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Increased network centrality of the anterior insula in early abstinence from alcohol

Erscheinung: 2021 / Addiction Biology

Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular–supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment.

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FMRI-based prediction of naltrexone response in alcohol use disorder: a replication study

Erscheinung: 2021 / European Archives of Psychiatry and Clinical Neuroscience

Pharmacological treatment in alcohol use disorder suffers from modest effect sizes. Efforts have been undertaken to identify patient characteristics that help to select individuals that benefit from pharmacological treatment. Previous studies indicated that neural alcohol cue-reactivity (CR) might provide a marker that identifies patients, which benefit from naltrexone treatment. We investigated the reproducibility of the association between ventral striatum (VS) activation and naltrexone (NTX) treatment response by analyzing data from a recent longitudinal clinical trial in N = 44 abstinent treatment-seeking alcohol-dependent patients. A follow-up was conducted over 3 months. We computed the percentage of significant voxels in VS and tested main effects and interactions with NTX treatment on relapse risk using Cox Regression models. We found a significant interaction effect between pre-treatment cue reactivity in the VS and NTX treatment on time to first heavy relapse (Hazard Ratio = 7.406, 95% CI 1.17–46.56, p = 0.033), such that the patient group with high VS activation (defined by a mean split) showed a significant medication effect (Hazard Ratio = 0.140, 95% CI 0.02–0.75, p = 0.022) with a number needed to treat of 3.4 [95% CI 2.413.5], while there was no significant effect in the group with low VS activation (Hazard Ratio = 0.726, p = 0.454). Thus, using an independent sample we replicated the previously described positive association between VS activation and NTX efficacy. Although our results should be considered cautiously in light of the small sample size, our results support the potential of neural alcohol CR as a tool for precision medicine approaches in alcohol dependence.

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Predicting participation in and success of a concurrent smoking cessation program during inpatient treatment for alcohol dependence

Erscheinung: 2021 / Psychiatria Danubina

Background: Predicting participation in and success of smoking cessation programs in alcohol dependent patients has yielded heterogeneous results. Moreover, these findings have rarely been based on prospective studies from clinical routine settings. Identifying predictors in prospective studies could help to tailor interventions that increase participation and success rates of smoking cessation therapies for these patients at a high risk for alcohol- and smoking-related morbidities and mortalities.

Subjects and methods: During inpatient alcohol dependence treatment, 99 nicotine dependent patients were recruited. 73 patients chose to participate in a voluntary smoking cessation program. Interviews and questionnaires were used at baseline and at discharge to assess a large set of variables covering smoking and alcohol related factors, general psychopathology, quality of life and personality traits. Multiple logistic regression models were calculated to predict participation in the smoking cessation program and smoking abstinence at follow-up three months after discharge.

Results: Participation in the smoking cessation program was predicted by higher stage of change, higher confidence in abstaining from smoking and lower perceived stress. Successful smoking cessation at follow-up was predicted by higher expectations of negative physical feelings due to smoking and lower expectations of temptations to smoke at baseline, and by lower number of daily smoked cigarettes at discharge.

Conclusion: Despite the small sample size, this prospective study gives a first indication of clinically relevant predictors of participation in and success of a smoking cessation program by exploring many previously reported predictors simultaneously. The findings and their implications for treatment allocation and optimization are discussed. 

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Activation of the Glucocorticoid Receptor Rapidly Triggers Calcium-dependent Serotonin Release in vitro

Erscheinung: 2021 / CNS Neuroscience & Therapeutics

Aims: Glucocorticoids rapidly provoke serotonin (5-HT) release in vivo. We aimed to investigate molecular mechanisms of glucocorticoid receptor (GR)-triggered 5-HT release.

Methods: Employing 1C11 cells to model 5-HT neurotransmission, immunofluorescence and Pearson's Correlation Coefficient were used to analyze colocalization of GR, 5-HT, vesicle membrane protein synaptotagmin 1 and vesicle dye FM4-64FX. FFN511 and FM4-64FX dyes as well as calcium imaging were used to visualize vesicular 5-HT release upon application of GR agonist dexamethasone, GR antagonist mifepristone and voltage-gated calcium channel (VGCC) inhibitors.

Results: GR, 5-HT, synaptotagmin 1 and FM4-64FX showed overlapping staining patterns, with Pearson's Correlation Coefficient indicating colocalization. Similarly to potassium chloride, dexamethasone caused a release of FFN511 and uptake of FM4-64FX, indicating vesicular 5-HT release. Mifepristone, calcium depletion and inhibition of L-type VGCC significantly diminished dexamethasone-induced vesicular 5-HT release.

