Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders.

Neuroscience and Biobehavioral Reviews 49 (2015) 32–42

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Review

Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders Máté D. Döbrössy ∗ , Luciano L. Furlanetti, Volker A. Coenen Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg-Medical Center, Germany

a r t i c l e

i n f o

Article history: Received 19 March 2014 Received in revised form 20 November 2014 Accepted 21 November 2014 Available online 9 December 2014 Keywords: Pre-clinical studies Electrical stimulation Deep brain stimulation Medial forebrain bundle Psychiatric disorders Depression

a b s t r a c t Modulating neuronal activity by electrical stimulation has expanded from the realm of motor indications into the field of psychiatric disorders in the past 10 years. The medial forebrain bundle (MFB), with a seminal role in motor, reward orientated and affect regulation behaviors, and its afferent and efferent loci, have been targeted in several DBS trials in patients with psychiatric disorders. However, little is known about the consequences of modulating the MFB in affective disorders. The paper reviews the relevant preclinical literature investigating electrical stimulation of regions associated with the MFB in the context of several models of psychiatric disorders, in particular depression. The clinical data is promising but limited, and pre-clinical studies are essential for improved understanding of the anatomy, the connectivity, and the consequences of stimulation of the MFB and regions associated with the neurocircuitry of psychiatric disorders. Current data suggests that the MFB is at a “privileged” position on this circuitry and its stimulation can simultaneously modulate activity at other key sites, such as the nucleus accumbens, the ventromedial prefrontal cortex or the ventral tegmental area. Future experimental work will need to shed light on the anti-depressive mechanisms of MFB stimulation in order to optimize clinical interventions. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrical stimulation of the MFB: intra-cranial self-stimulation (ICSS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MFB and the neurocircuitry of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early pre-clinical experience of chronic bilateral MFB DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DBS in animal models of psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Obsessive–compulsive disorder (OCD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Within the last decade electrical stimulation has been applied to patients with diverse psychiatric diseases, including for

∗ Corresponding author at: Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg-Medical Centre, Breisacher Str. 64, 79106 Freiburg, Germany. Tel.: +49 761 270 50360. E-mail address: [email protected] (M.D. Döbrössy). http://dx.doi.org/10.1016/j.neubiorev.2014.11.018 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

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treatment resistant major depressive disorder (Schlaepfer et al., 2010; Schlaepfer and Lieb, 2005). There is no general consensual hypothesis concerning the neurocircuitry of depression apart from the “network-model” which suggests that the multiple facets of the syndrome can arise from dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry (Mayberg, 1997). The lack of a key identified region is reflected in the DBS trials so far: there have been nearly as many targets as studies. A recent clinical trial stimulated the supero-lateral branch of the medial forebrain bundle (slMFB), a structure that projects and interacts with all the previously selected targets: the nucleus accumbens,

M.D. Döbrössy et al. / Neuroscience and Biobehavioral Reviews 49 (2015) 32–42

subgenual cingulate cortex, and the ventral capsule/ventral striatum (Anderson et al., 2012; Bewernick et al., 2012; Lozano et al., 2012; Malone et al., 2009). slMFB stimulation, perhaps by modulating all the other previously selected downstream targets, produced rapid and chronic anti-depressive effects at low stimulation intensity (Coenen et al., 2013; Schlaepfer et al., 2013). The rodent MFB bilaterally stretches from the ventral tegmental area (VTA) in the midbrain to olfactory tubercle in the forebrain, and contains an array of ascending and descending, mostly unmyelinated short nerve fibers. The complexity of this structure is underlined by literature describing around 50 fiber subcomponents and up to 13 different neurotransmitters associated with the MFB (Geeraedts et al., 1990a,b; Nieuwenhuys et al., 1982; Veening et al., 1982). Novel regulatory elements and components of the bundle have been described recently (Bourdy and Barrot, 2012). Due to its position, the MFB has often, but incorrectly been thought of as a synonym for the Lateral Hypothalamic Area (LHA), as large parts of the bundle are imbedded in the LHA. Indeed, neuroanatomical data suggests that many MFB efferent fibers do not passively transit the LHA, but send collaterals and synaptic contacts to this structure before exiting the LHA toward a variety of their target nuclei. The MFB’s intricate relationship with the LHA, and as a substrate of neural transmission between midbrain structures and key basal ganglia and frontal cortical areas, explains why manipulations of the bundle results in diverse motoric and non-motoric impairments. Early electrolytic lesion in the 1950s – destroying indiscriminately both fibers of passage and cell bodies – of the MFB/LHA gave rise to aphagic and adipsic rats which highlighted the LHA’S role in the regulation of food and drink intake (Anand and Brobeck, 1951; Teitelbaum and Epstein, 1962; Teitelbaum and Stellar, 1954). The development of these ideas coincided in time with the rise of intracranial self-stimulation (ICSS) of the MFB that lead to the persisting association of this structure with limbic areas involved in reward, hedonia, motivation, and addiction (Olds and Milner, 1954). The development of more sophisticated neuroanatomical understanding of the MFB in the 60s and 70s, particularly the ability to immunohistochemically map out and selectively lesion the dopaminergic system (Dahlström and Fuxe, 1964; Ungerstedt, 1970), lead to the final “layer” of functions assigned to the bundle, namely motor control, learning and emotional response selection (Björklund and Dunnett, 2007; Schultz, 2013, 2007). The aim of the current review is to consider the validity of the medial forebrain bundle (MFB) as a stimulation target in psychiatric disorders by examining the neurocircuitry implicated in the disease; furthermore, to examine the early pre-clinical evidence and relevance of ICSS studies to current DBS studies of animal models of psychiatric disorders such as addiction, obsessive–compulsive disorder and depression. The review also considers the viability of bilateral, chronic and continuous high-frequency stimulation of the MFB in rodents, and discusses what areas will need to be addressed in the future to accelerate our neurobiological and mechanistic understanding of this promising neuromodulation strategy. 2. Electrical stimulation of the MFB: intra-cranial self-stimulation (ICSS) The clinical use of electrical stimulation to map out deep brain structures and guide stereotactic functional operations came into use in the 40s and 50s (Spiegel et al., 1947; Spiegel and Wycis, 1952) with the first stimulation-based therapeutic applications carried out in the 60s (Hassler, 1961; Hassler et al., 1960). The electrical modulation of neural circuit activity in brain structures suspected to play a role in disease pathology lead to the symptomatic treatment using this approach in Parkinson’s, Tremor and Dystonia patients starting from the 80s, and to trials

