**1. Introduction**

Major depressive disorder (MDD) contributes significantly to the global disability burden and social burden [1,2]. In the US from 2005 to 2010, the economic burden of patients with major depressive disorder increased by 21.5% to \$210.5 billion [3]. The main symptoms of MDD include severe sadness, anxiety, cognitive deterioration, and suicidal thoughts [4]. Although its etiology is uncertain, genetic predisposition, developmental deficits, hormonal imbalance, and a stressful lifestyle may increase the risk for MDD [5–10].

Prior to the discovery of antidepressant medication, surgical ablation was used to effectively treat MDD in the US and Europe [11]. Pharmacological antidepressants first appeared in the late 20th century and these first-generation drugs became the first line treatment for depression [12]. However, newer generations of antidepressants were barely more effective than first-generation tricyclic antidepressants [13] and this has led to the emergence of treatment resistance. Treatment-resistant depression (TRD) is the failure to respond to the three different classes of treatment: antidepressants, psychotherapy, or electroconvulsive therapy given at a sufficient dose and time [14,15]. Approximately 20% to 30% of patients are refractory to pharmacotherapy and nearly 60% respond inadequately [16,17], which can result in worse clinical responses, leading to additional social burdens [18]. As the pathogenesis of MDD involves multiple structures, a broad-acting safe therapy needs to be developed [19,20].

With much progress in surgical techniques and advances in cardiac pacemakers, electrical stimulation has matured to become an adjustable stimulatory regimen [21]. Deep brain stimulation (DBS) is a procedure whereby deep brain structures are stimulated via precisely implanted electrodes. It was first used to alleviate movement disorders in patients with Parkinson's disease [22]. With advances in our understanding of the limbic circuitry, the focus has shifted to the antidepressant-like effects of DBS [23]. Some recent clinical studies have shown that DBS holds grea<sup>t</sup> promise in treating patients with TRD, and mechanistic studies in animals are currently in progress.

The use of DBS as a treatment for TRD was first proposed in a study by Kruger et al. on the differences in regional cerebral blood flow (rCBF) between remitted patients and bipolar depression (BD) patients [24]. They observed that rCBF in Brodmann Area 25 (BA25) was higher in remitted and BD patients compared to control patients and this was also seen in healthy patients with self-rated high negative affect [25]. Furthermore, Kruger et al. noted that mood provocation did not change the rCBF to this region in BD patients compared to MDD patients, indicating that dysfunction in the region was specific to depression [24]. Mayberg et al., who are pioneers of DBS as a treatment for depression, subsequently targeted BA25 after detecting metabolic abnormalities within the region that were consistent with those found in patients with TRD [19]. This landmark paper led to further developments in the application of DBS of this region as a treatment for depression.

Indeed, several research groups have used DBS to treat depression by targeting different brain regions in the limbic system. Jimenez et al. applied DBS to the inferior thalamic peduncle, whereas Schlaepfer et al. applied DBS in the nucleus accumbens core [26,27] and successfully performed DBS on the medial forebrain bundle [28]. With rapid developments in DBS as a treatment for TRD, research is now focusing on the subcallosal cingulate (SCC). This review aims to examine and consolidate clinical and preclinical research on the use of DBS as a treatment for depression, targeting the subcallosal cingulate in humans and the ventromedial prefrontal cortex, the anatomical correlate in rodents.

### **2. Outline of the Review**

The online PubMed database was searched for research articles in English using a Boolean operation with keywords including "deep brain stimulation" AND "depression" AND "subcallosal cingulate" OR "rodent" AND "medial prefrontal cortex". Relevant articles cited in the reference lists of the identified publications were also included. PubMed was utilized due to its extensive collection of indexed peer-reviewed journals. This review highlights the development of DBS as a treatment for TRD and discusses the findings and limitations of preclinical and clinical studies published in the recent decade. The neuroplasticity-dependent and -independent aspects of the molecular and cellular changes due to DBS are also discussed. Lastly, some potential approaches that may improve the precision, safety, and efficacy of DBS are proposed.

### **3. The Development of Deep Brain Stimulation as a Treatment for Depression**

Deep brain stimulation involves the stereotactic implantation of thin electrodes in deep brain structures that are used to deliver electrical stimulation generated by a subcutaneous pulse generator [29,30]. Stimulation is generally applied at either a low/moderate frequency (5–90 Hz) or high frequency (100–400 Hz). Since the inception of DBS, a number of studies have demonstrated that this modality has the ability to treat pain, obsessive-compulsive disorder, and Parkinson's disease [16,21,31]. Its e fficacy has been verified in Parkinson's disease patients, in which high frequency stimulation (HFS) of specific brain region(s) in the basal ganglia was able to stop tremors [21,32]. The use of DBS has been given FDA approval for the managemen<sup>t</sup> of obsessive-compulsive disorder since 2007, but it is only provided under a humanitarian device exemption [33,34].

The following sections summarize the clinical studies on deep brain stimulation in the subcallosal cingulate for treating patients with treatment-resistant depression and preclinical studies of deep brain stimulation in the medial prefrontal cortex (mPFC) of rodents.

