Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review

Deep brain stimulation for treatment-resistant depression:

Efficacy, safety and mechanisms of action
Rodney J. Anderson a , Mark A. Frye b , Osama A. Abulseoud b ,
Kendall H. Lee c,d , Jane A. McGillivray a , Michael Berk e , Susannah J. Tye a,c,f,∗
a
School of Psychology, Deakin University, Burwood, VIC, Australia
b
Department of Psychiatry, Mayo Clinic, Rochester, MN, USA
c
Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
d
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
e
School of Medicine, Deakin University, Geelong, VIC, Australia
f
Mental Health Research Institute, Melbourne, VIC, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Deep brain stimulation (DBS), a neuromodulation therapy that has been used successfully in the treatment
Received 26 February 2012 of symptoms associated with movement disorders, has recently undergone clinical trials for individu-
Received in revised form 6 June 2012 als suffering from treatment-resistant depression (TRD). Although the small patient numbers and open
Accepted 10 June 2012
label study design limit our ability to identify optimum targets and make definitive conclusions about
treatment efficacy, a review of the published research demonstrates significant reductions in depressive
Keywords:
symptomatology and high rates of remission in a severely treatment-resistant patient group. Despite
Deep brain stimulation
these encouraging results, an incomplete understanding of the mechanisms of action underlying the
Treatment resistant depression
Subgenual cingulate gyrus
therapeutic effects of DBS for TRD is highlighted, paralleling the incomplete understanding of the neu-
Nucleus accumbens roanatomy of mood regulation and treatment resistance. Proposed mechanisms of action include short
Ventral capsule and long-term local effects of stimulation at the neuronal level, to modulation of neural network activity.
Ventral striatum
Lateral Habenula © 2012 Elsevier Ltd. All rights reserved.
Inferior thalamic peduncle
Mood

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1921
1.1. Scope of this review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1921
2. Target selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1921
2.1. Subgenual cingulate gyrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923
2.2. Ventral capsule/ventral striatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923
2.3. Nucleus accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923
2.4. Inferior thalamic peduncle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923
2.5. Lateral habenula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923
3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1924
3.1. Subgenual cingulate gyrus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1924
3.2. Ventral capsule/ventral striatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
3.3. Nucleus accumbens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
3.4. Inferior thalamic peduncle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
3.5. Lateral habenula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
3.6. Safety and adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1925
3.7. Efficacy evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1926

∗ Corresponding author at: School of Psychology, Faculty of Health, Deakin University, Burwood, VIC 3125, Australia. Tel.: +61 3 9246 8157; fax: +61 3 9244 6858.
E-mail address: susannah.tye@deakin.edu.au (S.J. Tye).

0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neubiorev.2012.06.001
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933 1921

4. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1926

4.1. Local mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1926
4.2. Regional mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1927
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1929

1. Introduction 2003), anterior capsulotomy (Christmas et al., 2011), subcaudate

tractotomy (Poynton et al., 1995) and limbic leucotomy (Montoya
Major depressive disorder (MDD) is one of the most preva- et al., 2002); however, the procedures are inherently irreversible
lent mental illnesses, with lifetime prevalence rates reported to and can result in, albeit rare and often transient, serious adverse
be between 3% and 17% and annual incidence between 5% and events (Dougherty and Rauch, 2007; Greenberg et al., 2003). Vari-
7% (Andrade et al., 2003; Andrews et al., 2001; Hasin et al., 2005; ous other somatic treatments, including magnetic seizure therapy
Kessler et al., 2005a,b). A high rate of mortality is associated with (Kosel et al., 2003; Lisanby et al., 2003), epidural cortical stimulation
MDD, with an estimated overall relative risk compared to non- (Kopell et al., 2011; Nahas et al., 2010) and deep brain stimulation
depressed individuals of 1.81 (Cuijpers and Smit, 2002). Higher (DBS) (e.g., Mayberg et al., 2005) are in the experimental phase, or
suicide rates (Mykletun et al., 2007), which vary depending on pre- are undergoing clinical trials for TRD.
vious hospitalisation status (outpatients 2.2%, inpatients 4.0–8.6%, DBS involves the stereotactic implantation of electrodes into
Bostwick and Pankratz, 2000) and severity of depression (moderate specific neuroanatomical structures where continuous stimula-
3.1%, severe 13.8%, Brådvik et al., 2008), and cardiovascular dis- tion is applied via a stimulator device implanted subcutaneously
ease (Carney and Freedland, 2003; Mykletun et al., 2007; Wulsin below the clavicle (Tye et al., 2009). DBS has benefits over
et al., 1999) make significant contributions to an increased mortal- other forms of interventional somatic treatments in that it is
ity and a consequent shortened lifespan (De Hert et al., 2011). MDD non-ablative and therefore reversible, targets small specific struc-
is one of the leading causes of disability worldwide and the cause tures, has both acute and long-term effects, and can be adjusted
of more years lost due to disability than any other disease (World to attain an optimal therapeutic effect (Kennedy and Giacobbe,
Health Organisation, 2008). Over the next 10 years the disease bur- 2007; Schlaepfer et al., 2011). DBS has been used successfully
den associated with MDD is projected to increase, with estimates for the treatment of symptoms associated with movement disor-
that MDD will represent the second leading cause of disease bur- ders (Johnson et al., 2008) including Parkinson’s disease (Benabid,
den worldwide by 2020 (Murray and Lopez, 1997a,b), following 2003; The Deep-brain Stimulation for Parkinson’s Disease Study
ischemic heart disease. Group, 2001), essential tremor (Hariz et al., 2008) and dysto-
Complete remission (i.e., asymptomatic) from an episode of nia (Vidailhet et al., 2005). DBS has also been used to control
major depression is the goal of treatment, as residual or subsyn- epilepsy (Hodaie et al., 2002) and provide relief from chronic pain
dromal symptoms are associated with higher rates of relapse and (Kringelbach et al., 2007). More recently DBS has been utilised
recurrence and an overall poorer long-term prognosis (American for treatment-refractory neuropsychiatric indications including
Psychiatric Association, 2000; Bakish, 2001; Fava, 2003; Sadock Tourette’s syndrome (Kuhn et al., 2007; Maciunas et al., 2007;
and Sadock, 2007). Multiple, pharmacological and psychothera- Servello et al., 2008), obsessive–compulsive disorder (Abelson et al.,
peutic interventions have proven efficacious in the treatment of 2005; Greenberg et al., 2006; Lipsman et al., 2007) with a recent
MDD; however, approximately 30% of individuals suffering from humanitarian device exemption (HDE) by the Food and Drug
MDD fail to respond to these treatments (Warden et al., 2007). Administration in the US, and a small number of clinical trials of
This subset of individuals is often referred to as suffering from DBS for TRD have been published (see Table 1). Despite the inher-
treatment-resistant depression (TRD). Although there is debate ent methodological limitations of these early trials of DBS for TRD
over its clinical application (Hauptman et al., 2008; Rush et al., a significant reduction in depressive symptomatology has been
2003) TRD is generally defined as an inadequate clinical response to demonstrated in individuals suffering from severely treatment-
antidepressant treatments (including augmentation interventions, refractory depression.
Dodd et al., 2005) that have been administered at an effective dose
1.1. Scope of this review
for a sufficient duration (Fava, 2003; Hauptman et al., 2008; Rush
et al., 2003). The purpose of this review is to assess the efficacy and safety
Failing pharmacotherapy and psychotherapeutic interventions, of DBS for TRD and to examine the putative mechanisms of action
electroconvulsive therapy (ECT) has been used to treat TRD with underlying its therapeutic effects. This review is confined to stud-
acute antidepressant effects (Rasmussen et al., 2002) and although ies where DBS was used for the purpose of treating primary TRD,
there is a large body of evidence demonstrating efficacy (The UK ECT therefore studies were excluded where remission or improvement
Review Group, 2003), memory disturbances and a high relapse rate in depressive symptoms was achieved during DBS treatment for
(Rasmussen et al., 2002) limit its use (Kennedy and Giacobbe, 2007). other disorders (e.g., primary treatment-resistant OCD, Aouizerate
Repetitive transcranial magnetic stimulation (rTMS) has regulatory et al., 2004, 2009; and treatment of tardive diskinesia in a patient
approval for treatment of major depression that has failed to opti- with severe TRD, Kosel et al., 2007). The excluded studies however
mally respond to one prior antidepressant treatment for a current are important in improving our understanding of the neurobiol-
episode of major depression (O’Reardon et al., 2007), but its efficacy ogy of depression and treatment resistance, and also in guiding
is not comparable to ECT (Slotema et al., 2010). The maintenance selection of new DBS targets for TRD.
of response and response rates with greater treatment resistance
have yet to be investigated. Vagal nerve stimulation (VNS) also has 2. Target selection
regulatory approval for treatment of TRD (Rush et al., 2005). Opti-
mal dosing strategies and clinical predictors of response have not It could be argued that DBS, by targeting single neuroanatom-
been fully developed to optimise this treatment intervention (Rush ical structures, is an overly reductionistic approach to treating a
and Siefert, 2009). Ablative neurosurgery has also been performed psychological disorder that has been shown at the biological level
for severe TRD, including anterior cingulotomy (Dougherty et al., to involve various neuroanatomical structures, neurotransmitters,
 1922
Table 1
Deep brain stimulation for treatment-resistant depression: reviewed studies.

Target and study Number of Follow-up Sex ratio Mean age Mean age Patient responsesa Primary Stimulation parametersb
(extended/follow-up study) patients period in m/f at surgery MDD onset measure
months (SD) (SD)

R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933

Response Remission V Hz PW (␮s)

Subgenual cingulate gyrus

Mayberg et al. (2005) 6 6 3/3 47.0 (8) 29.5 (12) 66.6% 33.3% HDRS17 4.0 130 60
(Lozano et al. (2008)) 20 12 9/11 47.3 (10.4) 27.1 (8.3) 55.0% 35.0%c HDRS17 3.5–5.0 130 90
(Kennedy et al. (2011)) 20 39d 9/11 47.3 (10.4) 27.1 (8.3) 64.3% 42.9% HDRS17 4.3 124.7 70.6
Neimat et al. (2008) 1e 30 0/1 55 9 – –* HDRS17 4.5 130 60
Puigdemont et al. (2012) 8 12 2/6 47.4 (11.3) 24.9 (5.3) 62.5% 50.0% HDRS17 3.5–5.0 135 120–210
Holtzheimer et al. (2012) 10 24 3/7 40.0 (9.3) 20.3 (5.6) 92.0%h 58.0%f HDRS17 4–8 mA 130 91
Ventral capsule/ventral striatum
Malone et al. (2009) 15 23g 4/11 46.3 (10.8) 25.3 (10.5) 53.3% 40.0% HDRS24 6.7 127 113
(Malone (2010)) 17 37h NR 46.3 25.3 71.0% 35.0% MADRS 2.5–8.0 100–130 NR
Nucleus accumbens
Schlaepfer et al. (2008) 3 6–23 weeks 2/1 46.7 (13.7) NR 33.3% – HDRS24 4.0 145 90
(Bewernick et al. (2010)) 10 12–36 6/4 48.6 (11.7) 31.7 (13.2) 50.0%i 30.0%i HDRS28 1.5–10.0 100–150 60–210
(Bewernick et al. (2012)) 11 12–48 7/4 48.4 (11.1) 32.6 (12.4) 45.5% 9.0% HDRS28 1.5–10.0 100–150 60–210
Inferior thalamic peduncle
Jiménez et al. (2005) 1j 24 0/1 49 29 – –* HAM-D 2.0–2.5 130 450
Lateral habenula
*
Sartorius et al. (2010) 1 12 0/1 64 18 – – HAMD21 10.5 165 60

