874 research outputs found

    Bupropion administration increases resting-state functional connectivity in dorso-medial prefrontal cortex

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    Background: Patients on the selective serotonergic re-uptake inhibitors (SSRI) like citalopram report emotional blunting. We have shown previously that citalopram reduces resting-state functional connectivity (RSFC) in healthy volunteers in a number of brain regions including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic re-uptake inhibitor (DNRI) and is not reported to cause emotional blunting. However how bupropion affects RSFC in healthy controls remains unknown. Methods: Using a within subjects, repeated measures, double-blind, cross-over design we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/day) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (SN: amygdala and pregenual anterior cingulate cortex (pgACC)) and the central executive network (CEN: dorsal medial prefrontal cortex (dmPFC)). Mood and anhedonia measures were also recorded and examined in relation to RSFC. Results: Relative to placebo, bupropion increased RSFC in healthy volunteers between the dmPFC seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. Conclusions: These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared to SSRIs. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients

    Investigation of brain networks for personalized rTMS in healthy subjects and patients with major depressive disorder: A translational study

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    Depression is a complex psychiatric disorder with emotional dysregulation at its core. The first line of treatment includes cognitive behaviour therapy and pharmacological antidepressants. However, up to one third of patients with depression fail to respond to these treatment interventions. The past decades have seen an increasing use of repetitive Transcranial Magnetic Stimulation (rTMS) in clinical studies, as an alternative treatment for depression. Several large-scale, multicentre randomized controlled trials have led the Food and Drugs Administration (FDA), USA to approve two rTMS protocols for clinical application in the treatment of depression - 10 Hz rTMS and intermittent Theta Burst Stimulation (iTBS). However, only 30-50% of patients receiving rTMS respond to the treatment. The large variability in response to rTMS likely stems from multiple reasons, one being the targeting method currently employed for delivering rTMS at the left dorsolateral prefrontal cortex (DLPFC). Previous functional connectivity studies have shown that stimulation at left DLPFC targets with larger negative correlation to the subgenual anterior cingulate cortex (sgACC) may result in greater therapeutic response than those with lower negative correlation. However, current use of rTMS ignores functional connectivity in choosing the left DLPFC target, thus largely discarding functional architectural differences of the brain across subjects. Furthermore, despite widespread clinical use of rTMS, the basic network mechanisms behind these rTMS protocols remain elusive. This work presents a novel personalization method of left DLPFC target selection based on their negative functional connectivity to the sgACC. The default mode network (DMN) is a large-scale brain network commonly involved in self-referential thought processing and plays an essential role in the pathophysiology of depression. I use the novel personalization method and identical study designs to delineate DMN mechanisms from a single session of 10 Hz rTMS and iTBS in healthy subjects. Arguably, an understanding of basic mechanisms of clinically relevant rTMS protocols in healthy subjects will help improve the current therapeutic effect of rTMS, and possibly expand the therapeutic role of rTMS. My work shows, for the first time, strong but different modulations of DMN connectivity by single personalized sessions of 10 Hz rTMS and iTBS. Such modulations can be predicted using the personality trait harm avoidance (HA). Given that initial results show that the method is robust and reproducible, its adaptation to patient cohorts is likely to result in improved therapeutic benefits. Therefore, the novel method of personalization is translated to clinical setting by using accelerated iTBS (aiTBS) in patients with depression. Additionally, a comparison is made between effects resulting from personalized and nonpersonalized (10-20 EEG system F3 position) aiTBS in patients with depression. By evaluating the DMN, and heart rate variability, I show precise modulatory effects of personalized aiTBS, which is not seen in the standard aiTBS group. The work presented here introduces an important method to reduce variability and increase precision in rTMS modulation by personalizing the left DLPFC target selection. Even though DMN and cardiac effects already point towards the advantage of personalization, the still preliminary analysis fails to show significant differences in treatment response. Lack of greater therapeutic benefits viii from personalized aiTBS in this ongoing study probably stems from a still limited sample size. In case personalization proves clinically advantageous to standard iTBS by the final sample size, this work can sediment the first step towards systems medicine in the field of psychiatry.2022-02-0

    Fatal bilateral pneumonitis after locoregional thoracic chemoradiation in a transplanted patient under immunosuppressive therapy

