The priming effect of rewarding brain stimulation in rats depends on both the cost and strength of reward but survives blockade of D2-like dopamine receptors.

Receipt of an intense reward boosts motivation to work for more of that reward. This phenomenon is called the priming effect of rewards. Using a novel measurement method, we show that the priming effect of rewarding electrical brain stimulation depends on the cost, as well as on the strength, of the anticipated reward. Previous research on the priming effect of electrical brain stimulation utilized a runway paradigm in which running speed serves as the measure of motivation. In the present study, the measure of motivation was the vigour with which rats executed a two-lever response chain, in a standard operant-conditioning chamber, to earn rewarding electrical stimulation of the lateral hypothalamus. In a second experiment, we introduced a modification that entails self-administered priming stimulation and alternating blocks of primed and unprimed trials. Reliable, consistent priming effects of substantial magnitude were obtained in the modified paradigm, which is closely analogous to the runway paradigm. In a third experiment, the modified paradigm served to assess the dependence of the priming effect on dopamine D2-like receptors. The priming effect proved resilient to the effect of eticlopride, a selective D2-like receptor antagonist. These results are discussed within the framework of a new model of brain reward circuitry in which non-dopaminergic medial forebrain bundle fibers and dopamine axons provide parallel inputs to the final common paths for reward and incentive motivation.

Deep Brain Stimulation of the Medial Forebrain Bundle for Treatment-Resistant Depression: A Systematic Review Focused on the Long-Term Antidepressive Effect.

OBJECTIVE: Major depression affects millions of people worldwide and has important social and economic consequences. Since up to 30% of patients do not respond to several lines of antidepressive drugs, deep brain stimulation (DBS) has been evaluated for the management of treatment-resistant depression (TRD). The superolateral branch of the medial forebrain bundle (slMFB) appears as a "hypothesis-driven target" because of its role in the reward-seeking system, which is dysfunctional in depression. Although initial results of slMFB-DBS from open-label studies were promising and characterized by a rapid clinical response, long-term outcomes of neurostimulation for TRD deserve particular attention. Therefore, we performed a systematic review focused on the long-term outcome of slMFB-DBS. MATERIALS AND METHODS: A literature search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was conducted to identify all studies reporting changes in depression scores after one-year follow-up and beyond. Patient, disease, surgical, and outcome data were extracted for statistical analysis. The Montgomery-Åsberg Depression Rating Scale (ΔMADRS) was used as the clinical outcome, defined as percentage reduction from baseline to follow-up evaluation. Responders' and remitters' rates were also calculated. RESULTS: From 56 studies screened for review, six studies comprising 34 patients met the inclusion criteria and were analyzed. After one year of active stimulation, ΔMADRS was 60.7% ± 4%; responders' and remitters' rates were 83.8% and 61.5%, respectively. At the last follow-up, four to five years after the implantation, ΔMADRS reached 74.7% ± 4.6%. The most common side effects were stimulation related and reversible with parameter adjustments. CONCLUSIONS: slMFB-DBS appears to have a strong antidepressive effect that increases over the years. Nevertheless, to date, the overall number of patients receiving implantations is limited, and the slMFB-DBS surgical technique seems to have an important impact on the clinical outcome. Further multicentric studies in a larger population are needed to confirm slMFB-DBS clinical outcomes.

Delayed reinforcement hinders subsequent extinction.

In operant conditioning, animals associate their own behavior with a reinforcer, and the probability of the behavioral responses is increased. This form of learning is called reinforcement. In contrast, when the previously reinforced responses are no longer paired with a reinforcer, these responses are eventually extinguished. The effectiveness of reinforcement depends primarily on time intervals between reinforcers and responses, but it is not fully understood how the intervals affect subsequent extinction. To address this question, we performed electrical stimulation of the rat medial forebrain bundle (MFB), a part of the brain reward system, and an operant task in which the MFB was electrically stimulated 0.1 s (immediate condition) or 1 s (delayed condition) after the rat's nose was poked. During the first half of the task period (a reinforcement period), nose pokes were associated with MFB stimulation. In contrast, during the second half (an extinction period), we did not stimulate the MFB irrespective of nose pokes. We found that rats exhibited increased nose-poke behaviors during the reinforcement period under both conditions, whereas during the extinction period, nose pokes were more persistent in the delayed condition than in the immediate condition. The persistent responses in the extinction period were independent of responses in the reinforcement period. Therefore, reinforcement and extinction are driven by independent neural mechanisms.

Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns.

Major depressive disorder is one of the most common mental disorders, and more than 300 million of people suffer from depression worldwide. Recent clinical trials indicate that deep brain stimulation of the superolateral medial forebrain bundle (mfb) can have rapid and long-term antidepressant effects in patients with treatment-resistant depression. However, the mechanisms of action are elusive. In this study, using female rats, we demonstrate the antidepressant effects of selective optogenetic stimulation of the ventral tegmental area's dopaminergic (DA) neurons passing through the mfb and compare different stimulation patterns. Chronic mild unpredictable stress (CMUS) induced depressive-like, but not anxiety-like phenotype. Short-term and long-term stimulation demonstrated antidepressant effect (OSST) and improved anxiolytic effect (EPM), while long-term stimulation during CMUS induction prevented depressive-like behavior (OSST and USV) and improved anxiolytic effect (EPM). The results highlight that long-term accumulative stimulation on DA pathways is required for antidepressant and anxiolytic effect.

Opposing relationships of childhood threat and deprivation with stria terminalis white matter.

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress-related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post-traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.

Acupuncture Modulates Intracranial Self-Stimulation of the Medial Forebrain Bundle in Rats.

Acupuncture affects the central nervous system via the regulation of neurotransmitter transmission. We previously showed that Shemen (HT7) acupoint stimulation decreased cocaine-induced dopamine release in the nucleus accumbens. Here, we used the intracranial self-stimulation (ICSS) paradigm to evaluate whether HT stimulation regulates the brain reward function of rats. We found that HT stimulation triggered a rightward shift of the frequency-rate curve and elevated the ICSS thresholds. However, HT7 stimulation did not affect the threshold-lowering effects produced by cocaine. These results indicate that HT7 points only effectively regulates the ICSS thresholds of the medial forebrain bundle in drug-naïve rats.

Fast serotonin voltammetry as a versatile tool for mapping dynamic tissue architecture: I. Responses at carbon fibers describe local tissue physiology.

It is important to monitor serotonin neurochemistry in the context of brain disorders. Specifically, a better understanding of biophysical alterations and associated biochemical functionality within subregions of the brain will enable better of understanding of diseases such as depression. Fast voltammetric tools at carbon fiber microelectrodes provide an opportunity to make direct evoked and ambient serotonin measurements in vivo in mice. In this study, we characterize novel stimulation and measurement circuitries for serotonin analyses in brain regions relevant to psychiatric disease. Evoked and ambient serotonin in these brain areas, the CA2 region of the hippocampus and the medial prefrontal cortex, are compared to ambient and evoked serotonin in the substantia nigra pars reticulata, an area well established previously for serotonin measurements with fast voltammetry. Stimulation of a common axonal location evoked serotonin in all three brain regions. Differences are observed in the serotonin release and reuptake profiles between these three brain areas which we hypothesize to arise from tissue physiology heterogeneity around the carbon fiber microelectrodes. We validate this hypothesis mathematically and via confocal imaging. We thereby show that fast voltammetric methods can provide accurate information about local physiology and highlight implications for chemical mapping. Cover Image for this issue: doi: 10.1111/jnc.14739.

The Neurology of Acquired Pedophilia.

The clinicoanatomic cases of acquired pedophilia that have been published in the medical and forensic literature up to 2019 are reviewed. Twenty-two cases fit our inclusion criteria. All but one were men, and in only one case the injury was localized to the left hemisphere. Hypersexuality was present in 18 cases. The damaged areas fell within the frontotemporoinsular cortices and related subcortical nuclei; however, the anterior hypothalamus was spared. Damage to parts of the right frontotemporoinsular lobes with sparing of the anterior hypothalamus seems to be critical for the emergence of acquired pedophilia.

Deep Brain Stimulation of the Medial Forebrain Bundle in a Rodent Model of Depression: Exploring Dopaminergic Mechanisms with Raclopride and Micro-PET.

BACKGROUND: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. OBJECTIVES: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). METHODS: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. RESULTS: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. CONCLUSION: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.

Electric stimulation of the medial forebrain bundle influences sensorimotor gaiting in humans.

