The SCC is a part of the limbic cortex, located ventral to the genu of the corpus callosum (Fig. 19.2). The SCC region has been chosen as a target for DBS on the basis of previous findings, showing that this area is generally hyperactive in depressed patients, and that antidepressants and electroconvulsive therapy decreased the metabolism in this region [67–69]. Furthermore, the functional activity of the SCC region has been proposed as a predictor of the response to antidepressant treatments [70, 71]. So, the safety and efficacy of DBS in the SCC for treating resistant MDD is currently under investigation. Previous data from three independent clinical trials have demonstrated that DBS was effective in refractory MDD patients, showing an approximately 60% response rate [72–74]. During the follow-up period (3–6 years) a progressive reduction in the severity of depression symptoms was reported, with only 10% of patients failing to show a decrease in symptom scores [75]. Indeed, at final follow-up, 42.9% of patients were in remission [72]. Moreover, cognition function after SCC DBS was preserved in patients, indicating the safety of this stimulation target for MDD [76, 77]. However, despite the promising results reported in these open-label trials, the last multicenter prospective randomized trial failed to demonstrate the effectiveness of SCC DBS (letter from St. Jude Medical Clinical Study Management). Thus, further clinical trials must be carried out to elucidate the efficacy of this therapy for treating refractory MDD patients.

Many studies focused on the intrinsic mechanisms of SCC DBS have been performed in animal models of depression. The ventromedial prefrontal cortex (vmPFC) is the rodent cortical region homologous to the human SCC [78]. This region compromises the infralimbic and prelimbic cortices, and there is still considerable debate as to which part of the vmPFC is the best target to apply DBS [79, 80].

Preclinical behavioral studies indicated that short- and long-term DBS applied in the vmPFC induced an antidepressant-like effect in the FST [34, 35, 79–84] and a hedonic response in the SCT in naïve animals [35, 84]. In addition, an anxiolytic effect was described after acute vmPFC DBS in the home-cage emergence test and the novelty suppressed feeding (NSF) [39, 80, 82]. The NSF measures a rodent’s aversion to eating in a novel environment, and it is sensitive to chronic but not acute antidepressant treatment [85]. Therefore, the onset of action of DBS appears to be shorter than common antidepressant drugs.

Chronic DBS was able to reverse the depressive phenotype induced by the following animal models of depression: FSL, CUMS, olfactory bulbectomy (OBX), and chronic social defeat stress (CSDS) model [39, 84, 86–88]. The OBX produces a depressive behavior by disrupting the normal functioning of the limbic system [89], whereas the CSDS is based on the confrontation among conspecific animals to induce a psychosocial stress [90]. Furthermore, the anxiolytic effect of vmPFC was also demonstrated in the CUMS model of depression, increasing the time spent in the open arms in the EPM [86]. On the other hand, learning performance was not affected by vmPFC DBS in the MWM [46]. Overall, this indicates that DBS exerts an antidepressant response accompanied by an anxiolytic effect that is not associated to a cognitive impairment.

As occurred using NAc DBS, the spontaneous locomotor activity after acute or chronic DBS in the vmPFC remained unaltered [34, 39, 46, 80, 82, 86]. On the other hand, using the intracranial self-stimulation (ICSS) paradigm in FSL rats, it has been reported that the hedonic effect of DBS in the vmPFC does not depend on a direct modification of the mesolimbic dopaminergic reward system [84, 91].

The monoaminergic implication in the antidepressant-like effect induced by vmPFC DBS has been studied as a possible mechanism of action. Thus, vmPFC DBS was able to locally enhance 5-HT, NA, and DA at the site of stimulation [80, 87]. Nevertheless, the large majority of the studies available were carried out to discern the role of the serotonergic system. Despite 5-HT levels remaining unaltered in the dorsal raphe (DR) nucleus after vmPFC DBS, it has been shown to modulate the electrical activity of 5-HT neurons and enhance the glutamate concentration in this brain area [39, 80, 81, 88, 92]. This increase in the main excitatory neurotransmitter might trigger the drastic 5-HT release reported in DR projection areas, specifically in the vmPFC and hippocampus [80, 82].

But the relevance of the serotonergic system in the antidepressant-like effect of vmPFC DBS is still unclear, given that the two studies available showed opposite effects. In one of them, the antidepressant-like effect of vmPFC DBS persisted when the serononinergic neurotransmission was compromised, but in the other study this effect seemed to depend on the integrity of the 5-HT system [80, 82].

Additionally, DBS was able to potentiate neural plasticity in the DR neurons of naïve animals. Thus, an increase in excitatory presynaptic and postsynaptic densities was found, and in CSDS animals, DBS normalized dendritic arborization [81, 88]. vmPFC DBS also promoted synaptic plasticity locally, in the hippocampus and in the basolateral amygdala, even restoring the reduction induced by the CSDS model [88, 93].

The activation of specific intracellular cascades, such as the mammalian target of rapamycin (mTOR) pathway, has a rapid impact on synaptic plasticity. This pathway promotes the synthesis of several proteins involved in the function, formation, and maturation of new spine synapses [94], and it has been closely related to the antidepressant effect of drugs with a short onset of action [95]. DBS of the vmPFC increased cortical phosphorylation of Akt and cAMP-response element binding (CREB) [87], both components linked to the activation of mTOR signaling cascade. Moreover, an inhibitor of mTOR, temsirolimus, was able to block the antidepressant-like effect induced by vmPFC DBS, indicating that the mTOR pathway is a limiting factor [87].

