Deep brain stimulation in the context of addiction--a literature-based systematic evaluation

BACKGROUND: Deep Brain Stimulation (DBS) is established as option to treat Parkinson's Disease and essential tremor by now. Successful treatments of small samples suffering from dystonia, cluster headache or Tourette's Syndrome or from obessive-compulsive disorders and depression make a future extension of indication seem probable. In this context the efficiency of DBS for the treatment of addiction is being discussed. AIM AND METHODS: To assess the potential effects of DBS of different target areas on addiction a keyword-related research in Pubmed (National Library of Medicine, Washington) was undertaken and own research was integrated. FINDINGS: Only case reports and case series were being found, describing in total n = 28 patients. Dopamine replacement therapy dependence (DRTD) and pathological gambling (PG) were reported in conjunction with DBS of the nucleus subthalamicus (STN). Addiction to alcohol, nicotine and heroin were reported in conjunction with DBS of the nucleus accumbens (NAc). These findings were collected in a spreadsheet and discussed. CONCLUSIONS: For STN DBS remissions of PG and DRTD are only reported during the underlying treatment of Parkinson's disease. As method of action therefore the reduction of Parkinsonian medication seems more probable. For NAc DBS remissions of addiction to alcohol, nicotine and heroin are reported during the underlying treatment of heterogonous psychiatric disorders. In contrast to STN DBS this refers to possible, maybe supportive effects of NAc DBS. The exact methods of action are not well understood, but an high motivation of the patients to stay abstinent seems to be of relevance for the effect of NAc DBS.     

Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release

Recent publications have shown promising results of deep brain stimulation (DBS) in the nucleus accumbens for patients with obsessive compulsive disorder and major depressive disorder. Despite its increasing application in the clinical setting, the neurobiological mechanism of action of DBS is still uncertain. One of the possible effects of DBS might be phasic or tonic changes in monoamine release either locally in the target area or in a distant, connected region.In the present study we investigate whether unilateral DBS of the Nucleus Accumbens Core (NAc core) has a local effect on in vivo monoamine release. Freely moving animals were unilaterally stimulated with 300 μA or 400 μA (120 Hz, pulse width 80 μs) in the NAc core for 5 h. 1 h before and during stimulation we measured dopamine, serotonin, their metabolites and noradrenaline using in vivo microdialysis. We found no significant effect of stimulation on extracellular concentrations of monoaminergic neurotransmitters or their metabolites in the NAc core during stimulation. Our results suggest that the rapid effects of DBS in the NAc are not a result of changes in local monoamine release in the NAc core. For future directions it is interesting to note that several microdialysis and electrophysiology studies have shown effects of DBS in areas distant from the stimulation target.     

Deep brain stimulation affects conditioned and unconditioned anxiety in different brain areas

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) has proven to be an effective treatment for therapy refractory obsessive–compulsive disorder. Clinical observations show that anxiety symptoms decrease rapidly following DBS. As in clinical studies different regions are targeted, it is of principal interest to understand which brain area is responsible for the anxiolytic effect and whether high-frequency stimulation of different areas differentially affect unconditioned (innate) and conditioned (learned) anxiety. In this study, we examined the effect of stimulation in five brain areas in rats (NAc core and shell, bed nucleus of the stria terminalis (BNST), internal capsule (IC) and the ventral medial caudate nucleus (CAU)). The elevated plus maze was used to test the effect of stimulation on unconditioned anxiety, the Vogel conflict test for conditioned anxiety, and an activity test for general locomotor behaviour. We found different anxiolytic effects of stimulation in the five target areas. Stimulation of the CAU decreased both conditioned and unconditioned anxiety, while stimulation of the IC uniquely reduced conditioned anxiety. Remarkably, neither the accumbens nor the BNST stimulation affected conditioned or unconditioned anxiety. Locomotor activity increased with NAc core stimulation but decreased with the BNST. These findings suggest that (1) DBS may have a differential effect on unconditioned and conditioned anxiety depending on the stimulation area, and that (2) stimulation of the IC exclusively reduces conditioned anxiety. This suggests that the anxiolytic effects of DBS seen in OCD patients may not be induced by stimulation of the NAc, but rather by the IC.     

Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: An open-label pilot study

Background

Deep brain stimulation (DBS) is currently used to treat addiction, with the nucleus accumbens (NAc) as one promising target. The anterior limb of the internal capsule (ALIC) is also a potential target, as it carries fiber tracts connecting the mesocorticolimbic circuits that are crucially involved in several psychiatric disorders, including addiction. Stimulating the NAc and ALIC simultaneously may have a synergistic effect against addiction.

Deep Brain Stimulation Reduces Conflict-Related Theta and Error-Related Negativity in Patients With Obsessive–Compulsive Disorder

ObjectivesObsessive–compulsive disorder (OCD) is a psychiatric disorder with alterations of cortico-striato-thalamo-cortical loops and impaired performance monitoring. Electrophysiological markers such as conflict-related medial frontal theta (MFT) and error-related negativity (ERN) may be altered by clinically effective deep brain stimulation (DBS) of the anterior limb of the internal capsule and nucleus accumbens (ALIC/NAc). We hypothesized that ALIC/NAc DBS modulates electrophysiological performance monitoring markers.Materials and MethodsFifteen patients (six male) with otherwise treatment-refractory OCD receiving ALIC/NAc DBS performed a flanker task with EEG recordings at three sessions: presurgery and at follow-up with DBS on and off. We examined MFT, ERN, and task performance. Furthermore, we investigated interrelations with clinical efficacy and then explored the influence of the location of individual stimulation volumes on EEG modulations.ResultsMFT and ERN were significantly attenuated by DBS with differences most pronounced between presurgery and DBS-on states. Also, we observed reaction time slowing for erroneous responses during DBS-off. Larger presurgery ERN amplitudes were associated with decreased clinical efficacy. Exploratory anatomical analyses suggested that stimulation volumes encompassing the NAc were associated with MFT modulation, whereas ALIC stimulation was associated with modulation of the ERN and clinical efficacy.ConclusionALIC/NAc DBS diminished MFT and ERN, demonstrating modulation of the medial frontal performance monitoring system in OCD. Furthermore, our findings encourage further studies to explore the ERN as a potential predictor for clinical efficacy.     

Underlying neurobiology and clinical correlates of mania status after subthalamic nucleus deep brain stimulation in Parkinson's disease: a review of the literature

Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson's disease (PD). The authors review the current literature to identify the clinical correlates associated with subthalamic nucleus (STN) DBS-induced hypomania/mania in PD patients. Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male sex, and/or early-onset PD. STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanisms of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight toward development of future DBS mood-stabilization therapies.     

Deep brain stimulation for epilepsy in clinical practice and in animal models

Given the tremendous success of deep brain stimulation (DBS) for the treatment of movement and neuropsychiatric disorders, clinicians have begun to open up to the possible use of electrical stimulation for the treatment of patients with uncontrolled seizures. DBS of various neural targets has been investigated in clinical studies and animal studies, including the anterior nucleus of thalamus (ANT), cerebellum, hippocampus, subthalamic nucleus (STN), centromedian nucleus of the thalamus (CMT), caudate nucleus (CN). Recently, a large and multicenter trial (SANTE: Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy) was conducted and subsequently with encouraging results, making ANT the most well-established target for DBS in the treatment of epilepsy to date. Here, we endeavor to review mainly the animal studies and clinical studies of ANT DBS to further explore the more reliable target.     

Current Status of Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Clinical Review of Different Targets

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder that affects 2% of the general population. Despite optimal cognitive-behavioral and pharmacologic therapy, approximately 10% of patients remain treatment resistant. Currently, deep brain stimulation (DBS) is being investigated as an experimental therapy for treatment-refractory OCD. This review focuses on the efficacy and adverse events of all published DBS targets for OCD: anterior limb of the internal capsule, ventral striatum/ventral capsule, nucleus accumbens, nucleus subthalamicus, and inferior thalamic peduncle. Small studies with various designs indicate an overall average Yale-Brown Obsessive Compulsive Scale score decrease ranging from 6.8 to 31 points. The average overall responder rate is ±50%. The frequency of adverse events seems to be limited. Larger prospective studies including neuroimaging are needed to estimate adequately the true potential of DBS in treatment of OCD and to elucidate its underlying mechanism of action and optimal brain target. We conclude that DBS may be a promising and safe therapy for treatment-resistant OCD.     