BACKGROUND: Prepulse inhibition (PPI) of the acoustic startle response, a measurement of sensorimotor gaiting, is modulated by monoaminergic, presumably dopaminergic neurotransmission. Disturbances of the dopaminergic system can cause deficient PPI as found in neuropsychiatric diseases. A target specific influence of deep brain stimulation (DBS) on PPI has been shown in animal models of neuropsychiatric disorders. In the present study, three patients with early dementia of Alzheimer type underwent DBS of the median forebrain bundle (MFB) in a compassionate use program to maintain cognitive abilities. This provided us the unique possibility to investigate the effects of different stimulation conditions of DBS of the MFB on PPI in humans. RESULTS: Separate analysis of each patient consistently showed a frequency dependent pattern with a DBS-induced increase of PPI at 60 Hz and unchanged PPI at 20 or 130 Hz, as compared to sham stimulation. CONCLUSIONS: Our data demonstrate that electrical stimulation of the MFB modulates PPI in a frequency-dependent manner. PPI measurement could serve as a potential marker for optimization of DBS settings independent of the patient or the examiner.

Optimization of Medial Forebrain Bundle Stimulation Parameters for Operant Conditioning of Rats.

BACKGROUND: The medial forebrain bundle (MFB) is involved in the integration of pleasure and reward. Previous studies have used various stimulation parameters for operant conditioning, though the effectiveness of these parameters has not been systematically studied. OBJECTIVES: The purpose of the present study was to investigate the optimal MFB stimulation parameters for controlling the conditioned behavior of rats. METHODS: We evaluated four factors, including intensity, frequency, pulse duration, and train duration, to determine the effect of each on lever pressure applied by animals. We further compared burst and tonic stimulation in terms of learning and performance abilities. RESULTS: The number of lever presses increased with each factor. Animals in the burst stimulation group exhibited more lever presses. Furthermore, the average speed in the maze among burst stimulation group subjects was higher. CONCLUSION: We determined the optimal parameters for movement control of animals in operant conditioning and locomotor tasks by adjusting various electrical stimulation parameters. Our results reveal that a burst stimulation is more effective than a tonic stimulation for increasing the moving speed and number of lever presses. The use of this stimulation technique also allowed us to minimize the training required to control animal behavior.

Machine learning-aided personalized DTI tractographic planning for deep brain stimulation of the superolateral medial forebrain bundle using HAMLET.

BACKGROUND: Growing interest exists for superolateral medial forebrain bundle (slMFB) deep brain stimulation (DBS) in psychiatric disorders. The surgical approach warrants tractographic rendition. Commercial stereotactic planning systems use deterministic tractography which suffers from inherent limitations, is dependent on manual interaction (ROI definition), and has to be regarded as subjective. We aimed to develop an objective but patient-specific tracking of the slMFB which at the same time allows the use of a commercial surgical planning system in the context of deep brain stimulation. METHODS: The HAMLET (Hierarchical Harmonic Filters for Learning Tracts from Diffusion MRI) machine learning approach was introduced into the standardized workflow of slMFB DBS tractographic planning on the basis of patient-specific dMRI. Rendition of the slMFB with HAMLET serves as an objective comparison for the refinement of the deterministic tracking procedure. Our application focuses on the tractographic planning of DBS (N = 8) for major depression and OCD. RESULTS: Previous results have shown that only fibers belonging to the ventral tegmental area to prefrontal/orbitofrontal axis should be targeted. With the proposed technique, the deterministic tracking approach, that serves as the surgical planning data, can be refined, over-sprouting fibers are eliminated, bundle thickness is reduced in the target region, and thereby probably a more accurate targeting is facilitated. The HAMLET-driven method is meant to achieve a more objective surgical fiber display of the slMFB with deterministic tractography. CONCLUSIONS: The approach allows overlying the results of patient-specific planning from two different approaches (manual deterministic and machine learning HAMLET). HAMLET shows the slMFB as a volume and thus serves as an objective tracking corridor. It helps to refine results from deterministic tracking in the surgical workspace without interfering with any part of the standard software solution. We have now included this workflow in our daily clinical experimental work on slMFB DBS for psychiatric indications.

Arc protein expression after unilateral intracranial self-stimulation of the medial forebrain bundle is upregulated in specific nuclei of memory-related areas.

