Deep brain stimulation for treatment-refractory obsessive compulsive disorder: a systematic review.

BACKGROUND: Obsessive-compulsive disorder is one of the most disabling of all psychiatric illnesses. Despite available pharmacological and psychotherapeutic treatments about 10% of patients remain severely affected and are considered treatment-refractory. For some of these patients deep brain stimulation offers an appropriate treatment method. The scope of this article is to review the published data and to compare different target structures and their effectiveness. METHODS: PubMed search, last update June 2013, was conducted using the terms "deep brain stimulation" and "obsessive compulsive disorder". RESULTS: In total 25 studies were found that reported five deep brain stimulation target structures to treat obsessive-compulsive disorder: the anterior limb of the internal capsule (five studies including 14 patients), nucleus accumbens (eight studies including 37 patients), ventral capsule/ventral striatum (four studies including 29 patients), subthalamic nucleus (five studies including 23 patients) and inferior thalamic peduncle (two studies including 6 patients). Despite the anatomical diversity, deep brain stimulation treatment results in similar response rates for the first four target structures. Inferior thalamic peduncle deep brain stimulation results in higher response rates but these results have to be interpreted with caution due to a very small number of cases. Procedure and device related adverse events are relatively low, as well as stimulation or therapy related side effects. Most stimulation related side effects are transient and decline after stimulation parameters have been changed. CONCLUSION: Deep brain stimulation in treatment-refractory obsessive-compulsive disorder seems to be a relatively safe and promising treatment option. However, based on these studies no superior target structure could be identified. More research is needed to better understand mechanisms of action and response predictors that may help to develop a more personalized approach for these severely affected obsessive compulsive patients.

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations.

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.

Tractography-guided stimulation of somatosensory fibers for thalamic pain relief.

BACKGROUND: The spinothalamocortical tract (STC) is seen as a neural tract responsible for or involved in the generation or transmission of thalamic pain. Either the thalamus itself or the posterior limb of the internal capsule (PLIC) are targets for deep brain stimulation (DBS) in patients with thalamic pain, but due to its low contrast, conventional MRI cannot visualize the STC directly. OBJECTIVES: To show the feasibility of integrating diffusion tensor imaging-based tractography into the stereotactic treatment planning for identification of an object-oriented lead trajectory that allows STC-DBS with multiple electrode contacts. METHODS: Diffusion tensor imaging was performed in 4 patients with thalamic pain. The STC was modeled and integrated into the stereotactic treatment planning for DBS. DBS-lead implantation was done according to trajectory planning along the modeled STC at the level of the PLIC. RESULTS: After implantation, electrode stimulation was possible over a length of more than 20 mm with a tractography-based trajectory along the PLIC part of the STC. After a follow-up of 12 months, pain relief of more than 40% was achieved in 3 of 4 patients with rating on a visual analogue scale. In 1 patient, stimulation failed to reach any long-lasting positive effects. CONCLUSIONS: Integrating tractography data into stereotactic planning of DBS in thalamic pain is technically feasible. It can be used to identify a lead trajectory that allows for multiple contact stimulation along the STC at the level of the PLIC. Due to long-lasting positive stimulation effect, tractography-guided stimulation of sensory fibers seems to be beneficial for thalamic pain relief.

Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring.

Following recent advances in neuromodulation therapy for mental disorders, we treated one patient with severe alcohol addiction with deep brain stimulation (DBS) of the nucleus accumbens (NAc). Before and one year following the surgery, we assessed the effects of DBS within the NAc on the addiction as well as on psychometric scores and electrophysiological measures of cognitive control. In our patient, DBS achieved normalization of addictive behavior and craving. An electrophysiological marker of error processing (the error-related negativity) linked to anterior mid-cingulate cortex (aMCC) functioning was altered through DBS, an effect that could be reversed by periods without stimulation. Thus, this case supports the hypothesis that DBS of the NAc could have a positive effect on addiction trough a normalization of craving associated with aMCC dysfunction.

Nuclei accumbens phase synchrony predicts decision-making reversals following negative feedback.

The nucleus accumbens plays a key role in reinforcement-guided behaviors. Here, we report that electrophysiological oscillatory phase synchrony between the two nuclei accumbens may play a crucial role in using negative feedback to guide decision making. We recorded local field potentials from the human nucleus accumbens and the medial frontal cortex (via surface EEG) from patients who had deep brain stimulation electrodes implanted. Patients performed a reversal learning task in which they decided whether to alter their decision strategy following monetary losses. Strategy switches following losses were preceded by enhanced theta (4-8 Hz) phase synchrony between the nuclei accumbens, and a break-down of gamma (20-80 Hz)-alpha (8-12 Hz) coupling. Furthermore, the strength of the intersite phase synchrony predicted response time adjustments in the subsequent trial. These findings suggest that a neural network including the nucleus accumbens bilaterally becomes functionally connected via theta phase synchrony to signal the need to adjust behavior.