Abbreviations: SD, standard deviation; V, volts; mA, milliamps; Hz, hertz; PW, pulse-width; NR, not reported; MDD, major depressive disorder; BD, bipolar disorder.
a
As at last follow-up, unless indicated.
b
Mean parameters for entire group during the chronic phase of stimulation.
c
Remission or within one point of remission.
d
Mean follow-up period, range = 36–72 months.
e
Previous cingulotomy.
f
Calculation includes 8 of the original 10 MDD patients and 3 BD patients.
g
Mean follow-up period, range = 6–51 months.
h
Mean follow-up period, range = 14–67 months.
i
Assessed after 12 months post-surgery.
j
Comorbid borderline personality disorder and bulimia.
*
Case studies: however all patients achieved remission.
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
and genes (e.g., Sadock and Sadock, 2007). A host of psychological,
social, personality, lifestyle and environmental factors are thought
to contribute to the aetiology of major depressive disorder (Heim
and Nemeroff, 2001; Jacka et al., 2011a,b; Williams et al., 2011).
Indeed, complex interactions between biological and psychosocial
factors have been implicated in the aetiology of depression (e.g.,
Kendler et al., 2001). The models of depression driving DBS target
selection consider the target neuroanatomical structures as “nodes”
within dysfunctional neural circuits that modulate different aspects
of the depressive syndrome (Mayberg, 2003, 2006; Seminowicz
et al., 2004) via connections to limbic, cortical, and subcortical
areas (Giacobbe et al., 2009). Accumulating evidence from neu-
roimaging, neuropathological, lesion analysis, and post-mortem
studies implicates specific brain networks in the pathophysiol-
ogy of mood disorders (Drevets et al., 2008). The dysfunction in
these neural circuits is thought to involve a failure of intrinsic com-
pensatory measures under excessive allostatic load (Kapczinski
et al., 2008; McEwen, 2003) that maintain stable emotional states
under stress (Mayberg, 2003; McEwen, 2003), with variations
in these compensatory measures thought to involve interac-
tions between biological vulnerability, environmental stressors
and social factors (Caspi et al., 2003; Heim and Nemeroff, 2001;
Kendler et al., 2001, 2005a,b). This de-compensation, mediated by
inflammatory, and oxidative pathways, and the balance between
apoptosis and neurogenesis appears to underpin the process of
neuroprogression in the disorder (Berk et al., 2011; Maes et al.,
2011). Independent and interactive effects of these factors are
thought to underlie the heterogeneity in depressive symptomatol-
ogy (Mayberg, 2003, 2006, 2009; Seminowicz et al., 2004). These
networks include the limbic–cortical–striatal–pallidal–thalamic
network, formed by connections between the orbital and medial
prefrontal cortex, amygdala, hippocampal subiculum, ventrome-
dial striatum, mediodorsal and midline thalamic nuclei and ventral
pallidum (Ongür et al., 2003).
The orbital and medial prefrontal cortex is associated with two
extended networks, the orbital prefrontal network and the medial
prefrontal network (Drevets et al., 2008). The orbital prefrontal
network codes for affective characteristics of stimuli, including
reward, aversion, and relative value (Drevets et al., 2008; Ongür
and Price, 2000; Saleem et al., 2008). The medial prefrontal network
is involved in introspective functions such as mood and emotion,
and visceral reactions to emotional stimuli. The medial prefrontal
network includes the dorsomedial/dorsal anterolateral prefrontal
cortex (e.g., BA 9), the mid- and posterior cingulate cortex, a region
in the anterior superior temporal gyrus and sulcus, and the entorhi-
nal and posterior parahippocampal cortex (Drevets et al., 2008;
Kondo et al., 2005; Saleem et al., 2008). Elevated metabolism in
many structures within this circuitry has been reported during the
depressive phase (Drevets et al., 2002, 2008) of MDD. Conversely, in
recovered cases that experience depressive relapse under experi-
mental conditions involving serotonin or catecholamine depletion,
the metabolic activity increases in these regions as the depres-
sive symptoms return (Hasler et al., 2008; Neumeister et al., 2004).
Deep brain stimulation, as well as psychotherapy, has been shown
through neuroimaging studies to normalise the dysfunction in
these neural circuits following successful treatment (Mayberg,
2003, 2009; Mayberg et al., 2005; Ressler and Mayberg, 2007). Lev-
els of metabolic activity in these pathways additionally appear to
be germane to the pathophysiology of depression (Hamani et al.,
2011).
2.1. Subgenual cingulate gyrus
The subgenual cingulate gyrus (SCG), a region of the cingulate
gyrus located ventral to the genu of the corpus callosum (Fig. 1),
has shown hyperactivity, as measured by glucose metabolism and
1923
cerebral blood flow (CBF), in depressed patients compared with
healthy controls (Mayberg, 2003; Seminowicz et al., 2004) and
that hyperactivity in the SCG is correlated with depression symp-
tom severity (Kennedy et al., 2007). Increased activity was also
observed in the SCG during activities designed to induce sadness
in healthy volunteers (Mayberg et al., 1999). Conversely, there is
abundant evidence that SCG activity decreases following success-
ful treatment of depression with pharmacotherapy (e.g., sertraline,
Drevets et al., 2002; venlafaxine, Kennedy et al., 2007; fluoxetine,
Mayberg et al., 2000), somatic treatments (e.g., anterior cingulo-
tomy, Dougherty et al., 2003; rTMS, Mottaghy et al., 2002; ECT,
Nobler et al., 2001) and even in placebo responders (Mayberg et al.,
2002). Importantly it appears that functional changes in the SCG can
differentiate response to treatment versus nonresponse (Kennedy
et al., 2007; Mayberg et al., 2000) and that hyperactivity in the SCG
distinguishes more treatment resistant patients (Kennedy et al.,
2007; Seminowicz et al., 2004).
2.2. Ventral capsule/ventral striatum
The ventral capsule/ventral striatum (VC/VS) was selected as
a DBS target after reports of elevated mood and reduced depres-
sive symptom severity following ablative procedures for OCD and
MDD (e.g., Greenberg et al., 2003; Rück et al., 2008), and more
recently after DBS for refractory OCD with comorbid MDD (e.g.,
Abelson et al., 2005; Aouizerate et al., 2004, 2009; Gabriels et al.,
2003; Greenberg et al., 2006; Van Laere et al., 2006). Further sup-
porting the VC/VS as a DBS target for TRD are the findings from an
fMRI study (Epstein et al., 2006) that demonstrated that patients
suffering from major depressive disorder showed significantly less
activation bilaterally in the ventral striatum to positive stimuli
compared to healthy controls.
2.3. Nucleus accumbens
The nucleus accumbens (NAc), located where the head of the
caudate and the putamen meet, was chosen as a DBS target pri-
marily on the basis of its role in the anticipation and experience of
pleasure and reward (Heien and Wightman, 2006; Knutson et al.,
2001; Nestler and Carlezon, 2006; Schlaepfer et al., 2008) and goal-
directed behaviour (Goto and Grace, 2005), with dysfunction in the
NAc thought to play a key role in the anhedonic symptoms of MDD
(Gorwood, 2008; Nestler and Carlezon, 2006; Tremblay et al., 2005).
The dopaminergic innervation of the NAc in particular plays a key
role in mood regulation and the processing of reward (Arias-Carrión
et al., 2010; Malhi and Berk, 2007).
2.4. Inferior thalamic peduncle
The inferior thalamic peduncle (ITP), a bundle of fibres connect-
ing the dorsomedial thalamus to the orbital frontal cortex (Kopell
and Greenberg, 2008), was selected based on positron emission
tomography (PET) studies showing hyperactivity in the medial
thalamus and the orbitofrontal cortex in depressed patients (e.g.,
Drevets, 2000). Surgical lesions in an area including the ITP disrupt
the inhibitory action of the thalamo-orbitofrontal system, and have
significant antidepressant effects in preclinical models (Velasco
et al., 2005).
2.5. Lateral habenula
The lateral habenula (LHb), located on the dorsomedial surface
of the caudal thalamus, was chosen as a DBS target for TRD on the
basis of hypermetabolism observed in individuals suffering from
depression (Morris et al., 1999; Roiser et al., 2009) and in ani-
mal models of depression (Caldecott-Hazard et al., 1988; Shumake
1924 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Fig. 1. Deep brain stimulation targets for treatment-resistant depression. Location of DBS targets used for TRD and the published studies associated with them in parentheses.
and Gonzalez-Lima, 2003). Recent research has demonstrated a
reduction in depressive-like behaviours in animal models following
lesions (Yang et al., 2008), pharmacological inhibition (Winter et al.,
2011) and deep brain stimulation (Li et al., 2011) of the LHb. Fur-
ther, research in monkeys has shown that LHb neurons are excited
on the presentation of a punishment and the absence of a reward,
and code for a prediction error for punishments (Hikosaka, 2010;
Matsumoto and Hikosaka, 2007, 2008), thus possibly having a role
in the motivational aspects of the depressive syndrome.
3. Efficacy
Concordant with custom in antidepressant trials, all DBS for
TRD studies reviewed defined a clinically significant response as
a 50% reduction in the severity of depressive symptoms from
pre-operative baseline scores, as measured on a standardised,
clinician-rated instrument. Remission however is the ultimate goal,
and best correlates with functional recovery (Berk et al., 2008).
The primary instrument in most studies was the Hamilton Depres-
sion Rating Scale (HDRS; Hamilton, 1960). The Montgomery-Asberg
Depression Scale, (MADRS: Montgomery and Asberg, 1979) was
also frequently utilised. Measures of psychosocial functioning (e.g.,
Global Assessment of Function Scale (GAF)) and self-reported
depression symptom severity measures (e.g., Beck Depression
Inventory) were also commonly employed. Although inclusion
criteria varied, patients in each study exhibited high degrees of
treatment resistance including long histories of MDD, a current
major depressive episode (MDE), numerous courses of antidepres-
sants of different classes, augmentation/combination therapies,
failed psychotherapy and ECT.
3.1. Subgenual cingulate gyrus
The efficacy of DBS of the SCG has been demonstrated in three
independent studies (see Table 1). The first published was an ini-
tial six-month study of six patients (Mayberg et al., 2005) and
a 12-month extension, which included an additional 14 patients
(Lozano et al., 2008). Recently a 3–6 year follow-up of these 20
patients was published (Kennedy et al., 2011). Patients had elec-
trodes implanted bilaterally into white matter tracts adjacent to
the SCG. All patients reported acute positive effects when electrical
stimulation was initiated (e.g., Lozano et al., 2008) coinciding with
changes in positive and negative affect scores (PANAS, Watson and
Clark, 1988). During the follow-up period, a progressive reduction
in the severity of depression symptoms was reported, with only 10%
of patients failing to show a decrease in symptom scores. Signifi-
cantly, no patients experienced a worsening of symptoms relative
to baseline (Lozano et al., 2008). Different subgroups of symptoms
improved at different rates, with mood symptoms reaching max-
imum levels of improvement, and then plateauing three months
post-surgery (Lozano et al., 2008). Alternatively, somatic, sleep and
anxiety symptoms steadily improved throughout the 12-month
period (Lozano et al., 2008). At final follow-up (3–6 years) 42.9%
of patients were in remission (Kennedy et al., 2011).
Recently a second independent trial of DBS of the SCG was pub-
lished (Puigdemont et al., 2012) showing similar rates of response
and remission (see Table 1). After an initial sharp decline in depres-
sive symptoms in the first week of stimulation where 7 of the
8 patients reached the response criteria and 4 patients achieved
remission, an increase in depressive symptoms was observed,
followed by a progressive decrease in HDRS scores until final
follow-up (i.e., one year) (Puigdemont et al., 2012). A significant
decrease in all subscales of the HDRS17 , that is mood, anxiety,
somatic and sleep subscales, was reported as well as overall scores
(Puigdemont et al., 2012). Unlike previous attempts to explore the
relationship between therapeutic response and electrode location
