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.

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.

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.

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.

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.

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.

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.

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.

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.

Intracranial EEG correlates of expectancy and memory formation in the human hippocampus and nucleus accumbens.

The human brain is adept at anticipating upcoming events, but in a rapidly changing world, it is essential to detect and encode events that violate these expectancies. Unexpected events are more likely to be remembered than predictable events, but the underlying neural mechanisms for these effects remain unclear. We report intracranial EEG recordings from the hippocampus of epilepsy patients, and from the nucleus accumbens of depression patients. We found that unexpected stimuli enhance an early (187 ms) and a late (482 ms) hippocampal potential, and that the late potential is associated with successful memory encoding for these stimuli. Recordings from the nucleus accumbens revealed a late potential (peak at 475 ms), which increases in magnitude during unexpected items, but no subsequent memory effect and no early component. These results are consistent with the hypothesis that activity in a loop involving the hippocampus and the nucleus accumbens promotes encoding of unexpected events.

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.

Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression.

BACKGROUND: While most patients with depression respond to combinations of pharmacotherapy, psychotherapy, and electroconvulsive therapy (ECT), there are patients requiring other treatments. Deep brain stimulation (DBS) allows modulation of brain regions that are dysfunctional in depression. Since anhedonia is a feature of depression and there is evidence of dysfunction of the reward system, DBS to the nucleus accumbens (NAcc) might be promising. METHODS: Ten patients suffering from very resistant forms of depression (treatment-resistant depression [TRD]), not responding to pharmacotherapy, psychotherapy, or ECT, were implanted with bilateral DBS electrodes in the NAcc. The mean (+/-SD) length of the current episode was 10.8 (+/-7.5) years; the number of past treatment courses was 20.8 (+/-8.4); and the mean Hamilton Depression Rating Scale (HDRS) was 32.5 (+/-5.3). RESULTS: Twelve months following initiation of DBS treatment, five patients reached 50% reduction of the HDRS (responders, HDRS = 15.4 [+/-2.8]). The number of hedonic activities increased significantly. Interestingly, ratings of anxiety (Hamilton Anxiety Scale) were reduced in the whole group but more pronounced in the responders. The [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography data revealed that NAcc-DBS decreased metabolism in the subgenual cingulate and in prefrontal regions including orbital prefrontal cortex. A volume of interest analysis comparing responders and nonresponders identified metabolic decreases in the amygdala. CONCLUSIONS: We demonstrate antidepressant and antianhedonic effects of DBS to NAcc in patients suffering from TRD. In contrast to other DBS depression studies, there was also an antianxiety effect. These effects are correlated with localized metabolic changes.

Unilateral deep brain stimulation of the nucleus accumbens in patients with treatment-resistant obsessive-compulsive disorder: Outcomes after one year.

OBJECTIVE: To investigate the effects of unilateral deep brain stimulation (DBS) in the right nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Predominantly bilateral stimulation of the anterior limb of the internal capsule was utilized. METHODS: The study was designed as a double-blind sham-controlled crossover study. Patients received 3 months of deep brain stimulation followed by 3 months of sham stimulation, or vice versa. Subsequently, stimulation was continued unblinded for all patients. The primary outcome measure was the severity level of OCD, measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Secondary outcome measures were depressive symptoms, anxiety, psychological symptom severity, global functioning, quality of life, and cognitive function. RESULTS: The mean Y-BOCS scores decreased significantly from 32.2 (+/-4.0) at baseline to 25.4 (+/-6.7) after 12 months (p=0.012). Five out of ten patients showed a decrease of more than 25%, indicating at least a partial response. One patient showed a decrease in Y-BOCS severity greater than 35%. Similarly, depression, global functioning and quality of life improved within one year. In contrast, anxiety, global symptom severity and cognitive function showed no significant changes. In general, DBS was well-tolerated. CONCLUSIONS: DBS of the unilateral right nucleus accumbens showed encouraging results in patients with treatment-resistant OCD. Five out of ten patients reached at least a partial response after the first year.

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.