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ABSTRACT: BACKGROUND: Treatment-resistant major depressive disorder is a prevalent and debilitating condition. Deep brain stimulation to different targets has been proposed as a putative treatment. METHODS: In this pilot study, we assessed safety and efficacy of deep brain stimulation to the supero-lateral branch of the medial forebrain bundle in seven patients with highly refractory depression. Primary outcome criterion was severity of treatment-resistant major depressive disorder as assessed with the Montgomery-Åsberg Depression Rating Scale. General psychopathologic parameters, social functioning, and tolerance were assessed with standardized scales, the Global Assessment of Functioning scale, quality of life (Short-Form Health Survey Questionnaire), and neuropsychological tests. RESULTS: All patients showed strikingly similar intraoperative effects of increased appetitive motivation. Six patients attained the response criterion; response was rapid-mean Montgomery-Åsberg Depression Rating Scale of the whole sample was reduced by>50% at day 7 after onset of stimulation. At last observation (12-33 weeks), six patients were responders; among them, four were classified as remitters. Social functioning (Global Assessment of Functioning) improved in the sample as a whole from serious to mild impairment. Mean stimulation current was 2.86 mA; all side effects (strabismus at higher stimulation current, one small intracranial bleeding during surgery, infection at the implanted pulse generator site) could be resolved at short term. CONCLUSIONS: These preliminary findings suggest that bilateral stimulation of the supero-lateral branch of the medial forebrain bundle may significantly reduce symptoms in treatment-resistant major depressive disorder. Onset of antidepressant efficacy was rapid (days), and a higher proportion of the population responded at lower stimulation intensities than observed in previous studies.
Biological psychiatry 04/2013; · 8.93 Impact Factor
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ABSTRACT: Conceptualizations of the underlying neurobiology of major depression have changed their focus from dysfunctions of neurotransmission to dysfunctions of neurogenesis and neuroprotection. The "neurogenesis hypothesis of depression" posits that changes in the rate of neurogenesis are the underlying mechanism in the pathology and treatment of major depression. Stress, neuroinflammation, dysfunctional insulin regulation, oxidative stress, and alterations in neurotrophic factors possibly contribute to the development of depression. The influence of antidepressant therapies, namely pharmacotherapy and neuroprotectants, on cellular plasticity are summarized. A dysfunction of complex neuronal networks as a consequence of neural degeneration in neuropsychiatric diseases has led to the application of deep brain stimulation. We discuss the way depression seen in the light of the neurogenesis hypothesis can be used as a model disease for cerebral aging. A common pathological mechanism in depression and cerebral aging-a dysfunction of neuroprotection and neurogenesis-is discussed. This has implications for new treatment methods.
Dialogues in clinical neuroscience. 03/2013; 15(1):77-85.
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ABSTRACT: Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) was associated with antidepressant, anxiolytic, and procognitive effects in a small sample of patients suffering from treatment-resistant depression (TRD), followed over 1 year. Results of long-term follow-up of up to 4 years of NAcc-DBS are described in a group of 11 patients. Clinical effects, quality of life (QoL), cognition, and safety are reported. Eleven patients were stimulated with DBS bilateral to the NAcc. Main outcome measures were clinical effect (Hamilton Depression Rating Scale, Montgomery-Asperg Rating Scale of Depression, and Hamilton Anxiety Scale) QoL (SF-36), cognition and safety at baseline, 12 months (n=11), 24 months (n=10), and last follow-up (maximum 4 years, n=5). Analyses were performed in an intent-to-treat method with last observation carried forward, thus 11 patients contributed to each point in time. In all, 5 of 11 patients (45%) were classified as responders after 12 months and remained sustained responders without worsening of symptoms until last follow-up after 4 years. Both ratings of depression and anxiety were significantly reduced in the sample as a whole from first month of NAcc-DBS on. All patients improved in QoL measures. One non-responder committed suicide. No severe adverse events related to parameter change were reported. First-time, preliminary long-term data on NAcc-DBS have demonstrated a stable antidepressant and anxiolytic effect and an amelioration of QoL in this small sample of patients suffering from TRD. None of the responders of first year relapsed during the observational period (up to 4 years).
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2012; 37(9):1975-85. · 6.99 Impact Factor
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ABSTRACT: Deep brain stimulation (DBS) to the nucleus accumbens (NAcc-DBS) has antidepressant effects in patients suffering from treatment-resistant depression (TRD). However, limited information exists regarding the impact of NAcc-DBS on cognitive functioning. The aim of this study was to examine whether NAcc-DBS in patients with TRD has any cognitive effects.
A comprehensive neuropsychological battery was administered to 10 patients with TRD before onset of bilateral NAcc-DBS and after 1 year of DBS stimulation. Neuropsychological testing covered the domains of attention, learning and memory, executive functions, visual perception, and language. Performance was analyzed at baseline and after 1 year of continuous DBS.
No evidence was found for cognitive decline following NAcc-DBS comparing test results after 1 year of NAcc-DBS with baseline. However, significantly improved cognitive performance on tests of attention, learning and memory, executive functions and visual perception was found. In addition, there was a general trend towards cognitive enhancement from below average to average performance. These procognitive effects were independent of the antidepressant effects of NAcc-DBS or changes in NAcc-DBS parameters.
These results not only support cognitive safety of NAcc-DBS but also stress its beneficial role in augmenting cognitive performance in patients with TRD.