(Hamani et al., 2009) Puigdemont et al. (2012) found a significant
relationship between long-term response and the location of elec-
trodes, with responder patients having electrodes in BA24 of the
SCG rather than BA25.
Further evidence for the antidepressant efficacy and safety of
DBS for TRD has been provided in a subsequent independent study
of 17 patients (10 MDD; 7 BP) (Holtzheimer et al., 2012). Following
a four-week single blind sham stimulation condition, all patients
received open-label active stimulation for 24 weeks, followed
by a further single blind sham stimulation phase. A significant
reduction in depression as measured by the HDRS, Beck Depression
Inventory II and an increase in function according to the Global
Assessment of Functioning (GAF) was achieved following active
stimulation. An observational follow-up after two years of chronic
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
stimulation revealed high response and remission rates (92%
and 58%, respectively), with no recurrence of moderate or severe
episodes of depression at this time.
Further supporting the efficacy of the SCG as a DBS target for
TRD is a case study of a patient who had undergone a cingulotomy
for severe MDD, from which remission was achieved for a period
of six months before a relapse (Neimat et al., 2008). With contin-
uous DBS of the SCG the patient achieved remission, which was
sustained throughout the 30-month duration of the study. Even
though remission was significantly longer than any other treat-
ment the patient had undergone previously, and despite being a
case study, the fact that the patient had undergone a cingulotomy,
which ablates structures connected to the SCG, makes it difficult to
generalise results and efficacy of the DBS alone in this case.
3.2. Ventral capsule/ventral striatum
In a multicentre trial, 17 patients who received DBS for TRD, with
electrodes implanted bilaterally into the VC/VS region, showed
significant improvement in depressive symptomatology (Malone,
2010; Malone et al., 2009). The greatest reduction in mean depres-
sion symptom severity (i.e., ∼50%) was achieved after 3 months
of continuous stimulation, which was sustained at the 12-month
period (Malone et al., 2009). Significantly, all 17 patients’ saw a
reduction in depression rating scale scores from baseline to final
follow-up (variable follow-up periods). Additionally, a consistent
and significant improvement in GAF scores was observed through-
out the study. Suicidalilty, as measured by the MADRS suicidal
thoughts subscale (Montgomery and Asberg, 1979), decreased sig-
nificantly following one month of stimulation and was sustained
at the 12 month follow-up period (Malone, 2010). At final follow-
up (14–67 months) 35% of the patients had achieved remission
(Malone, 2010).
3.3. Nucleus accumbens
Ten patients suffering from severe TRD had electrodes
implanted bilaterally into the shell and core of the NAc, and the
ventral and medial internal capsule, however only the NAc targets
were stimulated (Bewernick et al., 2010; Schlaepfer et al., 2008).
The effects of one week of DBS in three of the patients was pub-
lished first (Schlaepfer et al., 2008), with stimulation manipulated
in a double-blind manner (switching the voltage off and on), associ-
ated with a consistent and significant drop in depression symptom
severity when the stimulator was on and an increase when off.
All three patients demonstrated decreases in symptom severity
during the first week of stimulation, however only one patient
had achieved a clinical response (Schlaepfer et al., 2008). After 12
months of continuous stimulation five out of the ten patients had
achieved a clinical response with three patients in remission for a
one month period (Bewernick et al., 2010). Patients demonstrated
a decrease in anhedonia, as measured by a significant increase in
activities on a list of 280 pleasant activities (Bewernick et al., 2010)
after 12 months of stimulation. Demonstrating the long-term sta-
bility of DBS of the NAc for TRD, patients that were considered
responders at 12 months continued to show a clinical response at a
2 year follow-up and a final follow-up of up to 4 years (Bewernick
et al., 2012) without a worsening of depression symptomatology.
As a group both responders and non-responders demonstrated a
significant drop in depression symptom severity when compared
with baseline measurements with non-responders experiencing a
sustained drop in depression symptom severity of greater than 10%
at both 12 and 24 month follow-up periods which was sustained at
final follow-up (Bewernick et al., 2012). Significant improvements
in anxiety (as measured by the HAMA) and hedonic activities as a
group were also reported (Bewernick et al., 2012).
1925
3.4. Inferior thalamic peduncle
A single patient with a 20-year history of MDD, with comor-
bid borderline personality disorder and bulimia, had electrodes
implanted bilaterally in and around the inferior thalamic pedun-
cle (Jiménez et al., 2005). This study differed from the other DBS
studies in that the patient was hospitalised and all antidepressant
medication withdrawn two months prior to surgery. Despite an
initial sharp decline in depression symptom scores to remission-
levels following implantation of the electrodes, after one week the
patient experienced a relapse. The patient then attained remission
coincident with the initiation of stimulation (Jiménez et al., 2005).
After eight months of stimulation, the electrodes were switched off
(double-blind) with a delay of two months before any decline was
seen in HDRS scores. When stimulation was reinstated, HDRS scores
returned to remission levels. As two months had elapsed before any
fluctuation in depression scores was observed and the patient did
not suffer a MDE within 10 months following cessation of stimu-
lation calls into question interpretations regarding efficacy of DBS
for this patient, although relapse typically follows some months
after discontinuation of effective pharmacotherapy for most disor-
ders. Other DBS studies for TRD have reported significant relapse of
depressive symptoms within much shorter periods of time during
blinded discontinuation studies (e.g., Schlaepfer et al., 2008).
3.5. Lateral habenula
A single patient with a 46-year history of MDD and demonstrat-
ing a high level of treatment resistance over the 9 years prior to
being considered for surgery received bilateral DBS in the stria
medullaris, the major afferent connection to the LHb (Sartorius
et al., 2010). The patient achieved remission after 4 months of stim-
ulation, which was sustained at final follow-up (at ∼12 months).
A dramatic relapse of depressive symptoms was observed after an
erroneous cessation of stimulation following treatment for a bicycle
accident; however, 12 weeks after the reinstatement of stimulation
the patient again achieved remission (Sartorius et al., 2010).
3.6. Safety and adverse events
Serious adverse events (e.g., suicide) were rare in the studies
reviewed and were deemed to be unrelated to the stimulation or
device failure (Bewernick et al., 2010; Holtzheimer et al., 2012;
Kennedy et al., 2011), rather, compliance, adverse psychosocial
events (Bewernick et al., 2010; Holtzheimer et al., 2012) and a
family history of completed suicide (Kennedy et al., 2011) were
considered important factors. Adverse events relating to the sur-
gical procedure (e.g., localised pain, local wound infection) were
also reported (e.g., Holtzheimer et al., 2012; Lozano et al., 2008;
Malone et al., 2009; Mayberg et al., 2005; Puigdemont et al., 2012;
Schlaepfer et al., 2008). In one study, electrodes were explanted
in three patients due to infections (Lozano et al., 2008; Mayberg
et al., 2005) without a worsening of depressive symptoms. Despite
an unknown aetiology of the infections Mayberg et al. (2005)
changed their protocol to have the electrodes and the pulse gen-
erator implanted in one surgical session; following this protocol,
a recent study (Puigdemont et al., 2012) reported no post-surgical
infections.
Acute adverse events related to the stimulation (e.g., effect;
DBS target; sweating; VC/VS, anxiety; ITP, NAc, VC/VS, light-
headedness; SCG, tachycardia; ITP, VC/VS, paresthesias; VC/VS,
NAc), generally occurring during a parameter change (e.g.,
Bewernick et al., 2010, 2012) or titration phase of stimulation (e.g.,
Jiménez et al., 2005; Lozano et al., 2008), were transient (Bewernick
et al., 2010) or were ameliorated by an additional change in stimu-
lation parameters (e.g., Bewernick et al., 2010; Jiménez et al., 2005;
1926 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Lozano et al., 2008; Malone, 2010; Malone et al., 2009; Mayberg
et al., 2005). Hypomania was observed in one study targeting the
VC/VS (Malone et al., 2009), however these patients had suffered
manic episodes prior to DBS surgery. Weak, subsyndromal symp-
toms of hypomania were experienced during a parameter change
by two patients receiving DBS of the NAc (Bewernick et al., 2012)
which resolved within 24 h. A relative increase in depression symp-
tom severity, although still below preoperative levels, was also
reported and was most often due to battery depletion or accidental
cessation of stimulation (Lozano et al., 2008; Malone et al., 2009;
Mayberg et al., 2005; Sartorius et al., 2010).
Results of neuropsychological testing revealed no negative
effects on cognitive function during DBS (Bewernick et al., 2010,
2012; Grubert et al., 2011; Holtzheimer et al., 2012; Jiménez
et al., 2005; Lozano et al., 2008; Malone et al., 2009; Mayberg
et al., 2005; Puigdemont et al., 2012), in fact, improvements were
reported in cognitive domains that were below average prior to
DBS (Bewernick et al., 2012; Grubert et al., 2011; Holtzheimer
et al., 2012; Jiménez et al., 2005; Malone et al., 2009; McNeely
et al., 2008). Interestingly the improvement in cognitive function
was not associated with the improvement in mood or stimulation
parameter changes (Grubert et al., 2011; McNeely et al., 2008). Neu-
ropsychological assessment of one group of patients (i.e., Lozano
et al., 2008; Mayberg et al., 2005) revealed a transient mild motor
slowing which had normalised by final follow-up (McNeely et al.,
2008).
3.7. Efficacy evaluation
The open-label design and uncontrolled nature of the DBS stud-
ies for TRD makes it difficult to rule out the possible influence
of placebo and non-specific factors on the therapeutic outcomes.
Spontaneous remission is also a possibility that needs to be consid-
ered, although this declines progressively with both chronicity and
number of failed trials of therapy (Trivedi et al., 2006). The small
sample sizes limit the ability to generalise the results, to evaluate
the differences between responders and non-responders, and to
determine the superiority of one target over another. Without large,
randomised, placebo-controlled studies these possibilities cannot
be ruled out, however, a number of factors can be used to argue
against the strong influence of a placebo effect and in favour of
electrical stimulation as a major factor in the therapeutic outcomes.
Even though some patients saw a rapid decrease in depres-
sion symptomatology within weeks after initial stimulation (e.g.,
Mayberg et al., 2005; Puigdemont et al., 2012; Schlaepfer et al.,
2008), typical of a placebo response, the gradual and sustained
improvement over the follow-up periods reported for all respon-
ders is inconsistent with a placebo response for MDD (Quitkin et al.,
1993). Another argument against a strong influence of a placebo
effect is the extreme level of treatment-resistance of all patients
within the studies reviewed. TRD patients have previously been
shown to have lower placebo response rates (e.g., Rush and Thase,
1997; Thase and Rush, 1997). Similarly, with increasing levels of
treatment-resistance and longer current episodes there is a reduced
chance of spontaneous remission (Rush and Thase, 1997; Rush et al.,
2003).
Additional evidence in support of stimulation as a major factor
in the therapeutic outcomes of the DBS studies can be observed
during the acute or titration phase of stimulation. In all stud-
ies reviewed, patients’ responses to stimulation were specific
to certain electrode contacts and parameters, were stimulation-
locked and reproducible even though patients were blind to the