### **4. Clinical and Preclinical Studies of SCC DBS for the Treatment of Depression**

Clinical studies of depression utilize rating scales of depression that assess changes in depressive symptoms in patients. Some scales are completed by the researcher such as the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS). These rating scales should allow more consistent assessment between patients, but can lack consensus in their interpretation among researchers, which could lead to misdiagnosis [35]. Another weakness of rating scales conducted in this manner is that the accuracy of the results is dependent on the communication skills of the patient, which might be hampered by the disease itself. Other scales are completed by patients such as the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Quick Inventory of Depressive Symptomatology (QIDS). These rating scales should allow for a more accurate reporting of depressive symptoms, although the number and/or depth of questions may vary across di fferent tests.

### *4.1. Progress in the Development of SCC-DBS*

Di fferent papers have referred to the SCC and similar regions under di fferent names, e.g., the subcallosal cingulate gyrus (SCG), the subgenual cingulate, as well as Brodmann areas. Di fferent historical names allow for di fferent historical context. The subgenual cortex is used more interchangeably with the term Brodmann Area 25, named after Korbinian Brodmann. The subgenual cortex is located in the cingulate region as a narrow band in the caudal portion of the subcallosal area adjacent to the paraterminal gyrus. By comparison, the SCG is comprised of Brodmann areas 25, 24, and 32 [36]; SCG circuits; and limbic structures. The SCG is pivotal in mood, learning, reward, and memory [37] and has been implicated as an aberrant region in MDD. As the SCC can be e ffectively targeted by antidepressants, this makes the SCG a potential target of DBS against TRD [38,39]. Tables 1 and 2 list 39 clinical studies on the treatment e fficacy of SCC-DBS for TRD.















\* ≥40% reduction in MADRS and average GAF in months 4–6 not worse than baseline; \*\* ≥50% reduction in HRSD-17 (HAMD-17) score from baseline; \*\*\* ≥40% reduction in HRSD-17 score from baseline; ♦ ≥40% reduction in MADRS compared to mean baseline; HAMD-24 scores or MADRS scores ≤ 10 after DBS; HRSD score < 8. HRSD score ≤ 8; Abbreviations: ATHF = Anti-depressant Treatment History Form, BA25 = Brodmann Area 25, BDI/-II = Beck Depression Inventory/-II, CGI, PGI, CANTAB = Clinician and Patient Global Impression of Severity and Improvement (CGI; PGI) and cognitive function (CANTAB); CVLT = California verbal learning test, DBS = deep brain stimulation, DWI = Diffusion-weighted imaging, ECG = electrocardiogram, ECT = electroconvulsive therapy, EDA = electrodermal activity, EEG = electroencephalography, GAF = Global assessment function, HAM-A = Hamilton Anxiety Rating Scale, HRSD-17/HDRS-17 = Hamilton Rating Scale for Depression/ Hamilton Depression Rating Scale, (f)MRI = (functional) magnetic resonance imaging; MADRS/MARDS = Montgomery-Åsberg Depression Rating Scale, MAOI = monoamine oxidase inhibitors, MDD = major depressive disorder, MDE = major depressive episodes, MMSE = Mini-Mental State Examination, NSAID = non-steroidal anti-inflammatory drug, NR = non-responsive, PET = positron emission tomography, QIDS/-SR = Quick Inventory of Depressive Symptomatology/-self report, Q-LES-Q = Quality of Life and Satisfaction Questionnaire, SCC = subcallosal cingulate, SCG = subcallosal cingulate gyrus, SCR = skin conductance response, QOL = Quality of Life Enjoyment and Satisfaction Questionnaire, TRD = treatment-resistant depression, WSAS = Work and Social Adjustment Scale.


**Table 2.** Summary of response and remission rates from clinical studies.

The first evidence-based clinical study on SCC-DBS was published by Mayberg et al. in 2005 [19]. Among six patients with an average of 5.6 years of major depressive episode (MDE), four responded to

the treatment, but three remitted or nearly remitted during the stimulation, even without changing medications. The authors found that the metabolic activity in the SCC normalized from a hyperactive state and was accompanied by reduced local blood flow as detected by Positron Emission Tomography (PET) [19]. In a study from 2003 to 2006 by Lozano et al. on chronic DBS in 20 patients with an average of 6.9 years of current MDE, 11 patients responded, but seven remitted [72], which was similar to the response and remission rates of Mayberg et al. In a 3.5-year follow-up study, the response rate was consistent across time points, but the remission rate increased from 18.8% to 42.9% at the last visit [18]. Both studies reported changes in structures distal to SCC after DBS, which explains the persistent response throughout the DBS treatments [18,72].

