*4.6. Electrode Implantation*

Several clinical DBS studies have also tried to improve the accuracy of electrode implantation in order to precisely target regions of interest. The pioneering work by Mayberg et al. used PET scans of pathological glucose metabolism to guide the electrode implantation. Riva-Posse et al. used individualized tractography maps based on a group connectome blueprint of past responders to DBS to identify optimal target regions for electrode implantation [49]. Riva-Posse et al. used a four-bundle white matter blueprint, which resulted in good clinical outcomes in eight out of 11 patients, which suggests that the use of this method could improve the precision of implantation. Similarly, Tsolaki et al. investigated the use of FMRIB Software Library (FSL) probabilistic tractography in SCC-DBS [50]. Several studies have used other methods to try to specify the optimal stimulation points. Choi et al. investigated the best contact positions that elicited the best response during intraoperative testing [57]. They used di ffusion-directed magnetic resonance imaging and patient-specific tractography maps to guide the implantation. They also used fiber tract probabilistic tractography to determine the putative fiber tract activation in patients, which was used to guide the electrode implantation for the best response, rather than the salient response. Contacts in the left hemisphere were found to produce the best consistent intraoperative response to DBS in seven out of nine patients at 6 months. Smart et al. validated this result in their study using local field potentials following unilateral HFS-DBS [46]. They found that left-sided stimulation evoked broadband e ffects, compared with right sided stimulation, which evoked only beta and gamma bands. Additionally, a decrease in theta bands was consistently accompanied by behavioral improvements. They concluded that the precision of electrodes in the left-hemisphere was more important and instructive than in the right hemisphere. In contrast, Guinjoan et al. and Howell et al. found that right hemisphere targets were critical for behavioral improvements [44,68]. Guinjoan et al. showed that right unilateral DBS could reverse and remit a patient's worsening mood induced by left unilateral DBS. Howell et al. showed that right cingulate bundle activation beyond a threshold could protract the recovery. Further research is needed to elucidate the di fferences in these studies.

### *4.7. Other Responses to DBS*

With regard to other potential responses to DBS, recent studies have attempted to characterize non-behavioral evoked responses. Conen et al. identified higher rCBF in patients at baseline and during DBS therapy compared to non-remitters and non-responders [48]. Riva-Posse et al. observed autonomic changes in responders undergoing DBS [41]. In a study by Smart et al., assessing the efficacy of DBS, they found consistent changes in left theta local field potentials, which could provide another consistent parameter to monitor. Based on this finding, they proceeded to adjust the contacts for one non-responder, who was able to achieve a response by the end of the study. In a study by Sankar et al. on responders and non-responders who had previously undergone SCG-DBS, they found that both groups had significant volume di fferences in the left and average SCG; in the right and average amygdala; and in the left, right, and average thalamus (Sankar et al. 2020). Additionally, non-responders had significantly greater grey matter volume compared to responders and a greater grey to white matter ratio. This important information provides ye<sup>t</sup> more criteria for assessing if a patient might respond to DBS. Expanding the breadth of data obtained during clinical trials has the potential to advise clinicians on the e fficacy of DBS, and to help predict non-responders and adjust the stimulation parameters. This will improve patient welfare and allows for a more accurate examination of the mechanisms of DBS in improving depressive-like symptoms.

Furthermore, it would be prudent to use preclinical results to advise clinical cases. In a previous preclinical study, Hamani et al. reported that DBS supplemented with tranylcypromine increased the antidepressant-like response in animals by 20%–30% compared to either treatment alone. They later reported on a patient who relapsed after 4 years of remission following DBS treatment [64]. Based on their previous work, they administered tranylcypromine before the DBS treatment, which allowed the patient to enter remission again.

### **5. Preclinical Studies of Electrical Stimulation in the Medial Prefrontal Cortex in Rodents**

Following the success of a number of preliminary clinical studies, several preclinical studies were conducted to investigate the antidepressant-like e ffects of DBS [79]. The mPFC in rats is widely regarded to be homologous to the SCC in humans. The mPFC together with the amygdala, hippocampus, and hypothalamus controls the stress response, autonomic functions, and cognition in rats [80–83]. Using PET imaging, glucose metabolism was observed to normalize in the mPFC from a hyperactive state following DBS, which was similarly observed in the SCC after 1 h of DBS [84]. However, the homology between subdivisions of mPFC and SCC is still under debate. The vmPFC can be further subdivided into the infralimbic (IL) and prelimbic (PrL) regions. Although there are overlaps, the IL and PrL innervate di fferent regions to di fferent extents, including the lateral hypothalamus, dorsal raphe nucleus, and amygdala, among e fferent regions [85–87]. The PrL has been shown to innervate to important limbic regions associated with SCC projections [87]. Meanwhile, the infralimbic cortex (IL) is believed to be structurally homologous based on comparisons involving tractography analysis [88–90]. Some assert that the whole ventromedial prefrontal cortex (vmPFC) is homologous to the SCC [91,92]. Others assert that the vmPFC is functionally distinct from the dorsal medial prefrontal cortex [70,91]. Nevertheless, the vmPFC is generally regarded as homologous to BA25, although a thorough understanding of specific correlations remains to be seen. Table 3 lists 29 preclinical studies on the e ffects of vmPFC-DBS on animal behaviors.