BACKGROUND: Intracranial Self-Stimulation (ICSS) of the medial forebrain bundle (MFB) is a deep brain stimulation procedure, which has a powerful enhancement effect on explicit and implicit memory. However, the downstream synaptic plasticity events of MFB-ICSS in memory related areas have not been described thoroughly. This study complements previous work studying the effect of MFB-ICSS on the expression of the activity-regulated cytoskeleton-associated (Arc) protein, which has been widely established as a synaptic plasticity marker. We provide new integrated measurements from memory related regions and take possible regional hemispheric differences into consideration. RESULTS: Arc protein expression levels were analyzed 4.5 h after MFB-ICSS by immunohistochemistry in the hippocampus, habenula, and memory related amygdalar and thalamic nuclei, in both the ipsilateral and contralateral hemispheres to the stimulating electrode location. MFB-ICSS was performed using the same paradigm which has previously been shown to facilitate memory. Our findings illustrate that MFB-ICSS upregulates the expression of Arc protein in the oriens and radiatum layers of ipsilateral CA1 and contralateral CA3 hippocampal regions; the hilus bilaterally, the lateral amygdala and dorsolateral thalamic areas as well as the central medial thalamic nucleus. In contrast, the central amygdala, mediodorsal and paraventricular thalamic nuclei, and the habenular complex did not show changes in Arc expression after MFB-ICSS. CONCLUSIONS: Our results expand our knowledge of which specific memory related areas MFB-ICSS activates and, motivates the definition of three functionally separate groups according to their Arc-related synaptic plasticity response: (1) the hippocampus and dorsolateral thalamic area, (2) the central medial thalamic area and (3) the lateral amygdala.

Deep brain stimulation of the supero-lateral branch of the medial forebrain bundle does not lead to changes in personality in patients suffering from severe depression.

BACKGROUND: Reports of changes in patients' social behavior during deep brain stimulation (DBS) raised the question whether DBS induces changes in personality. This study explored if (1) DBS is associated with changes in personality in patients suffering from treatment-resistant depression (TRD), (2) how personality dimensions and depression are associated, and (3) if TRD patients' self-ratings of personality are valid. METHODS: TRD patients were assessed before DBS (n = 30), 6 months (t2, n = 21), 2 (t3, n = 17) and 5 years (t4, n = 11) after the initiation of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB-DBS). Personality was measured with the NEO-Five-Factor Inventory (NEO-FFI), depression severity with Hamilton (HDRS), and Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Personality dimensions did not change with slMFB-DBS compared with baseline. Extraversion was negatively correlated with HDRS28 (r = -0.48, p < 0.05) and MADRS (r = -0.45, p < 0.05) at t2. Inter-rater reliability was high for the NEO-FFI at baseline (Cronbach's α = 0.74) and at t4 (α = 0.65). Extraversion [t(29) = -5.20; p < 0.001] and openness to experience [t(29) = -6.96; p < 0.001] differed statistically significant from the normative sample, and did not predict the antidepressant response. CONCLUSIONS: slMFB-DBS was not associated with a change in personality. The severity of depression was associated with extraversion. Personality of TRD patients differed from the healthy population and did not change with response, indicating a possible scar effect. Self-ratings of personality seem valid to assess personality during TRD.

Changes in the Serum Urate Level Can Predict the Development of Parkinsonism in the 6-Hydroxydopamine Animal Model.

Epidemiological studies indicate that a higher plasma level of uric acid (UA) associates with the reduced risk of Parkinson's disease (PD). To confirm the role of UA as a biomarker for PD, we evaluated changes in the serum UA level in the 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonism in rat. For this purpose, 6-OHDA was administered in the medial forebrain bundle by stereotaxic surgery. According to the apomorphine-induced rotational test, the increased intensity of behavioral symptoms as a function of time was associated with the further reduction of UA level. On the other hand, the level of UA increased in the midbrain of the injured hemisphere. The level of reduction in the serum UA level of rats with severe and moderate symptoms was significantly higher than that of rats with mild symptoms. The immunohistofluorescence and biochemical analyses showed that the serum UA level was also correlated with the death of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), reduced level of striatal dopamine, and severity of oxidative stress in the midbrain. The rats with mild symptoms also showed a significant decrease in TH-positive neurons and striatal dopamine level. These findings suggest a positive correlation between the level of reduction in the serum urate level and severity of 6-OHDA-induced Parkinsonism. In addition, our findings indicated that UA had no marked neuroprotective effects, at least at concentrations obtained in this study. On the other hand, UA was introduced as a biomarker for PD, as a significant decline was observed in the serum UA level of rats with mild behavioral symptoms but with significant dopaminergic cell death in the SNc.

Deep brain stimulation for bipolar disorder-review and outlook.

Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.

The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.

