Resolving dyskinesias at sustained anti-OCD efficacy by steering of DBS away from the anteromedial STN to the mesencephalic ventral tegmentum - case report.

Here we describe therapeutic results in a female patient who underwent bilateral slMFB DBS for OCD. During a 35-month long course of stimulation, she suffered from stimulation-induced dyskinesia of her right leg which we interpreted as co-stimulation of the adjacent anteromedial subthalamic nucleus (amSTN). After reprogramming to steer the stimulation away from the amSTN medial into the direction of the mesencephalic ventral tegmentum (MVT which contains the ventral tegmental area, VTA), the dyskinesias disappeared. Remarkably, anti-OCD efficacy in the presented patient was preserved and achieved with a bilateral stimulation which by our imaging study fully avoided the amSTN.

Effects of magnetic seizure therapy on anterograde and retrograde amnesia in treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) is the gold standard for treatment-resistant depression (TRD). However, cognitive side effects, mainly anterograde and retrograde amnesia, frequently occur. Magnetic seizure therapy (MST) is tested using more focal seizure induction. However, the suggestion MST may be more beneficial than ECT because it causes fewer amnesia have not yet been comprehensively investigated using common neuropsychological testing specifically for ECT. We aimed to examine whether MST causes anterograde and retrograde amnesia. METHODS: Ten patients with TRD were treated with MST (8.9 [2] treatments) at 100% machine output, a frequency of 100 Hz and 657.4 (62) pulses per train. The short form of the Autobiographical Memory Inventory was administered to test retrograde amnesia. Furthermore, an extended neuropsychological test battery, including verbal and nonverbal recall as well as recognition tasks, was used. RESULTS: We observed changes in retrograde amnesia, although they were not clinically relevant (mean: -0.42 ± 0.14). Furthermore, no anterograde amnesia as well as no effects on global cognitive status, attention, language, and executive functions after MST were measured. CONCLUSIONS: The cognitive safety and efficacy of MST in patients with TRD were indicated. However, the main limitations of the present study were the small sample and as a consequence, the low statistical power to detect changes after treatment. Therefore, our findings require replication in further studies. In addition, a direct comparison between MST and ECT in a larger sample should be performed before MST can be discussed as an alternative treatment approach to ECT in clinical practice.

Johann Bernhard Aloys von Gudden: The Unrecognized Role of the Psychiatrist and Neuroanatomist in Modern Stereotactic Neurosurgery.

Bernhard von Gudden was the founder of the famous school of psychiatry and neuroanatomy in Munich, Germany. Beyond his association with the mysterious death of King Ludwig II of Bavaria, not much is known about Bernhard von Gudden's work in neuroanatomy. He pioneered fiber tract mapping by studying the effects of neurodegeneration following brain lesions. His ideas and work lay the foundation for subsequent fiber tract mapping strategies including the latest method using diffusion tensor magnetic resonance. This paper describes and acknowledges his contribution to the field, now collectively known as connectomics, and describes how it has become an essential tool in modern stereotactic neurosurgery.

Machine learning-aided personalized DTI tractographic planning for deep brain stimulation of the superolateral medial forebrain bundle using HAMLET.