Conclusions: In close proximity to 5-HT releasing sites, activated GR rapidly triggers L-type VGCC-dependent vesicular 5-HT release. These findings provide a better understanding of the interrelationship between glucocorticoids and 5-HT relea

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Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

Erscheinung: 2021 / Scientific Reports

Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.

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Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

Erscheinung: 2021 / BMC Genomics

Background: RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology.

Results: We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses.

Conclusions: PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at bioinf.eva.mpg.de/PTEE

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Vaskuläre Rehabilitation Grundlagen, Voraussetzungen, Inhalte, Ergebnisse

Erscheinung: 2020 / Gefässchirurgie - Springer

Die Rehabilitation (Reha) nach Eingriffen am arteriellen Gefäßsystem der Beine und der Aorta ist gesetzliche Aufgabe der Krankenversicherungen und der Rentenversicherungen. Die Leitlinien der PAVK empfehlen die Reha nach interventionellen und operativen Eingriffen, hinsichtlich der Behandlung der Aortenerkrankungen sind sie jedoch nicht eindeutig. Die Antragsverfahren zur Reha sind uneinheitlich geregelt und das Angebot der rehabilitativen Leistungserbringer ist nicht transparent genug. Die Reha für Gefäßkrankheiten der Aorta und der unteren Extremitäten sind klar strukturiert und durch Leitlinien untersetzt. Die vaskuläre Reha ist für viele Aufgaben in der Behandlungskette von Gefäßpatienten ein prognostisch bedeutsames Verfahren. Gefäßpatienten nach interventionellen und operativen Eingriffen an den unteren Extremitäten profitieren von einer vaskulären Reha ebenso wie Gefäßpatienten nach Eingriffen an der Bauchaorta oder an der thorakalen Aorta.

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Relation between cognitive fatigue and circadian or stress related cortisol levels in MS patients

Erscheinung: 2020 / Multiple Sclerosis and related Disorders

Background: Cortisol levels are increased in MS patients. However, the relation between cortisol, cognitive fatigue and load is still unknown and is investigated in this study. Method: In 40 MS patients and 20 healthy controls, cortisol levels were assessed (in saliva) in the morning and afternoon, before and after 5 runs of a cognitively demanding divided attention task (lasting in total 25-minutes). MS patients were divided in those suffering from cognitive fatigue (MS-F) or not (MS-NF). Results: MS-NF patients showed elevated cortisol levels in the morning and in the afternoon before the reaction time task compared to healthy controls. Differences in cortisol levels among the four measurements were also larger compared to healthy controls and MS-F patients. These differences could not be explained by medication, EDSS score, MS course, age or gender. MS-NF patients also produced more omissions on the attention task compared to healthy controls and MS-F patients. MS-F patients experienced more fatigue after the attention task, but they did not show a task related performance decline. Conclusion: MS-NF patients, and not MS-F patients, deviate in cortisol release and task performance from healthy controls and from MS-F patients. We suggest that MS-NF patients suffer from a dysregulation of their circadian cortisol level.

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Can biofeedback-based training alleviate fatigue and vigilance performance in fatigued MS patients?

Erscheinung: 2020 / Neuropsychological Rehabilitation

MS related fatigue might be related to autonomous nervous system (ANS) dysfunctions or to inflammation related vagal (hyper-) activation. Consequently, influencing ANS status may lead to relieve of fatigue. We used two opposite biofeedback interventions to either increase sympathetic (“self-alert training”, SAT) or parasympathetic activation (“progressive muscle relaxation”, PMR). We recorded fatigue status of patients before and after a challenging vigilance task, their behavioural performance on this task, their skin conductance response (SCR), and parameters indicating parasympathetic activity concerning heart rate variability (HRV). We repeated these recordings after the biofeedback training sessions. Patients of the SAT group were able to learn to increase their SCR voluntarily. Patients of the PMR group showed increasing parameters indicating parasympathetic modulation of the HRV. The vigilance task increased their feeling of fatigue. However, there was no effect of biofeedback training on either fatigue status or performance on the vigilance task. Our results show that MS patients can learn to change voluntarily their ANS activity using biofeedback instructions based on SCR and this can be used in future studies to test the postulated link between ANS and fatigue. However, in this experimental intervention we were unable to document a relation between ANS activity and fatigue.

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Screening, Diagnose und Behandlung alkoholbezogener Störungen

Erscheinung: 2020 / AWMF - online

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