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in psychiatric disorders over the last decade (Krack et al., 2010; Lozano et al., 2012; Miocinovic et al., 2013; Schlaepfer et al., 2013, 2011). The development of electrical stimulation studies in basic, experimental research took a different path. Over the last sixty years, two principal types of stimulation approaches of the MFB have emerged: the first five decades have been dominated by animal models ICSS; and the last 10 years, the topic of the current review, saw the rise of pre-clinical exploration of DBS. In the early 50s Olds and Milner observed that a brief electrical pulse delivered into deep brain structures via an electrode increased the likelihood of the rats revisiting the zone that coincided temporally with the stimulus. In a follow-up study animals with electrodes implanted into areas associated with the lateral hypothalamic area were shown to self-administer ad libitum electrical stimulation by lever pressing in a Skinner box (Olds and Milner, 1954). The seminal investigation pointed out structures where self-stimulation had either neutral (caudate nucleus), or aversive behavior effects (medial lemniscus). Crucially, the paper was the first of many to discuss appetitive/reward/motivational behavior in terms of neural substrates in the brain along the MFB axis, particularly in the septum, the cingulate, and tegmentum areas. Indeed, the seminal Olds and Milner experiment opened the way for ICSS-led research into the Lateral Hypothalamic Syndrome, and later on into neurobiology of Addictive Disorders (Koob and Volkow, 2010; Wise, 2002, 1996a, 1996b). 3. MFB and the neurocircuitry of depression Olds and Milners’ ICSS of the MFB – and the studies it spurred – was principally in the context of addiction, but today it is accepted that there are significant overlaps in the neurocircuitry in various psychiatric diseases (Russo and Nestler, 2013). Depression is not a single disease, but a syndrome that covers a multitude of symptoms, and this is mirrored by the different nuclei and their associated neurocircuitry that are thought to be involved. The pathways involved in mood disorders have been the subject of many extensive papers (Nestler et al., 2002a,b; Nestler and Carlezon, 2006; Russo and Nestler, 2013) and is beyond the scope of the current review. The combination of imaging studies, post-mortem methods, and animal models have implicated structures associated with the MFB in depression such as the nucleus accumbens (NAC), the cingulate gyrus, the septum, the hippocampus, the amygdala, the pallidum, the medial thalamus, the hypothalamus, the VTA, the lateral habenula, or the periaqueductal gray (Price and Drevets, 2012). While focus in the past has been on aspects of the prefrontal cortex and the hippocampus, the pathways within the MFB connecting the VTA with the NAC, the mesolimbic dopaminergic (DA), and the VTA with the pre-frontal cortex, the mesocortical DA projection, have emerged as central substrates in the etiology of several psychiatric diseases, including depression. Anhedonia, the reduction of reward sensation or pleasure, a typical symptom in clinical depression as well as in the animal models used, is thought to be rooted in the deregulation of the VTA to NAC pathway (Russo and Nestler, 2013). Clinical data backs this up showing reduced activity in the NAC in depressed patients (Mayberg et al., 2000), as do certain animal models, for example the Flinders Sensitive Line (FSL) rats that have been selectively breed to express depression-like phenotypes (Friedman et al., 2005; Neumann et al., 2011). The VTA is a heterogeneous structure containing GABAergic and Glutaminergic neurons, but its the DAergic projections, making up around 60% of the efferents, whose phasic firing encode the reward signal at the level of the NAC (Dobi et al., 2010; Russo and Nestler, 2013; Schultz, 2013). The MFB, in particular the mesolimbic and the mesocortical DAergic pathways that pass through the bundle, is also considered to be the neural substrate for the so called SEEKING system, one

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of several hard-wired primary affective systems that also include, e.g. LUST, RAGE, and PLAY (Alcaro and Panksepp, 2011; Coenen et al., 2011b; Ikemoto and Panksepp, 1999; Panksepp, 2011, 2010). Within the conceptual framework of affective neuroscience, the SEEKING system ensures positive emotional and euphoric behaviors that support exploration, and controls appetitive learning (Panksepp, 1998). It is complimentary and overlapping, but not identical, with the “reward system”, as its primary function goes beyond reinforcement of pleasurable experiences: it drives activities essential for survival, and it serves as the neural substrate for emotions such as curiosity, excitement, and desire, for example (Panksepp, 2010). It is proposed that key symptoms observed in clinical depression and in experimental models, such as anhedonia, helplessness and hopelessness, are the result of the hypo-activity of the SEEKING system, and attempts at modulating this pathway offers a viable therapeutic strategy (Alcaro and Panksepp, 2011; Coenen et al., 2011b). 4. Early pre-clinical experience of chronic bilateral MFB DBS The identification of the MFB in its own right as an important future clinical target for neuromodulation in depression (Coenen et al., 2011b; Schlaepfer et al., 2013) necessitates further experimental investigation; however, the experimental stimulation of the MFB requires certain preconceived ideas to be revisited. On the back of the Olds and Milner work (Olds, 1963; Olds and Milner, 1954) came a series of influential studies suggesting that chronic MFB stimulation is not a viable option as it is detrimental to the animals’ health. Routtenberg and colleagues’ data suggested that animals with MFB electrodes, when given the choice between self-stimulation or food, ignored the food even when this eventually meant self-starvation (Routtenberg, 1968; Routtenberg and Kuznesof, 1967; Routtenberg and Lindy, 1965). The results highlighted the power of ICSS, pointing out that the perceived reward value of the MFB stimulation even outweighed the animals’ basic survival instinct of self-preservation by feeding itself. Although Routtenberg’s works are convincing within the context they were performed in, there are crucial differences between “ratled” ICSS and “investigator-led” DBS experimental designs. In the former, for example, there is an inevitable conditioned lever pressstimulation-reward association; in DBS studies the investigator is in control of the stimulation parameters and this decouples the stimulation from the rat’s action or the context. Furthermore, Routtenberg limited food availability during the period of ICSS, but the self-starvation scenario would probably not have arisen had the animals had ad libitum food access. Considering the encouraging clinical data following MFB stimulation in depressed patients (Schlaepfer et al., 2013), but keeping the Routtenberg studies in mind, the authors of this review (MDD, LLF, VAC) investigated the feasibility of bilateral, chronic and continuous bilateral DBS in the MFB in rodents. Bipolar electrodes were implanted into both MFBs of Sprague-Dawley rats, external to the VTA, but targeting projections originating from the A10 midbrain ascending dopaminergic neurons. The animals received continuous HFS up to 6 weeks with regular weight monitoring and intermittent behavioral assessment. The results showed that bilateral MFB stimulation (frequency 130 Hz, pulse width 100 ␮s, average current 290 ␮A) has a robust, reproducible, temporary and mild impact on welfare as shown by the rapid weight decrease, stabilization, and subsequent weight gain despite of the ongoing, chronic electrical stimulation. A short-lasting (24–72 h) increase in the explorative, searching and SEEKING type of behavior in the MFB stimulated animals is consistent with the proposed role of this structure both in healthy individuals and in clinical depression (Alcaro and Panksepp, 2011; Coenen et al., 2012a,b,