BACKGROUND: Growing interest exists for superolateral medial forebrain bundle (slMFB) deep brain stimulation (DBS) in psychiatric disorders. The surgical approach warrants tractographic rendition. Commercial stereotactic planning systems use deterministic tractography which suffers from inherent limitations, is dependent on manual interaction (ROI definition), and has to be regarded as subjective. We aimed to develop an objective but patient-specific tracking of the slMFB which at the same time allows the use of a commercial surgical planning system in the context of deep brain stimulation. METHODS: The HAMLET (Hierarchical Harmonic Filters for Learning Tracts from Diffusion MRI) machine learning approach was introduced into the standardized workflow of slMFB DBS tractographic planning on the basis of patient-specific dMRI. Rendition of the slMFB with HAMLET serves as an objective comparison for the refinement of the deterministic tracking procedure. Our application focuses on the tractographic planning of DBS (N = 8) for major depression and OCD. RESULTS: Previous results have shown that only fibers belonging to the ventral tegmental area to prefrontal/orbitofrontal axis should be targeted. With the proposed technique, the deterministic tracking approach, that serves as the surgical planning data, can be refined, over-sprouting fibers are eliminated, bundle thickness is reduced in the target region, and thereby probably a more accurate targeting is facilitated. The HAMLET-driven method is meant to achieve a more objective surgical fiber display of the slMFB with deterministic tractography. CONCLUSIONS: The approach allows overlying the results of patient-specific planning from two different approaches (manual deterministic and machine learning HAMLET). HAMLET shows the slMFB as a volume and thus serves as an objective tracking corridor. It helps to refine results from deterministic tracking in the surgical workspace without interfering with any part of the standard software solution. We have now included this workflow in our daily clinical experimental work on slMFB DBS for psychiatric indications.

Clinical Predictors of Response to Magnetic Seizure Therapy in Depression: A Preliminary Report.

OBJECTIVES: Magnetic seizure therapy (MST) is a novel convulsive brain stimulation method in clinical testing, which is used as an alternative for electroconvulsive therapy in patients with treatment-resistant depression (TRD). Preliminary studies have suggested that MST leads to fewer cognitive adverse effects than electroconvulsive therapy but has similar efficacy. However, the clinical predictors of response to MST have not been evaluated yet. This study aimed to investigate whether these predictors can be identified in patients with TRD. METHODS: Thirty-eight patients with TRD were included. As clinical predictors for treatment response, we used the diagnosis, sex, age, family history, and severity of depression, as well as the melancholic, psychotic, anxiety, and atypical depression symptoms. A response was defined as an improvement higher than 50% on the 28-item Hamilton Rating Scale for Depression. The binary logistic regression, stepwise linear regression, and effect sizes were calculated. RESULTS: We found that 68.4% of the patients responded to MST. The responders had significantly fewer previous depressive episodes, less severe depression, and fewer melancholic (anhedonia) and anxiety symptoms than the nonresponders. In addition, responders were more likely to have a positive family history of depression than nonresponders. In particular, the number of previous episodes and a family history of depression were significant predictors of the response to MST. CONCLUSIONS: We demonstrate that the chronicity, severity, and family history of depression, as well as the presence of melancholic and anxiety symptoms, can serve as clinical predictors of the response to MST. Further research with a larger sample size will be required to verify these preliminary findings.

Deep brain stimulation of the supero-lateral branch of the medial forebrain bundle does not lead to changes in personality in patients suffering from severe depression.

BACKGROUND: Reports of changes in patients' social behavior during deep brain stimulation (DBS) raised the question whether DBS induces changes in personality. This study explored if (1) DBS is associated with changes in personality in patients suffering from treatment-resistant depression (TRD), (2) how personality dimensions and depression are associated, and (3) if TRD patients' self-ratings of personality are valid. METHODS: TRD patients were assessed before DBS (n = 30), 6 months (t2, n = 21), 2 (t3, n = 17) and 5 years (t4, n = 11) after the initiation of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB-DBS). Personality was measured with the NEO-Five-Factor Inventory (NEO-FFI), depression severity with Hamilton (HDRS), and Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Personality dimensions did not change with slMFB-DBS compared with baseline. Extraversion was negatively correlated with HDRS28 (r = -0.48, p < 0.05) and MADRS (r = -0.45, p < 0.05) at t2. Inter-rater reliability was high for the NEO-FFI at baseline (Cronbach's α = 0.74) and at t4 (α = 0.65). Extraversion [t(29) = -5.20; p < 0.001] and openness to experience [t(29) = -6.96; p < 0.001] differed statistically significant from the normative sample, and did not predict the antidepressant response. CONCLUSIONS: slMFB-DBS was not associated with a change in personality. The severity of depression was associated with extraversion. Personality of TRD patients differed from the healthy population and did not change with response, indicating a possible scar effect. Self-ratings of personality seem valid to assess personality during TRD.