The World Journal of Biological Psychiatry 07/2011; 12(7):516-27. · 2.38 Impact Factor
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ABSTRACT: Major depression is a common mental health problem and associated with significant morbidity and mortality, including impaired social and physical functioning and increased risk for suicide. Electroconvulsive therapy (ECT) is highly efficacious in treatment-resistant depressive disorders, but cognitive side effects are frequently associated with the treatment. Magnetic seizure therapy (MST) is a form of convulsive therapy, using magnetic fields in order to induce therapeutic seizures. First studies suggested that cognitive side effects of MST, including postictal recovery time, are more benign than those resulting from ECT treatment. In this open-label study we tested the hypothesis that MST is associated with clinically significant antidepressant effects in treatment-resistant depression (TRD) as an add-on therapy to a controlled pharmacotherapy. Twenty patients suffering from TRD were randomly assigned to receive either MST or ECT starting from July 2006 until November 2008. Primary outcome measure was antidepressant response assessed by Montgomery Åsberg Depression Scale. Secondary outcome measures included Hamilton Depression Rating Scale, Hamilton Anxiety Scale, Beck Depression Inventory and 90-Item Symptom Checklist. Antidepressant response (improvement of 50% in MADRS ratings) was statistically significant and of similar size in both treatment groups. Cognitive side effects were observed in neither group. Characteristics in MST- and ECT-induced seizures were comparable, especially regarding ictal activity and postictal suppression. Thus, MST may be a potential alternative to ECT if efficacy and safety are validated in larger clinical trials.
Journal of psychiatric research 10/2010; 45(5):569-76. · 3.72 Impact Factor
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Bettina H Bewernick,
René Hurlemann,
Andreas Matusch,
Sarah Kayser,
Christiane Grubert,
Barbara Hadrysiewicz,
Nikolai Axmacher,
Matthias Lemke,
Deirdre Cooper-Mahkorn,
Michael X Cohen,
Holger Brockmann,
Doris Lenartz,
Volker Sturm,
Thomas E Schlaepfer
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ABSTRACT: 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.
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).
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.
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.
Biological psychiatry 11/2009; 67(2):110-6. · 8.93 Impact Factor
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ABSTRACT: Understanding and predicting other people's mental states and behavior are important prerequisites for social interactions. The capacity to attribute mental states such as desires, thoughts or intentions to oneself or others is referred to as mentalizing. The right posterior temporal cortex at the temporal-parietal junction has been associated with mentalizing but also with taking someone else's spatial perspective onto the world--possibly an important prerequisite for mentalizing. Here, we directly compared the neural correlates of mentalizing and perspective taking using the same stimulus material. We found significantly increased neural activity in the right posterior segment of the superior temporal sulcus only during mentalizing but not perspective taking. Our data further clarify the role of the posterior temporal cortex in social cognition by showing that it is involved in processing information from socially salient visual cues in situations that require the inference about other people's mental states.
Social Cognitive and Affective Neuroscience 10/2008; 3(3):279-89. · 6.13 Impact Factor
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ABSTRACT: The extrastriate body area (EBA) is traditionally considered a category-selective region for the visual processing of static images of the human body. Recent evidence challenges this view by showing motor-related modulations of EBA activity during self-generated movements. Here, we used functional MRI to investigate whether the EBA distinguishes self- from other-generated movements, a prerequisite for the sense of agency. Subjects performed joystick movements while the visual feedback was manipulated on half of the trials. The EBA was more active when the visual feedback was incongruent to the subjects' own executed movements. Furthermore, during correct feedback evaluation, the EBA showed enhanced functional connectivity to posterior parietal cortex, which has repeatedly been implicated in the detection of sensorimotor incongruence and the sense of agency. Our results suggest that the EBA represents the human body in a more integrative and dynamic manner, being able to detect an incongruence of internal body or action representations and external visual signals. In this way, the EBA might be able to support the disentangling of one's own behavior from another's.
NeuroImage 08/2007; 36(3):1004-14. · 5.89 Impact Factor
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ABSTRACT: Human self-consciousness relies on the ability to distinguish between oneself and others. We sought to explore the neural correlates involved in self-other representations by investigating two critical processes: perspective taking and agency. Although recent research has shed light on the neural processes underlying these phenomena, little is known about how they overlap or interact at the neural level. In a two-factorial functional magnetic resonance imaging (fMRI) experiment, participants played a ball-tossing game with two virtual characters ("avatars"). During an active/agency (ACT) task, subjects threw a ball to one of the avatars by pressing a button. During a passive/nonagency (PAS) task, they indicated which of the other avatars threw the ball. Both tasks were performed from a first-person perspective (1PP), in which subjects interacted from their own perspective, and a third-person perspective (3PP), in which subjects interacted from the perspective of an avatar with another location in space. fMRI analyses revealed overlapping activity in medial prefrontal regions associated with representations of one's own perspective and actions (1PP and ACT), and overlapping activity in temporal-occipital, premotor, and inferior frontal, as well as posterior parietal regions associated with representation of others' perspectives and actions (3PP and PAS). These findings provide evidence for distinct neural substrates underlying representations of the self and others and provide support for the idea that the medial prefrontal cortex crucially contributes to a neural basis of the self. The lack of a statistically significant interaction suggests that perspective taking and agency represent independent constituents of self-consciousness.
Journal of Cognitive Neuroscience 07/2006; 18(6):898-910. · 5.18 Impact Factor
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J. Cognitive Neuroscience. 01/2006; 18:898-910.
