Search

Background and Hypothesis Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. Study Design PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. Study Results Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of −0.46 (95% CI [−0.78; −0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. Conclusions Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.

Objective: Alcohol use disorder (AUD) is one of the most common psychiatric disorders worldwide. It often shows a chronic course, and pharmacological treatment is rather ineffective for maintaining abstinence. New non-invasive brain stimulation techniques could help to improve AUD symptoms by rebalancing and synchronizing the disturbed prefrontal brain function and thus reduce craving. This study aims at evaluating the use of gamma transcranial alternating current stimulation to improve clinical und neuropsychological symptoms in patients with AUD. Methods: In this small open label study, six patients suffering from AUD for several years underwent treatment with prefrontal gamma transcranial alternating current stimulation for 10 min twice daily respectively 20 min once per day for 10 days. Clinical and neuropsychological tests as well as craving were assessed over the course of treatment. Results: Scores of the Alcohol Craving Questionnaire decreased in all patients and cognitive functions assessed by word fluency and computer-based n-back test improved. Conclusions: This new non-invasive brain stimulation technique could be of interest in treating craving symptoms and in maintaining abstinence.

The application of transcranial direct current stimulation (tDCS) at home for the treatment of major depressive disorder (MDD) is the subject of current clinical trials. This is due to its positive safety profile, cost-effectiveness, and potential scalability for a wide outreach in clinical practice. Here, we provide a systematic review of the available studies and also a report on the results of a randomized controlled trial (RCT) on tDCS at home for the treatment of MDD. This trial had to be prematurely terminated due to safety concerns. The HomeDC trial is a double-blinded, placebo-controlled, parallel-group study. Patients with MDD (DSM-5) were randomized to active or sham tDCS. Patients conducted tDCS at home for 6 weeks with 5 sessions/week (30 min at 2 mA) anode over F3, cathode over F4. Sham tDCS resembled active tDCS, with ramp-in and ramp-out periods, but without intermittent stimulation. The study was prematurely terminated due to an accumulation of adverse events (AEs, skin lesions), so that only 11 patients were included. Feasibility was good. Safety monitoring was not sufficient enough to detect or prevent AEs within an appropriate timeframe. Regarding antidepressant effects, the reduction in depression scales over time was significant. However, active tDCS was not superior to sham tDCS in this regard. Both the conclusions from this review and the HomeDC trial show that there are several critical issues with the use of tDCS at home that need to be addressed. Nevertheless the array of transcranial electric simulation (TES) methods that this mode of application offers, including tDCS, is highly interesting and warrants further investigation in high quality RCTs. Trial registration: www.clinicaltrials.gov. Trial registration number: NCT05172505. Registration date: 12/13/2021, https://clinicaltrials.gov/ct2/show/NCT05172505. Graphical abstract *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers) **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma-statement.org/

Abstract The previously not studied photochemical degradation of sulfamethoxazole (SMX) to the isomer of SMX (ISO) was measured via a polychromatic (Xe) and a monochromatic (Hg) light source and accompanied by quantum chemical DFT calculations. In addition to the $$\mathrm{p}K_\mathrm{a} = \;7.0 \pm 0.1$$ p K a = 7.0 ± 0.1 of ISO, tautomer-dependent properties such as the $$K_\mathrm{OW}$$ K OW were measured and theoretically confirmed by DFT. The kinetics in solutions below and above the $$\mathrm{p}K_\mathrm{a} = 5.6$$ p K a = 5.6 of SMX were studied for the available and quantifiable products SMX, ISO, 3-amino-5-methylisoxazole (AMI), 2-amino-5-methyloxazole (AMO), and sulfanilic acid (SUA). The quantum yields of the neutral ($$\Phi _\mathrm{N}$$ Φ N ) and anionic $$\Phi _\mathrm{A}$$ Φ A ) forms of SMX ($$\Phi _\mathrm{A} = 0.03 \pm 0.001$$ Φ A = 0.03 ± 0.001 , $$\Phi _\mathrm{N} = 0.15 \pm 0.01$$ Φ N = 0.15 ± 0.01 ) and ISO ($$\Phi _\mathrm{A} = 0.05 \pm 0.01$$ Φ A = 0.05 ± 0.01 and $$\Phi _\mathrm{N} = 0.06 \pm 0.02$$ Φ N = 0.06 ± 0.02 ) were found to be wavelength-independent. In a competitive reaction to the formation of ISO from SMX, the degradation product TP271 is formed. Various proposed structures for TP271 described in the literature have been studied quantum mechanically and can be excluded for thermodynamic reasons. In real samples in a northern German surface water in summer 2021 mean concentrations of SMX were found in the range of 120 ng/L. In agreement with the pH-dependent yields, concentrations of ISO were low in the range of 8 ng/L. Graphical abstract

