Deep Brain Stimulation Of Nucleus Accumbens Research Articles

Cross-species brain-wide mapping reveals a conserved and coordinated network engaged by NAc DBS.

Nucleus accumbens (NAc) deep brain stimulation (DBS) has been increasingly explored as a treatment modality for refractory neuropsychiatric disorders. Uncovering the accumbens network that is engaged by DBS is a critical step forward in understanding how modulating this important node impacts the broader mesocorticolimbic circuit. Using whole-brain clearing and unbiased, brain-wide neural activity mapping, we found that NAc DBS increases neural activity in a coordinated mesocorticolimbic network in mice. Simultaneous intracranial electrophysiology recordings from the human NAc and brief stimulation epochs of homologous mesocorticolimbic nodes revealed similar connectivity. Altogether, these results identify specific connectivity conserved across species within the mesocorticolimbic circuit that may underlie mechanisms of NAc DBS.

Presurgical structural imaging and clinical outcome in combined bed nucleus of the stria terminalis–nucleus accumbens deep brain stimulation for treatment-resistant depression

BackgroundStructural imaging holds great potential for precise targeting and stimulation for deep brain stimulation (DBS). The anatomical information it provides may serve as potential biomarkers for predicting the efficacy of...

Safety and feasibility clinical trial of nucleus accumbens deep brain stimulation for treatment-refractory opioid use disorder.

There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment-refractory OUD. A prospective, open-label, single-arm study was conducted among participants with longstanding treatment-refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and 18FDG-PET neuroimaging. Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation-related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One participant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment-refractory OUD. A randomized, sham-controlled trial in a larger cohort of patients is being initiated.

Nucleus accumbens deep brain stimulation improves depressive-like behaviors through BDNF-mediated alterations in brain functional connectivity of dopaminergic pathway

Major depressive disorder (MDD), a common psychiatric condition, adversely affects patients’ moods and quality of life. Despite the development of various treatments, many patients with MDD remain vulnerable and inadequately controlled. Since anhedonia is a feature of depression and there is evidence of leading to metabolic disorder, deep brain stimulation (DBS) to the nucleus accumbens (NAc) might be promising in modulating the dopaminergic pathway. To determine whether NAc-DBS alters glucose metabolism via mitochondrial alteration and neurogenesis and whether these changes increase neural plasticity that improves behavioral functions in a chronic social defeat stress (CSDS) mouse model. The Lab-designed MR-compatible neural probes were implanted in the bilateral NAc of C57BL/6 mice with and without CSDS, followed by DBS or sham stimulation. All animals underwent open-field and sucrose preference testing, and brain resting-state functional MRI analysis. Meanwhile, we checked the placement of neural probes in each mouse by T2 images. By confirming the placement location, mice with incorrect probe placement (the negative control group) showed no significant therapeutic effects in behavioral performance and functional connectivity (FC) after receiving electrical stimulation and were excluded from further analysis. Western blotting, seahorse metabolic analysis, and electron microscopy were further applied for the investigation of NAc-DBS. We found NAc-DBS restored emotional deficits in CSDS-subjected mice. Concurrent with behavioral amelioration, the CSDS DBS-on group exhibited enhanced FC in the dopaminergic pathway with increased expression of BDNF- and NeuN-positive cells increased dopamine D1 receptor, dopamine D2 receptors, and TH in the medial prefrontal cortex, NAc, ventral hippocampus, ventral tegmental area, and amygdala. Increased pAMPK/total AMPK and PGC-1α levels, functions of oxidative phosphorylation, and mitochondrial biogenesis were also observed after NAc-DBS treatment. Our findings demonstrate that NAc-DBS can promote BDNF expression, which alters FC and metabolic profile in the dopaminergic pathway, suggesting a potential strategy for ameliorating emotional processes in individuals with MDD.

Inflammation and mitochondrial dysfunction in affective disorders-novel understandings, novel treatments?

BackgroundMitochondria are involved in energy production, oxidative balance, cell survival/apoptosis, immune response, and inflammation. A possible role in affective disorders has fueled research on mitochondrial targets for novel treatments. MethodsA systematic review of the literature was conducted, in Science Direct, Scopus and PubMed databases, from inception to 12th September 2022. Key words used were mitochondria AND/OR inflammation AND affective OR bipolar OR depression AND therapy OR treatment OR intervention. ResultsTwenty-one studies were included in the analysis. Animal studies (n=16) have shown positive results for Nucleus Accumbens Deep Brain Stimulation (NAc DBS), Near-Infrared Photobiomodulation (NIR-PBM), exercise, 48-hour fasting, and fluoxetine, Li, valproate, BI-11A7 Bid inhibitor, methylene blue (MB), AC-5216, atractylenolide-III (ALT-III), ONO-2952, oxytocin (OT), tocopherol-a, Coenzyme Q10 (CoQ10). Human studies (n=5) have tested adjunctive therapies, with NAC plus antioxidant combination therapy, triacetyl-uridine (TAU), cytidine add-on, and andacetyl-l-carnitine and a-lipoic acid combination, with positive (TAU), negative, or difficult-to-interpret results. LimitationsThe search was conducted on three databases only, and only articles written in English were included. Unpublished articles or research with negative results may have been missed. ConclusionMitochondria-targeting interventions are promising novel treatments for depression and bipolar disorder.