stimulation parameters. Additionally, during the chronic phase
of stimulation, discontinuation trials were conducted single blind
(Holtzheimer et al., 2012; Lozano et al., 2008; Mayberg et al.,
2005) and double blinded (Jiménez et al., 2005; Schlaepfer et al.,
2008) with depression scores increasing during the off period and
decreasing again when stimulation was reinstated. Even acciden-
tal cessation of stimulation or battery depletion, of which patients
were unaware, resulted in an increase in depressive symptoms
(e.g., Lozano et al., 2008; Malone et al., 2009; Mayberg et al., 2005;
Sartorius et al., 2010).
Antidepressant medication may have presented a confounding
factor in the interpretation of the therapeutic effects associated
with DBS for TRD. A majority of the studies made an attempt to
control for medication effects by holding medications and dosage
constant throughout the study period (e.g., Lozano et al., 2008;
Malone et al., 2009; Mayberg et al., 2005; Schlaepfer et al., 2008)
however, this does not rule out the possibility of synergistic effects
between DBS and antidepressant medications, even though fail-
ure of response to pharmacotherapy is a requirement for DBS.
Interactions between DBS for Parkinson’s disease and medica-
tions (i.e., dopaminergic drugs) have been shown to occur (e.g.,
The Deep-brain Stimulation for Parkinson’s Disease Study Group,
2001). Only one study removed all antidepressant medication
prior to surgery (i.e., Jiménez et al., 2005), and although remission
was achieved, it was a case study making it difficult to gener-
alise the results. Despite these limitations, DBS has demonstrated
dramatic, sustained reductions in depression symptoms and signif-
icant improvement in functioning in a large percentage of severely
treatment resistant patients. The mechanisms of action underlying
the therapeutic effects however are still incompletely understood.
4. Mechanisms of action
The mechanisms of action of DBS are still poorly understood
despite clinical efficacy across a number of disorders. The results of
preclinical research have increased our knowledge of the mecha-
nisms of action of DBS for TRD. By stimulating or pharmacologically
activating/deactivating homologous regions in the brains of exper-
imental animals antidepressant-like effects have been observed
(Falowski et al., 2011; Hamani et al., 2010a,b; Li et al., 2011;
Scopinho et al., 2010; Slattery et al., 2011; Winter et al., 2011;
Yang et al., 2008) utilising a number of behavioural assays. Any
description of the mechanisms of action of DBS for TRD will need
to be able to explain the behavioural effects of acute stimulation,
the progressive improvement in depressive symptomatology, and
CBF/metabolic changes in neuroanatomical structures distal to the
site of stimulation following months of continuous stimulation. To
this end a number of mechanisms have been hypothesised that
explain the effects of stimulation at the neuronal level through to
network-wide effects.
4.1. Local mechanisms
A number of variables need to be taken into account when
determining the activity at the site of stimulation, for example,
the volume of neural tissue activated depends on the stimu-
lation parameters, that is voltage, pulse-width and frequency
(Butson et al., 2007), the type of neural tissue stimulated, whether
white matter or grey matter, myelinated or unmyelinated axons
(Perlmutter and Mink, 2006) and the orientation of the neural ele-
ment with respect to the electric field (McIntyre et al., 2004a). With
the electric field decaying exponentially from the electrode contact
(Kuhn et al., 2009) distance is another factor that will determine
whether a neural element is stimulated.
Early research in the area of DBS for movement disorders sug-
gested a mechanism of action similar to that of a surgical lesion,
given similar effects were observed for both (Benabid, 2003) and
despite the logical fallacy (Montgomery and Gale, 2008) provided
a good working hypothesis. Blockade of voltage-gated currents
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
(Beurrier et al., 2001), membrane hyperpolarisation (Dostrovsky
and Lozano, 2002), neurotransmitter depletion (Anderson et al.,
2006; Iremonger et al., 2006) and synaptic inhibition (via release of
inhibitory neurotransmitters) (Dostrovsky et al., 2000) are mech-
anisms proposed to explain the lesion-like neuronal inhibition.
However, excitation and an increase in activation in the local area of
stimulation have also been demonstrated (Hashimoto et al., 2003;
Maurice et al., 2003). Reconciling these findings, McIntyre et al.
(2004b) showed that both suppression and activation of neuronal
activity during high frequency stimulation was possible, with the
decoupling of soma and axon activation, in which simultaneous
inhibition of the cell body and excitation of the axon can occur.
Although, these local mechanisms of action following stimulation
may contribute to our understanding of the therapeutic effects
of DBS, they do not directly explain the gradual and differential
improvements observed in depressive symptomatology recorded
over months of continuous stimulation. In line with this, local neu-
ral activity has been shown to return to baseline within seconds
after cessation of acute stimulation (Johnson et al., 2008).
Gradual and sustained improvements in depressive symp-
tomatology imply long-term changes in neuronal function with
continuous DBS. Support for long-term neuronal changes can be
seen in the blinded discontinuation studies where most patients
showed a level of sustained improvement in depressive symp-
tomatology. Moreover, when some symptoms did return, with
cessation of stimulation, they were well below pre-surgical lev-
els (e.g., Jiménez et al., 2005; Mayberg et al., 2005). Synaptic
plasticity (i.e., long term potentiation and long term depres-
sion) has been suggested as one of the mechanisms producing
long-term neural changes (Lujan et al., 2008), possibly reversing
disrupted neuroplasticity implicated in the neurobiology of depres-
sion (Duman, 2002; Pittenger and Duman, 2008). In support of this,
high-frequency stimulation has been shown, in animal research,
to induce synaptic plasticity (e.g., Shen et al., 2003). Secondary
messengers, long-term potentiation and long-term depression,
synthesis of proteins, changes in gene expression and increased
energy generation have all been suggested as mechanisms of long-
term change due to DBS (Kalbe et al., 2009; Salin et al., 2002; Schulte
et al., 2006; Temperli et al., 2003). Although explaining the long-
term effects of stimulation at the neuron level, a mechanism of
action also needs to explain the extensive effects on distal brain
regions during chronic stimulation, thus a neural network expla-
nation is required.
4.2. Regional mechanisms
The hypothesis that stimulus-evoked modulation of neuronal
network activity is responsible for the therapeutic effects of DBS
(Lujan et al., 2008; McIntyre et al., 2004a) incorporates both the
short and long-term effects of stimulation at the neuron level and
its impact via connections within networks thought to underlie
depression symptomatology (see Fig. 2). At the neuron level, a con-
sistent finding of the effects of high frequency stimulation is the
activation of structures immediately downstream (Anderson et al.,
2003; Hashimoto et al., 2003; Montgomery, 2006) and upstream
(Hashimoto et al., 2003; Maurice et al., 2003; McCracken and Grace,
2007; Montgomery, 2006) from the site of stimulation via ortho-
dromic and antidromic activation respectively (Dostrovsky and
Lozano, 2002; Grill et al., 2008; Hammond et al., 2008). Preclinical
research has shown that stimulation of DBS targets can increase
neurotransmitter release (Hamani et al., 2010b), induce neuro-
plastic changes (Falowski et al., 2011), and alter the power and
synchronisation of local field potential activity (McCracken and
Grace, 2007, 2009) in structures distal to the source of stimulation.
Data obtained from diffusion tensor imaging studies in humans,
tracer analysis in nonhuman primates and rodents have shown that
1927
targets used in DBS for TRD have connections to cortical, subcorti-
cal, limbic and brainstem regions that show profound changes in
CBF/metabolism following chronic stimulation; regions which are
linked to depressive symptomatology and their amelioration.
With connections to prefrontal areas the SCG, VC/VS, NAc,
ITP and the LHb (Fig. 2a) may be involved in the modulation of
the cognitive and mood symptoms of depression following DBS,
with medial, orbital and dorsolateral prefrontal areas implicated
in depressive symptomatology and recovery following successful
treatment (Drevets, 2007; Drevets et al., 2002; Liotti and Mayberg,
2001; Ongür and Price, 2000; Price and Drevets, 2010). FDG-PET
imaging acquired in seven of the ten patients receiving continuous
NAc DBS for 6 months (Bewernick et al., 2010) showed decreases
in metabolism, from baseline, in the orbitofrontal cortex and dor-
sal medial frontal gyrus. Similarly, significant decreases in glucose
metabolism in the medial and orbital frontal areas were reported
following 3 and 6 months of continuous DBS of the SCG (Lozano
et al., 2008). Decreases in CBF were observed in medial and orbital
frontal cortex and increases observed in dorsolateral prefrontal
regions (Mayberg et al., 2005). The increase in CBF in the dorsolat-
eral prefrontal cortex normalised baseline abnormalities relative
to healthy controls (Mayberg et al., 2005). Significant increases in
glucose metabolism were also observed in the dorsolateral and ven-
trolateral prefrontal areas, becoming significant after 6 months of
SCG stimulation (Lozano et al., 2008).
Preclinical research has supported these findings that stimu-
lation at DBS for TRD targets has the ability to alter activity in
regions of the frontal cortex involved in the symptomatology of
MDD. Neuroplasticity, demonstrated by morphological changes to
dendrites in pyramidal neurons, and changes to dopamine and
norepinephrine concentrations have been observed in the pre-
frontal cortex of rats following DBS of the NAc (Falowski et al.,
2011). DBS of the NAc in rats has also demonstrated changes in the
power of oscillations in local field potentials in the orbitofrontal
cortex and medial prefrontal cortex (McCracken and Grace, 2009).
The hypothalamus is involved in the regulation of sleep,
appetite and circadian rhythms, and is a key structure in the
hypothalamic–pituitary–adrenal axis, all considered dysregulated
in the depressive syndrome (Nestler et al., 2002; Swaab et al., 2005).
The SCG, VC/VS, NAc, and LHb DBS targets have direct connections
to the hypothalamus (Fig. 2a). A decrease in CBF from baseline was
observed in the hypothalamus of long-term responders at 3 and 6
months of SCG DBS (Lozano et al., 2008; Mayberg et al., 2005). The
amygdala, another subcortical structure with direct connections to
the DBS for TRD targets, has demonstrated increased metabolism
and CBF in depressed individuals compared with healthy controls
(Abercrombie et al., 1998; Drevets, 1999; Drevets et al., 1992; Price
and Drevets, 2010) which correlates with depressive symptom
severity (Drevets, 1999, 2003) and has been shown to normalise fol-
lowing successful antidepressant treatment (Drevets et al., 2002).
Despite an initial increase in metabolism in the amygdala after
one week of NAc DBS, possibly due to acute effects arising from
implantation of the electrode (Schlaepfer et al., 2008), significant
metabolic decreases in the amygdala of responders compared to
non-responders were observed in a volume of interest analysis
of FDG-PET data in a group of patients at a 6-month follow-up
(Bewernick et al., 2010).
With direct and indirect connections to brain stem areas includ-
ing the locus coeruleus, a major norepinephrine producing region,
the dorsal raphe nuclei, a serotonergic producing area and the
dopaminergic ventral tegmental area (Fig. 2a), the DBS for TRD
targets have the potential to have a significant impact on these
monoamines that have been shown to play a significant role in
depression and its treatment (Krishnan and Nestler, 2008; Ressler
and Nemeroff, 2000; Ruhé et al., 2007). Preclinical research has
shown that stimulation of the LHb increases serotonin (Kalén
1928 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933