Gamma transcranial alternating current stimulation (gamma tACS) is considered a non-invasive brain stimulation technique for modulation of cognitive performance and for treatment of psychiatric disorders. There is heterogeneous data on its effectiveness in improving working memory.In this randomized crossover study, we tested 22 patients with major depression and 21 healthy volunteers who received 20 min of active and sham 40 Hz gamma tACS over bilateral dorsolateral prefrontal cortex during a computerized n-back task in a cross-over design.We showed no improvement in reaction time and accuracy of working memory during active or sham stimulation in both groups, and no interaction between cognitive load and stimulation conditions.The present study suggests that a single session of gamma tACS does not affect cognition in depression. However, the bilateral electrode montage and learning or ceiling effects may have affected results. Overall, this study is in line with the heterogeneous results of previous gamma tACS studies, emphasizing that methodologies and study designs should be harmonized.

Non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) offer a promising alternative to psychotherapeutic and pharmacological treatments for depression. This paper aims to present a practical guide for its clinical implementation based on evidence from the literature as well as on the experience of a group of leading German experts in the field.The current evidence base for the use of rTMS in depression was examined via review of the literature. From the evidence and from clinical experience, recommendations for the use of rTMS in clinical practice were derived. All members of the of the German Society for Brain Stimulation in Psychiatry and all members of the sections Clinical Brain Stimulation and Experimental Brain Stimulation of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Mental Health were invited to participate in a poll on whether they consent with the recommendations.Among rTMS experts, a high consensus rate could be identified for clinical practice concerning the setting and the technical parameters of rTMS treatment in depression, indications and contra-indications, the relation of rTMS to other antidepressive treatment modalities and the frequency and management of side effects.

Introduction Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert therapeutic effects in major depressive disorder (MDD). Due to its beneficial safety profile, its easy mode of application and its cost-effectiveness, tDCS has recently been proposed for treatment at home, which would offer new chances for regionally wide spread and long-term application. However, tDCS at home has to meet new methodological challenges of handling and adherence, and data from randomized controlled trials (RCT) investigating this mode of application are still lacking. In this pilot RCT, we therefore investigate feasibility, safety and effectiveness of a new tDCS application set-up in MDD. Methods and analysis The HomeDC trial will be conducted as a double-blind, placebo-controlled, parallel-group design trial. Thirty-two patients with MDD will be randomized to active or sham tDCS. Patients will self-administer prefrontal tDCS for 6 weeks. Active tDCS will be conducted with anode over F3, cathode over F4, for 5 sessions/week, with a duration of 30min/day and 2mA stimulation intensity, whereas sham tDCS follows the identical protocol in electrode montage and timing but with ramp-in and ramp-out periods only without intermittent stimulation. Both conditions will be administered as monotherapy or adjunctive treatment to a stable dose of antidepressant medication. Feasibility, effectiveness and safety will be assessed, and adjunctive fMRI and e-field modelling will be conducted at baseline. Discussion For the HomeDC trial, technical requirements of a placebo-controlled trial in a home-based treatment setting with tDCS have been established. It addresses the crucial points of a home-based treatment approach with tDCS: uniform electrode positioning and frequent monitoring of stimulation parameters and adherence, ensuring an appropriate home treatment environment. This study will allow identifying constraints and further critical topics of this novel mode of application. Trial Registration www.clinicaltrials.gov. Trial registration number: NCT05172505. Registration date: 12/13/2021, https://clinicaltrials.gov/ct2/show/NCT05172505

ZUSAMMENFASSUNGZwangsgedanken und -handlungen sind für Betroffene meist quälend und können mit einer hohen Beeinträchtigung des sozialen und beruflichen Funktionsniveaus verbunden sein. Wir berichten von einer 30-jährigen Patientin mit bislang therapieresistenter Zwangsstörung, die mit transkranieller Gleichstromstimulation als Zusatzverfahren zur Medikation und Psychotherapie behandelt wurde. Zum Einsatz kam dabei eine für die Depressionsbehandlung typische Elektrodenplatzierung über beiden dorsolateralen präfrontalen Kortizes. Nach einer 3-wöchigen Behandlung mit 15 Stimulationen wurde eine deutliche Reduktion der Zwangssymptomatik erreicht, die auch 3 Wochen nach der Behandlung noch anhielt. Neue Therapieverfahren aus dem Bereich der nicht invasiven Hirnstimulation, wie die transkranielle Gleichstromstimulation, könnten bei therapieresistenter Zwangserkrankung einen potenziellen Behandlungsansatz darstellen.