Responsive nucleus accumbens deep brain stimulation for loss-of-control eating

Loss of control (LOC) eating is pervasive in eating disorders and obesity. The presence of this phenotype appears to predict treatment-resistance, including to gastric bypass surgery. Cravings that precede LOC over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). Responsive deep brain stimulation (DBS) guided by low frequency changes in the nucleus accumbens was previously found to block binge-like eating behavior in mice. Following this preclinical work, in a first-in-human pilot study, we recorded nucleus accumbens electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). We observed increased bilateral ventral NAc low frequency power and connectivity that appeared selective for states of food craving. We then used the peaks in nucleus accumbens electrophysiological signal that corresponded to increased low-frequency power to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss in both patients. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS in the context of LOC. Further work with increased sample sizes is required to determine the scalability of this approach. Research Category and Technology and Methods: Translational Research: 1. Deep Brain Stimulation (DBS)

The antidepressant effect of nucleus accumbens deep brain stimulation is mediated by parvalbumin-positive interneurons in the dorsal dentate gyrus

The nucleus accumbens (NAc) is a crucial region in the reward circuit and is related to anhedonia, the pivotal symptom of major depression disorder (MDD). Deep brain stimulation (DBS) of NAc has been identified as an effective treatment for severe refractory major depression; however, the underlying mechanism of NAc-DBS in MDD treatment remains elusive. Using the chronic unpredictable mild stress (CUMS) mouse model, we found NAc-DBS rescued depression-like behaviors, and reversed high gamma oscillation reduction and neurogenesis impairment in the dorsal dentate gyrus. Inactivation of parvalbumin (PV)-positive interneurons (PVI) in the dorsal DG led to depression-like behavior and decreased adult neurogenesis. Further investigation elucidated the VTA-DG GABAergic projection and CA1-NAc projection might jointly participate in NAc-DBS therapeutic mechanism. Disinhibition of the VTA-DG GABAergic projection had an antidepressant effect, and inhibition of the CA1-NAc projection reduced the antidepressant effect of DBS-NAc. Moreover, disinhibiting the VTA-DG GABAergic projection or activating the CA1-NAc projection could increase PVI activity in the dorsal DG. These results showed PVI in the dorsal DG as an essential target in depression and NAc-DBS antidepressant mechanisms.

Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating

Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach.

Aberrant impulse control circuitry in obesity

The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

Deep Brain Stimulation in Drug Addiction Treatment: Research Progress and Perspective.

Drug addiction is a chronic psychiatric disorder characterized by compulsive drug-seeking and drug-using behavior, and a tremendous socioeconomic burden to society. Current pharmacological and psychosocial methods have shown limited treatment effects for substance abuse. Deep Brain Stimulation (DBS) is a novel treatment for psychiatric disease and has gradually gained popularity in the treatment of addiction. Addiction is characterized by neuroplastic changes in the nucleus accumbens (NAc), a key structure in the brain reward system, and DBS in this region has shown promising treatment effects. In this paper, the research progress on DBS for drug addiction has been reviewed. Specifically, we discuss the mechanism of NAc DBS for addiction treatment and summarize the results of clinical trials on DBS treatment for addiction to psychoactive substances such as nicotine, alcohol, cocaine, opioids and methamphetamine/amphetamine. In addition, the treatment effects of DBS in other brain regions, such as the substantia nigra pars reticulata (SNr) and insula are discussed.

Phasic stimulation in the nucleus accumbens enhances learning after traumatic brain injury.

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality worldwide. Despite improvements in survival, treatments that improve functional outcome remain lacking. There is, therefore, a pressing need to develop novel treatments to improve functional recovery. Here, we investigated task-matched deep-brain stimulation of the nucleus accumbens (NAc) to augment reinforcement learning in a rodent model of TBI. We demonstrate that task-matched deep brain stimulation (DBS) of the NAc can enhance learning following TBI. We further demonstrate that animals receiving DBS exhibited greater behavioral improvement and enhanced neural proliferation. Treated animals recovered to an uninjured behavioral baseline and showed retention of improved performance even after stimulation was stopped. These results provide encouraging early evidence for the potential of NAc DBS to improve functional outcomes following TBI and that its effects may be broad, with alterations in neurogenesis and synaptogenesis.