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression.

Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression. Because a prominent clinical feature of depression is anhedonia--the inability to experience pleasure from previously pleasurable activities--and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward system--in which the nucleus accumbens is a key structure--are implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.

Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?

Chronic consumption of alcohol represents one of the greatest health and socioeconomic problems worldwide. We report on a 54-year-old patient with a severe anxiety disorder and secondary depressive disorder in whom bilateral deep brain stimulation (DBS) of the nucleus accumbens was carried out. Despite the absence of desired improvement in his primary disorder, we observed a remarkable although not primarily intended alleviation of the patient's comorbid alcohol dependency. Our case report demonstrates the extremely effective treatment of alcohol dependency by means of DBS of the nucleus accumbens and may reveal new prospects in overcoming therapy resistance in dependencies in general.

Mood improvement after deep brain stimulation of the internal globus pallidus for tardive dyskinesia in a patient suffering from major depression.

Deep brain stimulation (DBS) has the unique characteristic to very precisely target brain structures being part of functional brain circuits in order to reversibly modulate their function. It is an established adjunctive treatment of advanced Parkinson's disease and has virtually replaced ablative techniques in this indication. Several cases have been published relating effectiveness in neuroleptics-induced tardive dyskinesia. It is also investigated as a potential treatment of mood disorders. We report on the case of a 62 years old female suffering from a treatment refractory major depressive episode with comorbid neuroleptic-induced tardive dyskinesia. She was implanted a deep brain stimulation treatment system bilaterally in the globus pallidus internus and stimulated for 18 months. As well the dyskinesia as also the symptoms of depression improved substantially as measured by the Hamilton Rating Scale of Depression (HRSD) score and the Burke-Fahn-Marsden-Dystonia-Rating-Scale (BFMDRS) score. Scores dropped for HRSD from 26 at baseline preoperatively to 13 after 18 months; and for BFMDRS from 27 to 17.5. This case illustrates the potential of deep brain stimulation as a technique to be investigated in the treatment of severe and disabling psychiatric and movement disorders. DBS at different intracerebral targets being actually investigated for major depression might have similar antidepressant properties because they interact with the same cortico-basal ganglia-thalamocortical network found to be dysfunctional in major depression.

Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series.

BACKGROUND: The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. METHODS: In this retrospective trial, four patients (three female, one male) aged 31-48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. RESULTS: Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed "partial response" on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. CONCLUSION: MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders.

Motor Improvement and Emotional Stabilization in Patients With Tourette Syndrome After Deep Brain Stimulation of the Ventral Anterior and Ventrolateral Motor Part of the Thalamus.

BACKGROUND: Since its first application in 1999, the potential benefit of deep brain stimulation (DBS) in reducing symptoms of otherwise treatment-refractory Tourette syndrome (TS) has been documented in several publications. However, uncertainty regarding the ideal neural targets remains, and the eventuality of so far undocumented but possible negative long-term effects on personality fuels the debate about the ethical implications of DBS. METHODS: In this prospective open-label trial, eight patients (three female, five male) 19-56 years old with severe and medically intractable TS were treated with high-frequency DBS of the ventral anterior and ventrolateral motor part of the thalamus. To assess the course of TS, its clinical comorbidities, personality parameters, and self-perceived quality of life, patients underwent repeated psychiatric assessments at baseline and 6 and 12 months after DBS onset. RESULTS: Analysis indicated a strongly significant and beneficial effect of DBS on TS symptoms, trait anxiety, quality of life, and global functioning with an apparently low side-effect profile. In addition, presurgical compulsivity, anxiety, emotional dysregulation, and inhibition appeared to be significant predictors of surgery outcome. CONCLUSIONS: Trading off motor effects and desirable side effects against surgery-related risks and negative implications, stimulation of the ventral anterior and ventrolateral motor part of the thalamus seems to be a valuable option when considering DBS for TS.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: A Meta-Analysis of Treatment Outcome and Predictors of Response.