Deep brain stimulation (DBS) is a promising putative modality for the treatment of refractory psychiatric disorders such as major depression and obsessive-compulsive disorder (OCD). Several targets have been posited; however, a clear consensus on differential efficacy and possible modes of action remain unclear. DBS to the supero-lateral branch of the medial forebrain bundle (slMFB) has recently been introduced for major depression (MD). Due to our experience with slMFB stimulation for MD, and because OCD might be related to similar dysfunctions of the reward system, treatment with slMFB DBS seams meaningful. Here we describe our first 2 cases together with a hypothetical mode of action. We describe diffusion tensor imaging (DTI) fiber tractographically (FT)-assisted implantation of the bilateral DBS systems in 2 male patients. In a selected literature overview, we discuss the possible mode of action. Both patients were successfully implanted and stimulated. The follow-up time was 12 months. One patient showed a significant response (Yale-Brown Obsessive-Compulsive Scale [YBOCS] reduction by 35%); the other patient reached remission criteria 3 months after surgery (YBOCS<14) and showed mild OCD just above the remission criterion at 12 months follow-up. While the hypermetabolism theory for OCD involves the cortico-striato-thalamo-cortical (CSTC) network, we think that there is clinical evidence that the reward system plays a crucial role. Our findings suggest an important role of this network in mechanisms of disease development and recovery. In this uncontrolled case series, continuous bilateral DBS to the slMFB led to clinically significant improvements of ratings of OCD severity. Ongoing research focuses on the role of the reward system in OCD, and its yet-underestimated role in this underlying neurobiology of the disease.

A Hedonism Hub in the Human Brain.

Human values are abstract ideals that motivate behavior. The motivational nature of human values raises the possibility that they might be underpinned by brain structures that are particularly involved in motivated behavior and reward processing. We hypothesized that variation in subcortical hubs of the reward system and their main connecting pathway, the superolateral medial forebrain bundle (slMFB) is associated with individual value orientation. We conducted Pearson's correlation between the scores of 10 human values and the volumes of 14 subcortical structures and microstructural properties of the medial forebrain bundle in a sample of 87 participants, correcting for multiple comparisons (i.e.,190). We found a positive association between the value that people attach to hedonism and the volume of the left globus pallidus (GP).We then tested whether microstructural parameters (i.e., fractional anisotropy and myelin volume fraction) of the slMFB, which connects with the GP, are also associated to hedonism and found a significant, albeit in an uncorrected level, positive association between the myelin volume fraction within the left slMFB and hedonism scores. This is the first study to elucidate the relationship between the importance people attach to the human value of hedonism and structural variation in reward-related subcortical brain regions.

Arachnophobia alleviated by subthalamic nucleus stimulation for Parkinson's disease.

We report on a Parkinson patient with motor fluctuations and dyskinesias in whom deep brain stimulation (DBS) of the subthalamic nucleus (STN) not only improved motor symptoms but also pre-existing arachnophobia. Arachnophobia had been unchanged by the course of Parkinson's disease but rapidly improved with STN-DBS. Both, motor effects and the improvement of arachnophobia were stable during 2 years follow-up. To our knowledge this is the first report on STN stimulation effects on a specific phobia.

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

Preclinical and clinical evidence suggests that depression might be associated with a dysfunction in the reward/motivation circuitry. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has been shown in a recent clinical trial to provide a prompt and consistent improvement of depressive symptoms in treatment-resistant patients. In order to better understand the underlying mechanisms of neuromodulation in the context of depression, the effects of chronic bilateral MFB-DBS were assessed in a combined rodent model of depression and Parkinson's disease. Female Sprague-Dawley rats received unilateral 6-OHDA injection in the right MFB and were divided into three groups: CMS-STIM, CMS-noSTIM and control group. The CMS groups were submitted to chronic unpredictable mild stress (CMS) protocol for 6 weeks. MFB-DBS was applied only to the CMS-STIM group for 1 week. All groups were repeatedly probed on a series of behavioral tasks following each intervention, and to a postmortem histological analysis. CMS led to an increase in immobility in the forced swim test, to a decrease in sucrose solution consumption in the sucrose preference test, as well as to an increased production of ultrasonic vocalizations in the 22 kHz range, indicating increased negative affect. MFB-DBS reversed the anhedonic-like and despair-like behaviors. The results suggest that unilateral dopamine depletion did not preclude MFB-DBS in reversing depressive-like and anhedonic-like behavior in the rodent. Further understanding of the importance of hemispheric dominance in neuropsychiatric disorders is essential in order to optimize stimulation as a therapeutic strategy in these diseases.