An open-label prospective pilot trial of nucleus accumbens deep brain stimulation for children with autism spectrum disorder and severe, refractory self-injurious behavior: study protocol

BackgroundChildren and youth with autism spectrum disorder (ASD) may manifest self-injurious behaviors (SIB) that may become severe and refractory with limited pharmacologic or behavioral treatment options. Here, we present the protocol of a prospective, mixed-methods study to assess the safety and efficacy of deep brain stimulation (DBS) of the nucleus accumbens (NAcc) for children and youth with ASD and severe, refractory SIB.MethodsThis is a prospective, single-center, single-cohort, open-label, non-randomized pilot trial of 6 patients. Participants will be recruited through specialized behavioral clinics with persistent severe and refractory SIB following standard and intensive interventions. Following NAcc-DBS, participants will be enrolled in the study for 12 months. The primary objectives of the study are safety and feasibility, assessed by rate of recruitment and identification of factors impacting adherence to follow-up and study protocol. Potential treatment efficacy will be assessed by changes in the Children’s Yale-Brown Obsessive-Compulsive Scale in ASD (CYBOCS-ASD), the Behavior Problems Index (BPI), the Inventory of Statements about Self-Injury (ISAS) and the Repetitive Behavior Scale-Revised (RBS-R) questionnaires. Additional clinical outcomes will be assessed, including measures of participant and caregiver quality of life, actigraph measurements, and positron emission tomography (PET) changes following DBS.DiscussionThis study will be the first to evaluate the effect of DBS of the NAcc on a pediatric population in a controlled, prospective trial. Secondary outcomes will improve the understanding of behavioral, neuro-imaging, and electrophysiologic changes in children with ASD and SIB treated with DBS. This trial will provide an estimated effect size of NAcc-DBS for severe refractory SIB in children with ASD in preparation for future comparative trials.Trial registrationRegistration on ClinicalTrials.gov was completed on 12 June 2019 with the Identifier: NCT03982888.

Title of Article: The Antidepressant Effect of Nucleus Accumbens Deep Brain Stimulation is Mediated by Parvalbumin-Positive Interneurons in the Dorsal Dentate Gyrus

Title of Article: The Antidepressant Effect of Nucleus Accumbens Deep Brain Stimulation is Mediated by Parvalbumin-Positive Interneurons in the Dorsal Dentate Gyrus

Mood Regulatory Actions of Active and Sham Nucleus Accumbens Deep Brain Stimulation in Antidepressant Resistant Rats.

The antidepressant actions of deep brain stimulation (DBS) are associated with progressive neuroadaptations within the mood network, modulated in part, by neurotrophic mechanisms. We investigated the antidepressant-like effects of chronic nucleus accumbens (NAc) DBS and its association with change in glycogen synthase kinase 3 (GSK3) and mammalian target of rapamycin (mTOR) expression in the infralimbic cortex (IL), and the dorsal (dHIP) and ventral (vHIP) subregions of the hippocampus of antidepressant resistant rats. Antidepressant resistance was induced via daily injection of adrenocorticotropic hormone (ACTH; 100 μg/day; 15 days) and confirmed by non-response to tricyclic antidepressant treatment (imipramine, 10 mg/kg). Portable microdevices provided continuous bilateral NAc DBS (130 Hz, 200 μA, 90 μs) for 7 days. A control sham electrode group was included, together with ACTH- and saline-treated control groups. Home cage monitoring, open field, sucrose preference, and, forced swim behavioral tests were performed. Post-mortem levels of GSK3 and mTOR, total and phosphorylated, were determined with Western blot. As previously reported, ACTH treatment blocked the immobility-reducing effects of imipramine in the forced swim test. In contrast, treatment with either active DBS or sham electrode placement in the NAc significantly reduced forced swim immobility time in ACTH-treated animals. This was associated with increased homecage activity in the DBS and sham groups relative to ACTH and saline groups, however, no differences in locomotor activity were observed in the open field test, nor were any group differences seen for sucrose consumption across groups. The antidepressant-like actions of NAc DBS and sham electrode placements were associated with an increase in levels of IL and vHIP phospho-GSK3β and phospho-mTOR, however, no differences in these protein levels were observed in the dHIP region. These data suggest that early response to electrode placement in the NAc, irrespective of whether active DBS or sham, has antidepressant-like effects in the ACTH-model of antidepressant resistance associated with distal upregulation of phospho-GSK3β and phospho-mTOR in the IL and vHIP regions of the mood network.