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    Background: After thoracic radiotherapy a pneumonitis may occur, mostly confined to the irradiated volume of the lung. In general, it resolves spontaneously without long-term effects. Case Report: A 68-year-old man was diagnosed with a stage IIIA adenocarcinoma of the lung and was treated with sequential chemoradiation. He had a heart and kidney transplant for which an immunosuppressant was taken. During the fourth week of radiotherapy, he developed a bilateral interstitial pneumonia. Despite antibiotics and steroids, the patient died twelve days after the onset of complaints due to respiratory failure. Autopsy showed in all pulmonary lobes extensive diffuse alveolar damage, probably leading to respiratory insufficiency and death. Literature and Conclusion: Bilateral pneumonitis after radiotherapy is thought to be an immunologically-mediated response, which usually resolves without long-term effects. Since in radiation pneumonitis an increase in T-cells is described, the suppression of these cells by an immunosuppressant might have exaggerated the pulmonary toxicity

    Die Untersuchung der Effekte einer einzelnen subanästhetischen Ketamininfusion auf Symptome der Major Depression und ihr Zusammenhang mit neuralen Aktivierungsmustern in Kognitions- und Emotions-assoziierten Gehirnarealen

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    Background: Major Depressive Disorder (MDD) is still regarded as often difficult to treat due to its large variety in symptoms. Ketamine has demonstrated rapid antidepressant effects, already 24 h after a single subanaesthetic infusion, but is still lacking effective predictors for a positive treatment response. Objectives: The primary goal of this dissertation project was to investigate ketamine’s effect on distinct MDD symptom dimensions (i.e. cognitive, affective and somatic). Furthermore, by applying a working memory (WM) related functional Magnetic Resonance Imaging (fMRI) paradigm, this project focused on the detection of MDD symptom specific response predictors. Methods: We implemented a symptom-based approach by utilizing a three-factor solution of the Beck Depression Inventory (BDI) in a sample of 47 MDD patients 24 hours pre- and post- a single ketamine infusion. Subsequently, we accessed functional activity at baseline in correlation with MDD symptom improvements 24 h post-treatment in a subsample of 16 patients. Since aberrant functional activation in the default mode network (DMN) and the dorsolateral prefrontal cortex (DLPFC) has been associated with dysfunctional cognition-emotion interaction in MDD, we focused on the examination of these brain regions. Results: On the behavioral level our results indicated that ketamine influences MDD symptom dimensions to a different extent, whereby predominantly affecting the cognitive domain. On the neural level, we found evidence that a decreased DMN deactivation and elevated DLPFC activation predicts ketamine’s enhanced effect on cognitive symptoms. Conclusion: Taken together, these findings suggest that ketamine’s antidepressant efficacy is driven by a “pro-cognitive mechanism” that might be substantiated by an elevated capability for “adaptive adjustment” in the described functional networks.Hintergrund: Die Major Depression (MDD) gilt aufgrund ihrer großen Symptomvielfalt noch immer als häufig schwer zu behandeln. Ketamin zeigt bereits 24 h nach einer einzelnen subanästhetischen Infusion eine schnelle antidepressive Wirkung, wobei es weiterhin an wirksamen Prädiktoren für ein positives Ansprechen auf die Behandlung mangelt. Ziel: Das primäre Ziel dieses Dissertationsprojekts bestand darin, die Wirkung von Ketamin auf verschiedene MDD-Symptomdimensionen (d.h. kognitiv, affektiv und somatisch) zu untersuchen. Überdies lag der Fokus des Projektes darauf, durch die Anwendung eines Arbeitsgedächtnis-assoziierten funktionellen Magnetresonanztomographie (fMRT) Paradigmas MDD symptomspezifische Prädiktoren zu ermitteln. Methoden: Wir implementierten einen symptombasierten Ansatz, indem wir eine Drei-Faktoren-Lösung des Beck Depression Inventory (BDI) in einer Stichprobe von 47 MDD-Patienten 24 h prä und post einer einzelnen Ketamin Infusion anwendeten. Anschließend wurde die funktionelle Aktivität zu Studienbeginn im Zusammenhang mit MDD Symptomverbesserungen 24 h nach der Behandlung in einer Teilstichprobe von 16 Patienten untersucht. Weil funktionelle Abweichungen im Default Mode Network (DMN), sowie im Dorsolateralen Präfrontalen Cortex (DLPFC) mit dysfunktionalen Kognitions-Emotions Interaktionen in der Depression assoziiert werden, lag der Fokus unserer Untersuchungen auf diesen Regionen. Ergebnisse: Auf der Verhaltensebene deuten unsere Ergebnisse darauf hin, dass Ketamin MDD-Symptome in unterschiedlichem Ausmaß beeinflusst, wobei es hauptsächlich den kognitiven Bereich betrifft. Auf neuronaler Ebene fanden wir Hinweise darauf, dass eine verringerte DMN Deaktivierung und eine erhöhte DLPFC Aktivierung die verstärkte Wirkung von Ketamin auf kognitive Symptome prädiziert. Schlussfolgerung: Zusammengenommen lassen diese Ergebnisse darauf schliessen, dass die antidepressive Wirkung von Ketamin durch einen „prokognitiven Mechanismus“ getrieben wird, der durch eine erhöhte Fähigkeit zur „adaptiven Anpassung“ in den beschriebenen funktionellen Netzwerken zustande kommen könnte