Deep brain stimulation for bipolar disorder-review and outlook.

Research on deep brain stimulation (DBS) for treatment-resistant psychiatric disorders has established preliminary efficacy signals for treatment-resistant depression. There are only few studies on DBS that included patients suffering from bipolar disorder. This article gives an overview of these studies concerning DBS targets, antidepressant efficacy, and the occurrence of manic/hypomanic symptoms under stimulation. First, promising results show that all patients experienced significant improvement in depressive symptomatology. In a single case, hypomanic symptoms occurred, but they could be resolved by adjusting stimulation parameters. Furthermore, this article highlights important clinical differences between unipolar and bipolar depression that have to be considered throughout the course of treatment.

The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder.

Deep brain stimulation (DBS) is a promising putative modality for the treatment of refractory psychiatric disorders such as major depression and obsessive-compulsive disorder (OCD). Several targets have been posited; however, a clear consensus on differential efficacy and possible modes of action remain unclear. DBS to the supero-lateral branch of the medial forebrain bundle (slMFB) has recently been introduced for major depression (MD). Due to our experience with slMFB stimulation for MD, and because OCD might be related to similar dysfunctions of the reward system, treatment with slMFB DBS seams meaningful. Here we describe our first 2 cases together with a hypothetical mode of action. We describe diffusion tensor imaging (DTI) fiber tractographically (FT)-assisted implantation of the bilateral DBS systems in 2 male patients. In a selected literature overview, we discuss the possible mode of action. Both patients were successfully implanted and stimulated. The follow-up time was 12 months. One patient showed a significant response (Yale-Brown Obsessive-Compulsive Scale [YBOCS] reduction by 35%); the other patient reached remission criteria 3 months after surgery (YBOCS<14) and showed mild OCD just above the remission criterion at 12 months follow-up. While the hypermetabolism theory for OCD involves the cortico-striato-thalamo-cortical (CSTC) network, we think that there is clinical evidence that the reward system plays a crucial role. Our findings suggest an important role of this network in mechanisms of disease development and recovery. In this uncontrolled case series, continuous bilateral DBS to the slMFB led to clinically significant improvements of ratings of OCD severity. Ongoing research focuses on the role of the reward system in OCD, and its yet-underestimated role in this underlying neurobiology of the disease.

Degree of Postictal Suppression Depends on Seizure Induction Time in Magnetic Seizure Therapy and Electroconvulsive Therapy.

OBJECTIVES: Anesthesia is required for both magnetic seizure therapy (MST) and electroconvulsive therapy (ECT), although it has anticonvulsant properties. In this case, bispectral index (BIS) monitoring, a specific electroencephalogram-derived monitoring, can be used to find the optimal seizure induction time during anesthesia to elicit adequate seizures. A measurement of seizure adequacy in electroencephalogram is the postictal suppression. The purpose of this study was to investigate the influence of seizure induction time on the degree of postictal suppression by comparing BIS versus no-BIS monitoring in MST and ECT. METHODS: Twenty patients with treatment-resistant depression were randomly assigned to either MST or ECT. Each patient underwent 3 treatments with the determination of seizure induction time by defined prestimulation BIS (BIS condition) and 3 treatments with determination of seizure induction time by controlled clinical trial protocol (no-BIS condition). Statistical analysis was calculated by repeated-measures analysis of variance. RESULTS: The degree of postictal suppression was more pronounced in both MST and ECT, with BIS monitoring. In this connection, no differences between MST and ECT were found. Seizure induction time was significantly later in the BIS condition (181.3 ± 6 seconds) compared with the no-BIS condition (114.3 ± 12 seconds) (P < 0.001). CONCLUSIONS: Adequacy of seizures, in the form of the degree of postictal suppression, was superior by determining the seizure induction time with BIS in both MST and ECT. Further research is needed to investigate the correlation between the degree of postictal suppression and treatment response.

