Deep Brain Stimulation: Mechanisms Underpinning Antidepressant Effects

Chapter 33

Deep Brain Stimulation: Mechanisms Underpinning Antidepressant Effects Sonia Torres-Sanchez*,†,‡, Laura Perez-Caballero†,‡,§ and Esther Berrocoso†,‡,§ *Neuropsychopharmacology & Psychobiology Research Group, University of Ca´diz, Ca´diz, Spain † CIBER of Mental Health (CIBERSAM), Instituto de edicas de Ca´diz, INiBICA, Spain § Neuropsychopharmacology & Salud Carlos III, Spain ‡ Instituto de Investigacio´n e Innovacio´n en Ciencias Biom Psychobiology Research Group, Department of Psychology, Area of Psychobiology, University of Ca´diz, Ca´diz, Spain

INTRODUCTION Major depressive disorder (MDD) is a severe and common psychiatric illness with a high prevalence and is the leading cause of disability worldwide [1]. Despite our advances in understanding the pathophysiology of depression and the wide range of therapeutic options available, not all patients affected respond successfully to such treatments. Thus, 30%–40% of patients fail to respond to first-line treatments and between 5% and 10% also fail to respond to more aggressive therapies [2, 3]. This urgent need for more effective treatments led to the proposal that deep brain stimulation (DBS) may be a suitable alternative technique to treat refractory MDD patients. This therapy was originally developed for movement disorders, and currently, its use is approved by the US Food and Drugs Administration to treat essential tremor (1997), Parkinson disease (2002), dystonia (2003), and obsessive-compulsive disorder (2009). In addition, DBS is being tested to treat neurological pathologies other than MDD, such as anorexia nervosa or addiction. DBS is an innovative technique based on the intracranial implantation of stimulation electrodes that are permanently connected to a neurostimulator in order to deliver chronic electrical impulses that stimulate specific brain regions. This invasive technique implies stereotaxic surgery, yet the experience acquired over the past few decades indicates that this is a safe and well-tolerated therapy. The principal advantages of DBS compared to other approaches are the reversibility and the possibility of adjusting the stimulation parameters to achieve the required therapeutic effect as a function of the individual patient’s needs. The mechanism of action of DBS has not yet been defined, although efforts are ongoing to shed light on the events that underlie the therapeutic benefits associated to DBS. It was originally thought that, like classic ablative surgery, DBS produced its therapeutic effect by reducing activity in the target area. Nevertheless, following studies have shown that DBS restores brain activity and connectivity through neuromodulation, inducing long-term effects that may involve anatomical reorganization of the circuits affected [4]. In this chapter, the most relevant evidence regarding the mechanisms underlying the antidepressant effect of DBS when delivered to the main targets used will be reviewed.

Clinical Studies Several clinical trials have been performed to investigate the effects of DBS in several targets in patients suffering from refractory MDD, including: the subgenual cingulate cortex (SCC), the ventral capsule/ventral striatum (VC/VS) encompassing the nucleus accumbens (NAc), the medial forebrain bundle (MFB), the lateral habenula, and the inferior thalamic peduncle. However, the most important clinical trials targeted the SCC, VC/VS, and the MFB (Fig. 1). Resistant MDD patients enrolled in these trials met a primary diagnosis of MDD using the Structured Clinical Interview for DSM-IV and they fail to respond to treatment with antidepressant drugs of different types at adequate doses, duration and compliance (including augmentation or combination strategies), psychotherapy, and electroconvulsive therapy. In 2005, the first report showing the efficacy of DBS to treat resistant MDD patients was published. This clinical trial enrolled six patients in whom chronic and high-frequency DBS was administered to the SCC. This region was chosen because it is metabolically hyperactive in MDD patients and its activity is restored after a clinical response to several antidepressant therapies [5]. The results obtained in this pilot trial were notable, as four of the six patients included showed a Neurobiology of Depression. https://doi.org/10.1016/B978-0-12-813333-0.00033-0 Copyright © 2019 Elsevier Inc. All rights reserved.