In a case report by Neimat et al., a 55-year-old female TRD patient who relapsed after a subgenual cingulotomy, achieved sustained remission for up to 30 months with SCC-DBS treatment [74]. In a case reported by Guinjoan et al. in 2010, a 60-year-old male TRD patient responded to unilateral SCC-DBS in the right hemisphere, but unilateral stimulation in the left hemisphere worsened his mood. This is in line with the asymmetrical response to antidepressants in the SCC region. However, the authors noted a further study was needed with more patients to validate the e ffects of unilateral stimulation on mood enhancement [68].

Similarly, in a preliminary study in 2012 by Puigdemont et al. on eight patients with an average of 6.3 years of current MDE, they found that five patients responded at the end of the 12-month DBS, but three out of four final remitters remitted after 3 months of DBS [67]. Their cognitive functions were not exacerbated and their memory functions were actually improved in cognitive assessments in 2015 [56]. Concurrently, a clinical study conducted in three di fferent medical centers also reported similar e fficacies of SCC-DBS, suggesting that DBS has reliable stimulation e ffects. Among 21 patients with an average of 5 years of current MDE, 13 responded to the treatment and the rest performed better than at baseline by the end of the study, although one patient committing suicide by medication overdose [66].

### *4.2. Remission Rates*

Some previous studies reported higher initial response and/or remission rates compared to more recent studies [19,67,72]. In the study by Perez-Caballero et al., they suggested that electrode insertion-induced inflammation could a ffect response and remission rates. Four of the eight recruited patients took non-steroidal anti-inflammatory drugs (NSAIDs), which resulted in a diminished antidepressant response toward DBS, whereas the other four not taking NSAIDs gradually responded and remitted. The authors also analyzed the role of inflammation in the early DBS response in rats [59], which is discussed in a later section of this review. A later study in 2015 by Puigdemont et al. reported that remission was maintained in four out of five remitted patients in the 3-month active stimulation group, whereas only two patients remitted in the sham stimulation group. They concluded that continuous active stimulation was important in maintaining the therapeutic e ffect [55]. This was supported by an earlier case of a 27-year-old patient on DBS for 2 years whose symptoms worsened due to battery depletion, but improved again upon battery replacement [69].

Table 2 reflects the di fferent response and remission rates, at 6-month intervals, across the duration of the studies in Table 1. This reporting allows for a cursory longitudinal tracking in understanding how response and remission may change with time. Among the reviewed studies on DBS, the response rate ranged from 18% to 87.5% and remission rate ranged from 10% to 92% (excluding all case studies) across the di fferent time points (see Table 2), which were comparable to earlier clinical studies [19,72]. However, large-scale controlled trials are needed to further validate the e fficacy of DBS in patients with TRD. Some predictive markers discovered in these studies could facilitate the selection of more responsive patients and increase the safety of DBS. A noteworthy study by Holtzheimer and Mayberg demonstrated some changes in the response and remission rates with DBS [69]. The authors noted that several months after a response and/or remission in their depressive symptoms, worsening of symptoms was temporarily observed at 16 weeks. They attributed the temporary worsening of symptoms to

the di fficulty of some patients reintegrating into society. In an earlier study by Lozano et al. in 2008, they also observed a similar occurrence at 4 months. These findings highlight the complexity of treating neuropsychiatric diseases, as the recovery periods are not always consistent and can be a ffected by di fferent factors.

### *4.3. Significant Challenges in the Development of SCC-DBS*

A larger study that aimed to recruit 201 patients was conducted by Holtzheimer et al. in 2017 to further validate the therapeutic e ffects of DBS [15]. A futility analysis conducted after 90 patients had been recruited showed no significant di fferences between the DBS and sham groups, leading to the early termination of the study. During a 6-month double-blind trial, no significant di fferences were found in the response of the DBS group compared to the sham group. However, among 77 patients that received subsequent open-label DBS for up to 2 years, 38 responded and 20 remitted. Holtzheimer et al. o ffered several explanations for the observed result. First, the patients selected for the study had an average current episode duration of around 12 years, whereas most studies recruited patients with an average current depressive episode of about 3–5 years. Holtzheimer also posited the possibility of suboptimal contact during the first 12 months, further a ffecting the results. This landmark paper was initially thought to be the death knell for DBS as a treatment for TRD. However, a summit of key academics within the field determined that DBS protocols required further modification and patient recruitment needed refining to better assess the therapeutic e ffects of DBS for TRD [75]. Considering that multiple other studies showed the e fficacy and e ffectiveness of DBS for TRD, the conference considered several possibilities for the discrepancies in the findings, some conclusions were that DBS was initiated too early before optimal targeting was secured, a lack of specificity and standardization in the improvement of symptoms, high placebo e ffects typically seen in the treatment of psychiatric disorders, and study design. The heterogeneity of the symptoms of the disease was also emphasized, which suggested that di fferent circuitry might be involved in di fferent individuals. The key conclusions from the summit included that patient selection should be better and more refined, study designs should be either fast to fail or fast to succeed, registries should be established for better subject tracking, and longitudinal data should be collected. The paper stressed that the complexities of the disease were real and better experimental designs were needed to truly reflect the e ffects of DBS as a treatment for TRD for a better response and remission rate and to allow the elucidation of the mechanistic role of DBS.