Fig. 2. Regional mechanisms. Deep brain stimulation facilitates profound changes in areas distal the site of stimulation through connections to neuroanatomical regions
that are involved in depressive symptomatology. (a) Highly simplified, schematic representation of DBS targets and their connectivity to regions involved in depressive
symptomatology (connections from tract tracing experiments in humans and tracing studies in animals (LHb (Geisler and Trimble, 2008; Geisler and Zahm, 2005; Herkenham
and Nauta, 1977, 1979; Hikosaka et al., 2008); SCG (Chiba et al., 2001; Freedman et al., 2000; Gutman et al., 2009; Hamani et al., 2011; Johansen-Berg et al., 2008; Takagishi
and Chiba, 1991; Vertes, 2004); VC/VS (Gutman et al., 2009; Haber et al., 2006); NAc (Gutman et al., 2009; Johansen-Berg et al., 2008; Powell and Leman, 1976; Sturm et al.,
2003; Williams et al., 1977); ITP (Aggleton and Mishkin, 1984; Behrens et al., 2003; Velasco et al., 2005). (b) Key regions involved in depressive symptomatology (Brody et al.,
2001; Drevets, 2001, 2003, 2007; Fava and Kendler, 2000; Gorwood, 2008; Kringelbach, 2005; Krishnan and Nestler, 2008; Maletic et al., 2007; Mayberg et al., 1999; Nestler
et al., 2002; Ongür and Price, 2000). Abbreviations: ACG, anterior cingulate gyrus; DR, dorsal raphe; H, hypothalamus; LC, locus coeruleus; NAc, nucleus accumbens; OFC,
orbital frontal cortex; PFC, prefrontal cortex; SCG, subgenual cingulate gyrus; VTA, ventral tegmental area.
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
et al., 1989b), dopamine (Ji and Shepard, 2007; Lecourtier et al.,
2008; Matsumoto and Hikosaka, 2007) and norepinephrine (Kalén
et al., 1989a) concentrations. SCG stimulation increases hippocam-
pal serotonin levels (Hamani et al., 2010b) and NAc stimulation
increases both dopamine and serotonin concentrations in the NAc
(Sesia et al., 2010) and decreases dopamine and norepinephrine
levels in the prefrontal cortex (Falowski et al., 2011). Preclinical
research has also shown that the integrity of the serotonergic sys-
tem is important for the antidepressant-like effects observed in the
forced swim test following DBS of the ventromedial prefrontal cor-
tex, considered to be the rodent homologue of the human SCG,
whereas norepinephrine depleting lesions failed to influence the
antidepressant-like results (Hamani et al., 2010b).
The preceding discussion presents some of the significant work
undertaken to understand the mechanisms of action underlying the
therapeutic effects of DBS for TRD; it also highlights limitations in
our understanding. The mechanisms of action are likely to involve
an integration of acute and long-term effects of stimulation of the
target area with effects on distal brain regions within dysfunctional
neural networks. The fact that a number of different targets are
able to effectively ameliorate depressive symptoms, including all
subgroups of symptoms, in groups of severely treatment resistant
patients supports the need for a neural network explanation of
the mechanisms of action involving a number of neuroanatomical
regions in cortical–limbic circuits.
5. Conclusion
Although a limited number of studies have been conducted,
involving only small patient numbers, DBS for TRD has shown
very encouraging results, demonstrating significant and sustained
improvements in depressive symptomatology with remission
achieved in a large percentage of cases. Large randomised placebo-
controlled studies will be required for more robust interpretations
of efficacy. Despite the impressive therapeutic effects of DBS for
TRD, the mechanisms of action are still incompletely understood.
Research posits mechanisms operating at the neuron level through
to modulation of dysfunctional neural networks. Unpicking the
mechanisms and pathways operative in the clinical efficacy of DBS
has the additional potential to shed light on underlying pathophys-
iology, with broader implications for the development of therapies.
The impact of DBS on biomarkers and on other potential aetiologi-
cal factors involved in the pathophysiology of depression remains
a goal for future investigation.
References
Abelson, J.L., Curtis, G.C., Sagher, O., Albucher, R.C., Harrigan, M., Taylor,
S.F., Martis, B., Giordani, B., 2005. Deep brain stimulation for refractory
obsessive–compulsive disorder. Biological Psychiatry 57, 510–516.
Abercrombie, H.C., Schaefer, S.M., Larson, C.L., Oakes, T.R., Lindgren, K.A., Holden,
J.E., Perlman, S.B., Turski, P.A., Krahn, D.D., Benca, R.M., Davidson, R.J., 1998.
Metabolic rate in the right amygdala predicts negative affect in depressed
patients. Neuroreport 9, 3301–3307.
Aggleton, J.P., Mishkin, M., 1984. Projections of the amygdala to the thalamus in the
cynomolgus monkey. Journal of Comparative Neurology 222, 56–68.
American Psychiatric Association, 2000. Practice guideline for the treatment of
patients with major depressive disorder (revision). American Journal of Psy-
chiatry 157, 1–45.
Anderson, M.E., Postupna, N., Ruffo, M., 2003. Effects of high-frequency stimulation
in the internal globus pallidus on the activity of thalamic neurons in the awake
monkey. Journal of Neurophysiology 89, 1150–1160.
Anderson, T.R., Hu, B., Iremonger, K., Kiss, Z.H.T., 2006. Selective attenuation
of afferent synaptic transmission as a mechanism of thalamic deep brain
stimulation-induced tremor arrest. Journal of Neuroscience 26, 841–850.
Andrade, L., Caraveo-Anduaga, J.J., Berglund, P., Bijl, R.V., De Graaf, R., Vollebergh, W.,
Dragomirecka, E., Kohn, R., Keller, M., Kessler, R.C., Kawakami, N., Kiliç, C., Offord,
D., Ustun, T.B., Wittchen, H.-U., 2003. The epidemiology of major depressive
episodes: results from the international consortium of psychiatric epidemiology
(icpe) surveys. International Journal of Methods in Psychiatric Research 12, 3–21.
1929
Andrews, G., Henderson, S., Hall, W., 2001. Prevalence, comorbidity, disability and
service utilisation. Overview of the Australian national mental health survey.
British Journal of Psychiatry 178, 145–153.
Aouizerate, B., Cuny, E., Bardinet, E., Yelnik, J., Martin-Guehl, C., Rotge, J.-Y., Rougier,
A., Bioulac, B., Tignol, J., Mallet, L., Burbaud, P., Guehl, D., 2009. Distinct striatal
targets in treating obsessive–compulsive disorder and major depression. Journal
of Neurosurgery 111, 775–779.
Aouizerate, B., Cuny, E., Martin-Guehl, C., Guehl, D., Amieva, H., Benazzouz, A.,
Fabrigoule, C., Allard, M., Rougier, A., Bioulac, B., Tignol, J., Burbaud, P., 2004.
Deep brain stimulation of the ventral caudate nucleus in the treatment of
obsessive–compulsive disorder and major depression. Journal of Neurosurgery
101, 682–686.
Arias-Carrión, O., Stamelou, M., Murillo-Rodríguez, E., Menéndez-González, M.,
Pöppel, E., 2010. Dopaminergic reward system: a short integrative review. Inter-
national Archives of Medicine 3, 24.
Bakish, D., 2001. New standard of depression treatment: remission and full recovery.
Journal of Clinical Psychiatry 62, 5–9.
Behrens, T.E.J., Johansen-Berg, H., Woolrich, M.W., Smith, S.M., Wheeler-Kingshott,
C.A.M., Boulby, P.A., Barker, G.J., Sillery, E.L., Sheehan, K., Ciccarelli, O., Thompson,
A.J., Brady, J.M., Matthews, P.M., 2003. Non-invasive mapping of connections
between human thalamus and cortex using diffusion imaging. Nature Neuro-
science 6, 750–757.
Benabid, A.L., 2003. Deep brain stimulation for Parkinson’s disease. Current Opinion
in Neurobiology 13, 696–706.
Berk, M., Kapczinski, F., Andreazza, A.C., Dean, O.M., Giorlando, F., Maes, M., Yücel,
M., Gama, C.S., Dodd, S., Dean, B., Magalhães, P.V.S., Amminger, P., McGorry, P.,
Malhi, G.S., 2011. Pathways underlying neuroprogression in bipolar disorder:
focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience
and Biobehavioral Reviews 35, 804–817.
Berk, M., Ng, F., Wang, W.V., Calabrese, J.R., Mitchell, P.B., Malhi, G.S., Tohen, M.,
2008. The empirical redefinition of the psychometric criteria for remission in
bipolar disorder. Journal of Affective Disorders 106, 153–158.
Beurrier, C., Bioulac, B., Audin, J., Hammond, C., 2001. High-frequency stimulation
produces a transient blockade of voltage-gated currents in subthalamic neurons.
Journal of Neurophysiology 85, 1351–1356.
Bewernick, B.H., Hurlemann, R., Matusch, A., Kayser, S., Grubert, C., Hadrysiewicz,
B., Axmacher, N., Lemke, M., Cooper-Mahkorn, D., Cohen, M.X., Brockmann, H.,
Lenartz, D., Sturm, V., Schlaepfer, T.E., 2010. Nucleus accumbens deep brain
stimulation decreases ratings of depression and anxiety in treatment-resistant
depression. Biological Psychiatry 67, 110–116.
Bewernick, B.H., Kayser, S., Sturm, V., Schlaepfer, T.E., 2012. Long-term effects of
nucleus accumbens deep brain stimulation in treatment-resistant depression:
evidence for sustained efficacy. Neuropsychopharmacology, 1–11 (Epub ahead
of print).
Bostwick, J.M., Pankratz, V.S., 2000. Affective disorders and suicide risk: a reexami-
nation. American Journal of Psychiatry 157, 1925–1932.
Brådvik, L., Mattisson, C., Bogren, M., Nettelbladt, P., 2008. Long-term suicide risk of
depression in the lundby cohort 1947–1997 – severity and gender. Acta Psychi-
atrica Scandinavica 117, 185–191.
Brody, A.L., Saxena, S., Mandelkern, M.A., Fairbanks, L.A., Ho, M.L., Baxter, L.R., 2001.
Brain metabolic changes associated with symptom factor improvement in major
depressive disorder. Biological Psychiatry 50, 171–178.
Butson, C.R., Cooper, S.E., Henderson, J.M., McIntyre, C.C., 2007. Patient-specific anal-
ysis of the volume of tissue activated during deep brain stimulation. Neuroimage
34, 661–670.
Caldecott-Hazard, S., Mazziotta, J., Phelps, M., 1988. Cerebral correlates of depressed
behavior in rats, visualized using 14c-2-deoxyglucose autoradiography. Journal
of Neuroscience 8, 1951–1961.
Carney, R.M., Freedland, K.E., 2003. Depression, mortality, and medical mor-
bidity in patients with coronary heart disease. Biological Psychiatry 54,
241–247.
Caspi, A., Sugden, K., Moffitt, T.E., Taylor, A., Craig, I.W., Harrington, H., Mcclay,
J., Mill, J., Martin, J., Braithwaite, A., Poulton, R., 2003. Influence of life stress
on depression: moderation by a polymorphism in the 5-htt gene. Science 301,
386–389.
Chiba, T., Kayahara, T., Nakano, K., 2001. Efferent projections of infralimbic and pre-
limbic areas of the medial prefrontal cortex in the Japanese monkey, macaca
fuscata. Brain Research 888, 83–101.
Christmas, D., Eljamel, M.S., Butler, S., Hazari, H., MacVicar, R., Steele, J.D., Liv-
ingstone, A., Matthews, K., 2011. Long term outcome of thermal anterior
capsulotomy for chronic, treatment refractory depression. Journal of Neurology,
Neurosurgery and Psychiatry 82, 594–600.
Cuijpers, P., Smit, F., 2002. Excess mortality in depression: a meta-
analysis of community studies. Journal of Affective Disorders 72,
227–236.
De Hert, M., Correll, C.U., Bobes, J., Cetkovich-Bakmas, M., Cohen, D., Asai, I., Detraux,
J., Gautam, S., Möller, H.-J., Ndetei, D.M., Newcomer, J.W., Uwakwe, R., Leucht,
S., 2011. Physical illness in patients with severe mental disorders. I. Preva-
lence, impact of medications and disparities in health care. World Psychiatry 10,
52–77.
Dodd, S., Horgan, D., Malhi, G.S., Berk, M., 2005. To combine or not to combine? A
literature review of antidepressant combination therapy. Journal of Affective
Disorders 89, 1–11.
Dostrovsky, J.O., Levy, R., Wu, J.P., Hutchison, W.D., Tasker, R.R., Lozano, A.M., 2000.
Microstimulation-induced inhibition of neuronal firing in human globus pal-
lidus. Journal of Neurophysiology 84, 570–574.
1930 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Dostrovsky, J.O., Lozano, A.M., 2002. Mechanisms of deep brain stimulation. Move-
ment Disorders 17, S63–S68.
Dougherty, D.D., Rauch, S.L., 2007. Somatic therapies for treatment-resistant depres-
sion: new neurotherapeutic interventions. Psychiatric Clinics of North America
30, 31–37.
Dougherty, D.D., Weiss, A.P., Cosgrove, G.R., Alpert, N.M., Cassem, E.H., Nieren-
berg, A.A., Price, B.H., Mayberg, H.S., Fischman, A.J., Rauch, S.L., 2003. Cerebral
metabolic correlates as potential predictors of response to anterior cin-
gulotomy for treatment of major depression. Journal of Neurosurgery 99,
1010–1017.
Drevets, W.C., 1999. Prefrontal cortical-amygdalar metabolism in major depression.
Annals of the New York Academy of Sciences 877, 614–637.