The vapor pressure is a specific and temperature-dependent parameter that describes the volatility of a substance and thus its driving force for evaporation or sublimation into the gas phase. Depending on the magnitude of the vapor pressure, there are different methods for experimental determination. However, these are usually associated with a corresponding amount of effort and become less accurate as the vapor pressure decreases. For purposes of vapor pressure prediction, algorithms were developed that are usually based on quantitative structure–activity relationships (QSAR). The quantum mechanical (QM) approach followed here applies an alternative, much less empirical strategy, where the change in Gibbs free energy for the transition from the condensed to the gas phase is obtained from conformer ensembles computed for each phase separately. The results of this automatic, so-called CRENSO workflow are compared with experimentally determined vapor pressures for a large set of environmentally relevant compounds. In addition, comparisons are made with the single structure-based COSMO-RS QM approach, linear-free-energy relationships (LFER) as well as results from the SPARC program. We show that our CRENSO workflow is superior to conventional prediction models and provides reliable vapor pressures for liquids and sub-cooled liquids over a wide pressure range.

ZusammenfassungAlexithymie ist ein multidimensionales Konstrukt der Persönlichkeit, welches durch ein nach außen hin orientiertes Denken sowie Schwierigkeiten bei der Gefühlsbeschreibung und -identifizierung einer anderen Person gekennzeichnet ist. Obwohl sie bei psychiatrischen Patienten gut beschrieben ist, wurde ihr Vorkommen und die Pathophysiologie im Zusammenhang mit der Multiplen Sklerose (MS) erst neuerdings untersucht. In dieser narrativen Übersichtsarbeit sollen Prävalenzen, Ursachen, neurobiologische und klinische Befunde dargestellt werden. Die Prävalenz der Alexithymie in MS reicht von 10 bis 53%. Es scheint Assoziationen mit Angststörungen, Depressionen, Fatigue und einigen kognitiven Aspekten zu geben. Die Beziehung zu klinischen und klassischen kognitiven Variablen/Kriterien ist bislang wenig untersucht. Schlussendlich stellt eine Arbeit einen pathophysiologischen Bezug dar und diskutiert eine aberrante interhemisphärische Übertragung. Zusammenfassend zeigt die Alexithymie bei MS eine negative Auswirkung auf die Lebensqualität, deshalb stellt das Screening nach ihr einen wichtigen Punkt im Krankheitsmanagement dar. Ihre Beziehung zu klinischen, emotionalen und kognitiven Kofaktoren bedarf weiterer Untersuchungen. Größer angelegte Studien inklusive bildgebender Verfahren sind dringend notwendig, um ein besseres Verständnis für die neuronalen Mechanismen der Alexithymie bei MS zu gewinnen.

Following the great success of the first series of the Special Issue “Brain Stimulation and Neuroplasticity” [...]

In recent years noninvasive brain stimulation (NIBS) applications have emerged as a third and novel treatment option alongside psychopharmacology and psychotherapy in the treatment of mental diseases. It is assumed that NIBS could represent a supplement or (in some indications) even replacement to established therapeutic strategies, e.g. in disorders with high resistance to current treatment regimens, such as negative symptoms or cognitive impairments in schizophrenia. Although positive symptoms in schizophrenia can be treated sufficiently with antipsychotic drugs, patients with negative symptoms frequently suffer from persistent lack of impetus, cognitive decline, social withdrawal and loss of global functioning in the activities of daily life; however, in these cases, current treatment strategies exert only moderate effects, and new treatment options are urgently needed. This review article provides a summary of the clinical effects of new electrical NIBS methods, e.g. transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS) for the treatment of negative symptoms in schizophrenia. These new NIBS methods could help restore the disrupted neuronal networks and improve disturbed connectivity, especially of the left dorsolateral prefrontal cortex and left temporoparietal junction. Promising results are reported for the treatment of negative symptoms with tDCS, tACS and tRNS and could thus represent new therapeutic options in the treatment of schizophrenia.Über die letzten Jahre entwickelten sich Neuromodulationsverfahren zu einer dritten Säule neben Pharmakotherapie und Psychotherapie in der Behandlung psychischer Erkrankungen. Besonders in der Behandlung von Menschen mit einer Schizophrenie könnten Hirnstimulationsverfahren eine Alternative oder Ergänzung zu den etablierten Therapiestrategien darstellen. Die meist vorhandenen Positivsymptome können zumeist mit Antipsychotika adäquat behandelt werden. Gerade bei Patienten mit Schizophrenie besitzen jedoch Negativsymptome einen überdauernden Krankheitswert und beeinflussen den Verlauf durch globale Antriebsverarmung und beeinträchtigte Kognition im alltäglichen Leben negativ. Dieser Übersichtsartikel stellt eine Zusammenfassung über die verschiedenen nichtinvasiven Hirnstimulationsverfahren transkranielle Gleichstromstimulation (transcranial direct current stimulation, tDCS), Wechselstromstimulation (transcranial alternating current stimulation, tACS) sowie Rauschstromstimulation (transcranial random noise stimulation, tRNS) zur Behandlung der Negativsymptomatik bei Schizophrenie dar. Die neuen transkraniellen Hirnstimulationsverfahren könnten dabei helfen, gestörte neuronale Vernetzungen wieder herzustellen und die Konnektivität vor allem der dorsolateralen präfrontalen Anteile des Kortex zu verbessern. Einige Studien weisen auf eine Verbesserung der Negativsymptome durch Behandlung mit tDCS, tACS bzw. tRNS hin und könnten so neue Therapiemöglichkeiten in der Behandlung der Schizophrenie darstellen.