Deep brain stimulation for Parkinson’s disease

The surgical treatment of Parkinson’s disease has been through a revival phase over the last 20 years with the development of deep brain stimulation (DBS). Thalamic DBS was developed first and has proven to be a very effective treatment for tremor. The limitation is the lack of effect on other symptoms. Other targets were therefore investigated, and the procedure was applied to the subthalamic nucleus (STN) and the internal globus pallidus (GPi). STN stimulation can improve a wide range of symptoms and is currently the preferred target for many patients. Nevertheless, the morbidity seems higher than with other targets, and the selection criteria have to be quite strict. When STN DBS is not advised, thalamic DBS remains an option for patients with severe tremor, and GPi stimulation for those with severe dyskinesias. DBS remains a symptomatic treatment for a limited number of patients; it does not seem to alter the disease progression, and many patients are not suitable. There is, therefore, the need for further research into other targets and other approaches.     

脑深部电刺激治疗肌张力障碍

目的 探讨脑深部电刺激术(deep brain stimulation, DBS)治疗全身性、偏身性和节段性肌张力障碍的有效性和安全性,肌张力障碍患者治疗和术后程控的策略.方法 采用微电极记录下丘脑底核(subthalamic nucleus, STN)、苍白球内侧部(globus pallidus intemus, GPi)和丘脑腹中间核(ventrointermediate nucleus, Vim)埋置脑深部刺激器治疗肌张力障碍患者15例,同时记录患者对侧受累肌肉的电活动.其中13例患者的刺激靶点为STN(11例为双侧,2例为单侧),1例刺激靶点为单侧GPi,1例为Vim.结果 除1例严重全身肌张力障碍患者外,其余患者因随访时间长短,均有不同程度改善,改善率从22.0%～95.8%不等.其中随访时间超过12个月的患者症状改善率均大于48.6%.1例因全身扭动造成电极外露,颈、胸腹部切口感染,最终将DBS装置取出.另有1例患者因双侧上端的两个触点断路,再次手术将电极位置上移.所有患者均未出现因穿刺造成的颅内出血的永久并发症.结论 通过对现有DBS治疗肌张力障碍病例资料有效性和安全性的总结,DBS成为治疗肌张力障碍的一种新方法.     

Advancing deep brain stimulation for obsessive-compulsive disorder

Evaluation of: Denys D, Mantione M, Figee M et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch. Gen. Psychiatry 67(10), 1061-1068 (2010). Herein we review a prospective trial of deep brain stimulation (DBS) for the treatment of severely debilitating, medication-refractory obsessive-compulsive disorder (OCD) recently published in Archives of General Psychiatry by Denys et al. This prospective 16-subject study, while having some technical limitations, is an excellent addition to the existing literature supporting the use of DBS in the region of the nucleus accumbens for severe OCD. It provides further evidence of efficacy and safety, sham versus active stimulation evidence that this efficacy is real, and several key observations on how DBS interacts with the brain that can shed light on the neuropathophysiology of OCD itself.     

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy-refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti-compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD-like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole-induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.     