As mentioned above, neurotrophic factors and neurogenesis play an important role in the antidepressant response. The effect of DBS on neurogenesis is still not clear in naïve animals and opposite results have been reported using different protocols to address this issue [66, 81]. Nonetheless, chronic vmPFC DBS restored the reduction in adult hippocampal neurogenesis induced by stress in the CUMS model [86]. On the other hand, the most relevant neurotrophic factor related to affective disorders and the unique analyzed in clinical and preclinical DBS studies is BDNF. vmPFC DBS normalized the deficient BDNF levels in CUMS animals in the striatal, cortical, and hippocampal regions [46, 86, 96]. However, peripheral BDNF concentration has been evaluated in only four patients who received DBS of the SCC, and they showed a reduction in serum BDNF levels [97].

Many original studies have evaluated the activity of several brain areas after DBS through the molecular expression of neuronal activation markers. Thus, vmPFC DBS induced the activation of the neurons around the site of stimulation, as well as in other cortical regions such as piriform, entorhinal, and orbitofrontal cortices [34, 39, 80, 88]. Additionally, the activity of several distant regions directly connected to the vmPFC was increased by DBS, for instance the hippocampus, basolateral amygdala, insula, or LHb [34, 39, 80, 88]. Thus, DBS applied to this target is able to regulate the activity of several limbic areas included in the neuronal circuitry that regulates emotions.

The LHb is located dorsally to dorsal thalamus (Fig. 19.3). The LHb receives information from cortical and limbic structures and it is directly connected to dopaminergic-, noradrenergic-, and serotonergic-releasing midbrain areas [98]. This area constitutes a target for DBS as its volume tends to be reduced in depressed patients, and some authors have hypothesized that an overactivity in this region is related to MDD [99, 100]. In this context, a patient diagnosed with resistant MDD was treated with LHb DBS. The results showed the antidepressant response of this therapy; the patient achieved sustained remission from 4 to 12 months after the beginning of the treatment. Indeed, the patient suffered decay by the accidental cessation of stimulation, corroborating the effectiveness of this DBS target [101]. Thus, these promising results have led to the intention to carry out additional clinical trials using LHb DBS for resistant MDD. In fact, a single-center study enrolling six patients is currently being conducted (ClinicalTrials.​gov; identifier: NCT0198407).

The antidepressant-like effect of LHb DBS has been demonstrated in several animal models of depression. As such, DBS restored the depressive phenotype induced by CUMS, chronic ACTH administration, and in the learned helplessness (LH) model [39, 102–104]. This LH model is an experimental depression model based on exposure to repeated uncontrolled and inescapable stress, leading to helplessness [105].

Monoamine release was measured in CUMS animals after LHb DBS. Chronic exposure to unpredictable stressors provoked a reduction of 5-HT, NA and DA levels in the hippocampus and blood serum which is restored by LHb DBS [104].

An increase of BDNF was found in the blood serum of the patient treated with LHb DBS. Indeed, the BDNF levels were correlated with the improvement of depressive symptoms in this patient [106]. Furthermore, the antidepressant-like effect of LHb DBS has been preclinically linked with some molecular and cellular changes which could be crucial in the mechanism of action of DBS. In this way, LHb DBS regulates the local and cortical activation of the Ca²⁺/calmodulin-dependent protein kinase (CaMKII) intracellular pathway which modulates downstream signaling cascades involved, among others, in synaptic plasticity and neuronal survival [102]. New insights about cellular and molecular changes induced by LHb DBS could help in understanding the intrinsic mechanisms underpinning the antidepressant effect of DBS.

The MFB is a fiber tract connecting the midbrain tegmentum and elements of the limbic system (Fig. 19.4) which plays an important role in the reward system [107, 108]. Clinical studies have reported the efficacy of MFB DBS as a therapeutic approach for intractable MDD patients. The pilot trial included seven patients, and DBS in the MFB induced a rapid and chronic antidepressant response, with an 86% response rate at the last follow-up [109]. Additionally, a second study demonstrated a significant alleviation of depressive symptoms in two of three patients enrolled 6 months after the beginning of DBS [110]. Finally, a third trial was approved to study the effectiveness of the MFB DBS in 12 patients diagnosed with refractory MDD (ClinicalTrials.​gov; identifier: NCT01778790).

Preclinical data indicated that DBS in the MFB had an antidepressant-like effect in the FST [111] and that it reversed the anhedonic and depressive phenotype of FSL rats [91]. Surprisingly, MFB DBS induced an anxiety-like behavior assessed as an increase in the time spent in the closed arms in the EPM paradigm [91] without altering locomotor activity [111]. Only some molecular changes were evaluated after DBS is applied to the MFB. In this way, the effect of acute MFB DBS on monoamine release was assessed in the NAc and interestingly, no changes in DA or 5-HT release were reported [111]. Bearing in mind that the MFB is the fiber tract which connects the VTA with the NAc, and considering the antianhedonic effect of MFB DBS, this result was unexpected. Maybe instead of acute stimulation, chronic stimulation of the MFB could lead to a modification of monoaminergic neurotransmission.

In addition, stimulation of the MFB altered the activity pattern of a few brain areas, such as the piriform and prelimbic cortices, the shell portion of NAc, the anterior regions of the caudate/putamen, dorsomedial thalamic nuclei, LHb, and the VTA [111, 112]. This suggests that DBS of the MFB induces changes in areas widely linked to the pathophysiology of MDD.

The ITP is a bundle of fibers that connects the nonspecific thalamic system to the orbitofrontal cortex (Fig. 19.5), and DBS delivered in this region seems to be beneficial in refractory OCD patients [113]. However, only one case has been reported with regard to the efficacy of ITP stimulation in a refractory MDD patient, who achieved remission state from the first month of DBS [113–115]. Although the depressive symptomatology of this patient improved, she also suffered from bulimia and borderline personality disorder, making it difficult to extract conclusive data supporting the suitability of this target. Furthermore, up to now there are no preclinical data available that may help clarify the possible effectiveness of this therapy in this target brain area.