Arachnophobia alleviated by subthalamic nucleus stimulation for Parkinson's disease.

We report on a Parkinson patient with motor fluctuations and dyskinesias in whom deep brain stimulation (DBS) of the subthalamic nucleus (STN) not only improved motor symptoms but also pre-existing arachnophobia. Arachnophobia had been unchanged by the course of Parkinson's disease but rapidly improved with STN-DBS. Both, motor effects and the improvement of arachnophobia were stable during 2 years follow-up. To our knowledge this is the first report on STN stimulation effects on a specific phobia.

Aberrant NMDA receptor DNA methylation detected by epigenome-wide analysis of hippocampus and prefrontal cortex in major depression.

Current perspectives on the molecular underpinnings of major depressive disorder (MDD) posit a mechanistic role of epigenetic DNA modifications in mediating the interaction between environmental risk factors and a genetic predisposition. However, conclusive evidence for differential methylation signatures in the brain's epigenome of MDD patients as compared to controls is still lacking. To address this issue, we conducted a pilot study including an epigenome-wide methylation analysis in six individuals diagnosed with recurrent MDD and six control subjects matched for age and gender, with a priori focus on the hippocampus and prefrontal cortex as pathophysiologically relevant candidate regions. Our analysis revealed differential methylation profiles of 11 genes in hippocampus and 20 genes in prefrontal cortex, five of which were selected for replication of the methylation status using pyrosequencing. Among these replicated targets, GRIN2A was found to be hypermethylated in both prefrontal cortex and hippocampus. This finding may be of particular functional relevance as GRIN2A encodes the glutamatergic N-methyl-D-aspartate receptor subunit epsilon-1 (NR2A) and is known to be involved in a plethora of synaptic plasticity-related regulatory processes probably disturbed in MDD.

Effects of electroconvulsive therapy and magnetic seizure therapy on acute memory retrieval.

OBJECTIVES: Electroconvulsive therapy (ECT) is currently the most effective treatment for severe depression. However, it is frequently associated with negative cognitive side effects. Magnetic seizure therapy (MST) depicts an alternative, although experimental, convulsive treatment for major depression. Initial results suggest comparable antidepressant effects accompanied by a better side effect profile. However, no studies up to now have addressed acute retrieval disruption after MST in comparison to ECT. Therefore, we intended to broaden insight into the side effect profile of MST compared to ECT by examining the disruption of acute verbal memory processes after treatment. METHODS: Twenty depressed patients were randomly assigned to either MST (10 patients) or ECT (10 patients) treatment. On 2 treatment days and 2 treatment-free days, the patients memorized words using a controlled learning paradigm derived from the Batchelder and Riefer storage retrieval model. Four hours after memorization, the patients were asked to retrieve words freely (delayed recall) and a second time with the help of an additional cue constructed out of a hypernymic category (cued recall). By comparing memory performance on treatment days to control days, treatment-induced memory disruption was evaluated. RESULTS: After ECT, delayed recall was disturbed, whereas after MST, it was not. However, this difference in performance was no longer apparent upon cue application (cued recall). CONCLUSIONS: This study demonstrates that ECT-induced acute memory disruption measured by delayed recall is absent after MST, confirming its superior side effect profile. We hope that confirming advantages of MST over ECT will improve therapy options for patients with severe depression.

Neuromodulation for treatment resistant depression: state of the art and recommendations for clinical and scientific conduct.