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FIG. 1 General schematic illustration of DBS targets considered to treat refractory depression.

maintained response to the treatment and the clinical benefits were associated with reduced (measured by positron emission tomography) cerebral blood flow in the SCC region [6]. This study was extended to a series of 20 patients and an antidepressant response rate of around 55% and 35% remission rate were recorded after 6 months of SCC DBS, benefits that were also evident after 12 months [7]. The last follow-up of this cohort of patients (3–6 years) demonstrated the long-term efficacy and safety of this technique, showing 65% and 43% response and remission rates, respectively [8]. These promising data encouraged other studies to be carried out with DBS as a therapy for refractory MDD. Accordingly, uncontrolled open-label trials confirmed the efficacy of DBS in the SCC, as well as when applied to the VC/VS, NAc, and MFB (Table 1). In addition, the capacity of DBS to produce complete remission was observed in one patient when the lateral habenula or the inferior thalamic peduncle were targeted, indicating that further studies are needed to reinforce these targets as suitable to treat refractory MDD (Table 1). To corroborate the beneficial effect of DBS, randomized double-blind trials have been performed that include a crossover phase, showing that a large percentage of the patients exhibited relapse after stimulation ceased [12, 19, 28]. Nevertheless, industry-sponsored double-blind trials were designed using parallel cohorts in the initial period of the treatment and, unfortunately, no significant differences were evident between the patients who underwent DBS and patients who did not receive stimulation [16, 18]. The lack of efficacy observed in these latter clinical trials could be due to the trial design, yet despite these disappointing results, the safety of this approach has been demonstrated irrespective of the DBS target. Thus, it is well-tolerated procedure that provokes minimal neuropsychological impairment [29–31]. It is also interesting to note that an immediate antidepressant response has been reported in some clinical series, followed by a decay of the depressive symptomatology during the first month of treatment [11, 21]. This unexpected phenomenon was attributed to the microlesion induced by insertion of the stimulation electrodes during the surgical procedure. In addition to studying the safety and efficacy of this technique, clinical studies have attempted to define the mechanisms underlying the antidepressant effect of DBS and to identify the brain areas involved. In general, the results indicate that DBS modifies activity in the limbic system and cortical regions. Functional neuroimaging studies showed that SCC DBS significantly dampens metabolic activity in the medial and orbital frontal areas, and in the hypothalamus, whereas it is enhanced in the dorsolateral and ventrolateral prefrontal areas [6, 7]. DBS of the NAc diminishes glucose metabolism in the orbitofrontal cortex, frontal medial dorsal gyrus, and amygdala in patients who responded to long-term therapy [21]. Accordingly, DBS of both targets seems to regulate the activity of several brain areas involved in the circuitry of depressive disorder. Given that MDD patients present altered oscillatory activity, correlated to the severity of depression [32], electroencephalography recordings have been performed to study the effect of DBS on network dynamics. DBS alters neural oscillatory activity and coherence in multiple brain regions, evidence of the neuromodulatory capacity of this therapeutic approach [33–36]. Thus, neural oscillations at multiple bandwidths and synchrony between brain areas are both being studied to define the potential of DBS to restore the pathological disturbances in neural communication associated with MDD. In addition, further research into the use of this technique could identify biomarkers for the response to DBS. For instance, frontal theta cordance appears to be a good predictor of the response to SCC DBS [33]. Indeed, some effort has been made to identify biochemical biomarkers that predict the therapeutic response to DBS in patients. The expression of brain-derived neurotrophic factor (BDNF) is a marker that has been assessed in these patients and a decrease in the peripheral BDNF concentration was reported in four refractory MDD patients treated with SCC DBS [15]. This was an unexpected result as MDD patients have lower serum BDNF levels that appear to normalize after

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TABLE 1 Summary of Open-Label Clinical Trials Conducted to Evaluate the Efficacy of DBS for Treating Refractory Depression Target

Authors

Number of Patients

Follow-Up (months)

Response Rate (%)

Remission Rate (%)

Subgenual cingulate cortex

[6]

6

6

66.6

50

[9]

6

12

66.6

66.6

[7]

20

12

55

33.3

[8]

12

<72

64.3

42.9

[10]

21

12

29

[11]

8

12

62.5

50

[12]

10

24

92

58

[13]

6

9

[14]

5

24

20

[15]

4

6

50

[16]

77

<24

49

26

[17]