2011b). Importantly, the study demonstrated two critical points: firstly, that the continuous and chronic bilateral stimulation of the MFB in rodents is not detrimental to the animal’s health and can be developed as a platform to investigate the effects of neuromodulation in validated experimental models of depression. Secondly, MFB stimulation resulted in neuronal activation in infralimbic and prelimbic cortices, in NAC, and the dorsolateral thalamus, as shown by assessing c-fos expression in these key areas implicated in the neurocircuitry of depression. This confirms that MFB stimulation recruits multiple afferent and efferent connections which can result in the modification of a several targets, inducing short and long-term adaptations in local and distal neuronal activity. 5. DBS in animal models of psychiatric disorders DBS in animal models via intracerebral electrode(s) has only been carried out for about 15 years (Gubellini et al., 2009; Hamani and Nobrega, 2012; Tan et al., 2010). As the principal indication for DBS is Parkinson’s disease (PD), it is not surprising that the majority of the pre-clinical studies deal with the consequence of STN stimulation in rodent models of PD (not reviewed here). The pre-clinical models selected below are from three psychiatric disorders – addiction, obsessive–compulsive disorder and depression – have distinct symptoms but also dysfunctional neural substrates that overlap at key structures along the fronto-striatal or limbic pathways. Interestingly, little is known about targeting the MFB directly as an entity in models of psychiatric disorders; however, regions associated with the MFB pathways such as the VTA, the NAC, the ventromedial prefrontal cortex (vmPFC), the ventral prelimbic cortex (vPL), the lateral habenula (LHb) have been subject to investigation in all model disorders (Fig. 1). The NAC, a key component of the MFB, has been a clinical (and pre-clinical) stimulation target in all three cited psychiatric disorders. The VTA sends dopaminergic projections via the MFB to the NAC and via separate pathways to the prefrontal cortex; hyper or hypoactivity of this pathway is likely to be partially responsible for symptoms observed in several psychiatric disorders. In animal models, the optogenetic recruitment of VTA dopamine neurons altered the neural encoding of depression-related behaviors in the downstream NAC (Tye et al., 2013). Furthermore, the optogenetic inhibition of the mesolimbic VTA–NAC projection, rapidly induced resilience, whereas inhibition of the mesocortical VTA–mPFC projection promoted susceptibility in mice (Chaudhury et al., 2013). These results are relevant in the context of models of depression, but also for addiction and OCD. It is likely that DBS of the MFB recruits descending glutamatergic excitatory projections from the prefrontal cortex and NAC to the VTA and thereby modulates the dopamine system, key in both reward and motivational behaviors. Below we describe a selection of seminal pre-clinical studies investigating the effects and potential mechanisms of DBS in animal models of addiction, OCD, and depression (Table 1). 5.1. Addiction The original findings of Olds and Milner (Olds, 1963; Olds and Milner, 1954) laid the foundations that associated addiction research with electrical stimulation in the brain. However, whereas ICSS establishes a compulsion to seek a reward permitting the investigation of the mechanisms and circuitry involved, DBS has been studied as a potential clinical and therapeutic option in treating substance abuse and addiction (Kuhn et al., 2013; Voges et al., 2013). Two principal regions, the subthalamic nucleus (STN) and the NAC, implicating different pathways and rationale, have emerged as the targets with the most therapeutic relevance.


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Fig. 1. Target regions of stimulation in pre-clinical models of psychiatric disorders focusing on the medial forebrain bundle (MFB). The mesolimbic and mesocortical dopaminergic pathway (green circles), passing through the MFB, play a crucial role in health and disease, including in the pathology of psychiatric disorders. Serotonergic projections (in red) originating from the dorsal raphe nucleus also pass through the MFB. Over the recent years several regions associated with the MFB have been targeted in pre-clinical studies (shaded label), mainly in depression, OCD, and addiction. OB, olfactory bulb; OT, olfactory tubercle; vmPFC, ventromedial prefrontal cortex; CC, corpus callosum; Hipp, hippocampus; NAC, nucleus accumbens; DMT/LHb, dorsal-medial thalamus and lateral habenula; LH, lateral hypothalamus; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; VTA, ventral tegmental area; CB, cerebellum; DRN, dorsal raphe nucleus.