Research of Deep Brain Stimulation as a putative treatment for resistant psychiatric disorders might very well lead to the most significant development in clinical psychiatry of the last 40 years-possibly offering a rise of hope for patients to whom medicine had hitherto little to offer. Furthermore, translational research on neuromodulation will allow us to glean something about the underlying cause of patient's illnesses before figuring out a treatment that addresses the source of the problem. Major depression offers perhaps the best example of the rapid progress being made in understanding the biology of mental illness. Studies on the underlying neurobiology of major depression have typically focused on the description of biological differences between patients and healthy subjects such as alterations of monoaminergic or endocrine systems. Psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain, many of which may be unrelated to depression. We believe that more focused, targeted treatment approaches that modulate specific networks in the brain will prove a more effective approach to help treatment-resistant patients. In other words, whereas existing depression treatments approach this disease as a general brain dysfunction, a more complete and appropriate treatment will arise from thinking of depression as a dysfunction of specific brain networks that mediate mood and reward signals (Berton and Nestler, Nat Rev Neurosci 7 (2):137-151, 2006; Krishnan and Nestler, Nature 455(7215):894-902, 2008). A better understanding of defined dysfunctions in these networks will invariably lead to a better understanding of patients afflicted with depression and perhaps contribute to a de-stigmatization of psychiatric patients and the medical specialty treating them.

Nicotinic acetylcholine receptors contribute to learning-induced metaplasticity in the hippocampus.

Hippocampal learning is thought to induce metaplasticity, which can facilitate subsequent learning. Administered at single low doses, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). Placebo-controlled administration of a single low dose of memantine in a pharmaco-fMRI experiment may thus help characterize the role of α7 nAChRs in hippocampal metaplasticity. We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To specifically test this hypothesis, we devised a randomized controlled trial in which healthy volunteers were administered a 20-mg single oral dose of memantine or placebo and scanned on three subsequent runs of a hippocampal learning task. Our results indicate no discrepancies in behavioral learning between low-dose memantine- and placebo-treated participants in the first and second run of this task. In the third run, however, only the placebo-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning while leaving unimpaired hippocampal learning per se. Taken together, our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus.

Overnight deprivation from smoking disrupts amygdala responses to fear.

Cigarette smoking, a major, yet avoidable, cause of disability and premature death, is the most prevalent form of nicotine addiction. An emerging theme in the neurobiology of nicotine addiction is the integrity of the amygdala. Using functional MRI, amygdala responses during a face perception task were compared between 28 chronic smokers [14 females, 14 males; age, 26.3 (2.8) years; age at onset of smoking, 15.8 (2.6) years; years smoked, 9.1 (2.1); cigarettes per day, 17.1 (3.7); Fagerström test for nicotine dependence score, 4.1 (1.9); exhaled carbon-monoxide level, 17.8 (9.5) ppm] and 28 age- and education-matched nonsmokers [14 females, 14 males; age, 26.9 (2.4) years]. Subjects underwent imaging on two separate occasions 1 week apart: smoking satiety versus overnight smoking deprivation, in a randomized counterbalanced order. Our results show no difference in amygdala responses to faces between nonsmokers and satiated smokers. However, overnight deprivation from smoking was associated with a significantly lowered amygdala response to fear, an effect that was probabilistically mapped to the basolateral amygdala. We suggest that aberrant amygdala reactivity in overnight-deprived smokers may reflect a pre-existing vulnerability to smoking and/or increase the risk of smoking relapse after a cessation attempt.

"The Heart Asks Pleasure First"-Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive-Compulsive Disorder.

More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive-compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB's (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy.

The psychological burden of a two-stage exchange of infected total hip and knee arthroplasties.

Infection is one of the most challenging complications after total joint arthroplasties affecting up to 30,000 patients in the US per year. This study investigates the psycho-social burden induced by the two-stage intervention in infected hip or knee replacements. All patients were treated with a two-stage exchange and were assessed at three different timepoints regarding their psychological conditions. Our findings suggest that psychological sequelae after treatment of periprosthetic joint infection are clearly underestimated in the literature and psychological correlates and side effects should be further highlighted during the training process of young surgeons.

Diverging prefrontal cortex fiber connection routes to the subthalamic nucleus and the mesencephalic ventral tegmentum investigated with long range (normative) and short range (ex-vivo high resolution) 7T DTI.