15

<48

53.3

40

[18]

30

24

23.3

20

[19]

25

<15

40

20

[20]

3

<1

Response

[21]

10

12

50

[22]

11

<48

45.5

9

[20]

7

<7

85.7

57.1

[23]

8

12

75

50

[24]

3

6

33.3

Ventral capsule/ventral striatum

Nucleus accumbens

Medial forebrain bundle

Inferior thalamic peduncle

Lateral habenula

33

[25]

1

24

100

100

[26]

1

36

100

100

[27]

1

12

100

100

antidepressant treatment [37]. By contrast, DBS of the lateral habenula increases the BDNF in blood serum which correlates with a long-term antidepressant response, although this was only measured in one patient [38]. Further longitudinal studies will be necessary to detect peripheral biomarkers and to determine if the DBS antidepressant response is accompanied by neuroplastic changes, such as modifications to BDNF expression. Bearing in mind the heterogeneity of MDD patients and the ethical concerns regarding studies into the mechanism of action of DBS in these patients, controlled animal studies are likely to prove a useful alternative to address this issue [39].

Preclinical Studies The behavioral and neurobiological effects of DBS delivered to the rodent brain areas that anatomically correlate to the major clinical targets have been studied from a preclinical perspective [40, 41].

Behavioral Effects The effect of short-term and long-term high-frequency DBS on rodent behavior has been evaluated in experimental models of depression and using the best established paradigms. The ventromedial prefrontal cortex (vmPFC, covering the

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prelimbic and infralimbic cortex) is considered to be the rodent homologue of the human SCC. DBS applied to this cortical region induces an antidepressant-like effect in naı¨ve animals in the forced swimming test, the most accepted tool to predict antidepressant activity [42–46]. In addition, vmPFC DBS has a hedonic effect promoting sucrose preference in naı¨ve animals [43–45]. To evaluate additional aspects of depressive-like states, such as anxiety, the home-cage emergence test and noveltysuppressed feeding test have been used, the latter a test that is interestingly sensitive to chronic but not acute antidepressant medications [47]. Acute vmPFC DBS revealed an anxiolytic-like effect in both paradigms [43, 44, 48]. Hence, this therapy seems to produce an anxiolytic-like effect earlier than conventional antidepressant drugs. Furthermore, vmPFC DBS restored the depressive phenotypes induced by animal models of depression based on chronic stress exposure, including chronic social defeat stress (CSDS) [49] and chronic unpredictable mild stress (CUMS) [48, 50–52]. An effective antidepressant-like response has also been demonstrated in genetic models, such as the Flinders sensitive line (FSL) [53, 54] and the depressive rat line [55], and in the model of depression induced by olfactory bulbectomy that damages the circuitry regulating mood [56]. The immediate effect of DBS described in clinical trials has also been studied preclinically, demonstrating an initial antidepressant-like effect due to regional neuroinflammation upon electrode implantation into the vmPFC. In addition, both preclinical and clinical findings indicate that the initial antidepressant response was counteracted by anti-inflammatory drugs [46]. Thus, short-term amelioration of depressive symptoms following DBS surgical procedure appears to be caused by the implantation of the stimulation electrodes. The behavioral effect of DBS of the NAc has also been explored, producing an antidepressant- and hedonic-like effect in naı¨ve animals when assessed by forced swimming test and sucrose preference test, respectively [45, 48, 57]. Moreover, chronic NAc DBS reversed the depressive-like behavior in CUMS and FSL rats [48, 51, 54]. NAc DBS was also effective in models of depression resistant to standard antidepressants, such as the model based on chronic adrenocorticotropic hormone administration and high anxiety-related behavior animals [58, 59]. In addition, anxiolytic-like behavior following NAc DBS has been demonstrated in CUMS, high anxiety-related behavior animals, and in the Wistar-Kyoto rats, a strain that exhibits a depressive and anxiety-like phenotype [48, 59, 60]. There is little preclinical data from DBS targeting the MFB, although an antidepressant- and anxiolytic-like effect was observed in naı¨ve animals and in FSL rats [61–63]. Although the effect of DBS has been studied more for some targets than others, the beneficial behavioral responses of DBS appear to be independent of the target used. However, while the effect of DBS on neuropsychological function has often been investigated in clinical trials, how DBS affects cognitive processing has yet to be addressed in preclinical studies. A single study reported that vmPFC and NAc DBS neither impaired nor improved working memory [51]. Hence, the effect of DBS on cognition remains unclear, highlighting the need for further studies.