Drevets, W.C., 2000. Neuroimaging studies of mood disorders. Biological Psychiatry
48, 813–829.
Drevets, W.C., 2001. Neuroimaging and neuropathological studies of depression:
implications for the cognitive-emotional features of mood disorders. Current
Opinion in Neurobiology 11, 240–249.
Drevets, W.C., 2003. Neuroimaging abnormalities in the amygdala in mood disor-
ders. Annals of the New York Academy of Sciences 985, 420–444.
Drevets, W.C., 2007. Orbitofrontal cortex function and structure in depression.
Annals of the New York Academy of Sciences 1121, 499–527.
Drevets, W.C., Bogers, W., Raichle, M.E., 2002. Functional anatomical correlates of
antidepressant drug treatment assessed using pet measures of regional glucose
metabolism. European Neuropsychopharmacology 12, 527–544.
Drevets, W.C., Price, J.L., Furey, M.L., 2008. Brain structural and functional abnormal-
ities in mood disorders: implications for neurocircuitry models of depression.
Brain Structure and Function 213, 93–118.
Drevets, W.C., Videen, T.O., Price, J.L., Preskorn, S.H., Carmichael, S.T., Raichle, M.E.,
1992. A functional anatomical study of unipolar depression. Journal of Neuro-
science 12, 3628–3641.
Duman, R.S., 2002. Pathophysiology of depression: the concept of synaptic plasticity.
European Psychiatry 17 (Suppl. 3), 306–310.
Epstein, J., Pan, H., Kocsis, J.H., Yang, Y., Butler, T., Chusid, J., Hochberg, H., Mur-
rough, J., Strohmayer, E., Stern, E., Silbersweig, D.A., 2006. Lack of ventral striatal
response to positive stimuli in depressed versus normal subjects. American
Journal of Psychiatry 163, 1784–1790.
Falowski, S.M., Sharan, A., Reyes, B.A.S., Sikkema, C., Szot, P., Van Bockstaele, E.J.,
2011. An evaluation of neuroplasticity and behavior after deep brain stimulation
of the nucleus accumbens in an animal model of depression. Neurosurgery 69,
1281–1290.
Fava, M., 2003. Diagnosis and definition of treatment-resistant depression. Biological
Psychiatry 53, 649–659.
Fava, M., Kendler, K.S., 2000. Major depressive disorder. Neuron 28, 335–341.
Freedman, L.J., Insel, T.R., Smith, Y., 2000. Subcortical projections of area 25 (sub-
genual cortex) of the macaque monkey. Journal of Comparative Neurology 421,
172–188.
Gabriels, L., Cosyns, P., Nuttin, B., Demeulemeester, H., Gybels, J., 2003. Deep
brain stimulation for treatment-refractory obsessive–compulsive disorder:
psychopathological and neuropsychological outcome in three cases. Acta Psy-
chiatrica Scandinavica 107, 275–282.
Geisler, S., Trimble, M., 2008. The lateral habenula: no longer neglected. CNS Spec-
trums 13, 484–489.
Geisler, S., Zahm, D.S., 2005. Afferents of the ventral tegmental area in the
rat-anatomical substratum for integrative functions. Journal of Comparative
Neurology 490, 270–294.
Giacobbe, P., Mayberg, H.S., Lozano, A.M., 2009. Treatment resistant depression as a
failure of brain homeostatic mechanisms: implications for deep brain stimula-
tion. Experimental Neurology 219, 44–52.
Gorwood, P., 2008. Neurobiological mechanisms of anhedonia. Dialogues in Clinical
Neuroscience 10, 291–299.
Goto, Y., Grace, A.A., 2005. Dopaminergic modulation of limbic and cortical drive of
nucleus accumbens in goal-directed behavior. Nature Neuroscience 8, 805–812.
Greenberg, B., Price, L., Rauch, S., Friehs, G., Noren, G., Malone, D., Carpenter, L., Rezai,
A., Rasmussen, S., 2003. Neurosurgery for intractable obsessive–compulsive dis-
order and depression: critical issues. Neurosurgery Clinics of North America 14,
199–212.
Greenberg, B.D., Malone, D.A., Friehs, G.M., Rezai, A.R., Kubu, C.S., Malloy, P.F.,
Salloway, S.P., Okun, M.S., Goodman, W.K., Rasmussen, S.A., 2006. Three-year
outcomes in deep brain stimulation for highly resistant obsessive–compulsive
disorder. Neuropsychopharmacology 31, 2384–2393.
Grill, W.M., Cantrell, M.B., Robertson, M.S., 2008. Antidromic propagation of action
potentials in branched axons: implications for the mechanisms of action of deep
brain stimulation. Journal of Computational Neuroscience 24, 81–93.
Grubert, C., Hurlemann, R., Bewernick, B.H., Kayser, S., Hadrysiewicz, B., Axmacher,
N., Sturm, V., Schlaepfer, T.E., 2011. Neuropsychological safety of nucleus
accumbens deep brain stimulation for major depression: effects of 12-month
stimulation. World Journal of Biological Psychiatry 12, 516–527.
Gutman, D.A., Holtzheimer, P.E., Behrens, T.E.J., Johansen-berg, H., Mayberg, H.S.,
2009. A tractography analysis of two deep brain stimulation white matter targets
for depression. Biological Psychiatry 65, 276–282.
Haber, S.N., Kim, K.-S., Mailly, P., Calzavara, R., 2006. Reward-related cortical inputs
define a large striatal region in primates that interface with associative corti-
cal connections, providing a substrate for incentive-based learning. Journal of
Neuroscience 26, 8368–8376.
Hamani, C., Diwan, M., Isabella, S., Lozano, A.M., Nobrega, J.N., 2010a. Effects of dif-
ferent stimulation parameters on the antidepressant-like response of medial
prefrontal cortex deep brain stimulation in rats. Journal of Psychiatric Research
44, 683–687.
Hamani, C., Diwan, M., Macedo, C.E., Brandão, M.L., Shumake, J., Gonzalez-
lima, F., Raymond, R., Lozano, A.M., Fletcher, P.J., Nobrega, J.N., 2010b.
Antidepressant-like effects of medial prefrontal cortex deep brain stimulation
in rats. Biological Psychiatry 67, 117–124.
Hamani, C., Mayberg, H., Snyder, B., Giacobbe, P., Kennedy, S., Lozano, A.M., 2009.
Deep brain stimulation of the subcallosal cingulate gyrus for depression:
anatomical location of active contacts in clinical responders and a suggested
guideline for targeting. Journal of Neurosurgery 111, 1209–1215.
Hamani, C., Mayberg, H., Stone, S., Laxton, A., Haber, S., Lozano, A.M., 2011. The sub-
callosal cingulate gyrus in the context of major depression. Biological Psychiatry
69, 301–308.
Hamilton, M., 1960. A rating scale for depression. Journal of Neurology, Neurosurgery
and Psychiatry 23, 56–62.
Hammond, C., Ammari, R., Bioulac, B., Garcia, L., 2008. Latest view on the mechanism
of action of deep brain stimulation. Movement Disorders 23, 2111–2121.
Hariz, G.M., Blomstedt, P., Koskinen, L.O., 2008. Long-term effect of deep brain stimu-
lation for essential tremor on activities of daily living and health-related quality
of life. Acta Neurologica Scandinavica 118, 387–394.
Hashimoto, T., Elder, C.M., Okun, M.S., Patrick, S.K., Vitek, J.L., 2003. Stimulation of the
subthalamic nucleus changes the firing pattern of pallidal neurons. The Journal
of Neuroscience 23, 1916–1923.
Hasin, D.S., Goodwin, R.D., Stinson, F.S., Grant, B.F., 2005. Epidemiology of major
depressive disorder. Archives of General Psychiatry 62, 1097–1106.
Hasler, G., Fromm, S., Carlson, P.J., Luckenbaugh, D.A., Waldeck, T., Geraci, M.,
Roiser, J.P., Neumeister, A., Meyers, N., Charney, D.S., Drevets, W.C., 2008. Neu-
ral response to catecholamine depletion in unmedicated subjects with major
depressive disorder in remission and healthy subjects. Archives of General Psy-
chiatry 65, 521–531.
Hauptman, J.S., DeSalles, A.A., Espinoza, R., Sedrak, M., Ishida, W., 2008. Potential
surgical targets for deep brain stimulation in treatment-resistant depression.
Neurosurgical Focus 25, 1–9.
Heien, M.L.A.V., Wightman, R.M., 2006. Phasic dopamine signaling during behav-
ior, reward, and disease states. CNS & Neurological Disorders – Drug Targets 5,
99–108.
Heim, C., Nemeroff, C.B., 2001. The role of childhood trauma in the neurobiology of
mood and anxiety disorders: preclinical and clinical studies. Biological Psychi-
atry 49, 1023–1039.
Herkenham, M., Nauta, W.J., 1977. Afferent connections of the habenular nuclei in
the rat. A horseradish peroxidase study, with a note on the fiber-of-passage
problem. Journal of Comparative Neurology 173, 123–146.
Herkenham, M., Nauta, W.J., 1979. Efferent connections of the habenular nuclei in
the rat. Journal of Comparative Neurology 187, 19–47.
Hikosaka, O., 2010. The habenula: from stress evasion to value-based decision-
making. Nature Reviews Neuroscience 11, 503–513.
Hikosaka, O., Sesack, S.R., Lecourtier, L., Shepard, P.D., 2008. Habenula: crossroad
between the basal ganglia and the limbic system. Journal of Neuroscience 28,
11825–11829.
Hodaie, M., Wennberg, R.A., Dostrovsky, J.O., Lozano, A.M., 2002. Chronic anterior
thalamus stimulation for intractable epilepsy. Epilepsia 43, 603–608.
Holtzheimer, P.E., Kelley, M.E., Gross, R.E., Filkowski, M.M., Garlow, S.J., Barrocas,
A., Wint, D., Craighead, M.C., Kozarsky, J., Chismar, R., Moreines, J.L., Mewes, K.,
Posse, P.R., Gutman, D.A., Mayberg, H.S., 2012. Subcallosal cingulate deep brain
stimulation for treatment-resistant unipolar and bipolar depression. Archives
of General Psychiatry 69, 150–158.
Iremonger, K.J., Anderson, T.R., Hu, B., Kiss, Z.H.T., 2006. Cellular mechanisms
preventing sustained activation of cortex during subcortical high-frequency
stimulation. Journal of Neurophysiology 96, 613–621.
Jacka, F.N., Kremer, P.J., Berk, M., de Silva-Sanigorski, A.M., Moodie, M., Leslie, E.R.,
Pasco, J.A., Swinburn, B.A., 2011a. A prospective study of diet quality and mental
health in adolescents. PLoS One 6, e24805.
Jacka, F.N., Pasco, J.A., Williams, L.J., Leslie, E.R., Dodd, S., Nicholson, G.C., Kotowicz,
M.A., Berk, M., 2011b. Lower levels of physical activity in childhood asso-
ciated with adult depression. Journal of Science and Medicine in Sport 14,
222–226.
Ji, H., Shepard, P.D., 2007. Lateral habenula stimulation inhibits rat midbrain
dopamine neurons through a gaba(a) receptor-mediated mechanism. Journal
of Neuroscience 27, 6923–6930.
Jiménez, F., Velasco, F., Salin-Pascual, R., Hernández, J.A., Velasco, M., Criales, J.L.,
Nicolini, H., 2005. A patient with a resistant major depression disorder treated
with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery 57,
585–593.
Johansen-Berg, H., Gutman, D.A., Behrens, T.E., Matthews, P.M., Rushworth, M.F.S.,
Katz, E., Lozano, A.M., Mayberg, H.S., 2008. Anatomical connectivity of the
subgenual cingulate region targeted with deep brain stimulation for treatment-
resistant depression. Cerebral Cortex 18, 1374–1383.
Johnson, M.D., Miocinovic, S., McIntyre, C.C., Vitek, J.L., 2008. Mechanisms and tar-
gets of deep brain stimulation in movement disorders. Neurotherapeutics 5,
294–308.
Kalbe, E., Voges, J., Weber, T., Haarer, M., Baudrexel, S., Klein, J.C., Kessler, J., Sturm,
V., Heiss, W.D., Hilker, R., 2009. Frontal fdg-pet activity correlates with cognitive
outcome after stn-dbs in Parkinson disease. Neurology 72, 42–49.
Kalén, P., Lindvall, O., Björklund, A., 1989a. Electrical stimulation of the lateral
habenula increases hippocampal noradrenaline release as monitored by in vivo
microdialysis. Experimental Brain Research 76, 239–245.
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Kalén, P., Strecker, R.E., Rosengren, E., Björklund, A., 1989b. Regulation of striatal
serotonin release by the lateral habenula–dorsal raphe pathway in the rat as
demonstrated by in vivo microdialysis: role of excitatory amino acids and gaba.
Brain Research 492, 187–202.
Kapczinski, F., Vieta, E., Andreazza, A.C., Frey, B.N., Gomes, F.A., Tramontina, J.,
Kauer-Sant’anna, M., Grassi-Oliveira, R., Post, R.M., 2008. Allostatic load in bipo-
lar disorder: implications for pathophysiology and treatment. Neuroscience &
Biobehavioral Reviews 32, 675–692.
Kendler, K.S., Kuhn, J.W., Vittum, J., Prescott, C.A., Riley, B., 2005a. The interac-
tion of stressful life events and a serotonin transporter polymorphism in the
prediction of episodes of major depression. Archives of General Psychiatry 62,
529–535.
Kendler, K.S., Myers, J., Prescott, C.A., 2005b. Sex differences in the relationship
between social support and risk for major depression: a longitudinal study of
opposite-sex twin pairs. American Journal of Psychiatry 162, 250–256.
Kendler, K.S., Thornton, L.M., Gardner, C.O., 2001. Genetic risk, number of previ-
ous depressive episodes, and stressful life events in predicting onset of major
depression. American Journal of Psychiatry 158, 582–586.
Kennedy, S.H., Giacobbe, P., 2007. Treatment resistant depression – advances in
somatic therapies. Annals of Clinical Psychiatry 19, 279–287.
Kennedy, S.H., Giacobbe, P., Rizvi, S.J., Placenza, F.M., Nishikawa, Y., Mayberg, H.S.,
Lozano, A.M., 2011. Deep brain stimulation for treatment-resistant depression:
follow-up after 3 to 6 years. American Journal of Psychiatry 168, 502–510.
Kennedy, S.H., Konarski, J.Z., Segal, Z.V., Lau, M.A., Bieling, P.J., Mcintyre, R.S., May-
berg, H.S., 2007. Differences in brain glucose metabolism between responders to
cbt and venlafaxine in a 16-week randomized controlled trial. American Journal
of Psychiatry 164, 778–788.
Kessler, R.C., Berglund, P., Demler, O., Jin, R., Merikangas, K.R., Walters, E.E., 2005a.
Lifetime prevalence and age-of-onset distributions of dsm-iv disorders in the
national comorbidity survey replication. Archives of General Psychiatry 62,
593–602.
Kessler, R.C., Chiu, W.T., Demler, O., Walters, E.E., 2005b. Prevalence, severity, and
comorbidity of 12-month dsm-iv disorders in the national comorbidity survey
replication. Archives of General Psychiatry 62, 617–627.
Knutson, B., Adams, C.M., Fong, G.W., Hommer, D., 2001. Anticipation of increasing
monetary reward selectively recruits nucleus accumbens. Journal of Neuro-
science 21, 1–5.
Kondo, H., Saleem, K.S., Price, J.L., 2005. Differential connections of the perirhinal
and parahippocampal cortex with the orbital and medial prefrontal networks
in macaque monkeys. Journal of Comparative Neurology 493, 479–509.
Kopell, B.H., Greenberg, B.D., 2008. Anatomy and physiology of the basal ganglia:
implications for dbs in psychiatry. Neuroscience & Biobehavioral Reviews 32,
408–422.
Kopell, B.H., Halverson, J., Butson, C.R., Dickinson, M., Bobholz, J., Harsch, H., Rainey,
C., Kondziolka, D., Howland, R., Eskandar, E., Evans, K.C., Dougherty, D.D., 2011.
Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refrac-
tory major depressive disorder. Neurosurgery 69, 1015–1029 (discussion 1029).
Kosel, M., Frick, C., Lisanby, S.H., Fisch, H.-u., Schlaepfer, T.E., 2003. Magnetic seizure
therapy improves mood in refractory major depression. Neuropsychopharma-
cology 28, 2045–2048.
Kosel, M., Sturm, V., Frick, C., Lenartz, D., Zeidler, G., Brodesser, D., Schlaepfer, T.E.,
2007. Mood improvement after deep brain stimulation of the internal globus
pallidus for tardive dyskinesia in a patient suffering from major depression.
Journal of Psychiatric Research 41, 801–803.
Kringelbach, M.L., 2005. The human orbitofrontal cortex: linking reward to hedonic
experience. Nature Reviews Neuroscience 6, 691–702.
Kringelbach, M.L., Jenkinson, N., Green, A.L., Owen, S.L.F., Hansen, P.C., Cornelis-
sen, P.L., Holliday, I.E., Stein, J., Aziz, T.Z., 2007. Deep brain stimulation for
chronic pain investigated with magnetoencephalography. Neuroreport 18,
223–228.
Krishnan, V., Nestler, E.J., 2008. The molecular neurobiology of depression. Nature
455, 894–902.
Kuhn, J., Gaebel, W., Klosterkoetter, J., Woopen, C., 2009. Deep brain stimulation
as a new therapeutic approach in therapy-resistant mental disorders: ethical
aspects of investigational treatment. European Archives of Psychiatry and Clin-
ical Neuroscience 259, S135–S141.
Kuhn, J., Lenartz, D., Mai, J.K., Huff, W., Lee, S.-H., Koulousakis, A., Klosterkoet-
ter, J., Sturm, V., 2007. Deep brain stimulation of the nucleus accumbens and
the internal capsule in therapeutically refractory tourette-syndrome. Journal of
Neurology 254, 963–965.
Lecourtier, L., Defrancesco, A., Moghaddam, B., 2008. Differential tonic influence of
lateral habenula on prefrontal cortex and nucleus accumbens dopamine release.
European Journal of Neuroscience 27, 1755–1762.
Li, B., Piriz, J., Mirrione, M., Chung, C., Proulx, C.D., Schulz, D., Henn, F., Malinow, R.,
2011. Synaptic potentiation onto habenula neurons in the learned helplessness
model of depression. Nature 470, 535–539.
Liotti, M., Mayberg, H.S., 2001. The role of functional neuroimaging in the neuropsy-
chology of depression. Journal of Clinical and Experimental Neuropsychology
23, 121–136.
Lipsman, N., Neimat, J.S., Lozano, A.M., 2007. Deep brain stimulation for treatment-
refractory obsessive–compulsive disorder: the search for a valid target.
Neurosurgery 61, 1–13.
Lisanby, S.H., Luber, B., Schlaepfer, T.E., Sackeim, H.A., 2003. Safety and feasibility of
magnetic seizure therapy (mst) in major depression: randomized within-subject
comparison with electroconvulsive therapy. Neuropsychopharmacology 28,
1852–1865.
1931
Lozano, A.M., Mayberg, H.S., Giacobbe, P., Hamani, C., Craddock, R.C., Kennedy, S.H.,
2008. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant
depression. Biological Psychiatry 64, 461–467.
Lujan, J.L., Chaturvedi, A., Mcintyre, C.C., 2008. Tracking the mechanisms of deep
brain stimulation for neuropsychiatric disorders. Frontiers in Bioscience 13,
5892–5904.
Maciunas, R.J., Maddux, B.N., Riley, D.E., Whitney, C.M., Schoenberg, M.R., Ogrocki,
P.J., Albert, J.M., Gould, D.J., 2007. Prospective randomized double-blind trial
of bilateral thalamic deep brain stimulation in adults with tourette syndrome.
Journal of Neurosurgery 107, 1004–1014.
Maes, M., Leonard, B., Fernandez, A., Kubera, M., Nowak, G., Veerhuis, R., Gard-
ner, A., Ruckoanich, P., Geffard, M., Altamura, C., Galecki, P., Berk, M., 2011.
(Neuro)inflammation and neuroprogression as new pathways and drug targets
in depression: from antioxidants to kinase inhibitors. Progress in Neuro-
Psychopharmacology and Biological Psychiatry 35, 659–663.
Maletic, V., Robinson, M., Oakes, T., Iyengar, S., Ball, S.G., Russell, J., 2007. Neurobi-
ology of depression: an integrated view of key findings. International Journal of
Clinical Practice 61, 2030–2040.
Malhi, G.S., Berk, M., 2007. Does dopamine dysfunction drive depression? Acta Psy-
chiatrica Scandinavica. Supplementum 115, 116–124.
Malone, D.A., 2010. Use of deep brain stimulation in treatment-resistant depression.
Cleveland Clinic Journal of Medicine 77, S77–S80.
Malone, D.A., Dougherty, D.D., Rezai, A.R., Carpenter, L.L., Friehs, G.M., Eskandar,
E.N., Rauch, S.L., Rasmussen, S.A., Machado, A.G., Kubu, C.S., Tyrka, A.R., Price,
L.H., Stypulkowski, P.H., Giftakis, J.E., Rise, M.T., Malloy, P.F., Salloway, S.P.,
Greenberg, B.D., 2009. Deep brain stimulation of the ventral capsule/ventral
striatum for treatment-resistant depression. Biological Psychiatry 65,
267–275.
Matsumoto, M., Hikosaka, O., 2007. Lateral habenula as a source of negative reward
signals in dopamine neurons. Nature 447, 1111–1115.
Matsumoto, M., Hikosaka, O., 2008. Representation of negative motivational value
in the primate lateral habenula. Nature Neuroscience 12, 77–84.
Maurice, N., Thierry, A.-M., Glowinski, J., Deniau, J.-M., 2003. Spontaneous and
evoked activity of substantia nigra pars reticulata neurons during high-
frequency stimulation of the subthalamic nucleus. Journal of Neuroscience 23,
9929–9936.
Mayberg, H.S., 2003. Modulating dysfunctional limbic – cortical circuits in depres-
sion: towards development of brain-based algorithms for diagnosis and
optimised treatment. British Medical Bulletin 65, 193–207.
Mayberg, H.S., 2006. Defining neurocircuits in depression. Psychiatric Annals 36,
259–269.
Mayberg, H.S., 2009. Targeted electrode-based modulation of neural circuits for
depression. Journal of Clinical Investigation 119, 717–725.
Mayberg, H.S., Brannan, S.K., Tekell, J.L., Silva, J.A., Mahurin, R.K., Mcginnis, S., Jer-
abek, P.A., 2000. Regional metabolic effects of fluoxetine in major depression:
serial changes and relationship to clinical response. Biological Psychiatry 48,
830–843.
Mayberg, H.S., Liotti, M., Brannan, S.K., Mcginnis, S., Mahurin, R.K., Jerabek, P.A., Silva,
J.A., Tekell, J.L., Martin, C.C., Lancaster, J.L., Fox, P.T., 1999. Reciprocal limbic-
cortical function and negative mood: converging pet findings in depression and
normal sadness. American Journal of Psychiatry 156, 675–682.
Mayberg, H.S., Lozano, A.M., Voon, V., McNeely, H.E., Seminowicz, D.A., Hamani,
C., Schwalb, J.M., Kennedy, S.H., 2005. Deep brain stimulation for treatment-
resistant depression. Neuron 45, 651–660.
Mayberg, H.S., Silva, J.A., Brannan, S.K., Tekell, J.L., Mahurin, R.K., McGinnis, S., Jer-
abek, P.A., 2002. The functional neuroanatomy of the placebo effect. American
Journal of Psychiatry 159, 728–737.
McCracken, C.B., Grace, A.A., 2007. High-frequency deep brain stimulation of the
nucleus accumbens region suppresses neuronal activity and selectively modu-
lates afferent drive in rat orbitofrontal cortex in vivo. Journal of Neuroscience
27, 12601–12610.
McCracken, C.B., Grace, A.A., 2009. Nucleus accumbens deep brain stimulation pro-
duces region-specific alterations in local field potential oscillations and evoked
responses in vivo. Journal of Neuroscience 29, 5354–5363.
McEwen, B.S., 2003. Mood disorders and allostatic load. Biological Psychiatry 54,
200–207.
McIntyre, C.C., Grill, W.M., Sherman, D.L., Thakor, N.V., 2004a. Cellular effects of deep
brain stimulation: model-based analysis of activation and inhibition. Journal of
Neurophysiology 91, 1457–1469.
McIntyre, C.C., Savasta, M., Goff L.K.-l. Vitek, J.L., 2004b. Uncovering the mech-
anism(s) of action of deep brain stimulation: activation, inhibition, or both.
Clinical Neurophysiology 115, 1239–1248.
McNeely, H.E., Mayberg, H.S., Lozano, A.M., Kennedy, S.H., 2008. Neuropsychologi-
cal impact of cg25 deep brain stimulation for treatment-resistant depression:
preliminary results over 12 months. Journal of Nervous and Mental Disease 196,
405–410.
Montgomery, E.B., 2006. Effects of gpi stimulation on human thalamic neuronal
activity. Clinical Neurophysiology 117, 2691–2702.
Montgomery, E.B., Gale, J.T., 2008. Mechanisms of action of deep brain stimulation
(dbs). Neuroscience & Biobehavioral Reviews 32, 388–407.
Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive
to change. British Journal of Psychiatry 134, 382–389.
Montoya, A., Weiss, A.P., Price, B.H., Cassem, E.H., Dougherty, D.D., Nierenberg,
A.A., Rauch, S.L., Cosgrove, G.R., 2002. Magnetic resonance imaging-guided
stereotactic limbic leukotomy for treatment of intractable psychiatric disease.
Neurosurgery 50, 1043–1049 (discussion 1049–1052).
1932 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Morris, J.S., Smith, K.A., Cowen, P.J., Friston, K.J., Dolan, R.J., 1999. Covariation of
activity in habenula and dorsal raphé nuclei following tryptophan depletion.
Neuroimage 10, 163–172.
Mottaghy, F.M., Keller, C.E., Gangitano, M., Ly, J., Thall, M., Parker, J.A., Pascual-leone,
A., 2002. Correlation of cerebral blood flow and treatment effects of repetitive
transcranial magnetic stimulation in depressed patients. Psychiatry Research:
Neuroimaging 115, 1–14.
Murray, C.J.L., Lopez, A.D., 1997a. Alternative projections of mortality and disability
by cause 1990–2020: global burden of disease study. Lancet 349, 1498–1504.
Murray, C.J.L., Lopez, A.D., 1997b. Global mortality, disability, and the contribution
of risk factors: global burden of disease study. Lancet 349, 1436–1442.
Mykletun, A., Bjerkeset, O., Dewey, M., Prince, M., Overland, S., Stewart, R., 2007. Anx-
iety, depression, and cause-specific mortality: the hunt study. Psychosomatic
Medicine 69, 323–331.
Nahas, Z., Anderson, B.S., Borckardt, J., Arana, A.B., George, M.S., Reeves, S.T., Takacs,
I., 2010. Bilateral epidural prefrontal cortical stimulation for treatment-resistant
depression. Biological Psychiatry 67, 101–109.
Neimat, J.S., Hamani, C., Giacobbe, P., Merskey, H., Kennedy, S.H., Mayberg, H.S.,
Lozano, A.M., 2008. Neural stimulation successfully treats depression in patients
with prior ablative cingulotomy. American Journal of Psychiatry 165, 687–693.
Nestler, E.J., Barrot, M., Dileone, R.J., Eisch, A.J., Gold, S.J., Monteggia, L.M., 2002.
Neurobiology of depression. Neuron 34, 13–25.
Nestler, E.J., Carlezon, W.A., 2006. The mesolimbic dopamine reward circuit in
depression. Biological Psychiatry 59, 1151–1159.
Neumeister, A., Nugent, A.C., Waldeck, T., Geraci, M., Schwarz, M., Bonne, O., Bain,
E.E., Luckenbaugh, D.A., Herscovitch, P., Charney, D.S., Drevets, W.C., 2004. Neu-
ral and behavioral responses to tryptophan depletion in unmedicated patients
with remitted major depressive disorder and controls. Archives of General Psy-
chiatry 61, 765–773.
Nobler, M.S., Oquendo, M.A., Kegeles, L.S., Malone, K.M., Campbell, C., Sackeim, H.A.,
Mann, J.J., 2001. Decreased regional brain metabolism after ect. American Journal
of Psychiatry 158, 305–308.
O’Reardon, J.P., Solvason, H.B., Janicak, P.G., Sampson, S., Isenberg, K.E., Nahas, Z.,