A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation

BackgroundObsessive-compulsive disorder (OCD) has consistently been linked to abnormal frontostriatal activity. The electrophysiological disruption in this circuit, however, remains to be characterized. Objective/hypothesisThe primary goal of this study was to investigate the neuronal synchronization in OCD patients. We predicted aberrant oscillatory activity in frontal regions compared to healthy control subjects, which would be alleviated by deep brain stimulation (DBS) of the nucleus accumbens (NAc). MethodsWe compared scalp EEG recordings from nine patients with OCD treated with NAc-DBS with recordings from healthy controls, matched for age and gender. Within the patient group, EEG activity was compared with DBS turned off vs. stimulation at typical clinical settings (3.5 V, frequency of stimulation 130 Hz, pulse width 60 μs). In addition, intracranial EEG was recorded directly from depth macroelectrodes in the NAc in four OCD patients. ResultsCross-frequency coupling between the phase of alpha/low beta oscillations and amplitude of high gamma was significantly increased over midline frontal and parietal electrodes in patients when stimulation was turned off, compared to controls. Critically, in patients, beta (16–25 Hz) -gamma (110–166 Hz) phase amplitude coupling source localized to the ventromedial prefrontal cortex, and was reduced when NAc-DBS was active. In contrast, intracranial EEG recordings showed no beta-gamma phase amplitude coupling. The contribution of non-sinusoidal beta waveforms to this coupling are reported. ConclusionWe reveal an increased beta-gamma phase amplitude coupling in fronto-central scalp sensors in patients suffering from OCD, compared to healthy controls, which may derive from ventromedial prefrontal regions implicated in OCD and is normalized by DBS of the nucleus accumbens. This aberrant cross-frequency coupling could represent a biomarker of OCD, as well as a target for novel therapeutic approaches.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

Electrical high frequency stimulation of the nucleus accumbens shell does not modulate depressive-like behavior in rats

Deep brain stimulation (DBS) is an effective tool for treatment-resistant depression, though it is still unclear which brain area to target in order to get robust results. While research suggests that the nucleus accumbens (NAc) plays an important role in depression, studies using NAc DBS to improve depressive behavior have not been able to fully explain underlying molecular mechanisms. We therefore used unilateral high frequency stimulation of the NAc shell in rats to verify its effectiveness in treating depression and study involved neurotransmitter systems. Animals underwent social isolation and food deprivation to induce depressive-like symptoms, and performed the forced swim test (FST) to see possible changes in depressive behavior due to NAc shell stimulation. Neurotransmitter levels were measured using in-vivo microdialysis to detect DBS-induced changes. Non-treated control rats showed no significant difference between swimming and floating during FST, verifying that our depression model induced depressive-like symptoms in rats. Furthermore, stimulated and sham-operated animals showed a significant increase in mobility during FST compared to control rats, suggesting an improvement of depressive-like symptoms. However, stimulated rats did not differ from sham-operated rats in their behavior during FST, nor did neurotransmitter levels significantly changed in stimulated rats compared to control rats. Our data suggest that NAc shell stimulation did not alter depressive behavior in rats and had no effects on the molecular level. However, depressive behavior was positively altered when stimulation electrode and microdialysis probe were inserted simultaneously into the NAc shell, causing significant tissue damage and therefore possibly altering the glutamatergic system.

Open-label trial of anterior limb of internal capsule–nucleus accumbens deep brain stimulation for obsessive-compulsive disorder: insights gained

BackgroundFor more than 15 years, deep brain stimulation (DBS) has served as a last-resort treatment for severe treatment-resistant obsessive-compulsive disorder (OCD).MethodsFrom 2010 to 2016, 20 patients with OCD (10 men/10...

Nucleus accumbens deep brain stimulation for treatment-refractory anorexia nervosa: A two-year follow-up study

Nucleus accumbens deep brain stimulation for treatment-refractory anorexia nervosa: A two-year follow-up study

How Deep Brain Stimulation of the Nucleus Accumbens Affects the Cingulate Gyrus and Vice Versa.

The nucleus accumbens (NA) and the cingulate gyrus (CG) are two vital limbic brain structures. They have attracted attention as deep brain stimulation (DBS) targets in the treatment of common refractory psychiatric illness. The primary purpose of this article was to review the current knowledge regarding the way that NA DBS affects the CG and vice versa. Methodologically, a thorough literature review was performed. According to the current literature, NA DBS modulates the function of several brain areas including the CG cortex. It specifically causes activation in the ipsilateral CG cortex and voltage-dependent reduction of its blood oxygenation. It also reverses anterior mid-CG cortex dysfunction and decreases metabolism in the subgenual CG. Moreover, NA DBS that induces mirth inhibits the function of the anterior CG cortex and enhances effective connectivity from anterior CG to the ventral striatum. On the other hand, although it is highly probable that CG DBS affects the NA, the exact nature of its effects remains unclear. Despite the increasing interest in psychiatric DBS, the available data on how NA DBS affects the CG and vice versa are restricted. This conclusion probably reflects the high complexity of the limbic circuits and necessitates further research.