BACKGROUND: Deep brain stimulation (DBS) has been proposed as an alternative to ablative neurosurgery for severe treatment-resistant Obsessive-Compulsive Disorder (OCD), although with partially discrepant results probably related to differences in anatomical targetting and stimulation conditions. We sought to determine the efficacy and tolerability of DBS in OCD and the existence of clinical predictors of response using meta-analysis. METHODS: We searched the literature on DBS for OCD from 1999 through January 2014 using PubMed/MEDLINE and PsycINFO. We performed fixed and random-effect meta-analysis with score changes (pre-post DBS) on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) as the primary-outcome measure, and the number of responders to treatment, quality of life and acceptability as secondary measures. FINDINGS: Thirty-one studies involving 116 subjects were identified. Eighty-three subjects were implanted in striatal areas--anterior limb of the internal capsule, ventral capsule and ventral striatum, nucleus accumbens and ventral caudate--27 in the subthalamic nucleus and six in the inferior thalamic peduncle. Global percentage of Y-BOCS reduction was estimated at 45.1% and global percentage of responders at 60.0%. Better response was associated with older age at OCD onset and presence of sexual/religious obsessions and compulsions. No significant differences were detected in efficacy between targets. Five patients dropped out, but adverse effects were generally reported as mild, transient and reversible. CONCLUSIONS: Our analysis confirms that DBS constitutes a valid alternative to lesional surgery for severe, therapy-refractory OCD patients. Well-controlled, randomized studies with larger samples are needed to establish the optimal targeting and stimulation conditions and to extend the analysis of clinical predictors of outcome.

Obsessive-compulsive disorder: development of demand-controlled deep brain stimulation with methods from stochastic phase resetting.

Synchronization of neuronal firing is a hallmark of several neurological diseases. Recently, stimulation techniques have been developed which make it possible to desynchronize oscillatory neuronal activity in a mild and effective way, without suppressing the neurons' firing. As yet, these techniques are being used to establish demand-controlled deep brain stimulation (DBS) techniques for the therapy of movement disorders like severe Parkinson's disease or essential tremor. We here present a first conceptualization suggesting that the nucleus accumbens is a promising target for the standard, that is, permanent high-frequency, DBS in patients with severe and chronic obsessive-compulsive disorder (OCD). In addition, we explain how demand-controlled DBS techniques may be applied to the therapy of OCD in those cases that are refractory to behavioral therapies and pharmacological treatment.

The nucleus accumbens: a target for deep brain stimulation in obsessive-compulsive- and anxiety-disorders.

We considered clinical observations in patients with obsessive-compulsive- and anxiety-disorders, who underwent bilateral anterior capsulotomy, as well as anatomical and pathophysiological findings. Based on these considerations, we choose the shell region of the right nucleus accumbens as target for deep brain stimulation (DBS) in a pilot-series of four patients with severe obsessive-compulsive- and anxiety-disorders. Significant reduction in severity of symptoms has been achieved in three of four patients treated. Clinical results as well as a 15-O-H(2)O-PET study, perfomed in one patient during stimulation, speak in favour of the following hypothesis. As a central relay-structure between amygdala, basal ganglia, mesolimbic dopaminergic areas, mediodorsal thalamus and prefrontal cortex, the accumbens nucleus seems to play a modulatory role in information flow from the amygdaloid complex to the latter areas. If disturbed, imbalanced information flow from the amygdaloid complex could yield obsessive-compulsive- and anxiety-disorders, which can be counteracted by blocking the information flow within the shell region of the accumbens nucleus by deep brain stimulation.

Deep brain stimulation in addiction due to psychoactive substance use.

Addiction is one of the most challenging health problems. It is associated with enormous individual distress and tremendous socioeconomic consequences. Unfortunately, its underlying mechanisms are not fully understood, and pharmacological, psychological, or social interventions often fail to achieve long-lasting remission. Next to genetic, social, and contextual factors, a substance-induced dysfunction of the brain's reward system is considered a decisive factor for the establishment and maintenance of addiction. Due to its successful application and approval for several neurological disorders, deep brain stimulation (DBS) is known as a powerful tool for modulating dysregulated networks and has also been considered for substance addiction. Initial promising case reports of DBS in alcohol and heroin addiction in humans have recently been published. Likewise, results from animal studies mimicking different kinds of substance addiction point in a similar direction. The objective of this review is to provide an overview of the published results on DBS in addiction, and to discuss whether these preliminary results justify further research, given the novelty of this treatment approach.

Stimulate or degenerate: deep brain stimulation of the nucleus basalis Meynert in Alzheimer dementia.