    Short-term escitalopram treatment normalizes aberrant self-referential processing in major depressive disorder

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    Background: Increased self-focus and negative self-concept play an important role in depression. Antidepressants influence self-referential processing in healthy volunteers, but their function in self-processing of depressed patients remains unknown. Methods: Thirty-two depressed patients were randomly allocated to receive either escitalopram 10 mg or placebo for one week. After one week, neural responses to positive and negative self-referential adjectives and neutral control stimuli were assessed with functional magnetic resonance imaging. A group of matched healthy volunteers served as a control group. Results: Escitalopram decreased responses of medial fronto-parietal regions to self-referential words relative to non-emotional control stimuli, driven by increased responses to the control condition. Escitalopram also increased responses in the pre-defined region of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) to positive relative to negative words. Importantly, the changes in neural responses occurred before any effect on depressive symptoms, implying a direct effect of escitalopram. Furthermore, the placebo group had decreased responses of the MPFC and the ACC to positive self-referential processing relative to the matched healthy controls. However, neural responses of the escitalopram group and the healthy unmedicated controls were similar. Limitations: Differences between the groups in self-reported depression symptoms and personality traits may have influenced the results. Conclusion: One-week treatment with escitalopram normalized aberrant self-referential processing in depressed patients, shifting the focus from the self to the external environment and potentiating positive self-referential processing. This may be an important factor in mechanism of action of antidepressants.Peer reviewe

    The effect of repetitive transcranial magnetic stimulation and the brain-derived neurotrophic factor genotype on resting-state functional network connectivity.

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    This thesis studied the interaction of neural stimulation and genotype on functional connectivity in 67 healthy subjects. Neural stimulation was performed using repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC). The effect of genotype was studied for a well-known polymorphism in the brain-derived neurotrophic factor (BDNF), which is implicated in neuronal plasticity. Functional connectivity was assessed as the degree of correlation between well-established functional networks during resting-state. In short, this thesis investigated the effect of rTMS and the genotype for a polymorphism in the BDNF on the connectivity between resting-state functional connectivity networks in 67 healthy subjects. Functional connectivity networks represent reproducible patterns of temporally correlated hemodynamic signal fluctuations in the human brain, which are involved in fundamental neurocognitive processes and show alterations in psychiatric disorders such as schizophrenia and depression. rTMS of the right DLPFC has been shown to produce lasting effects on functional connectivity and has emerged as an effective treatment in these disorders. Another mechanism affecting functional connectivity is the valine66methionine (val66met) polymorphism in the gene for the BDNF. Both mechanisms have been linked to neuronal plasticity. However, the combined effect of BDNF genotype and rTMS on functional connectivity is not known. To fill this gap, this thesis studied the interaction of rTMS and genotype on functional connectivity in a sample of 67 healthy subjects. Subjects received 5Hz stimulation of the right DLPFC during one data collection session and sham stimulation of the identical stimulation site during the other session. Following both true and sham stimulation, a resting-state functional magnetic resonance imaging scan was performed. Subjects were genotyped for the val66met single-nucleotide polymorphism (rs6265) in the 5’ proregion of the gene for the BDNF. Met66met homozygotes and val66met heterozygotes were grouped as met66 carriers for further analysis, due to the low number of homozygotes. The sample population consisted of 26 met66 allele carriers and 41 val66 homozygotes. Independent component analysis was used to generate independent components from the resting-state functional magnetic resonance imaging data. These independent components were spatially correlated with canonical samples of resting-state networks to determine best matches for the default-mode network (DMN), executive control network (ECN) and salience network (SLN). The DMN was represented by three independent components, comprising predominantly superior posterior, inferior posterior and anterior nodes respectively. The ECN was split into two components, corresponding to left-hemispheric and right-hemispheric network nodes, respectively. The SLN was covered by a single independent component. Functional connectivity between the networks was measured by the correlation of their voxel time series. Statistical analysis of the networks’ Fisher r-to-z-transformed correlation coefficients was performed using a mixed analysis of variance approach. The results of this study are as follows: rTMS did not result in significant changes in inter-network connectivity compared to sham stimulation. This concurs with published studies, which also reported a lack of effect of repetitive transcranial stimulation of the right DLPFC on inter-network connectivity. There was also no effect of the BDNF polymorphism on connectivity between the networks of interest, which contrasts with a publication, utilizing a different approach to functional connectivity analysis, that reported altered connectivity between nodes of two networks in met66 carriers. However, an interaction effect emerged which suggests that rTMS effects are influenced by the BDNF genotype. Following stimulation, met66 allele carriers showed stronger connectivity between superior posterior parts of the DMN and left-hemispheric parts of the ECN compared to the sham condition. This finding remained significant after correction for multiple comparisons and the effect was not observed in val66 homozygote individuals. This is the first study to demonstrate that the BDNF val66met genotype modulates rTMS effects on inter-network functional connectivity. A tentative interpretation could be that the observed stimulation effect may be implicated in previously observed adverse effects of rTMS in patients with schizophrenia involving increased severity of hallucinations, as it mirrors functional connectivity abnormalities observed in schizophrenic patients that correlate with symptom intensity. Variations in the therapeutic effectiveness of rTMS in major depressive disorder could also conceivably be associated to genotype-associated differences in functional connectivity modulation, although the observed effects did not align with published findings concerning the influence of this genotype on presumed therapeutic mechanisms of action of rTMS involving functional connectivity. The results from this investigation should be used to guide further research into the mechanisms of action underlying the therapeutic, and adverse, effects of rTMS and into the genotype for BDNF as a potential cause for interindividual differences in therapeutic response. These results also suggest that the BDNF val66met genotype of subjects should be routinely determined in rTMS studies, especially in those observing therapeutic effects of rTMS in patients suffering from major depressive disorder and schizophrenia

