA and cortical areas [60, 61]. Therefore, the association between WG and stimulation of the limbic area should be confirmed by analyzing the connectivity between the VTA and cortical area. Fourth, we obtained PET data only in an “off DBS” state after the surgery. Therefore, it is difficult to attribute the changes in brain metabolism after DBS to the plasticity of the neural circuit or the washout process of therapeutic DBS.