OBJECTIVE: Deep brain stimulation (DBS) is a therapeutically effective neurosurgical method originally applied in movement disorders. Over time, the application of DBS has increasingly been considered as a therapeutic option for several neuropsychiatric disorders, including Gilles de la Tourette syndrome, obsessive compulsive disorder, major depression and addiction. Latest research suggests beneficial effects of DBS in Alzheimer dementia (AD). Because of the high prevalence and the considerable burden of the disease, we endeavored to discuss and reveal the challenges of DBS in AD. METHODS: Recent literature on the pathophysiology of AD, including translational data and human studies, has been studied to generate a fundamental hypothesis regarding the effects of electrical stimulation on cognition and to facilitate our ongoing pilot study regarding DBS of the nucleus basalis Meynert (NBM) in patients with AD. RESULTS: It is hypothesized that DBS in the nucleus basalis Meynert could probably improve or at least stabilize memory and cognitive functioning in patients with AD by facilitating neural oscillations and by enhancing the synthesis of nerve growth factors. CONCLUSIONS: Considering the large number of patients suffering from AD, there is a great need for novel and effective treatment methods. Our research provides insights into the theoretical background of DBS in AD. Providing that our hypothesis will be validated by our ongoing pilot study, DBS could be an opportunity in the treatment of AD.

Deep brain stimulation as a tool for improving cognitive functioning in Alzheimer's dementia: a systematic review.

Deep brain stimulation (DBS) is an established, in selected cases therapeutically effective, non-lesional treatment method delivering current rectangular pulses into dysfunctional brain structures via chronically implanted stimulation electrodes. DBS is a recognized method applied in movement disorders and is increasingly evaluated as a possible therapeutic option for psychiatric diseases such as refractory obsessive-compulsive disorders, Gilles de la Tourette syndrome, major depression, and substance-related addiction. Latest research indicates that DBS may be a method for improving cognitive functions in Alzheimer's dementia (AD). Translational data in healthy and AD animals appear to support this notion. Nevertheless, many aspects remain unclear, particularly with regard to the optimal target structure. The objective of this review is to present a systematic overview regarding published research on DBS and cognitive functioning in animal and human studies as well as to provide a systematic overview of the feasibility and efficacy of the treatment. We describe three studies investigating the effects of DBS in patients with dementia, using either the fornix or the nucleus basalis of Meynert (NBM) as a target. In total, we identified 25 animal studies with 10 brain structures being targeted: fornix, NBM, anterior caudate nucleus, dorsal striatum, anterior thalamic nucleus, midline thalamic nuclei, central thalamus, lateral hypothalamus, hippocampus (entorhinal cortex, perforant path), and amygdala. Considering the wide and diverse spectrum of targets, we add to this review a supposition about possible underlying mechanisms of operation and recommendations for further research.

DBS in the basolateral amygdala improves symptoms of autism and related self-injurious behavior: a case report and hypothesis on the pathogenesis of the disorder.

We treated a 13-year-old boy for life-threatening self-injurious behavior (SIB) and severe Kanner's autism with deep brain stimulation (DBS) in the amygdaloid complex as well as in the supra-amygdaloid projection system. Two DBS-electrodes were placed in both structures of each hemisphere. The stimulation contacts targeted the paralaminar, the basolateral (BL), the central amygdala as well as the supra-amygdaloid projection system. DBS was applied to each of these structures, but only stimulation of the BL part proved effective in improving SIB and core symptoms of the autism spectrum in the emotional, social, and even cognitive domains over a follow up of now 24 months. These results, which have been gained for the first time in a patient, support hypotheses, according to which the amygdala may be pivotal in the pathogeneses of autism and point to the special relevance of the BL part.

Deep brain stimulation for psychiatric disorders.

BACKGROUND: Deep brain stimulation (DBS), an established treatment for some movement disorders, is now being used experimentally to treat psychiatric disorders as well. In a number of recently published case series, DBS yielded an impressive therapeutic benefit in patients with medically intractable psychiatric diseases. METHODS: This review of the use of DBS to treat psychiatric disorders is based on literature retrieved from a selective Pubmed search for relevant keywords, reference works on the topic, and the authors' own research. RESULTS: Studies have been performed on the use of DBS to treat medically intractable obsessive-compulsive disorder, depressive disorders, and Tourette syndrome. The case numbers in the cited publications were small, yet at least some of them involved a methodologically sound investigation. Thus, in some studies, the strength of the effect was controlled with a double-blinded interval in which the stimulation was turned off. In general, the primary symptoms were found to improve markedly, by 35% to 70%, although not all patients responded to the treatment. Adverse effects of DBS were very rare in most studies and could usually be reversed by changing the stimulation parameters. CONCLUSIONS: The results of DBS for psychiatric disorders that have been published to date are encouraging. They open up a new perspective in the treatment of otherwise intractable disorders. Nonetheless, the efficacy, mechanism of action, and adverse effects of DBS for this indication still need to be further studied in methodologically adequate trials that meet the highest ethical standard.