    Measuring acute effects of subanesthetic ketamine on cerebrovascular hemodynamics in humans using TD-fNIRS

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    Quantifying neural activity in natural conditions (i.e. conditions comparable to the standard clinical patient experience) during the administration of psychedelics may further our scientific understanding of the effects and mechanisms of action. This data may facilitate the discovery of novel biomarkers enabling more personalized treatments and improved patient outcomes. In this single-blind, placebo-controlled study with a non-randomized design, we use time-domain functional near-infrared spectroscopy (TD-fNIRS) to measure acute brain dynamics after intramuscular subanesthetic ketamine (0.75 mg/kg) and placebo (saline) administration in healthy participants (n = 15, 8 females, 7 males, age 32.4 ± 7.5 years) in a clinical setting. We found that the ketamine administration caused an altered state of consciousness and changes in systemic physiology (e.g. increase in pulse rate and electrodermal activity). Furthermore, ketamine led to a brain-wide reduction in the fractional amplitude of low frequency fluctuations, and a decrease in the global brain connectivity of the prefrontal region. Lastly, we provide preliminary evidence that a combination of neural and physiological metrics may serve as predictors of subjective mystical experiences and reductions in depressive symptomatology. Overall, our study demonstrated the successful application of fNIRS neuroimaging to study the physiological effects of the psychoactive substance ketamine in humans, and can be regarded as an important step toward larger scale clinical fNIRS studies that can quantify the impact of psychedelics on the brain in standard clinical settings

    Sudarshan Kriya Yoga and Alteration in Depression Severity and Default Mode Network Connectivity

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    Major depressive disorder is one of the most common and burdensome psychiatric disorders. Many individuals still experience symptoms despite pharmacological treatment. Breathing techniques have shown potential for stress, depression, and anxiety reduction. A second promising treatment are mindfulness-based interventions, which have been shown to effectively decrease depression with fewer side effects than pharmacological agents. Both interventions are accessible via remote instruction. This study will investigate the effect of Sudarshan Kriya Yoga breathwork on depression symptoms. Using a prospective, randomized controlled trial, subjects will receive Sudarshan Kriya Yoga, Mindfulness Based Stress Reduction, or standard care for 8-weeks. We will measure changes in depressive symptoms using two validated depression inventories and will examine their effects on selected brain regions using resting-state functional magnetic resonance imaging. These results may guide an integrative approach for depression, expanding current options through a low-cost, low-risk, and accessible behavioral intervention adjunctive to concurrent pharmacological treatment
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