Introduction: A better understanding of how the hypothalamic-pituitary-adrenal (HPA) axis can be externally regulated is of major importance, especially because hyperreactivity to stress has been proposed as a key factor in the onset and maintenance of many psychiatric conditions. Over the past decades, numerous studies have investigated whether non-invasive brain stimulation (NIBS) can regulate HPA axis reactivity in acute stress situation. As the current results did not allow us to draw clear conclusions, we decided to conduct a systematic review of the literature investigating the effect of a single NIBS session on stress-induced cortisol release. Methods: We searched MEDLINE and Web Of Science for articles indexed through December 2021. Among the 246 articles identified, 15 fulfilled our inclusion criteria with a quality estimated between 52 and 93%. Results: Of the different NIBS used and targeted brain regions, stimulating the left dorsolateral prefrontal cortex, with either high frequency repetitive transcranial magnetic stimulation or anodal transcranial direct current stimulation, seems to be the most appropriate for reducing cortisol release in acute stress situations. Conclusions: Despite the heterogeneity of the stimulation parameters, the characteristics of participants, the modalities of cortisol collection, the timing of the NIBS session in relation to the stressor exposure, and methodological considerations, stimulating the left dorsolateral prefrontal cortex can be efficient to modulate stress-induced cortisol release.

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES.Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided.Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity.Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials. (C) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. Device appraisal showed moderate digitalization readiness, with high safety and the possibility of trial implementation, but low connectivity. Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; although they reached no consensus about aspects regarding methodological biases. We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.Graphical Abstract. Consensus Roadmap(A) Recruitment process. The study procedure started with defining the components of the research problem by the core research team. After defining the problems, two different sets of participants (the steering committee (SC) including key leaders of the field identified by the core team and the expert panel (EP) as a more diverse group of experts identified based on the number of publications based on a systematic review) were identified and were invited to participate in a Delphi study. The study facilitators (first and last authors) led the communications with the SC to design the initial questionnaire through an iterative approach. (B) Evidence synthesis: To collect the available evidence, companies producing portable tES (ptES) devices were contacted, based on the companies suggested by the SC and EP to provide details about the available devices. For mapping methodological processes of digitizing tES trials, two distinct strategies were performed and embedded into the questionnaire, namely SIPOC (Suppliers, Inputs, Process, Outputs, and Customer) and SWOT (Strengths, Weaknesses, Opportunities, and Threats) assessment were performed and embedded into the questionnaire. (C) Consensus development: In the next phase, the questionnaire was validated and finalized via collecting and summarizing opinions. Afterward, the SC and EP responded to the final questionnaire, and results were analyzed providing a list of recommendations for running tES digital trials based on a pre-registered consensus threshold.

Major depression is one of the most common psychiatric disorders with a high rate of treatment resistance where new treatment options are urgently warranted. One of these new options are non-invasive brain stimulation techniques like transcranial magnetic or electric stimulation. One of the latter is transcranial Alternating Current Stimulation (tACS) in various frequencies. Here, we report a case series of six patients suffering from major depression treated with tACS in gamma (40 Hz) frequency. Patients were randomized to two groups, receiving either two 10-min stimulations (group 1) or a 20-min stimulation or per day (group 2) over ten days. Hamilton Depression Rating Scale and Beck Depression Inventory decreased during treatment in both study groups by 85% and 78% (group 1), or 62% and 24% respectively (group 2). Results also showed an improvement in cognitive functions assessed by word fluency and n-back test. It is hypothesized that gamma tACS could help to synchronize disturbed frequency bands in frontal and prefrontal cortex areas and thus restore dysbalanced neural connectivity in psychiatric disorders.