Uncertainties concerning anatomy and function of cortico-subcortical projections have arisen during the recent years. A clear distinction between cortico-subthalamic (hyperdirect) and cortico-tegmental projections (superolateral medial forebrain bundle, slMFB) so far is elusive. Deep Brain Stimulation (DBS) of the slMFB (for major depression, MD and obsessive compulsive disorders, OCD) has on the one hand been interpreted as actually involving limbic (prefrontal) hyperdirect pathways. On the other hand slMFB's stimulation region in the mesencephalic ventral tegmentum is said to impact on other structures too, going beyond the antidepressant (or anti OCD) efficacy of sole modulation of the cortico-tegmental reward-associated pathways. We have here used a normative diffusion MRT template (HCP, n = 80) for long-range tractography and augmented this dataset with ex-vivo high resolution data (n = 1) in a stochastic brain space. We compared this data with histological information and used the high resolution ex-vivo data set to scrutinize the mesencephalic tegmentum for small fiber pathways present. Our work resolves an existing ambiguity between slMFB and prefrontal hyperdirect pathways which-for the first time-are described as co-existent. DBS of the slMFB does not appear to modulate prefrontal hyperdirect cortico-subthalamic but rather cortico-tegmental projections. Smaller fiber structures in the target region-as far as they can be discerned-appear not to be involved in slMFB DBS. Our work enfeebles previous anatomical criticism and strengthens the position of the slMFB DBS target for its use in MD and OCD.

Depression comorbidity in spinocerebellar ataxia.

This is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 genetically confirmed and clinically affected patients (117 SCA1, 163 SCA2, 139 SCA3, and 107 SCA6) using the Patient Health Questionnaire (PHQ). In addition, depressive status according to the examiner and the use of antidepressants was recorded. Depression self-assessment was compared with an interview-based psychiatric assessment in a subset of 26 patients. Depression prevalence estimates were 17.1% according to the PHQ algorithm and 15.4% when assessed clinically. The sensitivity of clinical impression compared with PHQ classification was low (0.35), whereas diagnostic accuracy of PHQ compared with psychiatric interview in the subset was high. Antidepressants were used by 17.7% of patients and in >10% of patients without current clinically relevant depressive symptoms. Depression profile in SCA did not differ from a sample of patients with major depressive disorder except for the movement-related item. Neither depression prevalence nor use of antidepressants differed between genetic subtypes, with only sleep disturbance more common in SCA3. In a multivariate analysis, ataxia severity and female sex independently predicted depressive status in SCA. The PHQ algorithmic classification is appropriate for use in SCA but should stimulate further psychiatric evaluation if depression is indicated. Despite a higher risk for depression with more severe disease, the relation of depressive symptoms to SCA neurodegeneration remains to be shown.

Chronic vagus nerve stimulation for treatment-resistant depression increases regional cerebral blood flow in the dorsolateral prefrontal cortex.

The purpose of the present study was to assess the effects of vagus nerve stimulation (VNS) therapy on regional cerebral blood flow (rCBF) in depressed patients. Regional cerebral blood flow (rCBF) was assessed by [(99m)Tc]-HMPAO-single photon emission computed tomography (SPECT) before and after 10weeks of VNS in patients participating in an open, uncontrolled European multi-center study investigating efficacy and safety of VNS. Patients suffered from major depression, with a baseline score of≥20 on the 24-item Hamilton Depression Rating Scale (HDRS) and had been unsuccessfully treated with at least two adequately prescribed antidepressant drugs. Data of 15 patients could be analyzed using SPM 2. After 10weeks of VNS (20Hz, 500µs pulse width, stimulation during 30s every 5min at the maximal comfortable level) rCBF was increased in the left dorsolateral/ventrolateral prefrontal cortex (Brodmann areas 46 and 47) and decreased in the right posterior cingulate area, the lingual gyrus and the left insula. Our findings are in line with earlier results which showed that VNS increases rCBF in the left dorsolateral prefrontal cortex. The modulation of the activity in this region could be associated with the antidepressant efficacy of VNS.