Neurobiological Effects The neurobiological effects of DBS have been evaluated to discern its possible mechanism of action. As such, the potential alterations induced by DBS to neurotransmitters, neurotrophic factors, adult neurogenesis, and intracellular signaling have been assessed. DBS acts on different neurotransmitter systems closely related to mood disorders and the antidepressant response. There is a large body of evidence demonstrating the implication of the serotonergic system in the antidepressant-like effect of vmPFC DBS. Indeed, some modifications have been reported in the dorsal raphe nucleus, the main source of serotonin (5-HT) in the brain. Plasticity induced by DBS in this nucleus promoted synaptogenesis, and these adaptations could reverse both the neuronal excitability and the dendritic arborization that is impaired in the CSDS model [42, 49]. In addition, DBS increased the glutamate in the dorsal raphe nucleus and modified the electrical activity of serotonergic neurons [42, 48, 49, 64]. These structural and physiological alterations in dorsal raphe neurons might explain the changes found in several of their projection areas. Indeed, vmPFC DBS enhanced local and hippocampal 5-HT release [44, 52], and it facilitated synaptic plasticity in these areas and in the basolateral amygdala, both in naı¨ve and CSDS animals [23, 49, 65]. In addition, synchrony between basolateral amygdala and hippocampus was enhanced by vmPFC DBS [66], which might indicate that DBS improves emotional and cognitive processes. Thus, serotonergic neurotransmission appears to be involved in the effect of vmPFC DBS. However, it remains unclear if the antidepressant-like effect depends on the integrity of this system, as conflicting data has been reported in this regard [43, 44]. Alternatively, vmPFC DBS increases the local release of both dopamine (DA) and noradrenaline in this cortical region [43, 44], while it does not alter DA levels in the NAc of FSL rats [54]. Hence, reward circuits may only participate weakly in the mechanism of action of vmPFC DBS. Interestingly, the antidepressant-like effect of vmPFC DBS persisted when the