Die Zwangsstörung hat oftmals einen chronischen Verlauf mit Therapieresistenz gegenüber Psychopharmakotherapie und Psychotherapie. Neue nichtinvasive Hirnstimulationsverfahren könnten helfen, Zwangssymptome zu vermindern. In diesem Fallbericht wird die Behandlung einer Patientin mit Zwangsstörung dargestellt, die mit 10 transkraniellen Wechselstromstimulationen in Gamma-Frequenz (40 Hz) im Rahmen eines Heilversuchs behandelt wurde. Die Yale-Brown Obsessive-Compulsive Scale verminderte sich von 70 auf 59 Punkte, und die Hamilton Depression Rating Scale sank von 25 auf 12 Punkte. Daneben konnte eine Verbesserung des Regensburger Wortflüssigkeitstests, des Pfadfindertests und eines computergestützten n-back-Tests verzeichnet werden. Eine Hypothese für die Verbesserung der Zwangsstörung durch Gamma-Wechselstromstimulation könnte eine Auswirkung auf die bei psychischen Erkrankungen (Depression, Zwangsstörung) veränderte alpha-Frequenz sein. Der hier vorgestellte Fall bestätigt die Ergebnisse einer früheren Fallserie und gibt Anlass zur weiteren Untersuchung dieses Verfahrens.Die Zwangsstörung hat oftmals einen chronischen Verlauf mit Therapieresistenz gegenüber Psychopharmakotherapie und Psychotherapie. Neue nichtinvasive Hirnstimulationsverfahren könnten helfen, Zwangssymptome zu vermindern. In diesem Fallbericht wird die Behandlung einer Patientin mit Zwangsstörung dargestellt, die mit 10 transkraniellen Wechselstromstimulationen in Gamma-Frequenz (40 Hz) im Rahmen eines Heilversuchs behandelt wurde. Die Yale-Brown Obsessive-Compulsive Scale verminderte sich von 70 auf 59 Punkte, und die Hamilton Depression Rating Scale sank von 25 auf 12 Punkte. Daneben konnte eine Verbesserung des Regensburger Wortflüssigkeitstests, des Pfadfindertests und eines computergestützten n-back-Tests verzeichnet werden. Eine Hypothese für die Verbesserung der Zwangsstörung durch Gamma-Wechselstromstimulation könnte eine Auswirkung auf die bei psychischen Erkrankungen (Depression, Zwangsstörung) veränderte alpha-Frequenz sein. Der hier vorgestellte Fall bestätigt die Ergebnisse einer früheren Fallserie und gibt Anlass zur weiteren Untersuchung dieses Verfahrens.

Fatigue is a frequent and debilitating symptom in patients with central nervous system diseases. Up to 90% of patients with multiple sclerosis (MS) suffer from fatigue that drastically affects the quality of life. MS patients also complain of anxiety and depressive symptoms and these three manifestations tend to cluster together in this clinical population. The objective of this work was to assess the effects of transcranial direct stimulation (tDCS), a noninvasive brain stimulation technique, on fatigue as well as anxiety and depressive symptoms. Eleven fatigued MS patients randomly received two blocks (active and sham tDCS) of five consecutive daily sessions of bifrontal tDCS (anode/cathode over the left/right prefrontal cortices, respectively) in a crossover manner, separated by a 3-week washout interval. Evaluation took place at day 1, day 5 (right after each block) and 1 week later. Active but not sham tDCS resulted in a significant improvement of fatigue at day 5 (p 0.05), an effect that seems to last at least 1 week following the stimulation (p = 0.05). Active tDCS also significantly improved anxiety symptoms, but the effect emerged 1 week later (p 0.05). No significant effects were obtained regarding depression (p 0.05). Bifrontal tDCS seems to modulate fatigue in PwMS. The observed anxiolytic effects could constitute delayed after effects of tDCS or might be mediated by fatigue improvement. These findings merit to be addressed in large-scale controlled trials.

Octanol/water (KOW), octanol/air (KOA), and hexadecane/air (KHdA) partition coefficients are calculated for 67 organic compounds of environmental concern using computational chemistry. The extended CRENSO workflow applied here includes the calculation of extensive conformer ensembles with semiempirical methods and refinement through density functional theory, taking into account solvation models, especially COSMO-RS, and thermostatistical contributions. This approach is particularly advantageous for describing large and nonrigid molecules. With regard to KOW and KHdA, one can refer to many experimental data from direct and indirect measurement methods, and very good matches with results from our quantum chemical workflow are evident. In the case of the KOA values, however, good matches are only obtained for the experimentally determined values. Larger systematic deviations between data computed here and available, nonexperimental quantitative structure-activity relationship literature data occur in particular for phthalic acid esters and organophosphate esters. From a critical analysis of the coefficients calculated in this work and comparison with available literature data, we conclude that the presented quantum chemical composite approach is the most powerful so far for calculating reliable partition coefficients because all physical contributions to the conformational free energy are considered and the structure ensembles for the two phases are generated independently and consistently.