Deep brain stimulation in the treatment of depression

Blomstedt P, Sjöberg RL, Hansson M, Bodlund O, Hariz MI. Deep brain stimulation in the treatment of depression. Objective: To present the technique of deep brain stimulation (DBS) and to evaluate the studies conducted on DBS in the treatment of therapy‐refractory major depressive disorder (MDD). Method: A review of the literature on DBS in the treatment of MDD was conducted. Results: The results of DBS in MDD have been presented in 2 case reports and 3 studies of 47 patients operated upon in 5 different target areas. Positive effects have been presented in all studies and side effects have been minor. DBS in the nucleus accumbens resulted in a mean reduction of Hamilton depression rating scale (HDRS) of 36% after 1 year and 30% of the 10 patients achieved remission. DBS in the internal capsule/ventral striatum resulted in a reduction of 44% after 1 year, and at the last evaluation after in mean 2 years, 40% of the 15 patients were in remission. The 20 patients with subcallosal cingulated gyrus DBS had a reduction of HDRS of 52% after 1 year, and 35% were within 1 point from remission or in remission. Conclusion: DBS is a promising treatment for therapy‐refractory MDD. The published experience is, however, limited, and the method is at present an experimental therapy.     

Weight change following deep brain stimulation for movement disorders

Patients with Parkinson’s disease (PD) and essential tremor (ET) tend to lose weight progressively over years. Weight gain following deep brain stimulation (DBS) of the subthalamic nucleus (STN) for treatment of PD has been documented in several studies that were limited by small sample size and exclusive focus on PD patients with STN stimulation. The current study was undertaken to examine weight change in a large sample of movement disorder patients following DBS. A retrospective review was undertaken of 182 patient charts following DBS of the STN, ventralis intermedius nucleus of the thalamus (VIM), and globus pallidus internus (GPi). Weight was collected preoperatively and postoperatively up to 24 months following surgery. Data were adjusted for baseline weight and multivariate linear regression was performed with repeated measures to assess weight change. Statistically significant mean weight gain of 1.8 kg (2.8% increase from baseline, p = 0.0113) was observed at a rate of approximately 1 kg per year up to 24 months following surgery. This gain was not predicted by age, gender, diagnosis, or stimulation target in a multivariate model. Significant mean weight gain of 2.3 kg (p = 0.0124) or 4.2% was observed in our PD patients. Most patients with PD and ET gain weight following DBS, and this gain is not predicted by age, gender, diagnosis, or stimulation target.     

Deep brain stimulation effects on gait variability in Parkinson's disease

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on fall risk in patients with Parkinson's disease (PD) currently remain unclear. Although several gait parameters, such as gait speed, have shown improvement with DBS, some studies have reported an increased fall risk following DBS. The purpose of this study was to examine the effect of bilateral DBS on gait variability, a marker of fall risk. The gait of 13 patients with idiopathic PD was analyzed to determine the influence of DBS, levodopa and both therapies together. Following treatment with both levodopa and STN DBS, subjects displayed improved gait speed, reduced gait variability (enhanced stability), and lower Unified Parkinson's Disease Rating Scale (UPDRS) scores. Although UPDRS scores improved with STN DBS alone, parallel improvements were not seen for gait variability. These findings suggest that different mechanisms may contribute to performance on UPDRS motor testing and gait stability in response to DBS. © 2009 Movement Disorder Society     

Statistical power of studies examining the cognitive effects of subthalamic nucleus deep brain stimulation in Parkinson's disease

It has been argued that neuropsychological studies generally possess adequate statistical power to detect large effect sizes. However, low statistical power is problematic in neuropsychological research involving clinical populations and novel interventions for which available sample sizes are often limited. One notable example of this problem is evident in the literature regarding the cognitive sequelae of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in persons with Parkinson's disease (PD). In the current review, a post hoc estimate of the statistical power of 30 studies examining cognitive effects of STN DBS in PD revealed adequate power to detect substantial cognitive declines (i.e., very large effect sizes), but surprisingly low estimated power to detect cognitive changes associated with conventionally small, medium, and large effect sizes. Such wide spread Type II error risk in the STN DBS cognitive outcomes literature may affect the clinical decision-making process as concerns the possible risk of postsurgical cognitive morbidity, as well as conceptual inferences to be drawn regarding the role of the STN in higher-level cognitive functions. Statistical and methodological recommendations (e.g., meta-analysis) are offered to enhance the power of current and future studies examining the neuropsychological sequelae of STN DBS in PD.     