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integrity of the noradrenergic system was compromised [43]. However, recent findings indicate that DBS enhanced electrical activity and tyrosine hydroxylase expression in the locus coeruleus nucleus and it is accompanied by significant changes in pontine-cortical network synchrony [67]. Thus, vmPFC DBS appears to be able to facilitate noradrenergic and dopaminergic neurotransmission. DBS of the vmPFC also increases local prefrontal glutamate efflux and the activation of AMPA receptors seems to be essential to achieve its antidepressant-like effect [44]. It is widely known that glutamatergic neurotransmission is regulated by glial cells, and significantly, the antidepressant-like effect of vmPFC DBS is counteracted by local glial damage [42], highlighting the possible involvement of the glutamatergic system. Given the close relationship between this neurotransmission system and the mammalian target of rapamycin (mTOR) signaling pathway, the effect of vmPFC DBS on this cascade has been evaluated. Local activation of specific elements in the mTOR signaling pathway is altered by vmPFC DBS and inhibiting the mTOR pathway blocks the antidepressant-like effect of vmPFC DBS [56]. Thus, this antidepressant-like effect of vmPFC DBS appears to be linked to the glutamatergic system and the synaptic plasticity triggered by activation of the mTOR pathway. The role of neurotrophic factors and hippocampal neurogenesis in the antidepressant response of conventional antidepressants is well-documented. In naı¨ve animals, vmPFC DBS does not appear to affect either neurogenesis or neurotrophic factors expression [42, 44, 50, 55, 68], whereas it normalized hippocampal neurogenesis and restored BDNF levels in several brain regions (such as the prefrontal cortex [PFC] and hippocampus) in CUMS animals. The latter effect is also being observed in the olfactory bulbectomy model of depression and in the depressive rat line [50, 51, 55, 56]. Therefore, vmPFC DBS appears to activate the catecholaminergic and glutamatergic neurotransmitter systems, normalizes BDNF concentrations and neurogenesis in animal models of depression, and promotes synaptic plasticity in brain structures associated with depression. The effect of NAc DBS on neurotransmitter systems has also been explored. In naı¨ve animals, short-term NAc DBS does not modify either local 5-HT and DA levels [69], or the electrical activity of ventral tegmental area neurons [70], the major dopaminergic input to the NAc. However, long-term NAc DBS augments the local release of both neurotransmitters [71]. Considering that the NAc receives projections from the PFC, the effect of NAc DBS on cortical neurotransmitter release has been evaluated. The 5-HT and DA release in the PFC depends on the duration of NAc DBS, increasing after short-term but not long-term DBS [71, 72]. In the medial PFC, NAc DBS does not appear to induce significant changes in noradrenaline [72]. Moreover, the effect of NAc DBS on neurotransmitter release has only been evaluated in the Wistar Kyoto rat model of depression. DBS unexpectedly reduces tyrosine hydroxylase expression and diminishes DA and noradrenaline levels in the PFC [60]. By contrast, DBS increases neuronal dendritic length in the NAc, suggesting a local neuromodulatory effect of DBS through the plasticity promoted in these neurons [60]. Unfortunately, the potential effect of NAc DBS on neuronal plasticity has not been studied in depth, although it may well be relevant to the antidepressant-like effect. Regarding adult hippocampal neurogenesis, while NAc DBS does not promote this phenomenon in naı¨ve animals [68], it does boost the generation of neurons in animals with high anxiety-related behavior [59]. Likewise, NAc DBS in CUMSdepressed rats increases BDNF levels in the dorsal hippocampus and striatum, but not locally, in the ventral hippocampus or in the ventral tegmental area [51]. Neurotrophic modifications induced by NAc DBS, as well as other neurochemical alterations, should be better studied in order to shed light on the mechanisms involved in the antidepressant response of this stimulation. Another target for DBS that has been explored is the MFB and, although little studied, 5-HT and DA levels remain unaltered in the NAc after MFB DBS [61], while there are no changes in DA release in the PFC [62]. The impact of MFB DBS on the dopaminergic system has been studied in several brain areas, showing a significant increase in the expression of both cortical D2 receptors and hippocampal DA transporter [62]. Further detailed studies will be necessary to discern the neurobiological modifications produced by MFB DBS and to understand how it might drive the antidepressant-like effect.

CONCLUSIONS This chapter provides an overview of the evidence that DBS produces benefits when treating depressive symptomatology, representing an alternative therapy for patients suffering from refractory MDD. The findings reported over the last decade suggest that the principal challenge at present is to determine the best target to apply DBS in order to achieve optimal clinical efficacy in each patient. As such, the detection of biomarkers that predict response could help identify patients who will achieve satisfactory benefits from this therapy and, maybe, predict the best target for each MDD patient.

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Another important issue for refractory MDD patients is to understand how DBS achieves its antidepressant effect and which specific processes are involved. This should not only favor DBS therapy, but might help identify novel therapeutic targets. The findings reviewed indicate that DBS acts through multiple mechanisms, including neurotransmitter release, neuronal modulation, and synaptic plasticity. Despite the preclinical data currently available, further studies will be crucial to discern the specific mechanism of action of DBS, contributing to the optimization of this technology.

ACKNOWLEDGMENTS This work was supported by grants from the “Ministerio de Economı´a y Competitividad” (MINECO), co-financed by “Fondo Europeo de Desarrollo Regional” FEDER “A way to build Europe” (SAF2015-68647-R; the “Instituto de Salud Carlos III (PI12/00915)); the “Centro de Investigacio´n Biomedica en Red de Salud Mental-CIBERSAM” (Spain; CB/07/09/0033); the “Consejerı´a de Economı´a, Innovacio´n, Ciencia y Empleo de la Junta de Andalucı´a” (Spain; CTS-510 and CTS-7748); “Fundacio´n Progreso y Salud de la Junta de Andalucı´a” (PI-0080-2017); and a 2015 NARSAD Young Investigator Grant from the Brain Behavior Research Foundation (NARSAD 23982). We would like to thank Dr. Mark Sefton (BiomedRed SL) for linguistic style corrections.

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