Clinically, STN DBS given to Parkinson’s patients has been observed not only to reduce the classical PD symptoms but also decrease medication abuse or impulse control disorders arising from dopamine dysregulation and long-term dopamine replacement (Witjas et al., 2012, 2005). Animal studies have substantiated the role STN might play in addiction by showing that lesioning the structure – classically associated with movement control and action selection – produces reduced motivation for cocaine intake but leaving the salient quality of food pellets intact (Baunez et al., 2005). Bilateral DBS in the rodent STN (bipolar, 130 Hz, 60 ␮s, ≤130 ␮A) confirmed these findings showing that stimulation can differentially affect reward contingencies by reducing lever pressing for i.v. cocaine self-administration but increasing the operant response for conventional sugar pellets (Rouaud et al., 2010). However, bilateral STN DBS (bipolar, 130 Hz, 60 ␮s, ≤150 ␮A) has also shown to partially inhibit dorsal raphe serotonergic neuron firing resulting in depressive-like behavioral phenotype in rodents (Temel et al., 2007). Another DBS target in models of addiction has been the NAC. Given our understanding of the neurocircuitry of addiction, and the involvement of the NAC in the process of reinforcement, the rationale for the stimulation of this target is more evident: blocking or disrupting dopaminergic transmission from the VTA could reduce or eliminate the reinforcing effects of the substance of abuse. Furthermore, as NAC stimulation in models of addiction and MFB stimulation in depression probably tap into related pathways, it is important to examine the evidence to identify common putative mechanisms. Unilaterally stimulating (bipolar, 130 Hz, 210 ␮s, 200–500 ␮A) the core of the NAC was shown to be sufficient to avoid morphine induced conditioned place preference, albeit, the animals demonstrated side effects such as muscular rigidity, and hypotonia, which might explain some of the phenotype (Liu et al., 2008). In a study looking at maintenance of addictive behavior following bilateral NAC shell stimulation (bipolar, 160 Hz, 60 ␮s, 150 ␮A), the authors reported a strong attenuation of the cocaine seeking behavior (Vassoler et al., 2008). Follow-up studies confirmed the primary role of the shell, and not the core, in this phenomenon and propose that the NAC stimulation activates cortical inhibitory interneurons that modulate shell activity. Similarly to the STN DBS, NAC shell DBS is specific to opiate based reinforcers and does not have an impact

on “natural” rewards like sugar (Pierce and Vassoler, 2013; Vassoler et al., 2013, 2008). Furthermore, it is the lateral aspect of the NAC shell that is associated with reward signaling, and this area receives input from the rostrolateral VTA (Roeper, 2013). Extrapolating to MFB DBS, it would seem that modulating this sub-pathway of the mesolimbic circuitry in models of depression could be crucial to reduce anhedonic symptoms. The limited effect on cocaine abuse was also reported following lateral hypothalamus (LH) and prefrontal cortex (PFC) stimulation; furthermore, it was demonstrated whereas repeated cocaine exposure leads to increase of GluR1 in the VTA and the NAC (Lu et al., 2003), LH and PFC DBS (monopolar, 20/100 Hz, 100 ␮s, 200–400 ␮A) resulted in the down regulation of this receptor in these key structures (Levy et al., 2007). A return to normal GluR1 levels in the VTA, accompanied by inhibition of cocaine seeking behavior was described following LHb stimulation (bipolar, 10/100 Hz, 500 ␮s, 200 ␮A) as well (Friedman et al., 2010); however, contrary to the DBS of other targets describe above, LHb stimulation (bipolar, 10/100 Hz, 500 ␮s, 200 ␮A) also reduced the self-administration of sucrose, a “natural” reinforcer (Friedman et al., 2011). Reflecting stimulation induced changes at the receptor level, NAC core DBS has also reduced glutamate (and increased GABA) release in the VTA which is thought to result in the reduction of activity in the mesocorticolimbic pathway (Yan et al., 2013). Changes in the glutamate/GABA balance in the VTA following MFB DBS are not known, but key depression symptoms are associated with the hypo-activity of the mesolimbic dopaminergic system, which is regulated by these two transmitters (Bourdy and Barrot, 2012). If MFB DBS is to relieve some of these symptoms, the prediction that needs to be tested is whether MFB stimulation increases glutamate and reduces GABA levels in the VTA, thereby increasing activity of the VTA dopamine output. 5.2. Obsessive–compulsive disorder (OCD) OCD in patients is characterized by insuppressible, repetitive and intrusive thoughts and actions that pathologically disrupt everyday life. In patients, OCD has been associated with metabolic hyperactivity in the striatum, the medial thalamus, and in the orbitofrontal cortex (OFC) (Swedo et al., 1989), and successful

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Table 1 Summary of key pre-clinical DBS studies in depression, addiction, and OCD. In the “Conditions” column, the parameters indicate the frequency (Hz), the pulse width (␮s), and the current (␮A) used for the stimulation, respectively. vmPFC, ventromedial prefrontal cortex; VTA, ventral tegmental area; NAC, nucleus accumbens; WMF, white matter fiber; LHb, lateral habenula; STN, subthalamic nucleus; LH, lateral hypothalamus; PFC, prefrontal cortex; BL/UL, bi- or unilateral stimulation; BP/MP, bi- or monopolar electrodes; SA, self-administration; CMS, chronic mild stress; DLP, depressive-like phenotype; FSL, Flinders Sensitive Line; SD, Sprague-Dawley; LE, Long–Evans; FST, forced swim test; HAB, high anxiety behavior; DA, dopamine; NA, noradrenalin; DRN, dorsal raphe nucleus; OFC, orbitofrontal cortex.

Depression

DBS target

Reference

Conditions

Comments

vmPFC

Hamani and Nóbrega (2010), Hamani et al. (2010, 2012) Rea et al. (2013)

BL, MP, 130 Hz, 90 ␮s, 100–300 ␮A 8 h/d up to 14 d BL, MP, 130 Hz, 100 ␮s, 300 ␮A 30 min/d up to 14 d UL, BP, 160 Hz, 60 ␮s, 150 ␮A 5 h/d for 7 d

CMS model/male SD rats Reversed DLP 5-HT implicated in relief FSL rats Reversed some DLP Chronic social defeat stress model; male mice Reversed phenotype; neuroplastic adaptation in 5-HT system CMS model/male SD rats Reversed anhedonic-like behavior, no effect on FST Male Wistar–Kyoto rats Reduced anxiety, increased exploration, increased DA and NA in PFC Male HAB mice Reversed DLP and anxiolytic phenotype Naïve male SD rats Similar antidepressant-like effects at all 3 sites despite distinct impact in regional brain activity Male FSL rats Reversed DLP; increased levels of prefrontal BDNF; restored normal VTA firing pattern CMS model/male Wistar rats Reduced DLP, increased DA/NA/5HT in blood serum and hippocampus Naïve SD rats Inhibition of DRN 5HT activity and induction of DLP

vmPFC vmPFC

Veerakumar et al. (2014)

NAC

Gersner et al. (2010)

NAC

Falowski et al. (2011)