Sleep complaints are commonly reported by patients with multiple sclerosis (PwMS). Several pharmacological and alternative interventions have been tried, but are usually faced by limited efficacy. Hence, exploring other methods such as transcranial direct current stimulation (tDCS), might be of interest. The aim of this study was to assess the effects of bifrontal tDCS on subjective (i.e., Epworth Sleepiness Scale (ESS)) and objective sleep measures (i.e., actigraphy).Seven patients completed the study. Patients randomly received two blocks of five daily sessions each in a crossover design (active and sham, with a washout interval of three weeks). The anode and cathode were placed over the left and right dorsolateral prefrontal cortices, respectively. Sleep assessment included ESS, sleep onset latency, total sleep duration, time in bed, sleep efficiency, waking after sleep onset, and number of awakenings.Compared to baseline scores (11.14 ± 4.06), significant decrease in ESS was obtained after active intervention (7.86 ± 4.18; p = 0.011), but not after sham intervention (9.57 ± 5.62; p = 0.142). No significant changes were observed with regards to actigraphy measures. Sessions were well tolerated, and no serious side-effects were reported at any time.Bifrontal tDCS resulted in significant improvement in daytime sleepiness, but did not yield any effect on objective sleep measures in PwMS. This discrepency might be explained by the modest association that could exist between objective and subjective sleep measures. In addition, it could be assumed that modulating objective sleep measures would require a larger sample size, more stimulation sessions, or modulation of other cortical areas.

Introduction: Depression is the most common morbidity during pregnancy. Available first-line therapy options are limited and depressive disorders in pregnant women are often untreated, leading to negative effects on maternal and fetal health. Objectives: The aim of this open-label pilot study is to extend evidence on the use of transcranial direct current stimulation (tDCS) as a treatment of antenatal depression and to point out options for the use of tDCS in this population. Methods: Six drug-free female patients with major depressive disorder during pregnancy (later than 10th gestational week) were included in this pilot study. Patients were treated with twice-daily tDCS (2 mA, 30 min, anode: F3, cathode: F4) over ten days during inpatient stay (Phase 1) and with once-daily tDCS over 10 days during an optional outpatient stay (Phase 2). Clinical (HAMD-21, BDI) and neuropsychological ratings (Trail Making Test A/B) were performed at baseline, after two and four weeks as well as an obstetric examination. Results: Six right-handed females (23–43 years, 12–33. gestational week) completed Phase 1, four patients additionally joined in Phase 2. tDCS was well tolerated and no adverse effects occurred. Clinical ratings showed an improvement of mean baseline HAMD-21 from 22.50 ± 7.56 to 13.67 ± 3.93 after week 2, and to 8.75 ± 4.99 after week 4. The mean baseline BDI was 26.00 ± 13.90 and declined to 11.17 ± 5.46 after week 2, and to 9.25 ± 3.30 after week 4. Conclusions: Statistically significant changes in HAMD-21 and BDI were observed after Phase 1. One patient achieved remission in terms of HAMD in Phase 1. Although this small-scale study lacks sham control, it shows clinical improvement and absence of adverse events in this critical population.

Methylxanthines are commonly recommended as anthropogenic markers, yet possible diffuse sources are largely unaccounted for. In this study, eight methylxanthines and xanthine were determined jointly in an entire river system for the first time. Overall, 49 samples were taken from the River Wietze (Lower Saxony, Germany) and its tributaries in four sampling campaigns. In addition, consecutive rainwater samples as well as influent and effluent samples from the largest adjacent municipal wastewater treatment plant (WWTP) were taken. All samples were enriched using SPE and analysed via LC-MS/MS. For xanthine, the standard addition method was applied. All investigated compounds were found in concentrations ranging from some dozen to some hundred ng L−1. For isocaffeine, 7-methylxanthine, and xanthine, measured concentrations in the River Wietze are the first available concentrations in surface water. Mass loads displayed a high seasonal variability and up to 144 g day−1 of methylxanthines were discharged into the receiving river. Municipal WWTPs were found to be an important and constant point source of all compounds. However, the high dependence of mass loads on discharges in the river as well as the detection of most methylxanthines at the blank site and in rainwater samples suggest additional diffuse introduction pathways. Solely the occurrence of isocaffeine in the River Wietze was found to be exclusively attributable to municipal wastewater discharge. Therefore, while caffeine and its degradation products are unsuitable for tracking the presence of treated or untreated wastewater in fluvial systems, isocaffeine can be recommended as a marker for the discharge of treated wastewater.

Wenn pharmakologische und psychotherapeutische Behandlungen der Depression nicht anschlagen, konnen Hirnstimulationsverfahren eingesetzt werden. Sie stimulieren gezielt die pathologisch veranderten Hirnregionen, um ihre neuronale Aktivitat zu normalisieren.