A review on microelectrode recording selection of features for machine learning in deep brain stimulation surgery for Parkinson’s disease

ObjectiveThis study seeks to systematically review the selection of features and algorithms for machine learning and automation in deep brain stimulation surgery (DBS) for Parkinson’s disease. This will assist in consolidating current knowledge and accuracy levels to allow greater understanding and research to be performed in automating this process, which could lead to improved clinical outcomes.MethodsA systematic literature review search was conducted for all studies that utilized machine learning and DBS in Parkinson’s disease.ResultsTen studies were identified from 2006 utilizing machine learning in DBS surgery for Parkinson’s disease. Different combinations of both spike independent and spike dependent features have been utilized with different machine learning algorithms to attempt to delineate the subthalamic nucleus (STN) and its surrounding structures.ConclusionThe state-of-the-art algorithms achieve good accuracy and error rates with relatively short computing time, however, the currently achievable accuracy is not sufficiently robust enough for clinical practice. Moreover, further research is required for identifying subterritories of the STN.SignificanceThis is a comprehensive summary of current machine learning algorithms that discriminate the STN and its adjacent structures for DBS surgery in Parkinson’s disease.     

Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.     

Parkinson's disease: deep brain stimulation

The effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal pallidum (GPi) on the parkinsonian triad and on levodopa-induced dyskinesias are very similar. The antiakinetic effect of STN DBS seems to be slightly better. On the contrary to pallidal DBS, stimulation of the STN allows to reduce dopaminergic treatment by more than 50p.100 on average. Moreover, the current drain is smaller in STN. Thus, the STN is a low budget target compared to the GPi. STN DBS seems to be as effective on PD tremor as stimulation of the classic thalamic target, the ventral intermediate nucleus (Vim), whereas Vim stimulation has no effect on akinesia and very little on levodopa-induced dyskinesias. Thus, the STN has become the main target nucleus for DBS in PD, which is most often performed bilaterally in one surgical procedure. There is a good correlation of the preoperative response to levodopa and postoperative effects of bilateral STN DBS and this defines the patient population. Given the large patient population, simple guidelines for patient selection are developed. The referring physician can preselect patients based mainly on age (less than 70), absence of dementia and presence of severe disability related to motor fluctuations or dyskinesias. It is the responsibility of the operating centre to determine the levodopa response, to confirm the diagnosis, to rule out contraindications and to make sure that the medical treatment cannot be further optimised. Severe surgical complications with permanent sequels are relatively rare, about 1p.100 per implanted side. The patient selection, the precision of the surgery and the quality of the postoperative follow-up are the three main determinants of success.     

Toward an electrophysiological “sweet spot” for deep brain stimulation in the subthalamic nucleus

Enhanced beta‐band activity recorded in patients suffering from Parkinson‘s Disease (PD) has been described as a potential physiomarker for disease severity. Beta power is suppressed by Levodopa intake and STN deep brain stimulation (DBS) and correlates with disease severity across patients. The aim of the present study was to explore the promising signature of the physiomarker in the spatial domain. Based on local field potential data acquired from 54 patients undergoing STN‐DBS, power values within alpha, beta, low beta, and high beta bands were calculated. Values were projected into common stereotactic space after DBS lead localization. Recorded beta power values were significantly higher at posterior and dorsal lead positions, as well as in active compared with inactive pairs. The peak of activity in the beta band was situated within the sensorimotor functional zone of the nucleus. In contrast, higher alpha activity was found in a more ventromedial region, potentially corresponding to associative or premotor functional zones of the STN. Beta‐ and alpha‐power peaks were then used as seeds in a fiber tracking experiment. Here, the beta‐site received more input from primary motor cortex whereas the alpha‐site was more strongly connected to premotor and prefrontal areas. The results summarize predominant spatial locations of frequency signatures recorded in STN‐DBS patients in a probabilistic fashion. The site of predominant beta‐activity may serve as an electrophysiologically determined target for optimal outcome in STN‐DBS for PD in the future. Hum Brain Mapp 38:3377–3390, 2017. © 2017 Wiley Periodicals, Inc.