NAC

Schmuckermair et al. (2013) Hamani et al. (2014)

UL, BP, 130 Hz, 60 ␮s, 100 ␮A 1 h/d for 7 d UL, MP, 130 Hz, 90 ␮s, 100 ␮A 4 h day 1; 2 h day 2

VTA

Friedman et al. (2008, 2009b, 2012)

UL, BP, 10 Hz, 1 ms, 300 ␮A 20 min prior test

LHb

Meng et al. (2011)

STN

Temel et al. (2007)

UL, BP, 150 Hz, 300 ␮s, 80–100 ␮A 7–28 d continuous BL, BP, 10–130 Hz, 60 ␮s, 3–150 ␮A Up to 3 min

STN

Rouaud et al. (2010)

NAC core

Liu et al. (2008)

NAC shell

Pierce and Vassoler (2013), Vassoler et al. (2008, 2013) Levy et al. (2007)

vmPFC/NAC/WMF

Addiction

LH/PFC

OCD

LHb

Friedman et al. (2010, 2011)

NAC

McCracken and Grace (2007, 2009)

UL, MP, 20 Hz, 200 ␮s, 400 ␮A 10 min/d for 10 d UL, BP, 120 Hz, 200 ms, 2 V 3 h/d or 14 d continuous

BL, BP, 130 Hz, 60 ␮s, 50–130 ␮A Prior/during testing UL, BP, 130 Hz, 210 ␮s, 200–500 ␮A 15 min/h for 3 h up to 10 d BL, BP, 160 Hz, 60 ␮s, 150 ␮A During 2 h testing

Naïve male LE rats Reduced self-administration for cocaine but not for sugar Naïve SD rats Avoided morphine induced conditioned place preference, but produced motor deficits Naïve male SD rats Attenuation of cocaine seeking behavior

BL, MP, 20 and 100 Hz, 100 ␮s, 200–400 ␮A 30 min/d for 10 d UL, BP, 10 Hz and 100 Hz, 500 ␮s, 200 ␮A 15 min

Naïve male SD rats Down regulation of GluR1 in VTA/NAC

UL, BL, 10 or 130 Hz, 100 ␮s, 200 ␮A 3 × 30 min sessions

treatments have shown to reduce metabolic activity in these areas (Van Laere et al., 2006). In clinical trials with more than 5 patients, DBS has been tested by targeting the ventral capsule/ventral striatum (Greenberg et al., 2010), the STN (Mallet et al., 2008), the anterior limb of the internal capsule (Huff et al., 2010; Nuttin et al., 1999), and the NAC (Denys et al., 2010; Figee et al., 2013). Interestingly, a recent publication points out that many clinical trials that reported to have targeted the NAC, actually stimulated the ventral internal capsule (Munckhof et al., 2013). Nevertheless, the response rates, independent of the target, ranged between 40 and 60% (Lipsman et al., 2013). The outcome suggests that, similar to other neuropsychiatric disorders, modulation of the underlying circuit considered to be involved in OCD – the frontal subcortical circuit encompassing the dorsolateral, orbitofrontal, and the anterior cingulate cortex projections to the ventral striatum/NAC, and further downstream via the globus pallidus, the substantia nigra and the thalamus (Pauls et al., 2014) – can provide some symptomatic relief. A more specific explanation has been put forward by Figee and colleagues who, in an elegant clinical study, argue that the NAC

Naïve male SD rats Down regulation of GluR1 in VTA, reduction in cocaine seeking and sucrose SA Combined 10/100 Hz stimulation best Naïve male SD rats Reduced neural activity in OFC

stimulation of OCD patients induced improvement in symptoms is based on increased striatal dopamine release (Figee et al., 2014). Although this needs to be verified, it is proposed that the rapid clinical improvement seen in the slMFB stimulated treatment resistant depressive patients are also dopamine related, and possible via a similar mechanism: either a direct effect on local dopamine release or an indirect effect on the mesocortical pathway activity mediated by changes in the glutamate/GABA balance at the level of the VTA (Schlaepfer et al., 2014, 2013). It is difficult to test and translate these clinical observations into preclinical studies as currently available animal models of OCD are very diverse and often lack construct validity (Camilla d’Angelo et al., 2013). Nevertheless, pre-clinical models are essential to promote our understanding of possible mechanisms underpinning symptoms. Recently, in a genetic model of “compulsive behavior”, optogenetic stimulation of inhibitory striatal neurons were shown to modulate corticostriatal activity to suppress the maladaptive behavior (Burguière et al., 2013). Additional rational in targeting the fronto-striatal system comes from wild-type rats where high