ZusammenfassungTrotz der Fortschritte in Psychopharmakologie und etablierter psychotherapeutischer Interventionen respondieren mehr als 40 % der Patienten mit Zwangsstörung nicht auf konventionelle Behandlungsversuche. Seit einigen Jahren gewinnen nicht-invasive Hirnstimulationsverfahren Bedeutung in der Behandlung psychiatrischer Erkrankungen. Die transkranielle Gleichstromstimulation (transcranial direct current stimulation – tDCS), ein nicht-invasives Hirnstimulationsverfahren mit Applikation eines niedrigen konstanten Gleichstroms zur Modulation neuronaler Netzwerkstrukturen, wird seit einiger Zeit als neues therapeutisches Verfahren beforscht, um Symptome behandlungsresistenter Zwangsstörungen zu verbessern. Ziel dieser Übersichtarbeit ist ein umfassender Überblick über den aktuellen Stand der Literatur zu diesem Thema sowie ein Ausblick auf zukünftige Anwendung der tDCS bei Zwangsstörungen. Die Suche in der NIH-Datenbank pubmed und eine erweitere manuelle Suche ergab eine bislang geringe Zahl von neun Fallberichten, drei offenen Studien und einer randomisierten Studie mit zwei aktiven Bedingungen. Plazebokontrollierte Studien liegen nicht vor. Eine Gesamtzahl von 78 Patienten erhielt aktive tDCS mit einer Vielzahl unterschiedlicher Elektrodenplatzierungen, wobei das Hauptziel der dorsolaterale präfrontale Kortex, der orbitofrontale Kortex oder (prä-)supplementär-motorische Areale waren. Trotz der Heterogenität der Stimulationsbedingungen zeigen die berichteten Fälle nicht nur eine Verbesserung von Zwangssymptomen, sondern auch von komorbiden Depressionen und Angststörungen bei Patienten mit therapieresistenter Zwangsstörung. Einschränkend ist festzuhalten, dass keine plazebokontrollierten Studien vorliegen und die bisherigen Resultate einer Bestätigung bedürfen.

The chemical background of olfactory perception has been subject of intensive research, but no available model can fully explain the sense of smell. There are also inconsistent results on the role of the isotopology of molecules. In experiments with human subjects it was found that the isotope effect is weak with acetone and D6‐acetone. In contrast, clear differences were observed in the perception of octanoic acid and D15‐octanoic acid. Furthermore, a trained sniffer dog was initially able to distinguish between these isotopologues of octanoic acid. In chromatographic measurements, the respective deuterated molecule showed weaker interaction with a non‐polar liquid phase. Quantum chemical calculations give evidence that deuterated octanoic acid binds more strongly to a model receptor than non‐deuterated. In contrast, the binding of the non‐deuterated molecule is stronger with acetone. The isotope effect is calculated in the framework of statistical mechanics. It results from a complicated interplay between various thermostatistical contributions to the non‐covalent free binding energies and it turns out to be very molecule‐specific. The vibrational terms including non‐classical zero‐point energies play about the same role as rotational/translational contributions and are larger than bond length effects for the differential isotope perception of odor for which general rules cannot be derived., The scent of deuterium: For a mechanistic understanding of the olfactory perception of molecules, it is an interesting aspect whether or not isotopological substances are perceived differently. To investigate this question, humans and a trained sniffer dog were exposed to deuterated and non‐deuterated substances. The experimental results, supplemented by quantum mechanical calculations, provide insights into the interaction of molecules with receptors.

Objective To evaluate the safety and temporal dynamic of the antiepileptic effect of spaced transcranial direct current stimulation (tDCS) in different focal epilepsies. Methods Cathodal tDCS with individual electrode placement was performed in 15 adults with drug resistant focal epilepsy. An amplitude of 2 mA was applied twice for 9 minutes, with an interstimulation interval of 20 minutes. Tolerability was assessed via the Comfort Rating Questionnaire and the frequency of interictal epileptiform discharges (IEDs) was sequentially compared between the 24 hours before and after tDCS. Results TDCS led to a significant reduction in the total number of IEDs/24 h by up to 68% (mean ± SD: −30.4 ± 21.1%, p = 0.001) as well as in seizure frequency (p = 0.041). The maximum IED reduction was observed between the 3rd and 21st hour after stimulation. Favorable clinical response was associated with structural etiology and clearly circumscribed epileptogenic foci but did not differ between frontal and temporal epilepsies. Overall, the tDCS treatment was well tolerated and did not lead to severe adverse events. Conclusions The spaced stimulation approach proved to be safe and well-tolerated in patients with drug-resistant unifocal epilepsies, leading to sustained IED and seizure frequency reduction. Significance Spaced tDCS induces mediate antiepileptic effects with promising therapeutic potential.