Mcdonald, W.M., Avery, D., Fitzgerald, P.B., Loo, C., Demitrack, M.A., George, M.S.,
Sackeim, H.A., 2007. Efficacy and safety of transcranial magnetic stimulation in
the acute treatment of major depression: a multisite randomized controlled
trial. Biological Psychiatry 62, 1208–1216.
Ongür, D., Ferry, A.T., Price, J.L., 2003. Architectonic subdivision of the human orbital
and medial prefrontal cortex. Journal of Comparative Neurology 460, 425–449.
Ongür, D., Price, J.L., 2000. The organization of networks within the orbital and
medial prefrontal cortex of rats, monkeys and humans. Cerebral Cortex 10,
206–219.
Perlmutter, J.S., Mink, J.W., 2006. Deep brain stimulation. Annual Review of Neuro-
science 29, 229–257.
Pittenger, C., Duman, R.S., 2008. Stress, depression, and neuroplasticity: a conver-
gence of mechanisms. Neuropsychopharmacology 33, 88–109.
Powell, E.W., Leman, R.B., 1976. Connections of the nucleus accumbens. Brain
Research 105, 389–403.
Poynton, A.M., Kartsounis, L.D., Bridges, P.K., 1995. A prospective clinical study of
stereotactic subcaudate tractotomy. Psychological Medicine 25, 763–770.
Price, J.L., Drevets, W.C., 2010. Neurocircuitry of mood disorders. Neuropsychophar-
macology 35, 192–216.
Puigdemont, D., Pérez-Egea, R., Portella, M.J., Molet, J., de Diego-Adeliño, J., Gironell,
A., Radua, J., Gómez-Anson, B., Rodríguez, R., Serra, M., de Quintana, C., Artigas,
F., Alvarez, E., Pérez, V., 2012. Deep brain stimulation of the subcallosal cingulate
gyrus: further evidence in treatment-resistant major depression. International
Journal of Neuropsychopharmacology 15, 121–133.
Quitkin, F.M., Stewart, J.W., McGrath, P.J., Nunes, E., Ocepeck-Welikson, K., Tricamo,
E., Rabkin, J.G., Klein, D.F., 1993. Further evidence that a placebo response to
antidepressants can be identified. American Journal of Psychiatry 150, 566–570.
Rasmussen, K.G., Sampson, S.M., Rummans, T.A., 2002. Electroconvulsive therapy
and newer modalities for the treatment of medication-refractory mental illness.
Mayo Clinic Proceedings 77, 552–556.
Ressler, K.J., Mayberg, H.S., 2007. Targeting abnormal neural circuits in mood and
anxiety disorders: from the laboratory to the clinic. Nature Neuroscience 10,
1116–1125.
Ressler, K.J., Nemeroff, C.B., 2000. Role of serotonergic and noradrenergic systems
in the pathophysiology of depression and anxiety disorders. Depression and
Anxiety 12, 2–19.
Roiser, J.P., Levy, J., Fromm, S.J., Nugent, A.C., Talagala, S.L., Hasler, G., Henn, F.A.,
Sahakian, B.J., Drevets, W.C., 2009. The effects of tryptophan depletion on neu-
ral responses to emotional words in remitted depression supplemental data.
Biological Psychiatry 66, 441–450.
Rück, C., Karlsson, A., Steele, J.D., Edman, G., Meyerson, B.A., Ericson, K., Nyman, H.,
Asberg, M., Svanborg, P., 2008. Capsulotomy for obsessive–compulsive disorder.
Archives of General Psychiatry 65, 914–922.
Ruhé, H.G., Mason, N.S., Schene, A.H., 2007. Mood is indirectly related to serotonin,
norepinephrine and dopamine levels in humans: a meta-analysis of monoamine
depletion studies. Molecular Psychiatry 12, 331–359.
Rush, A.J., Marangell, L.B., Sackeim, H.A., George, M.S., Brannan, S.K., Davis, S.M.,
Howland, R., Kling, M.A., Rittberg, B.R., Burke, W.J., Rapaport, M.H., Zajecka, J.,
Nierenberg, A.A., Husain, M.M., Ginsberg, D., Cooke, R.G., 2005. Vagus nerve
stimulation for treatment-resistant depression: a randomized, controlled acute
phase trial. Biological Psychiatry 58, 347–354.
Rush, A.J., Siefert, S.E., 2009. Clinical issues in considering vagus nerve stimulation
for treatment-resistant depression. Experimental Neurology 219, 36–43.
Rush, A.J., Thase, M.E., 1997. Strategies and tactics in the treatment of chronic depres-
sion. Journal of Clinical Psychiatry 58, 14–22.
Rush, A.J., Thase, M.E., Dube, S., 2003. Research issues in the study of difficult-to-treat
depression. Biological Psychiatry 53, 743–753.
Sadock, B., Sadock, V., 2007. Kaplan & Sadock’s Synopsis of Psychiatry: Behavioral
Sciences/Clinical Psychiatry, 10th ed. Lippincott Williams & Wilkins Publishers,
Philadelphia, PA, USA.
Saleem, K.S., Kondo, H., Price, J.L., 2008. Complementary circuits connecting the
orbital and medial prefrontal networks with the temporal, insular, and oper-
cular cortex in the macaque monkey. Journal of Comparative Neurology 506,
659–693.
Salin, P., Manrique, C., Forni, C., Goff, L.K.-l., 2002. High-frequency stimulation of
the subthalamic nucleus selectively reverses dopamine denervation-induced
cellular defects in the output structures of the basal ganglia in the rat. Journal
of Neuroscience 22, 5137–5148.
Sartorius, A., Kiening, K.L., Kirsch, P., von Gall, C.C., Haberkorn, U., Unterberg, A.W.,
Henn, F.A., Meyer-Lindenberg, A., 2010. Remission of major depression under
deep brain stimulation of the lateral habenula in a therapy-refractory patient.
Biological Psychiatry 67, e9–e11.
Schlaepfer, T.E., Bewernick, B., Kayser, S., Lenz, D., 2011. Modulating affect, cogni-
tion, and behavior – prospects of deep brain stimulation for treatment-resistant
psychiatric disorders. Frontiers in Integrative Neuroscience 5, 29.
Schlaepfer, T.E., Cohen, M.X., Frick, C., Kosel, M., Brodesser, D., Axmacher, N., Joe, A.Y.,
Kreft, M., Lenartz, D., Sturm, V., 2008. Deep brain stimulation to reward circuitry
alleviates anhedonia in refractory major depression. Neuropsychopharmacol-
ogy 33, 368–377.
Schulte, T., Brecht, S., Herdegen, T., Illert, M., Mehdorn, H.M., Hamel, W., 2006. Induc-
tion of immediate early gene expression by high-frequency stimulation of the
subthalamic nucleus in rats. Neuroscience 138, 1377–1385.
Scopinho, A.A., Scopinho, M., Lisboa, S.F., Correa, F.M.D.A., Guimarães, F.S., Joca,
S.R.L., 2010. Acute reversible inactivation of the ventral medial prefrontal cor-
tex induces antidepressant-like effects in rats. Behavioural Brain Research 214,
437–442.
Seminowicz, D.A., Mayberg, H.S., Mcintosh, A.R., Goldapple, K., Kennedy, S., Segal, Z.,
Rafi-Tari, S., 2004. Limbic–frontal circuitry in major depression: a path modeling
metanalysis. Neuroimage 22, 409–418.
Servello, D., Porta, M., Sassi, M., Brambilla, A., Robertson, M.M., 2008. Deep brain
stimulation in 18 patients with severe gilles de la tourette syndrome refractory
to treatment: the surgery and stimulation. Journal of Neurology, Neurosurgery
and Psychiatry 79, 136–142.
Sesia, T., Bulthuis, V., Tan, S., Lim, L.W., Vlamings, R., Blokland, A., Steinbusch, H.W.M.,
Sharp, T., Visser-Vandewalle, V., Temel, Y., 2010. Deep brain stimulation of
the nucleus accumbens shell increases impulsive behavior and tissue levels of
dopamine and serotonin. Experimental Neurology 225, 302–309.
Shen, K.-Z., Zhu, Z.-T., Munhall, A., Johnson, S.W., 2003. Synaptic plasticity in rat sub-
thalamic nucleus induced by high-frequency stimulation. Synapse 50, 314–319.
Shumake, J., Gonzalez-Lima, F., 2003. Brain systems underlying susceptibility to
helplessness and depression. Behavioral and Cognitive Neuroscience Reviews
2, 198–221.
Slattery, D.A., Neumann, I.D., Cryan, J.F., 2011. Transient inactivation of the
infralimbic cortex induces antidepressant-like effects in the rat. Journal of Psy-
chopharmacology 25, 1295–1303.
Slotema, C.W., Blom, J.D., Hoek, H.W., Sommer, I.E.C., 2010. Should we expand
the toolbox of psychiatric treatment methods to include repetitive transcra-
nial magnetic stimulation (rtms)? A meta-analysis of the efficacy of rtms in
psychiatric disorders. Journal of Clinical Psychiatry 71, 873–884.
Sturm, V., Lenartz, D., Koulousakis, A., Treuer, H., Herholz, K., Klein, J.C., Klosterkötter,
J., 2003. The nucleus accumbens: a target for deep brain stimulation in obsessive-
compulsive- and anxiety-disorders. Journal of Chemical Neuroanatomy 26,
293–299.
Swaab, D.F., Bao, A.-M., Lucassen, P.J., 2005. The stress system in the human brain in
depression and neurodegeneration. Ageing Research Reviews 4, 141–194.
Takagishi, M., Chiba, T., 1991. Efferent projections of the infralimbic (area 25) region
of the medial prefrontal cortex in the rat. An anterograde tracer pha-l study.
Brain Research 566, 26–39.
Temperli, P., Ghika, J., Villemure, J.G., Burkhard, P.R., Bogousslavsky, J., Vingerhoets,
F.J., 2003. How do parkinsonian signs return after discontinuation of subthalamic
dbs? Neurology 60, 78–81.
Thase, M.E., Rush, A.J., 1997. When at first you don’t succeed: sequential strate-
gies for antidepressant nonresponders. Journal of Clinical Psychiatry 58,
23–29.
The Deep-brain Stimulation for Parkinson’s Disease Study Group, 2001. Deep-
brain stimulation of the subthalamic nucleus or the pars interna of the globus
pallidus in Parkinson’s disease. The New England Journal of Medicine 345,
956–963.
The UK ECT Review Group, 2003. Efficacy and safety of electroconvulsive therapy
in depressive disorders: a systematic review and meta-analysis. Lancet 361,
799–808.
Tremblay, L.K., Naranjo, C.A., Graham, S.J., Herrmann, N., Mayberg, H.S., Hevenor, S.,
Busto, U.E., 2005. Functional neuroanatomical substrates of altered reward pro-
cessing in major depressive disorder revealed by a dopaminergic probe. Archives
of General Psychiatry 62, 1228–1236.
Trivedi, M.H., Fava, M., Wisniewski, S.R., Thase, M.E., Quitkin, F., Warden, D., Ritz, L.,
Nierenberg, A.A., Lebowitz, B., Biggs, M.M., Luther, J.F., Shores-Wilson, K., Rush,
A.J., 2006. Medication augmentation after the failure of ssris for depression. New
England Journal of Medicine 354, 1243–1252.
 R.J. Anderson et al. / Neuroscience and Biobehavioral Reviews 36 (2012) 1920–1933
Tye, S.J., Miller, A.D., Blaha, C.D., 2009. Differential corticosteroid receptor regulation
of mesoaccumbens dopamine efflux during the peak and nadir of the circadian
rhythm: a molecular equilibrium in the midbrain? Synapse 63, 982–990.
Van Laere, K., Nuttin, B., Gabriels, L., Dupont, P., Rasmussen, S., Greenberg, B.D.,
Cosyns, P., 2006. Metabolic imaging of anterior capsular stimulation in refractory
obsessive–compulsive disorder: a key role for the subgenual anterior cingulate
and ventral striatum. Journal of Nuclear Medicine 47, 740–747.
Velasco, F., Velasco, M., Jiménez, F., Velasco, A.L., Salin-pascual, R., 2005. Neu-
robiological background for performing surgical intervention in the inferior
thalamic peduncle for treatment of major depression disorders. Neurosurgery
57, 439–448.
Vertes, R.P., 2004. Differential projections of the infralimbic and prelimbic cortex in
the rat. Synapse 51, 32–58.
Vidailhet, M., Vercueil, L., Houeto, J., Krystkowiak, P., Benabid, A.L., Cornu, P.,
Lagrange, C., Montcel, S.T.D., Dormont, D., Grand, S., Blond, S., Detante, O., Pillon,
B., Ardouin, C., Agid, Y., Destée, A., Pollak, P., 2005. Bilateral deep-brain stimula-
tion of the globus pallidus in primary generalized dystonia. New England Journal
of Medicine 352, 459–467.
Warden, D., Rush, A.J., Trivedi, M.H., Fava, M., Wisniewski, S.R., 2007. The star*d
project results: a comprehensive review of findings. Current Psychiatry Reports
9, 449–459.
1933
Watson, D., Clark, L.A., 1988. Development and validation of brief measures of pos-
itive and negative affect: the panas scales. Journal of Personality and Social
Psychology 6, 1063–1070.
Williams, D.J., Crossman, A.R., Slater, P., 1977. The efferent projections of the nucleus
accumbens in the rat. Brain Research 130, 217–227.
Williams, L.J., Brennan, S.L., Henry, M.J., Berk, M., Jacka, F.N., Nicholson, G.C., Kotow-
icz, M.A., Pasco, J.A., 2011. Area-based socioeconomic status and mood disorders:
cross-sectional evidence from a cohort of randomly selected adult women.
Maturitas 69, 173–178.
Winter, C., Vollmayr, B., Djodari-Irani, A., Klein, J., Sartorius, A., 2011. Pharmaco-
logical inhibition of the lateral habenula improves depressive-like behavior in
an animal model of treatment resistant depression. Behavioural Brain Research
216, 463–465.
World Health Organisation, 2008. The Global Burden of Disease 2004 Update. World
Health Organisation, Geneva, Switzerland.
Wulsin, L.R., Vaillant, G.E., Wells, V.E., 1999. A systematic review of the mortality of
depression. Psychosomatic Medicine 61, 6–17.
Yang, L.-M., Hu, B., Xia, Y.-H., Zhang, B.-L., Zhao, H., 2008. Lateral habenula
lesions improve the behavioral response in depressed rats via increasing
the serotonin level in dorsal raphe nucleus. Behavioural Brain Research 188,
84–90.