frequency electrical stimulation (bipolar, 130 Hz, 100 ␮s, 200 ␮A) of the NAC reduced neural activity in the OFC via antidromic inhibition of corticostriatal pathways, laying the grounds for a possible mechanism by which DBS could produce therapeutic effects in OCD patients (McCracken and Grace, 2009, 2007). 5.3. Depression The clinical outcome of the DBS in depression has been summarized elsewhere (Anderson et al., 2012; Nangunoori et al., 2013; Schlaepfer et al., 2013). In short, around 130 patients worldwide in over 10 clinical trials have had DBS for treatment resistant depression, with variable response and remission rates across variable targets and trials. Experimental testing DBS in animal models of depression have only been done in the last five years and data interpretation is complicated by several issues. Firstly, investigators use several models, including ones were the depressive-like phenotypes are induced via the experimental protocol (e.g. chronic mild stress), or where the phenotype emerges spontaneously through selective breeding (e.g. Flinders Sensitive Line) (for reviews of models see Nestler et al., 2002a,b; Neumann et al., 2011). Although depression is a quintessentially human disorder with a much higher prevalence in the female vs. the male population, pre-clinical studies could improve by developing novel models based on species, such as the octodon degus, that exhibit a broader emotional spectrum than mice or rats (Colonnello et al., 2011); and by increasing the use of female animals as currently the majority of the studies use males. A final complication to interpreting the pre-clinical data – mirroring what has happened clinically – is the myriad of targets tested including the vmPFC, vPL, NAC, VTA, and LHb. In clinical trials, the most studied stimulation target for depression has been the subcallosal cingulate gyrus, and this is also reflected in the animal work. DBS of the vmPFC (monopolar, 130 Hz, 90 ␮s, 100–300 ␮A), the rat equivalent of the subcallosal cingulate gyrus, has shown to relieve some depressive-like phenotype as measured by the forced swim test (FST) in the chronic mild stress model, along with other tests sensitive to anxiety, or anhedonic-like behavior; however, no impact was observed on several other tests, such as the tail suspension test or conditioned defeat using wildtype/non-pathological rats (Hamani et al., 2012, 2010; Hamani and Nóbrega, 2010). Beyond demonstrating the therapeutic effects of high frequency vmPFC stimulation in their experimental work, Hamani and colleagues have significantly contributed to our understanding of DBS in models of depression in at least two other ways. Firstly, their studies highlight the role of serotonin in symptom relief, as the DBS mediated effects were only observed in animals with an intact 5-HT system (Hamani et al., 2012). This is supported by others showing that inhibition of dorsal raphe firing via STN stimulation (bipolar, 130 Hz, 60 ␮s, ≤150 ␮A) – depriving forebrain structures of serotonin – promotes depression-related behavior (Temel et al., 2007). Also, recent data proposes that it is the vmPFC stimulation (bipolar, 160 Hz, 60 ␮s, 150 ␮A) induced neuroplastic changes of the serotonergic system that could be responsible for the more progressive, and later onset mood improvements observed in clinical studies targeting the subcallosal cingulate gyrus (Veerakumar et al., 2014). Secondly, Hamani and others’ investigations on DBS mechanisms show that target inactivation – via excitotoxic or pharmacological means – on their own do not explain the anti-depressant like behaviors but that the observed effects arise from changing the activity of fiber pathways affected by the stimulation (Hamani and Nobrega, 2012; Veerakumar et al., 2014). The VTA is the origin of the mesolimbic and mesocortical dopaminergic projections and plays a crucial role in hedonia, motivation and learning. Although clinically it has not been targeted, electrical stimulation of the VTA has been tested experimentally

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by Friedman and colleagues. Indeed, they were the first to investigate the effectiveness of electrical stimulation of any target in a model of depression (as opposed to addiction or OCD), and importantly, they chose as their animal model a phenotypically and neurochemically relevant model for depression, the Flinders Sensitive Line (FSL) rats. FSL animals have been validated and used in psychiatric disorder research, outside of DBS, for over 25 years (Overstreet and Wegener, 2013). Importantly, FSL rats have many characteristics that resemble human depression such as depression-related behaviors, appetite and weight loss, changes in sleep patterns, increased anhedonia following chronic mild stress; electrical stimulation of the vmPFC (monopolar, 130 Hz, 100 ␮s, 300 ␮A) in FSL rats reduced some depressive-like behaviors associated with despair (forced-swim test) and anhedonia (sucrose consumption test) (Rea et al., 2013). Beyond the strong face and predictive validity, the FSL model shows strong construct validity as altered levels of BDNF, and changes in monoamine neurotransmission affecting the serotonergic, noradrenergic and dopaminergic systems have been describe in this model (Friedman et al., 2009b, 2005; Neumann et al., 2011; Overstreet, 2012). Friedman and colleagues’ work suggests that a single 20 min, low frequency electrical stimulation (bipolar, 10 Hz, 1 ms, 300 ␮A) protocol administered unilaterally in the VTA was sufficient to alleviate specifically the depressive-like phenotype (measured by a battery of tests) in FSL rats, and that this effect lasted at least up to 4 weeks; accompanying increase in prefrontal BDNF levels were also observed in the stimulated FSL rats (Friedman et al., 2009a). In order to explain the long-term adaptive effects of the acute intervention, the investigators studied the differences in the local field potentials in the VTA of FSL and controls (Sprague-Dawley rats) under normal conditions and following electrical stimulation. Interestingly, their work shows that the FSL rats’ difference in VTA firing bursts – characterized by smaller but more frequent firing – can be modified to resemble that of the controls’ if using an appropriately structured stimulation pattern, thereby restoring “normal” behavior as well (Friedman et al., 2012, 2008). The NAC, the principal target of the VTA dopaminergic efferents, is a “hot-spot” in the neurocircuitry of psychiatric disorders. Several clinical trials have targeted this structure in treatment resistant depression (Bewernick et al., 2012, 2010; Schlaepfer et al., 2008), and a few studies looked at the impact of NAC DBS in preclinical models of depression. Inducing the depressive-like phenotype in rats by exposing them to the chronic mild stress protocol, Gersner and colleagues showed that unilateral low-frequency stimulation (monopolar, 20 Hz, 200 ␮s, 400 ␮A) of the NAC (and ventral prelimbic cortex) could reverse reduced sucrose preference, but had no impact on the FST, or general activity; also, performance on the Morris Water Maze, a cognitive test, neither improved nor got worse (Gersner et al., 2010). The lack of impact on the FST, generally considered as the benchmark of a therapeutic effect in preclinical models of depression, leads to believe that the electrode placement (not defined in the paper), or the stimulation parameters (20 Hz, 10 min/d for 10 d) were not optimal. High frequency electrical stimulation of the NAC has been tested in “pathological” and spontaneous models of depression as well. Using Wistar–Kyoto rats, a selectively breed line showing depression-like phenotype similar to the FSL rats, investigators showed that high-frequency stimulation (bipolar, 120 Hz, 200 ms, 2 V) administered either for 3 h/d or continuously for 2 weeks reduced anxiety and increased the exploratory behavior in animals, but could not distinguish whether this was a general effect on locomotion or a specific reward/reinforcement related behavior. However, the study showed stimulation associated long-term adaptive plasticity in the prefrontal cortex in the guise of increased catecholamine levels (Falowski et al., 2011). In another study, high frequency stimulation (bipolar, 130 Hz, 60 ␮s, 100 ␮A) via