This chapter provides an overview of tDCS as a treatment for negative symptoms in schizophrenia. Negative symptoms are frequent during schizophrenia and have a debilitating impact on global functioning. They consist in lack of impetus and volition, impaired cognition, and social decline. Although positive symptoms of schizophrenia respond to antipsychotic pharmacotherapy, negative symptoms are usually refractory to pharmacotherapy. In this context, tDCS could help to improve such symptoms by restoring disturbed neural network connectivity in frontal hub regions. To date, there are several studies suggesting an improvement of negative symptoms by left-anodal and right-cathodal tDCS of the dorsolateral prefrontal cortex. Domiciliary use of tDCS could help to overcome difficulties in adherence in this severely ill population.

For the first time the occurrence of 25 organic micropollutants (OMPs) including; 11 personal care products (PCPs), six phthalate ester plasticizers (PEPs) and eight organophosphorus flame retardants (OPFRs) was investigated in 72 water samples obtained from five bays in the Uganda sector of Lake Victoria. In addition, an assessment of the potential ecotoxic risk of the target OMPs to aquatic organisms was conducted. Water samples were analyzed for the target OMPs using gas chromatography coupled with mass spectrometry (GC/MS). All the target PCPs were found in all the water samples with the exception of musk ketone and 2,6-di-tert-butylphenol. Triclosan (89–1400 ng L−1), benzophenone (36–1300 ng L−1), and 4-methylbenzylidine camphor (21–1500 ng L−1) were the most predominant PCPs. All the six plasticizers were found in all the water samples with dibutyl phthalate (350-16 000 ng L−1), and bis-(2-ethylhexyl) phthalate (210–23 000 ng L−1) detected at the highest concentrations. Five OPFRs out of the eight targeted were found in all the water samples. Tricresyl phosphate (25–8100 ng L−1), tris-(2-chloroethyl) phosphate (24–6500 ng L−1) and triphenyl phosphate (54–4300 ng L−1) were the most dominant OPFRs. The highest concentrations of OMPs were recorded in Murchison and Thurston Bays, presumably due to industrial wastewater effluents from the highly industrialized localities of the two Bays. Ecotoxicological risk assessment showed that PCPs (triclosan, musk ketone, and 4-MBC), plasticizers (dibutyl phthalate, bis-(2-ethylhexyl) adipate and bis-(2-ethylhexyl) phthalate) and OPFRs (tricresyl phosphate, triphenyl phosphate and tris-(2-chloroethyl) phosphate) pose a high ecotoxic risk to lives of aquatic organisms (risk quotients, RQ > 1).

Objectives Alexithymia is a personality construct that could occur in up to 53 % of patients with multiple sclerosis (MS). It entails difficulties in identifying and describing one’s feelings and an externally oriented thinking. The current work aims to assess the neural underpinnings of alexithymia in this population. Methods Forty-five patients with MS filled in the Toronto Alexithymia Scale (n = 17 with high alexithymia and n = 28 with low alexithymia). Brain magnetic resonance imaging was obtained for each patient and a morphometry algorithm (MorphoBox) was applied to calculate regional brain volumes. All patients underwent a clinical and neuropsychological evaluation which included measures for anxiety, depression, fatigue, daytime sleepiness, and basic and social cognition. Results Compared to patients with low alexithymia, patients with high alexithymia had significantly higher fatigue and depression ratings, and lower empathy scores. In addition, they had lower volumes of corpus callosum, deep white matter, pallidum bilaterally, and left thalamus. In the whole cohort, alexithymia scores were inversely correlated with gray matter (thalamus and pallidum bilaterally) and white matter volumes (corpus callosum and bilateral deep white matter) after controlling for covariates (ps Conclusion This study offers insights on the neuropsychological and neural substrates of alexithymia in MS. The current findings are consistent with alexithymia reports in other clinical populations, and suggest an association between alexithymia and atrophy of thalami, pallidum, corpus callosum and deep white matter in MS. Further research is needed to enhance the understanding of alexithymia mechanisms in this clinical context.

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a Hl-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance. (C) 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.

Non-invasive transcranial brain stimulation therapies, such as transcranial direct current stimulation, have been found to improve negative symptoms in schizophrenia. Another new technique is transcranial alternating current stimulation (tACS). Here we report a series of three patient treated with twice-daily 10min prefrontal 40Hz tACS stimulation over ten days. Patients showed an improvement in the Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, and subjective well-being. Furthermore, there was an improvement in the Trail Making Test and word fluency. ytACS merits further investigation in the treatment of schizophrenia symptoms.