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electrodes implanted unilaterally into the NAC of a mouse model showing enhanced depression- and anxiety-like behavior (HAB mice) reversed the animals’ depressive and anxiolytic phenotype (Schmuckermair et al., 2013). The experimental design permitted the authors to make the following additional conclusions: firstly, they showed that only the repeated (1 h/d for 7days) and not the single stimulation protocol worked; secondly, the stimulation was specific for the pathological/deregulated neural network as control mice with “normal” depression/anxiety levels were unaffected. However, the HAB mice did not respond to chronic serotonin reuptake inhibitors (while other models, e.g. the FSL rats do), which questions the construct/predictive validity of their chosen animal model under these conditions. The lateral habenula (LHb), associated with encoding of aversive and negative events, sends GABAergic inhibitory projections to the VTA and the rostromedial tegmental nucleus, a recently characterized structure considered as the master controller of VTA output activity (Barrot et al., 2012; Bourdy and Barrot, 2012). Clinical data suggests LHb hyperactive in depressed patients (Hikosaka, 2010), and muscimol administration in the LHb – disinhibiting VTA activity – has shown to have antidepressant activity in animal models of depression (Winter et al., 2011). Electrophysiological data from acute learned helplessness model of depression confirms the potentiation of excitatory input onto LHb neurons projecting to the VTA. The level of potentiation, reflecting the probability of GABA release by LHb neurons in the VTA, correlated with the behavior phenotype, and was reversed following LHb inactivation by high-frequency electrical stimulation (Li et al., 2011). Similarly, the reduction of depressive-like behavioral phenotype and the increase of serum and hippocampal tissue monoamine levels has also been reported following chronic unilateral DBS (bipolar, 150 Hz, 300 ␮s, 80–100 ␮A) of the LHb (Meng et al., 2011). The pre-clinical data discussed above suggests that stimulation of various targets can provide reduction in depressive-like phenotype in animal models. A recent – and so far only – study directly compared the effects of DBS (monopolar, 130 Hz, 90 ␮s, 100 ␮A) of three targets on behavior and neuronal pathway activation following stimulation of the vmPFC, the NAC, and the White Matter Fiber (the authors claim to be equivalent of the ventral capsule/ventral striatum) (Hamani et al., 2014). The animals used in the study were naïve rats (neither exposed to Chronic Mild Stress, nor from a validated model of depression), and the stimulation of the three targets gave rise to distinct patterns of neuronal activation. However, the anti-depressive-like behavioral effect, measured as reduced immobility in the FST, was similar across the three groups suggesting that activation of different pathways can produce similar outcomes. 6. Discussion and conclusion Pre-clinical studies of DBS in models of psychiatric diseases reviewed here point toward several legitimate stimulation targets, as nearly all resulted in some type of functional improvement (Table 1). Besides being a part of a dysfunctional network underlying addiction, OCD, and depression, the structures discussed have another point in common: many of their afferent and efferent connections pass through the MFB often reciprocally connecting numerous anatomically and functionally distinct mid- and forebrain structures. The target selection should be hypothesis based and be tested in appropriate experimental models. What are the arguments pleading next to the MFB as a good target for neuromodulation by electrical stimulation? This question will be examined focusing principally on depression, as this psychiatric disorder is the most relevant experimentally and clinically to the authors of this review. Pre-clinical and clinical evidence suggests that depression is associated with the dysfunction in the reward/motivation circuitry

subserved by the VTA to NAC/PFC ascending dopaminergic projections driving through the MFB (Blood et al., 2010; Martin-Soelch, 2009; Nestler and Carlezon, 2006; Russo and Nestler, 2013). The seminal symptoms seen in depression of reduced expressions of pleasure and decreased appetitive motivation are thought to be the behavioral manifestation of reduced dopaminergic transmission in the MFB, reflected in hypoactivity in the NAC, medial prefrontal cortex, the hippocampus, and the hyperactivity in the subcallosal cingulate gyrus (Mayberg, 2009; Russo and Nestler, 2013). Additional evidence for the implication of MFB in depressionlike behaviors comes from affective neuroscience, the systematic investigation of the neuroanatomical and neurochemical basis of emotions (Panksepp, 1998). This branch of neuroscience research over the years generated a substantial body of evidence demonstrating the role of the MFB in driving activities essential for survival, positive emotional and euphoric behaviors, as well as its involvement in general exploration, and appetitive learning (Alcaro and Panksepp, 2011; Coenen et al., 2011b; Panksepp, 2011; Panksepp and Lahvis, 2011). A lot is known about the substantia nigra (SN), the VTA and about their relationship with their forebrain targets, such as the NAC or the dorsal striatum. However, surprisingly little is understood about the physical attributes of the mesolimbic, mesocortical or the nigrostriatal ascending pathways that connect the nuclei: for example, leaving the A9 and A10 regions, until what point are the projections physically separate, and how do they relate to each other once in the bundle? In order to put the electrode placement within the MFB on rationale basis (for example stimulating selectively mesolimbic vs. nigrostriatal projections), future pre-clinical studies need to integrate imaging techniques, such as diffusion tension imaging, into their design. The clinical application of these approaches has improved our understanding of the human MFB and now should be applied in animal models too (Bürgel et al., 2009; Coenen et al., 2011a,b, 2012a,b). Additional evidence supporting the relevance of MFB DBS in depression comes from clinical data showing that bilateral stimulation of the supero-lateral branch of the MFB can relieve depression symptoms in a long lasting fashion (Schlaepfer et al., 2013). Similar results following stimulation of other targets, such as NAC or vmPFC, have been reported, but there are two important aspects that confirm the MFB as promising, unique and scientifically interesting target. Firstly, antidepressant efficacy was observed within days as opposed to a longer timescale seen in other studies. The reason for this observation consistent across the patients is not known; however, it could be due to the strategic position the MFB is in to modulate/synchronize the function of all the other key structures implicated in the network. Secondly, a patient with a surgical complication resulting in a unilateral lesion of the MFB did not respond to stimulation. This supports that idea an intact MFB mediates the effects seen in the responders, and that symptomatic relief requires bilateral stimulation (Coenen et al., 2013). MFB stimulation is thought to increase the activity in mesolimbic and mesocortical dopamine pathways by enhancing descending glutamatergic excitatory afferents to the VTA and thereby increasing VTA cell firing (Friedman et al., 2012; Ikemoto, 2010; Ikemoto and Wise, 2004); however, the mechanisms behind the rapid and chronic antidepressant action of electrical stimulation of the MFB are still uncertain today. The impact of MFB stimulation is most likely not restricted to the dopaminergic system: the serotonergic neurons from the dorsal raphe nucleus project to the SN and the VTA, and pass through the bundle on the way toward the striatum and prefrontal targets; given its connectivity, it is not surprising that serotonin has been implicated in affective, motivational and cognitive aspects of reward representation and processing as well (Cools et al., 2011; Kranz et al., 2010; Nakamura, 2013). Interestingly, similar to the inhibitory antidromic action of NAC stimulation on corticostriatal neurons originating in the orbitofrontal cortex


(McCracken and Grace, 2007), MFB stimulation has shown to evoke serotonin (and histamine) release in the midbrain, structures retrograde to the stimulating electrode (Hashemi et al., 2011). More needs to be known about the interplay in models of depression between dopamine and serotonin as the impact of the stimulation probably depends on the sum of actions of these two sometimes opposing, sometimes cooperating monoamines (Boureau and Dayan, 2011). Apart from preliminary data on plastic changes in the dorsal raphe nucleus following vmPFC stimulation (Veerakumar et al., 2014), little is known how local stimulation impacts on the global neurocircuitry, or how acute or chronic stimulation affects local and associated networks. Future studies need to integrate novel approaches such as fast scanning cyclic voltammetry to detect dopamine and serotonin, or micromachining technologies for neurotransmitter sensing and recording/stimulation that can be used in conjunction with standard deep brain stimulation devices. Furthermore, optogenetics – with the promise of stimulating specific neuronal populations and pathways – has taken preclinical neuromodulation studies into a new dimension. Electrical stimulation has pointed toward the involvement of mesolimbic dopamine in reinforcement and the expression of depression-related behavior, but it needed optogenetic methods – and the capacity to selectively activate or inhibit VTA dopamine neurons – to unambiguously demonstrate this (Chaudhury et al., 2013; Tye et al., 2013; Witten et al., 2011). Optogenetics already has, and will undoubtedly in the future, make significant contributions to our molecular, cellular and circuit-level understanding of many psychiatric disorders, including depression (Huang et al., 2012; Lobo et al., 2012). Indeed, as is the dream of some, if science and society can overcome the problems and the fears, optogenetics could move into the clinics in the near future (Chow and Boyden, 2013; LaLumiere, 2011). Until and beyond that day, however, both electrical stimulation and optogenetics should be exploited experimentally to increase our knowledge concerning the neurocircuitry associated with brain diseases and how neuromodulation can be optimized to benefit patients with psychiatric disorders. Acknowledgements The authors thank the financially support of the German Research Foundation (DFG) grant EXC 1086 BrainLinks-BrainTools to the University of Freiburg, Germany; and of the Stereotactic and Functional Neurosurgery Department, University Hospital, Freiburg, Germany; LLF is supported by the Deutscher Akademischer Austauschdienst (DAAD) and by a Brazilian governmental grant (CNPq). References Alcaro, A., Panksepp, J., 2011. The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression. Neurosci. Biobehav. Rev. 35, 1805–1820, http://dx.doi.org/10.1016/j.neubiorev.2011.03.002. Anand, B., Brobeck, J., 1951. Hypothalamic control of food intake in rats and cats. J. Biol. Med. 24, 123–140. Anderson, R.J., Frye, M.A., Abulseoud, O.A., Lee, K.H., McGillivray, J.A., Berk, M., Tye, S.J., 2012. Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neurosci. Biobehav. Rev. 36, 1920–1933, http://dx.doi.org/10.1016/j.neubiorev.2012.06.001. Barrot, M., Sesack, S.R., Georges, F., Pistis, M., Hong, S., Jhou, T.C., 2012. Braking dopamine systems: a new GABA master structure for mesolimbic and nigrostriatal functions. J. Neurosci. Off. J. Soc. Neurosci. 32, 14094–14101, http://dx.doi.org/10.1523/JNEUROSCI.3370-12.2012. Baunez, C., Dias, C., Cador, M., Amalric, M., 2005. The subthalamic nucleus exerts opposite control on cocaine and “natural” rewards. Nat. Neurosci. 8, 484–489, http://dx.doi.org/10.1038/nn1429. 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

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Hypothalamic adrenaline synthesis after stimulation of the medial forebrain bundle.

Medial forebrain bundle of the rat: III. Cytoarchitecture of the rostral (telencephalic) part of the medial forebrain bundle bed nucleus.

Interactions of septal evoked responses to stimulation of the fornix and medial forebrain bundle.

Activation and inhibition of the lateral hypothalamic neurones elicited by medial forebrain bundle stimulation.

Response of medial telencephalic neurons to stimulation in reinforcing sites in the medial forebrain bundle and ventral tegmental area.

Effect of substance P on medial forebrain bundle self-stimulation in rats following intracerebral administration.

Visualization of the medial forebrain bundle using diffusion tensor imaging.

Delayed drinking in response to electrical and thermal stimulation of the medial forebrain.

Effects of frequency and pattern of medial forebrain bundle stimulation on caudate dialysate dopamine and serotonin.

anterior hypothalamic neurones following medial forebrain bundle stimulation.

Cocaine: acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle.

Effects of anterior medial forebrain bundle lesions on self-stimulation with two different operant responses.

Differences in sensitivity to neuroleptic blockade: medial forebrain bundle versus frontal cortex self-stimulation.

Medial forebrain bundle of the rat: IV. Cytoarchitecture of the caudal (lateral hypothalamic) part of the medial forebrain bundle bed nucleus.

Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model.

Stimulation of the subcallosal fornix excites neurones in the cat preoptic region which project to the medial basal hypothalamus and in the medial forebrain bundle.

Strength-duration analysis of the organization of reinforcement pathways in the medial forebrain bundle of rats.

Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release.

White matter microstructure alterations of the medial forebrain bundle in melancholic depression.

Brain stem self-stimulation attenuated by lesions of medial forebrain bundle but not by lesions of locus coeruleus or the caudal ventral norepinephrine bundle.

Medial forebrain bundle projections to the nucleus of the diagonal band of Broca.

Enhanced dopamine receptor activation in accumbens and frontal cortex has opposite effects on medial forebrain bundle self-stimulation.

The distribution of changes in local cerebral energy metabolism associated with brain stimulation reward to the medial forebrain bundle of the rat.

Effects of dopaminergic drugs and acute medial forebrain bundle lesions on striatal acetylcholine levels.